The extent or spread of cancer is usually described as stages. The stage of the cancer is usually used to plan treatment. However, carcinoma of unknown primary (CUP) has already spread to other parts of the body when it is found. There is no standard staging system for CUP.

Sometimes childhood carcinoma of unknown primary recurs (comes back) after treatment.

Treatment of newly diagnosed carcinoma of unknown primary (CUP) in children depends on the following:

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of newly diagnosed CUP in children may include the following:

Sometimes childhood carcinoma of unknown primary can recur (come back) after treatment. If your child is diagnosed with a recurrent carcinoma of unknown primary, your child’s doctor will work with you to plan treatment.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For more information from the National Cancer Institute about carcinoma of unknown primary, see the following:

For more childhood cancer information and other general cancer resources, visit:

Cancers of unknown primary sites present as metastatic cancers for which precise primary tumor sites cannot be determined.[1] As an example, lymph nodes at the base of the skull may enlarge in relationship to a tumor on the face or scalp that is not evident by physical examination or radiographic imaging. Thus, modern imaging techniques may indicate the extent of the disease but not a primary site. Tumors such as adenocarcinomas, melanomas, and embryonal tumors, like rhabdomyosarcomas and neuroblastomas, may present in this way.

Less than 1% of all solid cancers of unknown primary sites occur in children. Because of the age-related incidence of tumor types, embryonal histologies are more common in children.[2]

References

1. Kuttesch JF, Parham DM, Kaste SC, et al.: Embryonal malignancies of unknown primary origin in children. Cancer 75 (1): 115-21, 1995. [PUBMED Abstract]
2. Pavlidis N, Pentheroudakis G: Cancer of unknown primary site. Lancet 379 (9824): 1428-35, 2012. [PUBMED Abstract]

For all patients who present with tumors from unknown primary sites, treatment is directed toward the specific histopathology of the tumor and is age-appropriate for the general type of cancer suspected, regardless of the sites involved.[1]

Studies in adults suggest that positron emission tomography (PET) imaging can be helpful in identifying cancers of unknown primary sites, particularly in patients whose tumors arise in the head and neck area.[2] A report in adults using fluorine F 18-fludeoxyglucose PET-computed tomography identified 42.5% of primary tumors in a group of cancers of unknown primary sites.[3]

The use of gene expression profiling and next-generation sequencing can enhance the ability to identify the putative tissue of origin and guide the selection of targeted agents for specific variants.[4–8]

In a study of 200 adult patients with carcinomas of unknown primary sites, 125 had adenocarcinomas and 75 had carcinomas without features of adenocarcinoma. Genomic alterations were found in 96% of the cases. The most common alterations were TP53 (55%), KRAS (20%), CDKN2A (19%), and MYC (12%). Clinically relevant and potentially actionable variants included KRAS (20%), CDKN2A (19%), MCL1 (10%), PTEN (7%), PIK3CA (9%), ERBB2 (8%), RICTOR (6%), BRAF (6%), and NF1 (4%). These findings suggest that genomic profiling can help identify potentially actionable targets, which could benefit patients clinically while reducing the complex, costly workup needed to search for a primary tumor site of origin.[9]

Despite reports of precision medicine studies in pediatric oncology, none of them have described a case of cancer of unknown primary site with a defined or actionable genomic alteration.[10]

References

1. Kuttesch JF, Parham DM, Kaste SC, et al.: Embryonal malignancies of unknown primary origin in children. Cancer 75 (1): 115-21, 1995. [PUBMED Abstract]
2. Bohuslavizki KH, Klutmann S, Kröger S, et al.: FDG PET detection of unknown primary tumors. J Nucl Med 41 (5): 816-22, 2000. [PUBMED Abstract]
3. Han A, Xue J, Hu M, et al.: Clinical value of 18F-FDG PET-CT in detecting primary tumor for patients with carcinoma of unknown primary. Cancer Epidemiol 36 (5): 470-5, 2012. [PUBMED Abstract]
4. Tothill RW, Li J, Mileshkin L, et al.: Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary. J Pathol 231 (4): 413-23, 2013. [PUBMED Abstract]
5. Varadhachary GR, Talantov D, Raber MN, et al.: Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol 26 (27): 4442-8, 2008. [PUBMED Abstract]
6. Fizazi K, Greco FA, Pavlidis N, et al.: Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 26 (Suppl 5): v133-8, 2015. [PUBMED Abstract]
7. Greco FA, Lennington WJ, Spigel DR, et al.: Poorly differentiated neoplasms of unknown primary site: diagnostic usefulness of a molecular cancer classifier assay. Mol Diagn Ther 19 (2): 91-7, 2015. [PUBMED Abstract]
8. Gatalica Z, Millis SZ, Vranic S, et al.: Comprehensive tumor profiling identifies numerous biomarkers of drug response in cancers of unknown primary site: analysis of 1806 cases. Oncotarget 5 (23): 12440-7, 2014. [PUBMED Abstract]
9. Ross JS, Wang K, Gay L, et al.: Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Site: New Routes to Targeted Therapies. JAMA Oncol 1 (1): 40-9, 2015. [PUBMED Abstract]
10. Mody RJ, Prensner JR, Everett J, et al.: Precision medicine in pediatric oncology: Lessons learned and next steps. Pediatr Blood Cancer 64 (3): , 2017. [PUBMED Abstract]

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3–5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people in the United States. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] In children and adolescents, the designation of a rare tumor is not uniform among international groups, as follows:

These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the small number of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer, such as Cancer of Unknown Primary Treatment.

References

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 25, 2025.
5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
6. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr. [PUBMED Abstract]
7. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017. [PUBMED Abstract]
8. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017. [PUBMED Abstract]
9. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019. [PUBMED Abstract]
10. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children’s Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010. [PUBMED Abstract]

Chemotherapy, targeted therapy, and radiation therapy may be used to treat childhood cancers of unknown primary sites. The appropriate and relevant treatments, according to the general category of carcinoma or sarcoma (depending on the histological findings, symptoms, and extent of tumor), are initiated as early as possible.[1]

For more information, see Cancer of Unknown Primary Treatment.

References

1. Morris GJ, Greco FA, Hainsworth JD, et al.: Cancer of unknown primary site. Semin Oncol 37 (2): 71-9, 2010. [PUBMED Abstract]

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was comprehensively reviewed.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Anatomy

Uveal melanomas can arise in the anterior (iris) or the posterior (ciliary body or choroid) uveal tract.[6] Most uveal tract melanomas originate in the choroid. The ciliary body is a less common site of origin, and the iris is the least common. The comparatively low incidence of iris melanomas has been attributed to the characteristic features of these tumors; they tend to be smaller, slower growing, and relatively dormant compared with their posterior counterparts. Iris melanomas rarely metastasize.[7] Melanomas of the posterior uveal tract generally have a more malignant histological appearance; are detected later; and metastasize more frequently than iris melanomas. The typical choroidal melanoma is a brown, elevated, dome-shaped subretinal mass. The degree of pigmentation ranges from dark brown to totally amelanotic.

Most uveal melanomas are initially completely asymptomatic. As the tumor enlarges, it may cause distortion of the pupil (iris melanoma), blurred vision (ciliary body melanoma), or markedly decreased visual acuity caused by secondary retinal detachment (choroidal melanoma). Serous detachment of the retina may occur. If extensive detachment occurs, secondary angle-closure glaucoma occasionally develops. Clinically, several lesions simulate uveal melanoma, including metastatic carcinoma, posterior scleritis, and benign tumors, such as nevi and hemangiomas.[8]

Enlarge

References

1. Singh AD, Topham A: Incidence of uveal melanoma in the United States: 1973-1997. Ophthalmology 110 (5): 956-61, 2003. [PUBMED Abstract]
2. Inskip PD, Devesa SS, Fraumeni JF: Trends in the incidence of ocular melanoma in the United States, 1974-1998. Cancer Causes Control 14 (3): 251-7, 2003. [PUBMED Abstract]
3. Singh AD, Bergman L, Seregard S: Uveal melanoma: epidemiologic aspects. Ophthalmol Clin North Am 18 (1): 75-84, viii, 2005. [PUBMED Abstract]
4. Weis E, Shah CP, Lajous M, et al.: The association between host susceptibility factors and uveal melanoma: a meta-analysis. Arch Ophthalmol 124 (1): 54-60, 2006. [PUBMED Abstract]
5. Harris RB, Griffith K, Moon TE: Trends in the incidence of nonmelanoma skin cancers in southeastern Arizona, 1985-1996. J Am Acad Dermatol 45 (4): 528-36, 2001. [PUBMED Abstract]
6. Uveal melanoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 805–17.
7. Yap-Veloso MI, Simmons RB, Simmons RJ: Iris melanomas: diagnosis and management. Int Ophthalmol Clin 37 (4): 87-100, 1997 Fall. [PUBMED Abstract]
8. Eye and ocular adnexa. In: Rosai J: Ackerman’s Surgical Pathology. 8th ed. Mosby, 1996, pp 2449-2508.
9. Albert DM, Kulkarni AD: Intraocular melanoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 2090-8.
10. Shields CL, Furuta M, Berman EL, et al.: Choroidal nevus transformation into melanoma: analysis of 2514 consecutive cases. Arch Ophthalmol 127 (8): 981-7, 2009. [PUBMED Abstract]
11. Gragoudas ES, Egan KM, Seddon JM, et al.: Survival of patients with metastases from uveal melanoma. Ophthalmology 98 (3): 383-9; discussion 390, 1991. [PUBMED Abstract]
12. Introduction to melanocytic tumors of the uvea. In: Shields JA, Shields CL: Intraocular Tumors: A Text and Atlas. Saunders, 1992, pp 45-59.

Primary intraocular melanomas originate from melanocytes in the uveal tract.[1] The following four distinct cellular types are recognized in intraocular melanoma (revised Callender classification):[2]

Most primary intraocular melanomas contain variable proportions of epithelioid, spindle-A, and spindle-B cells (mixed-cell melanomas). Pure epithelioid-cell primary melanomas are infrequent (approximately 3% of cases).[1] In the Collaborative Ocular Melanoma Study, mixed-cell melanomas predominated (86% of cases).[3]

References

1. Klintworth GK, Scroggs MW: The eye and ocular adnexa. In: Sternberg SS, ed.: Diagnostic Surgical Pathology. Lippincott Williams & Wilkins, 1999, pp 994-6.
2. Grossniklaus HE, Green WR: Uveal tumors. In: Garner A, Klintworth GK, eds.: Pathobiology of Ocular Disease: A Dynamic Approach. 2nd ed. M. Dekker, 1994, pp 1423-77.
3. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol 125 (6): 745-66, 1998. [PUBMED Abstract]

References

1. Factors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol 115 (12): 1537-44, 1997. [PUBMED Abstract]
2. Diener-West M, Earle JD, Fine SL, et al.: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, II: characteristics of patients enrolled and not enrolled. COMS Report No. 17. Arch Ophthalmol 119 (7): 951-65, 2001. [PUBMED Abstract]
3. Shields CL, Shields JA, De Potter P, et al.: Diffuse choroidal melanoma. Clinical features predictive of metastasis. Arch Ophthalmol 114 (8): 956-63, 1996. [PUBMED Abstract]
4. Scott IU, Murray TG, Hughes JR: Evaluation of imaging techniques for detection of extraocular extension of choroidal melanoma. Arch Ophthalmol 116 (7): 897-9, 1998. [PUBMED Abstract]
5. Romero JM, Finger PT, Iezzi R, et al.: Three-dimensional ultrasonography of choroidal melanoma: extrascleral extension. Am J Ophthalmol 126 (6): 842-4, 1998. [PUBMED Abstract]
6. Echography (ultrasound) procedures for the Collaborative Ocular Melanoma Study (COMS), Report no. 12, Part I. J Ophthalmic Nurs Technol 18 (4): 143-9, 1999 Jul-Aug. [PUBMED Abstract]
7. Uveal melanoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 805–17.
8. Dithmar S, Diaz CE, Grossniklaus HE: Intraocular melanoma spread to regional lymph nodes: report of two cases. Retina 20 (1): 76-9, 2000. [PUBMED Abstract]
9. Diener-West M, Reynolds SM, Agugliaro DJ, et al.: Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol 123 (12): 1639-43, 2005. [PUBMED Abstract]
10. Shields CL, Santos MC, Shields JA, et al.: Extraocular extension of unrecognized choroidal melanoma simulating a primary optic nerve tumor: report of two cases. Ophthalmology 106 (7): 1349-52, 1999. [PUBMED Abstract]
11. Singh AD, Shields JA, Shields CL, et al.: Choroidal melanoma metastatic to the contralateral choroid. Am J Ophthalmol 132 (6): 941-3, 2001. [PUBMED Abstract]
12. Mäkitie T, Summanen P, Tarkkanen A, et al.: Tumor-infiltrating macrophages (CD68(+) cells) and prognosis in malignant uveal melanoma. Invest Ophthalmol Vis Sci 42 (7): 1414-21, 2001. [PUBMED Abstract]

References

1. Shields CL, Shields JA, Perez N, et al.: Primary transpupillary thermotherapy for small choroidal melanoma in 256 consecutive cases: outcomes and limitations. Ophthalmology 109 (2): 225-34, 2002. [PUBMED Abstract]
2. Augsburger JJ: Is observation really appropriate for small choroidal melanomas. Trans Am Ophthalmol Soc 91: 147-68; discussion 169-75, 1993. [PUBMED Abstract]
3. Shields CL, Cater J, Shields JA, et al.: Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol 118 (3): 360-4, 2000. [PUBMED Abstract]
4. Robertson DM, Buettner H, Bennett SR: Transpupillary thermotherapy as primary treatment for small choroidal melanomas. Arch Ophthalmol 117 (11): 1512-9, 1999. [PUBMED Abstract]
5. Factors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol 115 (12): 1537-44, 1997. [PUBMED Abstract]
6. Zimmerman LE, McLean IW, Foster WD: Statistical analysis of follow-up data concerning uveal melanomas, and the influence of enucleation. Ophthalmology 87 (6): 557-64, 1980. [PUBMED Abstract]
7. De Potter P, Shields CL, Shields JA: New treatment modalities for uveal melanoma. Curr Opin Ophthalmol 7 (3): 27-32, 1996. [PUBMED Abstract]
8. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma II: initial mortality findings. COMS report no. 10. Am J Ophthalmol 125 (6): 779-96, 1998. [PUBMED Abstract]
9. Hawkins BS; Collaborative Ocular Melanoma Study Group: The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma: IV. Ten-year mortality findings and prognostic factors. COMS report number 24. Am J Ophthalmol 138 (6): 936-51, 2004. [PUBMED Abstract]
10. Damato B: The role of eyewall resection in uveal melanoma management. Int Ophthalmol Clin 46 (1): 81-93, 2006. [PUBMED Abstract]
11. Bechrakis NE, Bornfeld N, Zöller I, et al.: Iodine 125 plaque brachytherapy versus transscleral tumor resection in the treatment of large uveal melanomas. Ophthalmology 109 (10): 1855-61, 2002. [PUBMED Abstract]
12. Bechrakis NE, Petousis V, Willerding G, et al.: Ten-year results of transscleral resection of large uveal melanomas: local tumour control and metastatic rate. Br J Ophthalmol 94 (4): 460-6, 2010. [PUBMED Abstract]
13. Hsueh EC, Essner R, Foshag LJ, et al.: Prolonged survival after complete resection of metastases from intraocular melanoma. Cancer 100 (1): 122-9, 2004. [PUBMED Abstract]
14. Pawlik TM, Zorzi D, Abdalla EK, et al.: Hepatic resection for metastatic melanoma: distinct patterns of recurrence and prognosis for ocular versus cutaneous disease. Ann Surg Oncol 13 (5): 712-20, 2006. [PUBMED Abstract]
15. Albert DM, Kulkarni AD: Intraocular melanoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 2090-8.
16. Shields CL, Shields JA, Cater J, et al.: Plaque radiotherapy for uveal melanoma: long-term visual outcome in 1106 consecutive patients. Arch Ophthalmol 118 (9): 1219-28, 2000. [PUBMED Abstract]
17. Diener-West M, Earle JD, Fine SL, et al.: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS Report No. 18. Arch Ophthalmol 119 (7): 969-82, 2001. [PUBMED Abstract]
18. Collaborative Ocular Melanoma Study Group: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Arch Ophthalmol 124 (12): 1684-93, 2006. [PUBMED Abstract]
19. Melia M, Moy CS, Reynolds SM, et al.: Quality of life after iodine 125 brachytherapy vs enucleation for choroidal melanoma: 5-year results from the Collaborative Ocular Melanoma Study: COMS QOLS Report No. 3. Arch Ophthalmol 124 (2): 226-38, 2006. [PUBMED Abstract]
20. Char DH, Kroll S, Phillips TL, et al.: Late radiation failures after iodine 125 brachytherapy for uveal melanoma compared with charged-particle (proton or helium ion) therapy. Ophthalmology 109 (10): 1850-4, 2002. [PUBMED Abstract]
21. Gragoudas E, Li W, Goitein M, et al.: Evidence-based estimates of outcome in patients irradiated for intraocular melanoma. Arch Ophthalmol 120 (12): 1665-71, 2002. [PUBMED Abstract]
22. Caujolle JP, Mammar H, Chamorey E, et al.: Proton beam radiotherapy for uveal melanomas at nice teaching hospital: 16 years’ experience. Int J Radiat Oncol Biol Phys 78 (1): 98-103, 2010. [PUBMED Abstract]
23. Tsuji H, Ishikawa H, Yanagi T, et al.: Carbon-ion radiotherapy for locally advanced or unfavorably located choroidal melanoma: a Phase I/II dose-escalation study. Int J Radiat Oncol Biol Phys 67 (3): 857-62, 2007. [PUBMED Abstract]
24. Char DH, Quivey JM, Castro JR, et al.: Helium ions versus iodine 125 brachytherapy in the management of uveal melanoma. A prospective, randomized, dynamically balanced trial. Ophthalmology 100 (10): 1547-54, 1993. [PUBMED Abstract]
25. Gragoudas ES, Lane AM, Regan S, et al.: A randomized controlled trial of varying radiation doses in the treatment of choroidal melanoma. Arch Ophthalmol 118 (6): 773-8, 2000. [PUBMED Abstract]
26. Modorati G, Miserocchi E, Galli L, et al.: Gamma knife radiosurgery for uveal melanoma: 12 years of experience. Br J Ophthalmol 93 (1): 40-4, 2009. [PUBMED Abstract]
27. Muller K, Nowak PJ, de Pan C, et al.: Effectiveness of fractionated stereotactic radiotherapy for uveal melanoma. Int J Radiat Oncol Biol Phys 63 (1): 116-22, 2005. [PUBMED Abstract]
28. Dieckmann K, Georg D, Bogner J, et al.: Optimizing LINAC-based stereotactic radiotherapy of uveal melanomas: 7 years’ clinical experience. Int J Radiat Oncol Biol Phys 66 (4 Suppl 1): 47-52, 2006.
29. Harbour JW, Meredith TA, Thompson PA, et al.: Transpupillary thermotherapy versus plaque radiotherapy for suspected choroidal melanomas. Ophthalmology 110 (11): 2207-14; discussion 2215, 2003. [PUBMED Abstract]
30. Pilotto E, Vujosevic S, De Belvis V, et al.: Long-term choroidal vascular changes after iodine brachytherapy versus transpupillary thermotherapy for choroidal melanoma. Eur J Ophthalmol 19 (4): 646-53, 2009 Jul-Aug. [PUBMED Abstract]
31. Desjardins L, Lumbroso-Le Rouic L, Levy-Gabriel C, et al.: Combined proton beam radiotherapy and transpupillary thermotherapy for large uveal melanomas: a randomized study of 151 patients. Ophthalmic Res 38 (5): 255-60, 2006. [PUBMED Abstract]

Melanocytic stromal proliferations and nevi of the iris are the most common tumors of the iris, but melanoma is rare.[1,2] Clinical differentiation between an iris nevus and a melanoma might sometimes be difficult and, at times, impossible. Melanomas of the iris are usually small discrete lesions, although they may occasionally be diffuse, infiltrative, or multiple and may result in heterochromia, chronic uveitis, or spontaneous hemorrhage into the anterior chamber of the eye (hyphema). Iris melanomas that involve more than 66% of the angle circumference are associated with secondary glaucoma.[3]

Routine evaluation of iris melanomas includes gonioscopy, transillumination of the globe, and indirect ophthalmoscopy with 360° of scleral depression. Photographic documentation is essential to verify progression in size or growth of the tumor.[4] Anterior segment fluorescein angiography may be helpful to demonstrate the vascularity of the lesion but is not diagnostic. High-resolution ultrasound biomicroscopy can be used to measure small lesions (basal dimensions and thickness) and to assess tumor involvement of the anterior ciliary body, angle, and overlying sclera.[5] The main disadvantage with this technology is its limited penetration of large lesions. In these cases, conventional ultrasonography is more accurate.

In general, patients with iris melanomas have relatively good outcomes. Only about 3% of these melanomas metastasize within 5 years.[1] Iris melanomas are predominantly of the spindle-cell type and are usually smaller in size than posterior melanomas. Clinical features, including prominent tumor vascularity, rapid growth, and heterogeneous pigmentation, are associated with an epithelioid cell component.[6] Involvement of the iridocorneal angles is frequently associated with ciliary body invasion.[6]

Because iris melanomas are rare and have a good prognosis, clinical trials with sufficient power are impractical. Therefore, treatment experience is based principally on case series and case reports. Conservative management is generally advocated whenever possible, but surgical intervention may be justified with unequivocal tumor growth or extensive disease at initial examination.

References

1. Albert DM, Kulkarni AD: Intraocular melanoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 2090-8.
2. Starr OD, Patel DV, Allen JP, et al.: Iris melanoma: pathology, prognosis and surgical intervention. Clin Experiment Ophthalmol 32 (3): 294-6, 2004. [PUBMED Abstract]
3. Marcus DM, Sahel JA, Jakobiec FA, et al.: Pigmented tumors of the iris. In: Albert DM, Jakobiec FA, eds.: Principles and Practice of Ophthalmology. WB Saunders Co., 1994, pp 3198-3208.
4. Yap-Veloso MI, Simmons RB, Simmons RJ: Iris melanomas: diagnosis and management. Int Ophthalmol Clin 37 (4): 87-100, 1997 Fall. [PUBMED Abstract]
5. Pavlin CJ, McWhae JA, McGowan HD, et al.: Ultrasound biomicroscopy of anterior segment tumors. Ophthalmology 99 (8): 1220-8, 1992. [PUBMED Abstract]
6. Conway RM, Chua WC, Qureshi C, et al.: Primary iris melanoma: diagnostic features and outcome of conservative surgical treatment. Br J Ophthalmol 85 (7): 848-54, 2001. [PUBMED Abstract]
7. Melanocytic tumors of the iris stroma. In: Shields JA: Diagnosis and Management of Intraocular Tumors. C.V. Mosby Company, 1983, pp 83-121.
8. Shields CL, Shields JA, De Potter P, et al.: Treatment of non-resectable malignant iris tumours with custom designed plaque radiotherapy. Br J Ophthalmol 79 (4): 306-12, 1995. [PUBMED Abstract]

Melanoma involving the ciliary body is rare and patients have a poor prognosis. In some cases, diagnosis may be difficult because of similarity to other eye diseases. The differential diagnosis of ciliary body melanoma is considered in cases of unilateral pigmentary glaucoma and chronic uveitis.[1]

Ultrasound biomicroscopy can be used to evaluate tumor shape, thickness, margins, reflectivity, and local invasion.[2,3] Patients with tumors greater than 7 mm in thickness are at increased risk of metastatic disease and melanoma-related death compared with patients with thinner tumors.[4]

References

1. Nguyen QD, Foster CS: Ciliary body melanoma masquerading as chronic uveitis. Ocul Immunol Inflamm 6 (4): 253-6, 1998. [PUBMED Abstract]
2. Marigo FA, Finger PT, McCormick SA, et al.: Iris and ciliary body melanomas: ultrasound biomicroscopy with histopathologic correlation. Arch Ophthalmol 118 (11): 1515-21, 2000. [PUBMED Abstract]
3. Daftari I, Barash D, Lin S, et al.: Use of high-frequency ultrasound imaging to improve delineation of anterior uveal melanoma for proton irradiation. Phys Med Biol 46 (2): 579-90, 2001. [PUBMED Abstract]
4. Gündüz K, Shields CL, Shields JA, et al.: Plaque radiotherapy of uveal melanoma with predominant ciliary body involvement. Arch Ophthalmol 117 (2): 170-7, 1999. [PUBMED Abstract]
5. Finger PT: Plaque radiation therapy for malignant melanoma of the iris and ciliary body. Am J Ophthalmol 132 (3): 328-35, 2001. [PUBMED Abstract]
6. Munzenrider JE: Uveal melanomas. Conservation treatment. Hematol Oncol Clin North Am 15 (2): 389-402, 2001. [PUBMED Abstract]
7. Char DH, Kroll SM, Castro J: Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 125 (1): 81-9, 1998. [PUBMED Abstract]
8. De Potter P: [Choroidal melanoma: current therapeutic approaches] J Fr Ophtalmol 25 (2): 203-11, 2002. [PUBMED Abstract]
9. De Potter P, Shields CL, Shields JA: New treatment modalities for uveal melanoma. Curr Opin Ophthalmol 7 (3): 27-32, 1996. [PUBMED Abstract]
10. Char DH, Miller T, Crawford JB: Uveal tumour resection. Br J Ophthalmol 85 (10): 1213-9, 2001. [PUBMED Abstract]

A wide range of 5-year mortality rates has been reported for patients with small choroidal melanomas, with an average rate of about 16%.[1,2] Several studies indicate that the two most important clinical factors predictive of mortality are larger tumor size at the time of treatment and documentation of tumor growth.[3]

The management of small choroidal melanomas is controversial. The likelihood of progression from the time of diagnosis to growth warranting treatment has not been well characterized. Many ophthalmologists advocate initial observation. This initial management strategy is justified on several grounds, including difficulty in establishing a correct diagnosis, lack of documented efficacy for globe-conserving treatments, and concerns for severe treatment-related morbidity. Others have advocated earlier therapeutic intervention.[4–6]

References

1. Diener-West M, Hawkins BS, Markowitz JA, et al.: A review of mortality from choroidal melanoma. II. A meta-analysis of 5-year mortality rates following enucleation, 1966 through 1988. Arch Ophthalmol 110 (2): 245-50, 1992. [PUBMED Abstract]
2. Mortality in patients with small choroidal melanoma. COMS report no. 4. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol 115 (7): 886-93, 1997. [PUBMED Abstract]
3. Shields CL, Shields JA, Kiratli H, et al.: Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology 102 (9): 1351-61, 1995. [PUBMED Abstract]
4. Shields CL, Cater J, Shields JA, et al.: Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol 118 (3): 360-4, 2000. [PUBMED Abstract]
5. Shields CL, Shields JA, Perez N, et al.: Primary transpupillary thermotherapy for small choroidal melanoma in 256 consecutive cases: outcomes and limitations. Ophthalmology 109 (2): 225-34, 2002. [PUBMED Abstract]
6. Robertson DM, Buettner H, Bennett SR: Transpupillary thermotherapy as primary treatment for small choroidal melanomas. Arch Ophthalmol 117 (11): 1512-9, 1999. [PUBMED Abstract]
7. Shields CL, Shields JA, Gündüz K, et al.: Radiation therapy for uveal malignant melanoma. Ophthalmic Surg Lasers 29 (5): 397-409, 1998. [PUBMED Abstract]
8. Finger PT: Radiation therapy for choroidal melanoma. Surv Ophthalmol 42 (3): 215-32, 1997 Nov-Dec. [PUBMED Abstract]
9. Munzenrider JE: Uveal melanomas. Conservation treatment. Hematol Oncol Clin North Am 15 (2): 389-402, 2001. [PUBMED Abstract]
10. Char DH, Kroll SM, Castro J: Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 125 (1): 81-9, 1998. [PUBMED Abstract]
11. Woodburn R, Danis R, Timmerman R, et al.: Preliminary experience in the treatment of choroidal melanoma with gamma knife radiosurgery. J Neurosurg 93 (Suppl 3): 177-9, 2000. [PUBMED Abstract]
12. Modorati G, Miserocchi E, Galli L, et al.: Gamma knife radiosurgery for uveal melanoma: 12 years of experience. Br J Ophthalmol 93 (1): 40-4, 2009. [PUBMED Abstract]
13. Muller K, Nowak PJ, de Pan C, et al.: Effectiveness of fractionated stereotactic radiotherapy for uveal melanoma. Int J Radiat Oncol Biol Phys 63 (1): 116-22, 2005. [PUBMED Abstract]
14. Shields CL, Shields JA: Transpupillary thermotherapy for choroidal melanoma. Curr Opin Ophthalmol 10 (3): 197-203, 1999. [PUBMED Abstract]
15. Godfrey DG, Waldron RG, Capone A: Transpupillary thermotherapy for small choroidal melanoma. Am J Ophthalmol 128 (1): 88-93, 1999. [PUBMED Abstract]
16. Bartlema YM, Oosterhuis JA, Journée-De Korver JG, et al.: Combined plaque radiotherapy and transpupillary thermotherapy in choroidal melanoma: 5 years’ experience. Br J Ophthalmol 87 (11): 1370-3, 2003. [PUBMED Abstract]
17. Harbour JW, Meredith TA, Thompson PA, et al.: Transpupillary thermotherapy versus plaque radiotherapy for suspected choroidal melanomas. Ophthalmology 110 (11): 2207-14; discussion 2215, 2003. [PUBMED Abstract]
18. Pilotto E, Vujosevic S, De Belvis V, et al.: Long-term choroidal vascular changes after iodine brachytherapy versus transpupillary thermotherapy for choroidal melanoma. Eur J Ophthalmol 19 (4): 646-53, 2009 Jul-Aug. [PUBMED Abstract]
19. Char DH, Miller T, Crawford JB: Uveal tumour resection. Br J Ophthalmol 85 (10): 1213-9, 2001. [PUBMED Abstract]
20. Shields JA, Shields CL: Atlas of Intraocular Tumors. Lippincott Williams & Wilkins, 1999.

Eye-sparing radiation therapy, either by plaque brachytherapy or external beam, is the preferred option for most patients with medium-sized choroidal melanoma. Enucleation remains the standard therapy for large choroidal melanomas and melanomas that cause severe glaucoma or invade the optic nerve.

References

1. Karvat A, Duzenli C, Ma R, et al.: The treatment of choroidal melanoma with 198 Au plaque brachytherapy. Radiother Oncol 59 (2): 153-6, 2001. [PUBMED Abstract]
2. Tabandeh H, Chaudhry NA, Murray TG, et al.: Intraoperative echographic localization of iodine-125 episcleral plaque for brachytherapy of choroidal melanoma. Am J Ophthalmol 129 (2): 199-204, 2000. [PUBMED Abstract]
3. Diener-West M, Earle JD, Fine SL, et al.: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS Report No. 18. Arch Ophthalmol 119 (7): 969-82, 2001. [PUBMED Abstract]
4. Melia BM, Abramson DH, Albert DM, et al.: Collaborative ocular melanoma study (COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma. I. Visual acuity after 3 years COMS report no. 16. Ophthalmology 108 (2): 348-66, 2001. [PUBMED Abstract]
5. Char DH, Quivey JM, Castro JR, et al.: Helium ions versus iodine 125 brachytherapy in the management of uveal melanoma. A prospective, randomized, dynamically balanced trial. Ophthalmology 100 (10): 1547-54, 1993. [PUBMED Abstract]
6. Fuss M, Loredo LN, Blacharski PA, et al.: Proton radiation therapy for medium and large choroidal melanoma: preservation of the eye and its functionality. Int J Radiat Oncol Biol Phys 49 (4): 1053-9, 2001. [PUBMED Abstract]
7. Char DH, Kroll SM, Castro J: Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 125 (1): 81-9, 1998. [PUBMED Abstract]
8. Char DH, Miller T, Crawford JB: Uveal tumour resection. Br J Ophthalmol 85 (10): 1213-9, 2001. [PUBMED Abstract]
9. Peyman GA, Juarez CP, Diamond JG, et al.: Ten years experience with eye wall resection for uveal malignant melanomas. Ophthalmology 91 (12): 1720-5, 1984. [PUBMED Abstract]
10. Seregard S, Landau I: Transpupillary thermotherapy as an adjunct to ruthenium plaque radiotherapy for choroidal melanoma. Acta Ophthalmol Scand 79 (1): 19-22, 2001. [PUBMED Abstract]
11. Shields JA: The expanding role of laser photocoagulation for intraocular tumors. The 1993 H. Christian Zweng Memorial Lecture. Retina 14 (4): 310-22, 1994. [PUBMED Abstract]

Extrascleral extension is associated with a poor prognosis. For patients with gross tumor involvement of the orbit, treatment requires orbital exenteration. However, there is no evidence that such radical surgery will prolong survival. Most patients with localized or encapsulated extraocular extension are not exenterated. This subject is controversial.[1–5]

No effective method of systemic treatment has been identified for patients with metastatic ocular melanoma. Clinical trials are an option for these patients.

References

1. Shammas HF, Blodi FC: Prognostic factors in choroidal and ciliary body melanomas. Arch Ophthalmol 95 (1): 63-9, 1977. [PUBMED Abstract]
2. Pach JM, Robertson DM, Taney BS, et al.: Prognostic factors in choroidal and ciliary body melanomas with extrascleral extension. Am J Ophthalmol 101 (3): 325-31, 1986. [PUBMED Abstract]
3. Kersten RC, Tse DT, Anderson RL, et al.: The role of orbital exenteration in choroidal melanoma with extrascleral extension. Ophthalmology 92 (3): 436-43, 1985. [PUBMED Abstract]
4. Hykin PG, McCartney AC, Plowman PN, et al.: Postenucleation orbital radiotherapy for the treatment of malignant melanoma of the choroid with extrascleral extension. Br J Ophthalmol 74 (1): 36-9, 1990. [PUBMED Abstract]
5. Gündüz K, Shields CL, Shields JA, et al.: Plaque radiotherapy for management of ciliary body and choroidal melanoma with extraocular extension. Am J Ophthalmol 130 (1): 97-102, 2000. [PUBMED Abstract]

The prognosis for any patient with recurring or relapsing disease is poor, regardless of cell type or stage. The question and selection of further treatment depends on many factors, including the extent of the lesion, age and health of the patient, prior treatment, site of recurrence, and individual patient considerations. Surgical resection of metastases diagnosed after initial management of ocular melanoma in single-center case series of highly selected patients has been reported. The extent to which the occasional favorable outcomes are the result of strong selection factors is not clear, so this approach cannot be considered standard.[1]

Eligible patients should consider participation in clinical trials whenever possible.

References

1. Hsueh EC, Essner R, Foshag LJ, et al.: Prolonged survival after complete resection of metastases from intraocular melanoma. Cancer 100 (1): 122-9, 2004. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries containing information related to skin cancer screening include the following:

References

1. Buechi R, Faes L, Bachmann LM, et al.: Evidence assessing the diagnostic performance of medical smartphone apps: a systematic review and exploratory meta-analysis. BMJ Open 7 (12): e018280, 2017. [PUBMED Abstract]
2. Kassianos AP, Emery JD, Murchie P, et al.: Smartphone applications for melanoma detection by community, patient and generalist clinician users: a review. Br J Dermatol 172 (6): 1507-1518, 2015. [PUBMED Abstract]
3. Wolf JA, Moreau JF, Akilov O, et al.: Diagnostic inaccuracy of smartphone applications for melanoma detection. JAMA Dermatol 149 (4): 422-6, 2013. [PUBMED Abstract]
4. Udrea A, Mitra GD, Costea D, et al.: Accuracy of a smartphone application for triage of skin lesions based on machine learning algorithms. J Eur Acad Dermatol Venereol 34 (3): 648-655, 2020. [PUBMED Abstract]
5. Hekler A, Utikal JS, Enk AH, et al.: Superior skin cancer classification by the combination of human and artificial intelligence. Eur J Cancer 120: 114-121, 2019. [PUBMED Abstract]
6. Esteva A, Kuprel B, Novoa RA, et al.: Dermatologist-level classification of skin cancer with deep neural networks. Nature 542 (7639): 115-118, 2017. [PUBMED Abstract]
7. Phillips M, Marsden H, Jaffe W, et al.: Assessment of Accuracy of an Artificial Intelligence Algorithm to Detect Melanoma in Images of Skin Lesions. JAMA Netw Open 2 (10): e1913436, 2019. [PUBMED Abstract]

There are two main types of skin cancer:

BCC and SCC are the most common forms of skin cancer but have substantially better prognoses than the less common, generally more aggressive melanoma.

Keratinocyte carcinoma is the most commonly occurring cancer in the United States. Its incidence appears to be increasing in some [1] but not all [2] areas of the United States. Overall U.S. incidence rates have likely been increasing for a number of years.[3,4] At least some of this increase may be attributable to increased skin cancer awareness and resultant increasing investigation and biopsy of skin lesions. A precise estimate of the total number and incidence rate of keratinocyte carcinoma is not possible because reporting to cancer registries is not required. However, it was estimated that in 2012, 5.4 million cases of keratinocyte carcinoma were diagnosed among 3.3 million people in the United States.[5] That number exceeds all other cases of cancer estimated by the American Cancer Society for 2025, which is about 2 million.[5]

Melanoma is reportable in U.S. cancer registries, so there are more reliable estimates of incidence than for keratinocyte carcinoma. In 2025, it is estimated that 104,960 individuals in the United States will be diagnosed with invasive melanoma and 107,240 will be diagnosed with melanoma in situ. Approximately 8,430 individuals will die of melanoma in 2025. Since the early 2000s, melanoma incidence rates among individuals younger than 50 years have stabilized in women but declined by about 1% per year in men. However, among individuals aged 50 years and older in recent years, the incidence rates appeared to have stabilized in men but increased by about 3% per year in women.[5] From 2013 to 2022, melanoma mortality rates declined by about 4% per year and 3% per year in men and women, respectively.[5]

A study of skin biopsy rates in relation to melanoma incidence rates obtained from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute indicated that much of the observed increase in incidence between 1986 and 2001 was confined to local disease and was most likely caused by overdiagnosis as a result of increased skin biopsy rates during this period.[6] A second study that used SEER data between 2002 and 2009 reported similar findings.[7]

The incidence of melanoma also increased in children and adolescents until 2001. However, between 2001 and 2022, there was a 4.3% reduction in the yearly incidence rate of melanoma among children and adolescents in the National Childhood Cancer Registry databases.[8] During that time, the average annual incidence in this group was exceptionally low (4.5 per 1 million), which may have resulted in spurious trends.[8] Nevertheless, similar trends have been seen in Sweden.[9] In the U.S. study of pediatric melanoma, nearly one-half of the patients had local disease (22% of patients had in situ disease, and 25% of patients had superficial spreading), and nearly one-half of the patients had disease with a thickness of less than one millimeter. Given that mortality from pediatric melanoma had been fairly stable during those years,[10] it is likely that the increase in incidence could be explained, at least in part, by overdiagnosis.

References

1. Athas WF, Hunt WC, Key CR: Changes in nonmelanoma skin cancer incidence between 1977-1978 and 1998-1999 in Northcentral New Mexico. Cancer Epidemiol Biomarkers Prev 12 (10): 1105-8, 2003. [PUBMED Abstract]
2. Harris RB, Griffith K, Moon TE: Trends in the incidence of nonmelanoma skin cancers in southeastern Arizona, 1985-1996. J Am Acad Dermatol 45 (4): 528-36, 2001. [PUBMED Abstract]
3. Rogers HW, Weinstock MA, Harris AR, et al.: Incidence estimate of nonmelanoma skin cancer in the United States, 2006. Arch Dermatol 146 (3): 283-7, 2010. [PUBMED Abstract]
4. Leiter U, Eigentler T, Garbe C: Epidemiology of skin cancer. Adv Exp Med Biol 810: 120-40, 2014. [PUBMED Abstract]
5. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
6. Welch HG, Woloshin S, Schwartz LM: Skin biopsy rates and incidence of melanoma: population based ecological study. BMJ 331 (7515): 481, 2005. [PUBMED Abstract]
7. Weinstock MA, Lott JP, Wang Q, et al.: Skin biopsy utilization and melanoma incidence among Medicare beneficiaries. Br J Dermatol 176 (4): 949-954, 2017. [PUBMED Abstract]
8. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 25, 2025.
9. Austin MT, Xing Y, Hayes-Jordan AA, et al.: Melanoma incidence rises for children and adolescents: an epidemiologic review of pediatric melanoma in the United States. J Pediatr Surg 48 (11): 2207-13, 2013. [PUBMED Abstract]
10. Lewis KG: Trends in pediatric melanoma mortality in the United States, 1968 through 2004. Dermatol Surg 34 (2): 152-9, 2008. [PUBMED Abstract]

Epidemiological evidence suggests that exposure to UV radiation and the sensitivity of an individual’s skin to UV radiation are risk factors for skin cancer, although the type of exposure (high-intensity and short-duration vs. chronic exposure) and pattern of exposure (continuous vs. intermittent) may differ among the three main types of skin cancer.[1–3] In addition, genetic predisposition and the immune system may play roles in the pathogenesis of skin cancers.[4] Organ-transplant recipients receiving immunosuppressive drugs are at elevated risk of skin cancers, particularly squamous cell carcinoma (SCC). Arsenic exposure also increases the risk of cutaneous SCC.[5,6]

The incidence of melanoma rises rapidly in White individuals after age 20 years. Fair-skinned individuals exposed to the sun are at higher risk. Individuals with certain types of pigmented lesions (dysplastic or atypical nevi), with several large nondysplastic nevi, many small nevi, or moderate freckling have a twofold to threefold increased risk of developing melanoma.[7] Individuals with familial dysplastic nevus syndrome or with several dysplastic or atypical nevi are at high (>fivefold) risk of developing melanoma.[4,7]

It is important to note that, for the general population, most melanomas may not arise from preexisting nevi. A meta-analysis of studies published between 1948 and 2016 found that the prevalence of nevus-associated melanomas was only 29%, compared with 71% for the prevalence of de novo melanomas.[8]

References

1. Koh HK: Cutaneous melanoma. N Engl J Med 325 (3): 171-82, 1991. [PUBMED Abstract]
2. Preston DS, Stern RS: Nonmelanoma cancers of the skin. N Engl J Med 327 (23): 1649-62, 1992. [PUBMED Abstract]
3. English DR, Armstrong BK, Kricker A, et al.: Case-control study of sun exposure and squamous cell carcinoma of the skin. Int J Cancer 77 (3): 347-53, 1998. [PUBMED Abstract]
4. Hawkes JE, Truong A, Meyer LJ: Genetic predisposition to melanoma. Semin Oncol 43 (5): 591-597, 2016. [PUBMED Abstract]
5. Thomas VD, Aasi SZ, Wilson LD, et al.: Cancer of the skin. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Vols. 1 & 2. 8th ed. Lippincott Williams & Wilkins, 2008, pp 1863-87.
6. Le Mire L, Hollowood K, Gray D, et al.: Melanomas in renal transplant recipients. Br J Dermatol 154 (3): 472-7, 2006. [PUBMED Abstract]
7. Gandini S, Sera F, Cattaruzza MS, et al.: Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. Eur J Cancer 41 (1): 28-44, 2005. [PUBMED Abstract]
8. Pampena R, Kyrgidis A, Lallas A, et al.: A meta-analysis of nevus-associated melanoma: Prevalence and practical implications. J Am Acad Dermatol 77 (5): 938-945.e4, 2017. [PUBMED Abstract]

Observer variability among physicians has been noted in the evaluation of skin lesions and subsequent biopsy specimens. A systematic review of 32 studies that compared the accuracy of dermatologists and primary care physicians in making a clinical diagnosis of melanoma concluded that there was no statistically significant difference in accuracy. However, the results were inconclusive, owing to small sample sizes and study design weaknesses.[1] Subsequent studies have noted a higher accuracy for dermatologists in the diagnosis of melanocytic lesions,[2,3] yet there is a shortage of dermatologists to meet the demands of population-level screening.

A study of 187 pathologists who practiced in the United States found that cases of moderately dysplastic nevi to early-stage invasive melanoma had less than 50% agreement with a reference diagnosis defined by consensus of experienced pathologists.[4] At a U.S. population level, it is estimated that 82.8% (95% confidence interval, 81.0%–84.5%) of melanocytic skin biopsy diagnoses would be verified if they were reviewed by a consensus reference panel of experienced pathologists.[4] In addition, differentiating between benign and malignant melanocytic tumors during histological examinations of biopsy specimens has been shown to be inconsistent, even in the hands of experienced dermatopathologists.[5,6] This variability in the diagnosis of melanocytic lesions undermines the results of studies that examine screening effectiveness and also may undermine the effectiveness of any screening intervention. Furthermore, this finding suggests that requesting a second opinion regarding the pathology of biopsy specimens may be important.[5–7] A standardized approach to pathologists’ classifying of the interpretations of melanocytic skin lesions may also reduce confusion and improve communication between clinicians.[4,6,8,9]

References

1. Chen SC, Bravata DM, Weil E, et al.: A comparison of dermatologists’ and primary care physicians’ accuracy in diagnosing melanoma: a systematic review. Arch Dermatol 137 (12): 1627-34, 2001. [PUBMED Abstract]
2. Chen SC, Pennie ML, Kolm P, et al.: Diagnosing and managing cutaneous pigmented lesions: primary care physicians versus dermatologists. J Gen Intern Med 21 (7): 678-82, 2006. [PUBMED Abstract]
3. Corbo MD, Wismer J: Agreement between dermatologists and primary care practitioners in the diagnosis of malignant melanoma: review of the literature. J Cutan Med Surg 16 (5): 306-10, 2012 Sep-Oct. [PUBMED Abstract]
4. Elmore JG, Barnhill RL, Elder DE, et al.: Pathologists’ diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study. BMJ 357: j2813, 2017. [PUBMED Abstract]
5. Farmer ER, Gonin R, Hanna MP: Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. Hum Pathol 27 (6): 528-31, 1996. [PUBMED Abstract]
6. Lott JP, Elmore JG, Zhao GA, et al.: Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group. J Am Acad Dermatol 75 (2): 356-63, 2016. [PUBMED Abstract]
7. Piepkorn MW, Longton GM, Reisch LM, et al.: Assessment of Second-Opinion Strategies for Diagnoses of Cutaneous Melanocytic Lesions. JAMA Netw Open 2 (10): e1912597, 2019. [PUBMED Abstract]
8. Piepkorn MW, Barnhill RL, Elder DE, et al.: The MPATH-Dx reporting schema for melanocytic proliferations and melanoma. J Am Acad Dermatol 70 (1): 131-41, 2014. [PUBMED Abstract]
9. Radick AC, Reisch LM, Shucard HL, et al.: Terminology for melanocytic skin lesions and the MPATH-Dx classification schema: A survey of dermatopathologists. J Cutan Pathol 48 (6): 733-738, 2021. [PUBMED Abstract]

More than 90% of melanomas that arise in the skin can be recognized with the naked eye. Very often there is a prolonged horizontal growth phase, during which the tumor expands centrifugally beneath the epidermis but does not invade the underlying dermis. This horizontal growth phase may provide lead time for early detection. Melanoma is more easily cured if treated before the onset of the vertical growth phase with its metastatic potential.[1]

The probability of tumor recurrence within 10 years after curative resection is less than 10% with tumors less than 1.4 mm in thickness. For patients with tumors less than 0.76 mm in thickness, the likelihood of recurrence is less than 1% in 10 years.[2]

A systematic review of skin cancer screening examined evidence available through mid-2005. The review concluded that direct evidence of improved health outcomes associated with skin cancer screening is lacking.[3] An updated review published in 2016 found limited evidence that skin cancer screening reduces melanoma mortality.[4,5]

No randomized trials evaluating the efficacy of skin cancer screening on mortality have been completed. A population-based trial (using cluster randomization) to determine the effect of skin cancer screening on melanoma mortality was initiated in Queensland, Australia, but lost its funding after the initial pilot phase, and no health outcomes were ever reported.[6]

Two ecological studies have been conducted using data from Germany. The first study was a pilot project conducted in 2003 and 2004, in which a skin cancer screening program was implemented in one federal state. Suggestion of a reduction in melanoma mortality with screening led to the establishment of countywide skin cancer screening programs in 2008.[7,8] The programs offered a whole-body skin examination once every 2 years for individuals older than 35 years. The second ecological study compared the melanoma mortality experience in Germany with the melanoma mortality experience of subregions of 22 European countries—none of which had organized screening programs—for the years 2000 to 2013. After adjustment for potential confounders, Germany and the 22 European regions had similar malignant mortality rates, suggesting no benefit of screening.[9]

References

1. Friedman RJ, Rigel DS, Kopf AW: Early detection of malignant melanoma: the role of physician examination and self-examination of the skin. CA Cancer J Clin 35 (3): 130-51, 1985 May-Jun. [PUBMED Abstract]
2. Blois MS, Sagebiel RW, Abarbanel RM, et al.: Malignant melanoma of the skin. I. The association of tumor depth and type, and patient sex, age, and site with survival. Cancer 52 (7): 1330-41, 1983. [PUBMED Abstract]
3. Wolff T, Tai E, Miller T: Screening for skin cancer: an update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 150 (3): 194-8, 2009. [PUBMED Abstract]
4. Wernli KJ, Henrikson NB, Morrison CC, et al.: Screening for Skin Cancer in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA 316 (4): 436-47, 2016. [PUBMED Abstract]
5. Bibbins-Domingo K, Grossman DC, Curry SJ, et al.: Screening for Skin Cancer: US Preventive Services Task Force Recommendation Statement. JAMA 316 (4): 429-35, 2016. [PUBMED Abstract]
6. Aitken JF, Elwood JM, Lowe JB, et al.: A randomised trial of population screening for melanoma. J Med Screen 9 (1): 33-7, 2002. [PUBMED Abstract]
7. Katalinic A, Waldmann A, Weinstock MA, et al.: Does skin cancer screening save lives? An observational study comparing trends in melanoma mortality in regions with and without screening. Cancer 118 (21): 5395-402, 2012. [PUBMED Abstract]
8. Eisemann N, Waldmann A, Holleczek B, et al.: Observed and expected mortality in the German skin cancer screening pilot project SCREEN. J Med Screen 25 (3): 166-168, 2018. [PUBMED Abstract]
9. Kaiser M, Schiller J, Schreckenberger C: The effectiveness of a population-based skin cancer screening program: evidence from Germany. Eur J Health Econ 19 (3): 355-367, 2018. [PUBMED Abstract]

Harms have not been well studied or reported in quantitative terms, but the potential for adverse consequences from skin cancer screening exists. In the SCREEN pilot project in Germany, 4.4% of all screened participants underwent a skin excision for a suspicious lesion, but most biopsies did not result in a cancer diagnosis. The detection rate was especially affected by age. One case of melanoma was detected per 28 excisions overall (for both men and women), while 52 skin excisions were required to detect one melanoma in men aged 20 to 34 years.[1]

Visual examination of the skin in asymptomatic individuals may lead to cosmetic or functional complications of diagnostic or treatment interventions and psychological effects of being labeled with a potentially fatal disease. However, robust data on the frequency of such events are lacking. Other harmful consequences are overdiagnosis, leading to the detection of biologically benign disease that would otherwise go undetected,[2–4] and possible misdiagnosis of a benign lesion as malignant. For more information, see the Accuracy of Making a Clinical Diagnosis of Melanoma section.

References

1. Waldmann A, Nolte S, Geller AC, et al.: Frequency of excisions and yields of malignant skin tumors in a population-based screening intervention of 360,288 whole-body examinations. Arch Dermatol 148 (8): 903-10, 2012. [PUBMED Abstract]
2. Welch HG, Woloshin S, Schwartz LM: Skin biopsy rates and incidence of melanoma: population based ecological study. BMJ 331 (7515): 481, 2005. [PUBMED Abstract]
3. Weinstock MA, Lott JP, Wang Q, et al.: Skin biopsy utilization and melanoma incidence among Medicare beneficiaries. Br J Dermatol 176 (4): 949-954, 2017. [PUBMED Abstract]
4. Schoffer O, Schülein S, Arand G, et al.: Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011. BMC Cancer 16 (1): 936, 2016. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Incidence and Mortality of Skin Cancer

Added American Cancer Society as reference 5.

Updated statistics with estimated new cases of melanoma and melanoma in situ and deaths due to melanoma for 2025. Also revised text to state that from 2013 to 2022, melanoma mortality rates declined by about 4% per year and 3% per year in men and women, respectively.

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Melanoma is a malignant tumor of melanocytes, which are the cells that make the pigment melanin and are derived from the neural crest. Although most melanomas arise in the skin, they may also arise from mucosal surfaces or at other sites to which neural crest cells migrate, including the uveal tract. Uveal melanomas differ significantly from cutaneous melanoma in incidence, prognostic factors, molecular characteristics, and treatment. For more information, visit Intraocular (Uveal) Melanoma Treatment.

Anatomy

Enlarge

Clinical Features

Melanoma occurs predominantly in adults, and more than 50% of the cases arise in apparently normal areas of the skin. Melanoma can occur anywhere, including on mucosal surfaces and the uvea. However, in women it occurs more commonly on the extremities, and in men it occurs most commonly on the trunk or head and neck.[4]

Early signs in a nevus that would suggest a malignant change include:

• Darker or variable discoloration.
• Itching.
• An increase in size or the development of satellite lesions.
• Ulceration or bleeding (later signs).

A common acronym used by medical professionals and the lay public to identify the suspicious features of pigmented lesions that may reflect malignant change is ABCDE:[5]

• Asymmetry of the lesion.
• Border irregularity.
• Color variation.
• Diameter >6 mm.
• Evolution or change in the lesion.

Enlarge

References

1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
2. Melanoma. Bethesda, Md: National Library of Medicine, 2012. Available online. Last accessed May 1, 2025.
3. Bleyer A, O’Leary M, Barr R, et al., eds.: Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975-2000. National Cancer Institute, 2006. NIH Pub. No. 06-5767. Available online. Last accessed May 1, 2025.
4. Slingluff CI Jr, Flaherty K, Rosenberg SA, et al.: Cutaneous melanoma. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 1643-91.
5. Abbasi NR, Shaw HM, Rigel DS, et al.: Early diagnosis of cutaneous melanoma: revisiting the ABCD criteria. JAMA 292 (22): 2771-6, 2004. [PUBMED Abstract]
6. Corona R, Mele A, Amini M, et al.: Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol 14 (4): 1218-23, 1996. [PUBMED Abstract]
7. Farmer ER, Gonin R, Hanna MP: Discordance in the histopathologic diagnosis of melanoma and melanocytic nevi between expert pathologists. Hum Pathol 27 (6): 528-31, 1996. [PUBMED Abstract]
8. Balch CM, Soong S, Ross MI, et al.: Long-term results of a multi-institutional randomized trial comparing prognostic factors and surgical results for intermediate thickness melanomas (1.0 to 4.0 mm). Intergroup Melanoma Surgical Trial. Ann Surg Oncol 7 (2): 87-97, 2000. [PUBMED Abstract]
9. Manola J, Atkins M, Ibrahim J, et al.: Prognostic factors in metastatic melanoma: a pooled analysis of Eastern Cooperative Oncology Group trials. J Clin Oncol 18 (22): 3782-93, 2000. [PUBMED Abstract]
10. Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 563–85.
11. Balch CM, Gershenwald JE, Soong SJ, et al.: Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27 (36): 6199-206, 2009. [PUBMED Abstract]
12. Shen P, Guenther JM, Wanek LA, et al.: Can elective lymph node dissection decrease the frequency and mortality rate of late melanoma recurrences? Ann Surg Oncol 7 (2): 114-9, 2000. [PUBMED Abstract]
13. Tsao H, Cosimi AB, Sober AJ: Ultra-late recurrence (15 years or longer) of cutaneous melanoma. Cancer 79 (12): 2361-70, 1997. [PUBMED Abstract]
14. Sarac E, Wilhelmi J, Thomas I, et al.: Late recurrence of melanoma after 10 years – Is the course of the disease different from early recurrences? J Eur Acad Dermatol Venereol 34 (5): 977-983, 2020. [PUBMED Abstract]
15. Faries MB, Steen S, Ye X, et al.: Late recurrence in melanoma: clinical implications of lost dormancy. J Am Coll Surg 217 (1): 27-34; discussion 34-6, 2013. [PUBMED Abstract]
16. McLaughlin CC, Wu XC, Jemal A, et al.: Incidence of noncutaneous melanomas in the U.S. Cancer 103 (5): 1000-7, 2005. [PUBMED Abstract]
17. Hayward NK, Wilmott JS, Waddell N, et al.: Whole-genome landscapes of major melanoma subtypes. Nature 545 (7653): 175-180, 2017. [PUBMED Abstract]
18. Thomas NE, Kricker A, Waxweiler WT, et al.: Comparison of clinicopathologic features and survival of histopathologically amelanotic and pigmented melanomas: a population-based study. JAMA Dermatol 150 (12): 1306-314, 2014. [PUBMED Abstract]

The descriptive terms for clinicopathological cellular subtypes of malignant melanoma are of historical interest only; they do not have independent prognostic or therapeutic significance. These cellular subtypes include:

References

1. Cancer Genome Atlas Network: Genomic Classification of Cutaneous Melanoma. Cell 161 (7): 1681-96, 2015. [PUBMED Abstract]
2. Van Raamsdonk CD, Bezrookove V, Green G, et al.: Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457 (7229): 599-602, 2009. [PUBMED Abstract]
3. Van Raamsdonk CD, Griewank KG, Crosby MB, et al.: Mutations in GNA11 in uveal melanoma. N Engl J Med 363 (23): 2191-9, 2010. [PUBMED Abstract]

Clinical staging is based on the thickness and ulceration status of the primary tumor, and whether the tumor has spread to regional lymph nodes or distant sites. For melanoma that is clinically confined to the primary site, the chance of lymph node or systemic metastases increases as the thickness and depth of local invasion increases, which worsens the prognosis. Melanoma can spread by local extension (through lymphatics) and/or by hematogenous routes to distant sites. Any organ may be involved by metastases, but the lungs and liver are common sites.

The microstage of malignant melanoma is determined on histological examination by the vertical thickness of the lesion in millimeters (Breslow classification) and/or the anatomical level of local invasion (Clark classification). The Breslow thickness is more reproducible and more accurately predicts subsequent behavior of malignant melanoma in lesions thicker than 1.5 mm and should always be reported.

Accurate microstaging of the primary tumor requires careful histological evaluation of the entire specimen by an experienced pathologist.

AJCC Stage Groupings and TNM Definitions

The American Joint Committee on Cancer (AJCC) has designated staging by TNM (tumor, node, metastasis) classification to define melanoma.[1]

Cancers staged using this staging system include cutaneous melanoma. Cancers not staged using this system include melanoma of the conjunctiva; melanoma of the uvea; mucosal melanoma arising in the head and neck; mucosal melanoma of the urethra, vagina, rectum, and anus; Merkel cell carcinoma; and squamous cell carcinoma.[1]

AJCC Prognostic Stage Groups-Clinical (cTNM)

Table 3. Definition of cTNM Stage 0a

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bThickness and ulceration status not applicable.
0	Tis, N0, M0	Tis = Melanoma in situ.b	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 4. Definition of cTNM Stages IA and IBa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
IA	T1a, N0, M0	T1a = <0.8 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
IB	T1b, N0, M0	T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
	T2a, N0, M0	T2a = >1.0–2.0 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 5. Definition of cTNM Stages IIA, IIB, and IICa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
IIA	T2b, N0, M0	T2b = >1.0–2.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
	T3a, N0, M0	T3a = >2.0–4.0 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
IIB	T3b, N0, M0	T3b = >2.0–4.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
	T4a, N0, M0	T4a = >4.0 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.
IIC	T4b, N0, M0	T4b = >4.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 6. Definition of cTNM Stage IIIa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bFor example, diagnosis by curettage.
cFor example, unknown primary or completely regressed melanoma.
dThickness and ulceration status not applicable.
eDetected by sentinel lymph node biopsy.
III	Any T, Tis, ≥N1, M0	TX = Primary tumor cannot be assessed.b,d	N1a = One clinically occult nodee /in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
		T0 = No evidence of primary tumor.c,d
		Tis = Melanoma in situ.d	N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.
		T1a = <0.8 mm/without ulceration.	N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
		T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N2a = Two or three clinically occult nodese/in-transit, satellite, and/or microsatellite metastases not present.
		T2a = >1.0–2.0 mm/without ulceration.	N2b = Two or three nodes at least one of which was clinically detected/in-transit, satellite, and or microsatellite metastases not present.
		T2b = >1.0–2.0 mm/with ulceration.	N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present.
		T3a = >2.0–4.0 mm/without ulceration.	N3a = Four or more clinically occult nodese/in-transit, satellite, and/or microsatellite metastases not present.
		T3b = >2.0–4.0 mm/with ulceration.	N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present.
		T4a = >4.0 mm/without ulceration.	N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.
		T4b = >4.0 mm/with ulceration.

Table 7. Definition of cTNM Stage IVa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; c = clinical; CNS = central nervous system; LDH = lactate dehydrogenase; No. = number.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bFor example, sentinel lymph node biopsy not performed, regional nodes previously removed for another reason. (Exception: pathological N category is not required for T1 melanomas, use cN).
IV	Any T, Any N, M1	Any T = Visit Table 6 for description.	NX = Regional nodes not assessed;b N0 = No regional metastases; ≥N1 = Visit Table 6 for description.	M1 = Evidence of distant metastasis.
				–M1a = Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes [M1a(0) = LDH not elevated; M1a(1) = LDH elevated].
				–M1b = Distant metastasis to lung with or without M1a sites of disease [M1b(0) = LDH not elevated; M1b(1) = LDH elevated].
				–M1c = Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease [M1c(0) = LDH not elevated; OR M1c(1) = LDH elevated].
				–M1d = Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease [M1d(0) = LDH not elevated; M1d(1) = LDH elevated].

AJCC Prognostic Stage Groups-Pathological (pTNM)

Table 8. Definition of pTNM Stage 0a,b

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)	Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis; cN = clinical N; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bPathological stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes to complete pathological staging; use cN information to assign their pathological stage.
cThickness and ulceration status not applicable.
0	Tis, N0, M0	Tis = Melanoma in situ.b,c	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.	Enlarge

Table 9. Definition of pTNM Stages IA and IBa,b

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)	Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis; cN = clinical N; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bPathological stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes to complete pathological staging; use cN information to assign their pathological stage.
IA	T1a, N0, M0	T1a = <0.8 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.	Enlarge
	T1b, N0, M0	T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.
IB	T2a, N0, M0	T2a = >1.0–2.0 mm/without ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.

Table 10. Definition of pTNM Stages IIA, IIB, and IICa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)	Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
IIA	T2b, N0, M0	T2b = >1.0–2.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.	Enlarge
	T3a, N0, M0	T3a = >2.0–4.0 mm/without ulceration.
IIB	T3b, N0, M0	T3b = >2.0–4.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.	Enlarge
	T4a, N0, M0	T4a = >4.0 mm/without ulceration.
IIC	T4b, N0, M0	T4b = >4.0 mm/with ulceration.	N0 = No regional metastases detected.	M0 = No evidence of distant metastasis.	Enlarge

Table 11. Definition of pTNM Stages IIIA, IIIB, IIIC, and IIIDa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)
T = primary tumor; N = regional lymph node; M = distant metastasis; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bDetected by sentinel lymph node biopsy.
cFor example, unknown primary or completely regressed melanoma.
dThickness and ulceration status not applicable.
IIIA	T1a/b–T2a, N1a or N2a, M0	T1a = <0.8 mm/without ulceration/T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N1a = One clinically occult nodeb/in-transit, satellite, and/or microsatellite metastases not present; OR N2a = Two or three clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
		T2a = >1.0–2.0 mm/without ulceration.
IIIB	T0, N1b, N1c, M0	T0 = No evidence of primary tumor.c,d	N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
	T1a/b–T2a, N1b/c or N2b, M0	T1a = <0.8 mm/without ulceration/T1b <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present;/N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present; OR	M0 = No evidence of distant metastasis.
		T2a = >1.0–2.0 mm/without ulceration.
			N2b = Two or three nodes at least one of which was clinically detected/in-transit, satellite, and or microsatellite metastases not present.
	T2b/T3a, N1a–N2b, M0	T2b = >1.0–2.0 mm/with ulceration/T3a = >2.0–4.0 mm/without ulceration.	N1a = One clinically occult nodeb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.
			N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
			N2a = Two or three clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N2b = Two or three nodes, at least one of which was clinically detected/in-transit, satellite, and/or microsatellite metastases not present.
IIIC	T0, N2b, N2c, N3b, or N3c, M0	T0 = No evidence of primary tumor.c,d	N2b = Two or three nodes, at least one of which was clinically detected/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present.
			N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present; OR
			N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.
	T1a–T3a, N2c or N3a/b/c, M0	T1a = <0.8 mm/without ulceration/T1b = <0.8 mm with ulceration; 0.8–1.0 mm with or without ulceration.	N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present; OR	M0 = No evidence of distant metastasis.
		T2a = >1.0–2.0 mm/without ulceration.
		T2b = >1.0–2.0 mm/with ulceration.
			N3a = Four or more clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present.
		T3a = >2.0–4.0 mm/without ulceration.	N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.
	T3b/T4a, Any N ≥N1, M0	T3b = >2.0–4.0 mm/with ulceration/T4a = >4.0 mm/without ulceration.	N1a = One clinically occult nodeb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.
			N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
			N2a = Two or three clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N2b = Two or three nodes, at least one of which was clinically detected/in-transit, satellite, and/or microsatellite metastases not present.
			N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present.
			N3a = Four or more clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present.
			N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.
	T4b, N1a–N2c, M0	T4b = >4.0 mm/with ulceration.	N1a = One clinically occult nodeb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N1b = One clinically detected node/in-transit, satellite, and/or microsatellite metastases not present.
			N1c = No regional lymph node disease/in-transit, satellite, and/or microsatellite metastases present.
			N2a = Two or three clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.
			N2b = Two or three nodes, at least one of which was clinically detected/in-transit, satellite, and/or microsatellite metastases not present.
			N2c = One clinically occult or clinically detected node/in-transit, satellite, and/or microsatellite metastases present.
IIID	T4b, N3a/b/c, M0	T4b = >4.0 mm/with ulceration.	N3a = Four or more clinically occult nodesb/in-transit, satellite, and/or microsatellite metastases not present.	M0 = No evidence of distant metastasis.
			N3b = Four or more nodes, at least one of which was clinically detected, or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases not present.
			N3c = Two or more clinically occult or clinically detected nodes and/or presence of any number of matted nodes/in-transit, satellite, and/or microsatellite metastases present.

Table 12. Definition of pTNM Stage IVa

Stage	TNM	T Category (Thickness/Ulceration Status)	N Category (No. of Tumor-Involved Regional Lymph Nodes/Presence of In-Transit, Satellite, and/or Microsatellite Metastases)	M Category (Anatomic Site/LDH Level)	Illustration
T = primary tumor; N = regional lymph node; M = distant metastasis; cN = clinical N; CNS = central nervous system; LDH = lactate dehydrogenase; No. = number; p = pathological.
aAdapted from AJCC: Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 563–85.
bFor example, sentinel lymph node biopsy not performed, regional nodes previously removed for another reason. (Exception: pathological N category is not required for T1 melanomas, use cN).
cPathological stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes to complete pathological staging; use cN information to assign their pathological stage.
dThickness and ulceration status not applicable.
IV	Any T, Tis, Any N, M1	Any T = Visit Table 6 for description.	NX = Regional nodes not assessed;d N0 = No regional metastases; ≥N1 = Visit Table 6 for description.	M1 = Evidence of distant metastasis.	Enlarge
		Tis = Melanoma in situ.b,c		–M1a = Distant metastasis to skin, soft tissue including muscle, and/or nonregional lymph nodes [M1a(0) = LDH not elevated; M1a(1) = LDH elevated].
				–M1b = Distant metastasis to lung with or without M1a sites of disease [M1b(0) = LDH not elevated; M1b(1) = LDH elevated].
				–M1c – Distant metastasis to non-CNS visceral sites with or without M1a or M1b sites of disease [M1c(0) = LDH not elevated; M1c(1) = LDH elevated].
				–M1d = Distant metastasis to CNS with or without M1a, M1b, or M1c sites of disease [M1d(0) = LDH not elevated; M1d(1) = LDH elevated].

References

1. Melanoma of the Skin. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 563–85.

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6. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998. [PUBMED Abstract]
7. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000. [PUBMED Abstract]
8. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998. [PUBMED Abstract]
9. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998. [PUBMED Abstract]
10. Wong SL, Balch CM, Hurley P, et al.: Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30 (23): 2912-8, 2012. [PUBMED Abstract]
11. Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1): 7-17, 1996. [PUBMED Abstract]
12. Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000. [PUBMED Abstract]
13. Eggermont AM, Suciu S, Santinami M, et al.: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372 (9633): 117-26, 2008. [PUBMED Abstract]
14. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study–United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004. [PUBMED Abstract]
15. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011. [PUBMED Abstract]
16. Leitao MM, Cheng X, Hamilton AL, et al.: Gynecologic Cancer InterGroup (GCIG) consensus review for vulvovaginal melanomas. Int J Gynecol Cancer 24 (9 Suppl 3): S117-22, 2014. [PUBMED Abstract]
17. Trifirò G, Travaini LL, Sanvito F, et al.: Sentinel node detection by lymphoscintigraphy and sentinel lymph node biopsy in vulvar melanoma. Eur J Nucl Med Mol Imaging 37 (4): 736-41, 2010. [PUBMED Abstract]
18. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.: Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 375 (19): 1845-1855, 2016. [PUBMED Abstract]
19. Tarhini AA, Lee SJ, Hodi FS, et al.: Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol 38 (6): 567-575, 2020. [PUBMED Abstract]
20. Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000. [PUBMED Abstract]
21. Eggermont AMM, Blank CU, Mandala M, et al.: Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med 378 (19): 1789-1801, 2018. [PUBMED Abstract]
22. Long GV, Hauschild A, Santinami M, et al.: Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med 377 (19): 1813-1823, 2017. [PUBMED Abstract]
23. Maio M, Lewis K, Demidov L, et al.: Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 19 (4): 510-520, 2018. [PUBMED Abstract]
24. Patel SP, Othus M, Chen Y, et al.: Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med 388 (9): 813-823, 2023. [PUBMED Abstract]
25. Tawbi HA, Schadendorf D, Lipson EJ, et al.: Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med 386 (1): 24-34, 2022. [PUBMED Abstract]
26. Hauschild A, Grob JJ, Demidov LV, et al.: Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380 (9839): 358-65, 2012. [PUBMED Abstract]
27. Dummer R, Ascierto PA, Gogas HJ, et al.: Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19 (10): 1315-1327, 2018. [PUBMED Abstract]
28. Flaherty KT, Robert C, Hersey P, et al.: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367 (2): 107-14, 2012. [PUBMED Abstract]
29. Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008. [PUBMED Abstract]
30. Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011. [PUBMED Abstract]
31. Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011. [PUBMED Abstract]
32. Gutzmer R, Stroyakovskiy D, Gogas H, et al.: Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 395 (10240): 1835-1844, 2020. [PUBMED Abstract]
33. Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999. [PUBMED Abstract]
34. Middleton MR, Grob JJ, Aaronson N, et al.: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1): 158-66, 2000. [PUBMED Abstract]
35. Avril MF, Aamdal S, Grob JJ, et al.: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22 (6): 1118-25, 2004. [PUBMED Abstract]
36. Robert C, Thomas L, Bondarenko I, et al.: Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364 (26): 2517-26, 2011. [PUBMED Abstract]
37. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999. [PUBMED Abstract]
38. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001. [PUBMED Abstract]

References

1. Kunishige JH, Doan L, Brodland DG, et al.: Comparison of surgical margins for lentigo maligna versus melanoma in situ. J Am Acad Dermatol 81 (1): 204-212, 2019. [PUBMED Abstract]
2. Ellison PM, Zitelli JA, Brodland DG: Mohs micrographic surgery for melanoma: A prospective multicenter study. J Am Acad Dermatol 81 (3): 767-774, 2019. [PUBMED Abstract]

References

1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991. [PUBMED Abstract]
2. Veronesi U, Cascinelli N, Adamus J, et al.: Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 318 (18): 1159-62, 1988. [PUBMED Abstract]
3. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000. [PUBMED Abstract]
4. Balch CM, Soong SJ, Smith T, et al.: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8 (2): 101-8, 2001. [PUBMED Abstract]
5. Essner R, Conforti A, Kelley MC, et al.: Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma. Ann Surg Oncol 6 (5): 442-9, 1999 Jul-Aug. [PUBMED Abstract]
6. Gershenwald JE, Thompson W, Mansfield PF, et al.: Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17 (3): 976-83, 1999. [PUBMED Abstract]
7. Mraz-Gernhard S, Sagebiel RW, Kashani-Sabet M, et al.: Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma. Arch Dermatol 134 (8): 983-7, 1998. [PUBMED Abstract]
8. Morton DL, Thompson JF, Cochran AJ, et al.: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355 (13): 1307-17, 2006. [PUBMED Abstract]
9. Faries MB, Thompson JF, Cochran AJ, et al.: Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 376 (23): 2211-2222, 2017. [PUBMED Abstract]
10. Leiter U, Stadler R, Mauch C, et al.: Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 17 (6): 757-767, 2016. [PUBMED Abstract]

References

1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991. [PUBMED Abstract]
2. Veronesi U, Cascinelli N, Adamus J, et al.: Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 318 (18): 1159-62, 1988. [PUBMED Abstract]
3. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000. [PUBMED Abstract]
4. Khayat D, Rixe O, Martin G, et al.: Surgical margins in cutaneous melanoma (2 cm versus 5 cm for lesions measuring less than 2.1-mm thick). Cancer 97 (8): 1941-6, 2003. [PUBMED Abstract]
5. Balch CM, Urist MM, Karakousis CP, et al.: Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 218 (3): 262-7; discussion 267-9, 1993. [PUBMED Abstract]
6. Haydu LE, Stollman JT, Scolyer RA, et al.: Minimum Safe Pathologic Excision Margins for Primary Cutaneous Melanomas (1-2 mm in Thickness): Analysis of 2131 Patients Treated at a Single Center. Ann Surg Oncol 23 (4): 1071-81, 2016. [PUBMED Abstract]
7. Hudson LE, Maithel SK, Carlson GW, et al.: 1 or 2 cm margins of excision for T2 melanomas: do they impact recurrence or survival? Ann Surg Oncol 20 (1): 346-51, 2013. [PUBMED Abstract]
8. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998. [PUBMED Abstract]
9. Essner R, Conforti A, Kelley MC, et al.: Efficacy of lymphatic mapping, sentinel lymphadenectomy, and selective complete lymph node dissection as a therapeutic procedure for early-stage melanoma. Ann Surg Oncol 6 (5): 442-9, 1999 Jul-Aug. [PUBMED Abstract]
10. Gershenwald JE, Thompson W, Mansfield PF, et al.: Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17 (3): 976-83, 1999. [PUBMED Abstract]
11. Mraz-Gernhard S, Sagebiel RW, Kashani-Sabet M, et al.: Prediction of sentinel lymph node micrometastasis by histological features in primary cutaneous malignant melanoma. Arch Dermatol 134 (8): 983-7, 1998. [PUBMED Abstract]
12. Morton DL, Thompson JF, Cochran AJ, et al.: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355 (13): 1307-17, 2006. [PUBMED Abstract]
13. Faries MB, Thompson JF, Cochran AJ, et al.: Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 376 (23): 2211-2222, 2017. [PUBMED Abstract]
14. Leiter U, Stadler R, Mauch C, et al.: Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 17 (6): 757-767, 2016. [PUBMED Abstract]
15. Morton DL, Thompson JF, Cochran AJ, et al.: Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med 370 (7): 599-609, 2014. [PUBMED Abstract]

References

1. Utjés D, Malmstedt J, Teras J, et al.: 2-cm versus 4-cm surgical excision margins for primary cutaneous melanoma thicker than 2 mm: long-term follow-up of a multicentre, randomised trial. Lancet 394 (10197): 471-477, 2019. [PUBMED Abstract]
2. Balch CM, Urist MM, Karakousis CP, et al.: Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 218 (3): 262-7; discussion 267-9, 1993. [PUBMED Abstract]
3. Thomas JM, Newton-Bishop J, A’Hern R, et al.: Excision margins in high-risk malignant melanoma. N Engl J Med 350 (8): 757-66, 2004. [PUBMED Abstract]
4. Hayes AJ, Maynard L, Coombes G, et al.: Wide versus narrow excision margins for high-risk, primary cutaneous melanomas: long-term follow-up of survival in a randomised trial. Lancet Oncol 17 (2): 184-192, 2016. [PUBMED Abstract]
5. Gershenwald JE, Thompson W, Mansfield PF, et al.: Multi-institutional melanoma lymphatic mapping experience: the prognostic value of sentinel lymph node status in 612 stage I or II melanoma patients. J Clin Oncol 17 (3): 976-83, 1999. [PUBMED Abstract]
6. McMasters KM, Reintgen DS, Ross MI, et al.: Sentinel lymph node biopsy for melanoma: controversy despite widespread agreement. J Clin Oncol 19 (11): 2851-5, 2001. [PUBMED Abstract]
7. Cherpelis BS, Haddad F, Messina J, et al.: Sentinel lymph node micrometastasis and other histologic factors that predict outcome in patients with thicker melanomas. J Am Acad Dermatol 44 (5): 762-6, 2001. [PUBMED Abstract]
8. Essner R: The role of lymphoscintigraphy and sentinel node mapping in assessing patient risk in melanoma. Semin Oncol 24 (1 Suppl 4): S8-10, 1997. [PUBMED Abstract]
9. Chan AD, Morton DL: Sentinel node detection in malignant melanoma. Recent Results Cancer Res 157: 161-77, 2000. [PUBMED Abstract]
10. Morton DL, Wen DR, Wong JH, et al.: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 127 (4): 392-9, 1992. [PUBMED Abstract]
11. Reintgen D, Cruse CW, Wells K, et al.: The orderly progression of melanoma nodal metastases. Ann Surg 220 (6): 759-67, 1994. [PUBMED Abstract]
12. Thompson JF, McCarthy WH, Bosch CM, et al.: Sentinel lymph node status as an indicator of the presence of metastatic melanoma in regional lymph nodes. Melanoma Res 5 (4): 255-60, 1995. [PUBMED Abstract]
13. Uren RF, Howman-Giles R, Thompson JF, et al.: Lymphoscintigraphy to identify sentinel lymph nodes in patients with melanoma. Melanoma Res 4 (6): 395-9, 1994. [PUBMED Abstract]
14. Bostick P, Essner R, Glass E, et al.: Comparison of blue dye and probe-assisted intraoperative lymphatic mapping in melanoma to identify sentinel nodes in 100 lymphatic basins. Arch Surg 134 (1): 43-9, 1999. [PUBMED Abstract]
15. Faries MB, Thompson JF, Cochran AJ, et al.: Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 376 (23): 2211-2222, 2017. [PUBMED Abstract]
16. Leiter U, Stadler R, Mauch C, et al.: Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 17 (6): 757-767, 2016. [PUBMED Abstract]
17. Luke JJ, Rutkowski P, Queirolo P, et al.: Pembrolizumab versus placebo as adjuvant therapy in completely resected stage IIB or IIC melanoma (KEYNOTE-716): a randomised, double-blind, phase 3 trial. Lancet 399 (10336): 1718-1729, 2022. [PUBMED Abstract]
18. Long GV, Luke JJ, Khattak MA, et al.: Pembrolizumab versus placebo as adjuvant therapy in resected stage IIB or IIC melanoma (KEYNOTE-716): distant metastasis-free survival results of a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol 23 (11): 1378-1388, 2022. [PUBMED Abstract]
19. Luke JJ, Ascierto PA, Khattak MA, et al.: Pembrolizumab Versus Placebo as Adjuvant Therapy in Resected Stage IIB or IIC Melanoma: Final Analysis of Distant Metastasis-Free Survival in the Phase III KEYNOTE-716 Study. J Clin Oncol 42 (14): 1619-1624, 2024. [PUBMED Abstract]

References

1. Veronesi U, Cascinelli N: Narrow excision (1-cm margin). A safe procedure for thin cutaneous melanoma. Arch Surg 126 (4): 438-41, 1991. [PUBMED Abstract]
2. Veronesi U, Cascinelli N, Adamus J, et al.: Thin stage I primary cutaneous malignant melanoma. Comparison of excision with margins of 1 or 3 cm. N Engl J Med 318 (18): 1159-62, 1988. [PUBMED Abstract]
3. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000. [PUBMED Abstract]
4. Cohn-Cedermark G, Rutqvist LE, Andersson R, et al.: Long term results of a randomized study by the Swedish Melanoma Study Group on 2-cm versus 5-cm resection margins for patients with cutaneous melanoma with a tumor thickness of 0.8-2.0 mm. Cancer 89 (7): 1495-501, 2000. [PUBMED Abstract]
5. Balch CM, Soong SJ, Smith T, et al.: Long-term results of a prospective surgical trial comparing 2 cm vs. 4 cm excision margins for 740 patients with 1-4 mm melanomas. Ann Surg Oncol 8 (2): 101-8, 2001. [PUBMED Abstract]
6. Heaton KM, Sussman JJ, Gershenwald JE, et al.: Surgical margins and prognostic factors in patients with thick (>4mm) primary melanoma. Ann Surg Oncol 5 (4): 322-8, 1998. [PUBMED Abstract]
7. Balch CM, Urist MM, Karakousis CP, et al.: Efficacy of 2-cm surgical margins for intermediate-thickness melanomas (1 to 4 mm). Results of a multi-institutional randomized surgical trial. Ann Surg 218 (3): 262-7; discussion 267-9, 1993. [PUBMED Abstract]
8. Shen P, Wanek LA, Morton DL: Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol 7 (8): 554-9; discussion 560-1, 2000. [PUBMED Abstract]
9. Hochwald SN, Coit DG: Role of elective lymph node dissection in melanoma. Semin Surg Oncol 14 (4): 276-82, 1998. [PUBMED Abstract]
10. Cascinelli N, Morabito A, Santinami M, et al.: Immediate or delayed dissection of regional nodes in patients with melanoma of the trunk: a randomised trial. WHO Melanoma Programme. Lancet 351 (9105): 793-6, 1998. [PUBMED Abstract]
11. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998. [PUBMED Abstract]
12. Wong SL, Balch CM, Hurley P, et al.: Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J Clin Oncol 30 (23): 2912-8, 2012. [PUBMED Abstract]
13. Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1): 7-17, 1996. [PUBMED Abstract]
14. Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000. [PUBMED Abstract]
15. Eggermont AM, Suciu S, Santinami M, et al.: Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet 372 (9633): 117-26, 2008. [PUBMED Abstract]
16. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study–United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004. [PUBMED Abstract]
17. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011. [PUBMED Abstract]
18. Faries MB, Thompson JF, Cochran AJ, et al.: Completion Dissection or Observation for Sentinel-Node Metastasis in Melanoma. N Engl J Med 376 (23): 2211-2222, 2017. [PUBMED Abstract]
19. Leiter U, Stadler R, Mauch C, et al.: Complete lymph node dissection versus no dissection in patients with sentinel lymph node biopsy positive melanoma (DeCOG-SLT): a multicentre, randomised, phase 3 trial. Lancet Oncol 17 (6): 757-767, 2016. [PUBMED Abstract]
20. Patel SP, Othus M, Chen Y, et al.: Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma. N Engl J Med 388 (9): 813-823, 2023. [PUBMED Abstract]
21. Blank CU, Lucas MW, Scolyer RA, et al.: Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma. N Engl J Med 391 (18): 1696-1708, 2024. [PUBMED Abstract]
22. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.: Prolonged Survival in Stage III Melanoma with Ipilimumab Adjuvant Therapy. N Engl J Med 375 (19): 1845-1855, 2016. [PUBMED Abstract]
23. Tarhini AA, Lee SJ, Hodi FS, et al.: Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol 38 (6): 567-575, 2020. [PUBMED Abstract]
24. Weber J, Mandala M, Del Vecchio M, et al.: Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. N Engl J Med 377 (19): 1824-1835, 2017. [PUBMED Abstract]
25. Eggermont AMM, Blank CU, Mandala M, et al.: Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. N Engl J Med 378 (19): 1789-1801, 2018. [PUBMED Abstract]
26. Long GV, Hauschild A, Santinami M, et al.: Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med 377 (19): 1813-1823, 2017. [PUBMED Abstract]
27. Maio M, Lewis K, Demidov L, et al.: Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol 19 (4): 510-520, 2018. [PUBMED Abstract]
28. Ascierto PA, Del Vecchio M, Mandalá M, et al.: Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 21 (11): 1465-1477, 2020. [PUBMED Abstract]
29. Eggermont AMM, Blank CU, Mandalà M, et al.: Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 22 (5): 643-654, 2021. [PUBMED Abstract]
30. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al.: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol 16 (5): 522-30, 2015. [PUBMED Abstract]
31. Dummer R, Hauschild A, Santinami M, et al.: Five-Year Analysis of Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med 383 (12): 1139-1148, 2020. [PUBMED Abstract]
32. Long GV, Hauschild A, Santinami M, et al.: Final Results for Adjuvant Dabrafenib plus Trametinib in Stage III Melanoma. N Engl J Med 391 (18): 1709-1720, 2024. [PUBMED Abstract]

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7. Hodi FS, O’Day SJ, McDermott DF, et al.: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363 (8): 711-23, 2010. [PUBMED Abstract]
8. Yervoy (Ipilimumab): Immune-Mediated Adverse Reaction Management Guide. Princeton, NJ: Bristol-Myers Squibb, 2011. Available online. Last accessed May 1, 2025.
9. Atkins MB, Lotze MT, Dutcher JP, et al.: High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17 (7): 2105-16, 1999. [PUBMED Abstract]
10. Atkins MB, Kunkel L, Sznol M, et al.: High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long-term survival update. Cancer J Sci Am 6 (Suppl 1): S11-4, 2000. [PUBMED Abstract]
11. Postow MA, Chesney J, Pavlick AC, et al.: Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372 (21): 2006-17, 2015. [PUBMED Abstract]
12. Larkin J, Chiarion-Sileni V, Gonzalez R, et al.: Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 373 (1): 23-34, 2015. [PUBMED Abstract]
13. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al.: Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 377 (14): 1345-1356, 2017. [PUBMED Abstract]
14. Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al.: Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med 392 (1): 11-22, 2025. [PUBMED Abstract]
15. Tawbi HA, Forsyth PA, Algazi A, et al.: Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med 379 (8): 722-730, 2018. [PUBMED Abstract]
16. Tawbi HA, Schadendorf D, Lipson EJ, et al.: Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma. N Engl J Med 386 (1): 24-34, 2022. [PUBMED Abstract]
17. Heidorn SJ, Milagre C, Whittaker S, et al.: Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 140 (2): 209-21, 2010. [PUBMED Abstract]
18. Hatzivassiliou G, Song K, Yen I, et al.: RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 464 (7287): 431-5, 2010. [PUBMED Abstract]
19. Poulikakos PI, Zhang C, Bollag G, et al.: RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464 (7287): 427-30, 2010. [PUBMED Abstract]
20. Su F, Viros A, Milagre C, et al.: RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 366 (3): 207-15, 2012. [PUBMED Abstract]
21. Chapman PB, Hauschild A, Robert C, et al.: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364 (26): 2507-16, 2011. [PUBMED Abstract]
22. Sosman JA, Kim KB, Schuchter L, et al.: Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Engl J Med 366 (8): 707-14, 2012. [PUBMED Abstract]
23. Hauschild A, Grob JJ, Demidov LV, et al.: Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380 (9839): 358-65, 2012. [PUBMED Abstract]
24. Flaherty KT, Robert C, Hersey P, et al.: Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med 367 (2): 107-14, 2012. [PUBMED Abstract]
25. Hodi FS, Friedlander P, Corless CL, et al.: Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol 26 (12): 2046-51, 2008. [PUBMED Abstract]
26. Guo J, Si L, Kong Y, et al.: Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29 (21): 2904-9, 2011. [PUBMED Abstract]
27. Carvajal RD, Antonescu CR, Wolchok JD, et al.: KIT as a therapeutic target in metastatic melanoma. JAMA 305 (22): 2327-34, 2011. [PUBMED Abstract]
28. Long GV, Stroyakovskiy D, Gogas H, et al.: Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 371 (20): 1877-88, 2014. [PUBMED Abstract]
29. Long GV, Stroyakovskiy D, Gogas H, et al.: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386 (9992): 444-51, 2015. [PUBMED Abstract]
30. Robert C, Karaszewska B, Schachter J, et al.: Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med 372 (1): 30-9, 2015. [PUBMED Abstract]
31. Robert C, Grob JJ, Stroyakovskiy D, et al.: Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med 381 (7): 626-636, 2019. [PUBMED Abstract]
32. Larkin J, Ascierto PA, Dréno B, et al.: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371 (20): 1867-76, 2014. [PUBMED Abstract]
33. Dummer R, Ascierto PA, Gogas HJ, et al.: Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol 19 (5): 603-615, 2018. [PUBMED Abstract]
34. Dummer R, Ascierto PA, Gogas HJ, et al.: Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19 (10): 1315-1327, 2018. [PUBMED Abstract]
35. Gutzmer R, Stroyakovskiy D, Gogas H, et al.: Atezolizumab, vemurafenib, and cobimetinib as first-line treatment for unresectable advanced BRAFV600 mutation-positive melanoma (IMspire150): primary analysis of the randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 395 (10240): 1835-1844, 2020. [PUBMED Abstract]
36. Chesney J, Lewis KD, Kluger H, et al.: Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer 10 (12): , 2022. [PUBMED Abstract]
37. Medina T, Chesney JA, Whitman E, et al.: Long-term efficacy and safety of lifileucel tumor-infiltrating lymphocyte (TIL) cell therapy in patients with advanced melanoma: a 4-year analysis of the C-144–01 study. [Abstract] J Immunother Cancer 11 (Suppl 1): A-776, 873, 2023.
38. Andtbacka RH, Kaufman HL, Collichio F, et al.: Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma. J Clin Oncol 33 (25): 2780-8, 2015. [PUBMED Abstract]
39. Leo F, Cagini L, Rocmans P, et al.: Lung metastases from melanoma: when is surgical treatment warranted? Br J Cancer 83 (5): 569-72, 2000. [PUBMED Abstract]
40. Ollila DW, Hsueh EC, Stern SL, et al.: Metastasectomy for recurrent stage IV melanoma. J Surg Oncol 71 (4): 209-13, 1999. [PUBMED Abstract]
41. Gutman H, Hess KR, Kokotsakis JA, et al.: Surgery for abdominal metastases of cutaneous melanoma. World J Surg 25 (6): 750-8, 2001. [PUBMED Abstract]
42. Chapman PB, Einhorn LH, Meyers ML, et al.: Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 17 (9): 2745-51, 1999. [PUBMED Abstract]
43. Middleton MR, Grob JJ, Aaronson N, et al.: Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 18 (1): 158-66, 2000. [PUBMED Abstract]
44. Avril MF, Aamdal S, Grob JJ, et al.: Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22 (6): 1118-25, 2004. [PUBMED Abstract]
45. Anderson CM, Buzaid AC, Legha SS: Systemic treatments for advanced cutaneous melanoma. Oncology (Huntingt) 9 (11): 1149-58; discussion 1163-4, 1167-8, 1995. [PUBMED Abstract]
46. Wagner JD, Gordon MS, Chuang TY, et al.: Current therapy of cutaneous melanoma. Plast Reconstr Surg 105 (5): 1774-99; quiz 1800-1, 2000. [PUBMED Abstract]
47. Mays SR, Nelson BR: Current therapy of cutaneous melanoma. Cutis 63 (5): 293-8, 1999. [PUBMED Abstract]
48. Patel PM, Suciu S, Mortier L, et al.: Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer 47 (10): 1476-83, 2011. [PUBMED Abstract]
49. Kirkwood JM, Strawderman MH, Ernstoff MS, et al.: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14 (1): 7-17, 1996. [PUBMED Abstract]
50. Kirkwood JM, Ibrahim JG, Sondak VK, et al.: High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18 (12): 2444-58, 2000. [PUBMED Abstract]
51. Kirkwood JM, Ibrahim J, Lawson DH, et al.: High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin Oncol 19 (5): 1430-6, 2001. [PUBMED Abstract]
52. Hancock BW, Wheatley K, Harris S, et al.: Adjuvant interferon in high-risk melanoma: the AIM HIGH Study–United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma. J Clin Oncol 22 (1): 53-61, 2004. [PUBMED Abstract]
53. Koops HS, Vaglini M, Suciu S, et al.: Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. J Clin Oncol 16 (9): 2906-12, 1998. [PUBMED Abstract]
54. Lee ML, Tomsu K, Von Eschen KB: Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 10 (1): 81-92, 2000. [PUBMED Abstract]
55. Ives NJ, Stowe RL, Lorigan P, et al.: Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol 25 (34): 5426-34, 2007. [PUBMED Abstract]
56. Rate WR, Solin LJ, Turrisi AT: Palliative radiotherapy for metastatic malignant melanoma: brain metastases, bone metastases, and spinal cord compression. Int J Radiat Oncol Biol Phys 15 (4): 859-64, 1988. [PUBMED Abstract]
57. Herbert SH, Solin LJ, Rate WR, et al.: The effect of palliative radiation therapy on epidural compression due to metastatic malignant melanoma. Cancer 67 (10): 2472-6, 1991. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment of Stage II Melanoma

Revised text about the results of a trial that randomly assigned patients with completely resected stage IIB or stage IIC melanoma to receive either pembrolizumab or placebo (cited Luke et al. as reference 19).

Treatment of Resectable Stage III Melanoma

Revised text about the final analysis results of a multinational double-blind trial that randomly assigned patients with stage IIIA, IIIB, or IIIC melanoma with BRAF V600E or V600K pathogenic variants who underwent completion lymphadenectomy to receive either dabrafenib plus trametinib or two matched placebo tablets (cited Long et al. as reference 32).

Treatment of Unresectable Stage III, Stage IV, and Recurrent Melanoma

Revised the list of treatment options for unresectable stage III, stage IV, and recurrent melanoma to include tumor-infiltrating lymphocyte therapy.

Revised text about the final analysis results of an international double-blind trial that randomly assigned 945 previously untreated patients with unresectable stage III or IV melanoma to receive nivolumab plus placebo, nivolumab plus ipilimumab followed by nivolumab, or ipilimumab plus placebo (cited Wolchok et al. as reference 14).

Added Tumor-infiltrating lymphocyte therapy as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

Cancer stage describes the extent of cancer in the body, such as the size of the tumor, whether it has spread, and how far it has spread from where it first formed. It is important to know the stage of Merkel cell cancer to plan the best treatment.

There are several staging systems for cancer that describe the extent of the cancer. Merkel cell carcinoma staging usually uses the TNM staging system. The cancer may be described by this staging system in your pathology report. Based on the TNM results, a stage (I, II, III, or IV, also written as 1, 2, 3, or 4) is assigned to your cancer. When talking to you about your diagnosis, your doctor may describe the cancer as one of these stages.

Learn about tests to stage Merkel cell carcinoma. Learn more about Cancer Staging.

The following stages are used for Merkel cell carcinoma:

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Stage 0 (carcinoma in situ)

In stage 0, abnormal Merkel cells are found in the top layer of skin. These abnormal cells may become cancer and spread into nearby normal tissue.

Stage I (also called Stage 1) Merkel cell carcinoma

In stage I, the tumor is 2 centimeters or smaller.

Stage II (also called Stage 2) Merkel cell carcinoma

Stage II Merkel cell carcinoma is divided into stages IIA and IIB.

• In stage IIA, the tumor is larger than 2 centimeters.
• In stage IIB, the tumor has spread to nearby connective tissue, muscle, cartilage, or bone.

Stage III (also called Stage 3) Merkel cell carcinoma

Stage III Merkel cell carcinoma is divided into stages IIIA and IIIB.

In stage IIIA, either of the following is found:

• the tumor may be any size and may have spread to nearby connective tissue, muscle, cartilage, or bone. A lymph node cannot be felt during a physical exam but cancer is found in the lymph node by sentinel lymph node biopsy or after the lymph node is removed and checked under a microscope for signs of cancer; or
• a swollen lymph node is felt during a physical exam and/or seen on an imaging test. When the lymph node is removed and checked under a microscope for signs of cancer, cancer is found in the lymph node. The place where the cancer began is not known.

In stage IIIB, the tumor may be any size and:

• may have spread to nearby connective tissue, muscle, cartilage, or bone. A swollen lymph node is felt during a physical exam and/or seen on an imaging test. When the lymph node is removed and checked under a microscope for signs of cancer, cancer is found in the lymph node; or
• cancer is in a lymph vessel between the primary tumor and lymph nodes that are near or far away. Cancer may have spread to lymph nodes.

Stage IV (also called Stage 4) Merkel cell carcinoma

In stage IV, the tumor has spread to skin that is not close to the primary tumor or to other parts of the body, such as the liver, lung, bone, or brain.

Stage IV Merkel cell carcinoma is also called metastatic Merkel cell carcinoma. Metastatic cancer happens when cancer cells travel through the lymphatic system or blood and form tumors in other parts of the body. The metastatic tumor is the same type of cancer as the primary tumor. For example, if Merkel cell carcinoma spreads to the liver, the cancer cells in the liver are actually Merkel cell carcinoma cells. The disease is called metastatic Merkel cell carcinoma, not liver cancer. Learn more in Metastatic Cancer: When Cancer Spreads.

Treatment of stage I and stage II Merkel cell carcinoma may include:

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of stage III Merkel cell carcinoma may include:

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of stage IV Merkel cell carcinoma may include:

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of recurrent Merkel cell carcinoma may include:

Learn more about these treatments in the Treatment Option Overview.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

For more information from the National Cancer Institute about Merkel cell carcinoma, visit:

For general cancer information and other resources from the National Cancer Institute, visit:

Merkel cell carcinoma (MCC) was originally described by Toker in 1972 as trabecular carcinoma of the skin.[1] Other names for MCC include Toker tumor, primary small cell carcinoma of the skin, primary cutaneous neuroendocrine tumor, and malignant trichodiscoma.[2]

MCC is an aggressive neuroendocrine carcinoma arising in the dermoepidermal junction (see Figure 1), and it is the second most common cause of skin cancer death after melanoma.[3,4] Although the exact origin and function of the Merkel cell remains under investigation, it is thought to have features of both epithelial and neuroendocrine origin and arise in cells with touch-sensitivity function (mechanoreceptors).[5–11]

Therapeutic options have been historically limited for patients with advanced disease. However, new immunotherapeutic approaches are associated with durable responses.[12]

Anatomy

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Incidence and Mortality

MCC incidence increases progressively with age. There are few cases in patients younger than 50 years, and the median age at diagnosis is about 65 years (see Figure 2).[13] Incidence is considerably greater in White individuals than in Black individuals and slightly greater in men than in women.[13–17]

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MCC occurs most frequently in sun-exposed areas of skin, particularly the head and neck, followed by the extremities, and then the trunk.[5,16,18] Incidence has been reported to be greater in geographic regions with higher levels of ultraviolet B sunlight.[16]

As of 2013, MCC had an annual incidence of 0.7 cases per 100,000 people in the United States.[19] The incidence has been increasing over the past several decades, almost doubling in the United States between 2000 and 2013. This rise is potentially related to more accurate diagnostic pathology tools, improved clinical awareness of MCC, an aging population, increased sun exposure in susceptible populations, and improved registry tools. The incidence is also higher in immunosuppressed populations (HIV, hematologic malignancies, immunosuppressive medications, etc.).[20] Approximately 25,000 cases of MCC have been recorded in the United States since 2000, including more than 2,200 incident cases reported in 2014 to the National Program of Cancer Registries/SEER combined registries, which captures more than 98% of the U.S. population and the ten most common sites of MCC (see Table 1).[17]

Table 1. The Ten Most Common Sites for Merkel Cell Carcinoma (SEER 1973–2006)a

Anatomical Site	Cases (%)
NOS = not otherwise specified; SEER = Surveillance, Epidemiology, and End Results Program.
aAlbores-Saavedra J et al: Merkel cell carcinoma demographics, morphology, and survival based on 3,870 cases: A population-based study. J Cutan Pathol. Reprinted with permission © 2009. Published by Wiley-Blackwell. All rights reserved.[17]
Skin, face	1,041 (26.9)
Skin of upper limb and shoulder	853 (22.0)
Skin of lower limb and hip	578 (14.9)
Skin of trunk	410 (10.6)
Skin of scalp and neck	348 (9.0)
Skin, NOS	234 (6.0)
External ear	120 (3.1)
Eyelid	98 (2.5)
Skin of lip	91 (2.4)
Unknown primary site	31 (0.8)
Total	3,804 (98.3)

In various cases series, up to 97% of MCCs arise in the skin. MCC primaries in other sites were very rare, as were MCCs from unknown primary sites.[17]

SEER registry data have shown excess risk of MCC as a first or second cancer in patients with several primary cancers.[21] National cancer registries from three Scandinavian countries have identified a variety of second cancers diagnosed after MCC.[22]

Prognosis

The most significant prognostic parameters for MCC include tumor size and the presence of locoregional or distant metastases. These factors form the basis of the American Joint Committee on Cancer staging system for MCC.[59,60] Although an increasing primary tumor size correlates with an increased risk of metastatic disease, MCC tumors of any size have significant risk of occult metastasis, supporting the use of sentinel lymph node biopsy for all cases.[61] Additional features of the primary tumor, such as lymphovascular invasion and tumor growth pattern, may also have prognostic significance. Clinically detectable nodal disease is associated with worse outcome than microscopic metastases.[55,59] Other findings associated with worse prognosis include sheet-like involvement in lymph node metastases and an increasing number of metastatic lymph nodes.[60,62]

The bulk of MCC literature is from small case series, which are subject to many confounding factors. For this reason, the relapse and survival rates reported by stage vary widely in the literature. In general, lower-stage disease is associated with better overall survival.[63] For more information, see the Potential Prognostic Factors section.

Outcomes from patients presenting with small volume local disease and pathologically confirmed cancer-negative lymph nodes report a cause-specific 5-year survival rate exceeding 90% in one report.[44,55][Level of evidence C2]

A tabular summary of treatment results of MCC from 12 series illustrates the difficulty in comparing outcome data among series.[7]

Using the SEER Program registry MCC staging system adopted in 1973, MCC survival data (1973–2006) by stage is summarized in Figure 3.[17]

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References

1. Toker C: Trabecular carcinoma of the skin. Arch Dermatol 105 (1): 107-10, 1972. [PUBMED Abstract]
2. Schwartz RA, Lambert WC: The Merkel cell carcinoma: a 50-year retrospect. J Surg Oncol 89 (1): 5, 2005. [PUBMED Abstract]
3. Agelli M, Clegg LX, Becker JC, et al.: The etiology and epidemiology of merkel cell carcinoma. Curr Probl Cancer 34 (1): 14-37, 2010 Jan-Feb. [PUBMED Abstract]
4. Harms PW: Update on Merkel Cell Carcinoma. Clin Lab Med 37 (3): 485-501, 2017. [PUBMED Abstract]
5. Nghiem P, McKee PH, Haynes HA: Merkel cell (cutaneous neuroendocrine) carcinoma. In: Sober AJ, Haluska FG, eds.: Skin Cancer. BC Decker Inc., 2001, pp 127-141.
6. Nghiem P, James N: Merkel cell carcinoma. In: Wolff K, Goldsmith LA, Katz SI, et al., eds.: Fitzpatrick’s Dermatology in General Medicine. 7th ed. McGraw-Hill , 2008, pp 1087-94.
7. Eng TY, Boersma MG, Fuller CD, et al.: A comprehensive review of the treatment of Merkel cell carcinoma. Am J Clin Oncol 30 (6): 624-36, 2007. [PUBMED Abstract]
8. Medina-Franco H, Urist MM, Fiveash J, et al.: Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 8 (3): 204-8, 2001. [PUBMED Abstract]
9. Busse PM, Clark JR, Muse VV, et al.: Case records of the Massachusetts General Hospital. Case 19-2008. A 63-year-old HIV-positive man with cutaneous Merkel-cell carcinoma. N Engl J Med 358 (25): 2717-23, 2008. [PUBMED Abstract]
10. Rockville Merkel Cell Carcinoma Group: Merkel cell carcinoma: recent progress and current priorities on etiology, pathogenesis, and clinical management. J Clin Oncol 27 (24): 4021-6, 2009. [PUBMED Abstract]
11. Calder KB, Smoller BR: New insights into merkel cell carcinoma. Adv Anat Pathol 17 (3): 155-61, 2010. [PUBMED Abstract]
12. Cassler NM, Merrill D, Bichakjian CK, et al.: Merkel Cell Carcinoma Therapeutic Update. Curr Treat Options Oncol 17 (7): 36, 2016. [PUBMED Abstract]
13. Agelli M, Clegg LX: Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol 49 (5): 832-41, 2003. [PUBMED Abstract]
14. Hodgson NC: Merkel cell carcinoma: changing incidence trends. J Surg Oncol 89 (1): 1-4, 2005. [PUBMED Abstract]
15. Young JL, Ward KC, Ries LAG: Cancer of rare sites. In: Ries LAG, Young JL, Keel GE, et al., eds.: SEER Survival Monograph: Cancer Survival Among Adults: U. S. SEER Program, 1988-2001, Patient and Tumor Characteristics. National Cancer Institute, 2007. NIH Pub. No. 07-6215, pp 251-61.
16. Miller RW, Rabkin CS: Merkel cell carcinoma and melanoma: etiological similarities and differences. Cancer Epidemiol Biomarkers Prev 8 (2): 153-8, 1999. [PUBMED Abstract]
17. Albores-Saavedra J, Batich K, Chable-Montero F, et al.: Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol 37 (1): 20-7, 2010. [PUBMED Abstract]
18. Heath M, Jaimes N, Lemos B, et al.: Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features. J Am Acad Dermatol 58 (3): 375-81, 2008. [PUBMED Abstract]
19. Paulson KG, Park SY, Vandeven NA, et al.: Merkel cell carcinoma: Current US incidence and projected increases based on changing demographics. J Am Acad Dermatol 78 (3): 457-463.e2, 2018. [PUBMED Abstract]
20. Ma JE, Brewer JD: Merkel cell carcinoma in immunosuppressed patients. Cancers (Basel) 6 (3): 1328-50, 2014. [PUBMED Abstract]
21. Howard RA, Dores GM, Curtis RE, et al.: Merkel cell carcinoma and multiple primary cancers. Cancer Epidemiol Biomarkers Prev 15 (8): 1545-9, 2006. [PUBMED Abstract]
22. Bzhalava D, Bray F, Storm H, et al.: Risk of second cancers after the diagnosis of Merkel cell carcinoma in Scandinavia. Br J Cancer 104 (1): 178-80, 2011. [PUBMED Abstract]
23. Lunder EJ, Stern RS: Merkel-cell carcinomas in patients treated with methoxsalen and ultraviolet A radiation. N Engl J Med 339 (17): 1247-8, 1998. [PUBMED Abstract]
24. Feng H, Shuda M, Chang Y, et al.: Clonal integration of a polyomavirus in human Merkel cell carcinoma. Science 319 (5866): 1096-100, 2008. [PUBMED Abstract]
25. Garneski KM, Warcola AH, Feng Q, et al.: Merkel cell polyomavirus is more frequently present in North American than Australian Merkel cell carcinoma tumors. J Invest Dermatol 129 (1): 246-8, 2009. [PUBMED Abstract]
26. Becker JC, Houben R, Ugurel S, et al.: MC polyomavirus is frequently present in Merkel cell carcinoma of European patients. J Invest Dermatol 129 (1): 248-50, 2009. [PUBMED Abstract]
27. Kassem A, Schöpflin A, Diaz C, et al.: Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene. Cancer Res 68 (13): 5009-13, 2008. [PUBMED Abstract]
28. Houben R, Schrama D, Becker JC: Molecular pathogenesis of Merkel cell carcinoma. Exp Dermatol 18 (3): 193-8, 2009. [PUBMED Abstract]
29. Paik JY, Hall G, Clarkson A, et al.: Immunohistochemistry for Merkel cell polyomavirus is highly specific but not sensitive for the diagnosis of Merkel cell carcinoma in the Australian population. Hum Pathol 42 (10): 1385-90, 2011. [PUBMED Abstract]
30. Andres C, Belloni B, Puchta U, et al.: Prevalence of MCPyV in Merkel cell carcinoma and non-MCC tumors. J Cutan Pathol 37 (1): 28-34, 2010. [PUBMED Abstract]
31. Kassem A, Technau K, Kurz AK, et al.: Merkel cell polyomavirus sequences are frequently detected in nonmelanoma skin cancer of immunosuppressed patients. Int J Cancer 125 (2): 356-61, 2009. [PUBMED Abstract]
32. Foulongne V, Dereure O, Kluger N, et al.: Merkel cell polyomavirus DNA detection in lesional and nonlesional skin from patients with Merkel cell carcinoma or other skin diseases. Br J Dermatol 162 (1): 59-63, 2010. [PUBMED Abstract]
33. DeCaprio JA: Does detection of Merkel cell polyomavirus in Merkel cell carcinoma provide prognostic information? J Natl Cancer Inst 101 (13): 905-7, 2009. [PUBMED Abstract]
34. Laude HC, Jonchère B, Maubec E, et al.: Distinct merkel cell polyomavirus molecular features in tumour and non tumour specimens from patients with merkel cell carcinoma. PLoS Pathog 6 (8): , 2010. [PUBMED Abstract]
35. Buck CB, Lowy DR: Immune readouts may have prognostic value for the course of merkel cell carcinoma, a virally associated disease. J Clin Oncol 29 (12): 1506-8, 2011. [PUBMED Abstract]
36. Lemos B, Nghiem P: Merkel cell carcinoma: more deaths but still no pathway to blame. J Invest Dermatol 127 (9): 2100-3, 2007. [PUBMED Abstract]
37. Seattle Cancer Care Alliance: Merkel Cell Carcinoma Information for Patients and Their Physicians: Clinical Photos/Images. Seattle, Wa: Seattle Cancer Care Alliance Skin Oncology Clinic, 2009. Available online. Last accessed May 9, 2025.
38. Gupta SG, Wang LC, Peñas PF, et al.: Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 142 (6): 685-90, 2006. [PUBMED Abstract]
39. Anderson SE, Beer KT, Banic A, et al.: MRI of merkel cell carcinoma: histologic correlation and review of the literature. AJR Am J Roentgenol 185 (6): 1441-8, 2005. [PUBMED Abstract]
40. Iagaru A, Quon A, McDougall IR, et al.: Merkel cell carcinoma: Is there a role for 2-deoxy-2-[f-18]fluoro-D-glucose-positron emission tomography/computed tomography? Mol Imaging Biol 8 (4): 212-7, 2006 Jul-Aug. [PUBMED Abstract]
41. Belhocine T, Pierard GE, Frühling J, et al.: Clinical added-value of 18FDG PET in neuroendocrine-merkel cell carcinoma. Oncol Rep 16 (2): 347-52, 2006. [PUBMED Abstract]
42. Missotten GS, de Wolff-Rouendaal D, de Keizer RJ: Merkel cell carcinoma of the eyelid review of the literature and report of patients with Merkel cell carcinoma showing spontaneous regression. Ophthalmology 115 (1): 195-201, 2008. [PUBMED Abstract]
43. Richetta AG, Mancini M, Torroni A, et al.: Total spontaneous regression of advanced merkel cell carcinoma after biopsy: review and a new case. Dermatol Surg 34 (6): 815-22, 2008. [PUBMED Abstract]
44. Allen PJ, Bowne WB, Jaques DP, et al.: Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 23 (10): 2300-9, 2005. [PUBMED Abstract]
45. Stokes JB, Graw KS, Dengel LT, et al.: Patients with Merkel cell carcinoma tumors < or = 1.0 cm in diameter are unlikely to harbor regional lymph node metastasis. J Clin Oncol 27 (23): 3772-7, 2009. [PUBMED Abstract]
46. Jabbour J, Cumming R, Scolyer RA, et al.: Merkel cell carcinoma: assessing the effect of wide local excision, lymph node dissection, and radiotherapy on recurrence and survival in early-stage disease–results from a review of 82 consecutive cases diagnosed between 1992 and 2004. Ann Surg Oncol 14 (6): 1943-52, 2007. [PUBMED Abstract]
47. Henness S, Vereecken P: Management of Merkel tumours: an evidence-based review. Curr Opin Oncol 20 (3): 280-6, 2008. [PUBMED Abstract]
48. Skelton HG, Smith KJ, Hitchcock CL, et al.: Merkel cell carcinoma: analysis of clinical, histologic, and immunohistologic features of 132 cases with relation to survival. J Am Acad Dermatol 37 (5 Pt 1): 734-9, 1997. [PUBMED Abstract]
49. Sandel HD, Day T, Richardson MS, et al.: Merkel cell carcinoma: does tumor size or depth of invasion correlate with recurrence, metastasis, or patient survival? Laryngoscope 116 (5): 791-5, 2006. [PUBMED Abstract]
50. Llombart B, Monteagudo C, López-Guerrero JA, et al.: Clinicopathological and immunohistochemical analysis of 20 cases of Merkel cell carcinoma in search of prognostic markers. Histopathology 46 (6): 622-34, 2005. [PUBMED Abstract]
51. Senchenkov A, Barnes SA, Moran SL: Predictors of survival and recurrence in the surgical treatment of merkel cell carcinoma of the extremities. J Surg Oncol 95 (3): 229-34, 2007. [PUBMED Abstract]
52. Goldberg SR, Neifeld JP, Frable WJ: Prognostic value of tumor thickness in patients with Merkel cell carcinoma. J Surg Oncol 95 (8): 618-22, 2007. [PUBMED Abstract]
53. Heath ML, Nghiem P: Merkel cell carcinoma: if no breslow, then what? J Surg Oncol 95 (8): 614-5, 2007. [PUBMED Abstract]
54. Tai P: Merkel cell cancer: update on biology and treatment. Curr Opin Oncol 20 (2): 196-200, 2008. [PUBMED Abstract]
55. Andea AA, Coit DG, Amin B, et al.: Merkel cell carcinoma: histologic features and prognosis. Cancer 113 (9): 2549-58, 2008. [PUBMED Abstract]
56. Paulson KG, Iyer JG, Tegeder AR, et al.: Transcriptome-wide studies of merkel cell carcinoma and validation of intratumoral CD8+ lymphocyte invasion as an independent predictor of survival. J Clin Oncol 29 (12): 1539-46, 2011. [PUBMED Abstract]
57. Fields RC, Busam KJ, Chou JF, et al.: Recurrence and survival in patients undergoing sentinel lymph node biopsy for merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg Oncol 18 (9): 2529-37, 2011. [PUBMED Abstract]
58. Sihto H, Kukko H, Koljonen V, et al.: Clinical factors associated with Merkel cell polyomavirus infection in Merkel cell carcinoma. J Natl Cancer Inst 101 (13): 938-45, 2009. [PUBMED Abstract]
59. Harms KL, Healy MA, Nghiem P, et al.: Analysis of Prognostic Factors from 9387 Merkel Cell Carcinoma Cases Forms the Basis for the New 8th Edition AJCC Staging System. Ann Surg Oncol 23 (11): 3564-3571, 2016. [PUBMED Abstract]
60. Iyer JG, Storer BE, Paulson KG, et al.: Relationships among primary tumor size, number of involved nodes, and survival for 8044 cases of Merkel cell carcinoma. J Am Acad Dermatol 70 (4): 637-643, 2014. [PUBMED Abstract]
61. Schwartz JL, Griffith KA, Lowe L, et al.: Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol 29 (8): 1036-41, 2011. [PUBMED Abstract]
62. Ko JS, Prieto VG, Elson PJ, et al.: Histological pattern of Merkel cell carcinoma sentinel lymph node metastasis improves stratification of Stage III patients. Mod Pathol 29 (2): 122-30, 2016. [PUBMED Abstract]
63. Eng TY, Boersma MG, Fuller CD, et al.: Treatment of merkel cell carcinoma. Am J Clin Oncol 27 (5): 510-5, 2004. [PUBMED Abstract]

Although the exact origin and function of the Merkel cell remains under investigation, it is thought to have features of both epithelial and neuroendocrine origin and arise in cells with touch-sensitivity function (mechanoreceptors).[1–4]

Characteristic histopathological features include dense core cytoplasmic neurosecretory granules on electron microscopy and cytokeratin-20 on immunohistochemistry (see Figure 4).[5]

A panel of immunoreagents (see Figure 4) can distinguish between Merkel cell carcinoma (MCC) and other similar-appearing tumors including neuroendocrine carcinoma of the lung (i.e., small cell carcinoma), lymphoma, peripheral primitive neuroectodermal tumor, metastatic carcinoid tumor, and small cell melanoma.[5]

Enlarge

Histologically, MCC has been classified into three distinct subtypes:[6–9]

Mixtures of variants are common.[6–8] Although some small retrospective case series have suggested correlations between certain histological features and outcome, the evidence remains uncertain.[10–12]

One group has suggested a list of 12 elements that should be described in pathology reports of resected primary lesions and nine elements to be described in pathology reports of sentinel lymph nodes. The prognostic significance of these elements has not been validated prospectively.[13]

If the following data are recorded for every patient with MCC, any patient can be staged with the existing or new staging system:

The College of American Pathologists has published a protocol for the examination of specimens from patients with MCC of the skin.[14]

For more information, see the Stage Information for Merkel Cell Carcinoma section.

The histological variants of MCC are shown in Figure 5. [15]

Enlarge

References

1. Nghiem P, McKee PH, Haynes HA: Merkel cell (cutaneous neuroendocrine) carcinoma. In: Sober AJ, Haluska FG, eds.: Skin Cancer. BC Decker Inc., 2001, pp 127-141.
2. Bichakjian CK, Nghiem P, Johnson T, et al.: Merkel Cell Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 549-62.
3. Eng TY, Boersma MG, Fuller CD, et al.: A comprehensive review of the treatment of Merkel cell carcinoma. Am J Clin Oncol 30 (6): 624-36, 2007. [PUBMED Abstract]
4. Medina-Franco H, Urist MM, Fiveash J, et al.: Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 8 (3): 204-8, 2001. [PUBMED Abstract]
5. Busse PM, Clark JR, Muse VV, et al.: Case records of the Massachusetts General Hospital. Case 19-2008. A 63-year-old HIV-positive man with cutaneous Merkel-cell carcinoma. N Engl J Med 358 (25): 2717-23, 2008. [PUBMED Abstract]
6. Haag ML, Glass LF, Fenske NA: Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg 21 (8): 669-83, 1995. [PUBMED Abstract]
7. Ratner D, Nelson BR, Brown MD, et al.: Merkel cell carcinoma. J Am Acad Dermatol 29 (2 Pt 1): 143-56, 1993. [PUBMED Abstract]
8. Gould VE, Moll R, Moll I, et al.: Neuroendocrine (Merkel) cells of the skin: hyperplasias, dysplasias, and neoplasms. Lab Invest 52 (4): 334-53, 1985. [PUBMED Abstract]
9. Albores-Saavedra J, Batich K, Chable-Montero F, et al.: Merkel cell carcinoma demographics, morphology, and survival based on 3870 cases: a population based study. J Cutan Pathol 37 (1): 20-7, 2010. [PUBMED Abstract]
10. Alam M: Management of Merkel cell carcinoma: What we know. Arch Dermatol 142 (6): 771-4, 2006. [PUBMED Abstract]
11. Heath ML, Nghiem P: Merkel cell carcinoma: if no breslow, then what? J Surg Oncol 95 (8): 614-5, 2007. [PUBMED Abstract]
12. Andea AA, Coit DG, Amin B, et al.: Merkel cell carcinoma: histologic features and prognosis. Cancer 113 (9): 2549-58, 2008. [PUBMED Abstract]
13. Bichakjian CK, Lowe L, Lao CD, et al.: Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer 110 (1): 1-12, 2007. [PUBMED Abstract]
14. Rao P, Balzer BL, Lemos BD, et al.: Protocol for the examination of specimens from patients with merkel cell carcinoma of the skin. Arch Pathol Lab Med 134 (3): 341-4, 2010. [PUBMED Abstract]
15. Goessling W, McKee PH, Mayer RJ: Merkel cell carcinoma. J Clin Oncol 20 (2): 588-98, 2002. [PUBMED Abstract]

Previously, five competing staging systems have been used to describe Merkel cell carcinoma (MCC) in most publications.

These staging systems are highly inconsistent with each other. Stage III disease can mean anything from advanced local disease to nodal disease to distant metastatic disease. Furthermore, all MCC staging systems in use have been based on fewer than 300 patients.

Before the new AJCC consensus staging system was published, the most recent Memorial Sloan Kettering Cancer Center (MSKCC) four-stage system was favored because it was based on the largest number of patients and was the best validated.[1] The stages in the MSKCC system included:

One group has suggested a list of 12 elements that should be described in pathology reports of resected primary lesions and nine elements to be described in pathology reports of sentinel lymph nodes. The prognostic significance of these elements has not been validated prospectively.[8] The 2009 AJCC staging manual also specifies a variety of factors that should be collected prospectively on pathology reports.

References

1. Andea AA, Coit DG, Amin B, et al.: Merkel cell carcinoma: histologic features and prognosis. Cancer 113 (9): 2549-58, 2008. [PUBMED Abstract]
2. Yiengpruksawan A, Coit DG, Thaler HT, et al.: Merkel cell carcinoma. Prognosis and management. Arch Surg 126 (12): 1514-9, 1991. [PUBMED Abstract]
3. Allen PJ, Zhang ZF, Coit DG: Surgical management of Merkel cell carcinoma. Ann Surg 229 (1): 97-105, 1999. [PUBMED Abstract]
4. Allen PJ, Bowne WB, Jaques DP, et al.: Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 23 (10): 2300-9, 2005. [PUBMED Abstract]
5. Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017.
6. Clark JR, Veness MJ, Gilbert R, et al.: Merkel cell carcinoma of the head and neck: is adjuvant radiotherapy necessary? Head Neck 29 (3): 249-57, 2007. [PUBMED Abstract]
7. Bichakjian CK, Nghiem P, Johnson T, et al.: Merkel Cell Carcinoma. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 549-62.
8. Bichakjian CK, Lowe L, Lao CD, et al.: Merkel cell carcinoma: critical review with guidelines for multidisciplinary management. Cancer 110 (1): 1-12, 2007. [PUBMED Abstract]

Merkel cell carcinoma (MCC) is an uncommon tumor. Most clinical management recommendations in the literature are based on case series that describe a relatively small number of patients who were not entered on formal clinical trials, evaluated with uniform clinical staging procedures, treated with uniform treatment protocols, or provided with regular, prescribed follow-up. These reports are also confounded by potential selection bias, referral bias, and short follow-up. They are underpowered to detect modest differences in outcome.

In addition, outcomes of patients with American Joint Committee on Cancer stage I and stage II disease are often reported together. In the absence of results from clinical trials with prescribed work-up, treatments, and follow-up, most patients with MCC have been treated using institutional or practitioner preferences that consider the specifics of each case as well as patient preference.

There are two competing philosophies about the most appropriate method of treating MCC. In the first philosophy, MCC is treated like other nonmelanoma skin cancers, with an emphasis on treating local-regional disease with surgery and radiation therapy, as appropriate. In the second philosophy, MCC is treated according to its biological features. This approach makes it analogous to small cell lung cancer, which is assumed to be a systemic disease, and leads to a more routine recommendation of systematic adjuvant chemotherapy.[1]

References

1. Busse PM, Clark JR, Muse VV, et al.: Case records of the Massachusetts General Hospital. Case 19-2008. A 63-year-old HIV-positive man with cutaneous Merkel-cell carcinoma. N Engl J Med 358 (25): 2717-23, 2008. [PUBMED Abstract]
2. Medina-Franco H, Urist MM, Fiveash J, et al.: Multimodality treatment of Merkel cell carcinoma: case series and literature review of 1024 cases. Ann Surg Oncol 8 (3): 204-8, 2001. [PUBMED Abstract]
3. Nghiem P, James N: Merkel cell carcinoma. In: Wolff K, Goldsmith LA, Katz SI, et al., eds.: Fitzpatrick’s Dermatology in General Medicine. 7th ed. McGraw-Hill , 2008, pp 1087-94.
4. Allen PJ, Bowne WB, Jaques DP, et al.: Merkel cell carcinoma: prognosis and treatment of patients from a single institution. J Clin Oncol 23 (10): 2300-9, 2005. [PUBMED Abstract]
5. Goessling W, McKee PH, Mayer RJ: Merkel cell carcinoma. J Clin Oncol 20 (2): 588-98, 2002. [PUBMED Abstract]
6. Senchenkov A, Barnes SA, Moran SL: Predictors of survival and recurrence in the surgical treatment of merkel cell carcinoma of the extremities. J Surg Oncol 95 (3): 229-34, 2007. [PUBMED Abstract]
7. Nghiem P, McKee PH, Haynes HA: Merkel cell (cutaneous neuroendocrine) carcinoma. In: Sober AJ, Haluska FG, eds.: Skin Cancer. BC Decker Inc., 2001, pp 127-141.
8. Boyer JD, Zitelli JA, Brodland DG, et al.: Local control of primary Merkel cell carcinoma: review of 45 cases treated with Mohs micrographic surgery with and without adjuvant radiation. J Am Acad Dermatol 47 (6): 885-92, 2002. [PUBMED Abstract]
9. Wilson LD, Gruber SB: Merkel cell carcinoma and the controversial role of adjuvant radiation therapy: clinical choices in the absence of statistical evidence. J Am Acad Dermatol 50 (3): 435-7; discussion 437-8, 2004. [PUBMED Abstract]
10. Gollard R, Weber R, Kosty MP, et al.: Merkel cell carcinoma: review of 22 cases with surgical, pathologic, and therapeutic considerations. Cancer 88 (8): 1842-51, 2000. [PUBMED Abstract]
11. Eng TY, Boersma MG, Fuller CD, et al.: A comprehensive review of the treatment of Merkel cell carcinoma. Am J Clin Oncol 30 (6): 624-36, 2007. [PUBMED Abstract]
12. Gupta SG, Wang LC, Peñas PF, et al.: Sentinel lymph node biopsy for evaluation and treatment of patients with Merkel cell carcinoma: The Dana-Farber experience and meta-analysis of the literature. Arch Dermatol 142 (6): 685-90, 2006. [PUBMED Abstract]
13. Stokes JB, Graw KS, Dengel LT, et al.: Patients with Merkel cell carcinoma tumors < or = 1.0 cm in diameter are unlikely to harbor regional lymph node metastasis. J Clin Oncol 27 (23): 3772-7, 2009. [PUBMED Abstract]
14. Haag ML, Glass LF, Fenske NA: Merkel cell carcinoma. Diagnosis and treatment. Dermatol Surg 21 (8): 669-83, 1995. [PUBMED Abstract]
15. Ratner D, Nelson BR, Brown MD, et al.: Merkel cell carcinoma. J Am Acad Dermatol 29 (2 Pt 1): 143-56, 1993. [PUBMED Abstract]
16. Yiengpruksawan A, Coit DG, Thaler HT, et al.: Merkel cell carcinoma. Prognosis and management. Arch Surg 126 (12): 1514-9, 1991. [PUBMED Abstract]
17. Messina JL, Reintgen DS, Cruse CW, et al.: Selective lymphadenectomy in patients with Merkel cell (cutaneous neuroendocrine) carcinoma. Ann Surg Oncol 4 (5): 389-95, 1997 Jul-Aug. [PUBMED Abstract]
18. Hill AD, Brady MS, Coit DG: Intraoperative lymphatic mapping and sentinel lymph node biopsy for Merkel cell carcinoma. Br J Surg 86 (4): 518-21, 1999. [PUBMED Abstract]
19. Wasserberg N, Schachter J, Fenig E, et al.: Applicability of the sentinel node technique to Merkel cell carcinoma. Dermatol Surg 26 (2): 138-41, 2000. [PUBMED Abstract]
20. Rodrigues LK, Leong SP, Kashani-Sabet M, et al.: Early experience with sentinel lymph node mapping for Merkel cell carcinoma. J Am Acad Dermatol 45 (2): 303-8, 2001. [PUBMED Abstract]
21. Mehrany K, Otley CC, Weenig RH, et al.: A meta-analysis of the prognostic significance of sentinel lymph node status in Merkel cell carcinoma. Dermatol Surg 28 (2): 113-7; discussion 117, 2002. [PUBMED Abstract]
22. Schwartz JL, Griffith KA, Lowe L, et al.: Features predicting sentinel lymph node positivity in Merkel cell carcinoma. J Clin Oncol 29 (8): 1036-41, 2011. [PUBMED Abstract]
23. Fields RC, Busam KJ, Chou JF, et al.: Recurrence and survival in patients undergoing sentinel lymph node biopsy for merkel cell carcinoma: analysis of 153 patients from a single institution. Ann Surg Oncol 18 (9): 2529-37, 2011. [PUBMED Abstract]
24. Maza S, Trefzer U, Hofmann M, et al.: Impact of sentinel lymph node biopsy in patients with Merkel cell carcinoma: results of a prospective study and review of the literature. Eur J Nucl Med Mol Imaging 33 (4): 433-40, 2006. [PUBMED Abstract]
25. Goepfert H, Remmler D, Silva E, et al.: Merkel cell carcinoma (endocrine carcinoma of the skin) of the head and neck. Arch Otolaryngol 110 (11): 707-12, 1984. [PUBMED Abstract]
26. Lewis KG, Weinstock MA, Weaver AL, et al.: Adjuvant local irradiation for Merkel cell carcinoma. Arch Dermatol 142 (6): 693-700, 2006. [PUBMED Abstract]
27. Veness MJ, Perera L, McCourt J, et al.: Merkel cell carcinoma: improved outcome with adjuvant radiotherapy. ANZ J Surg 75 (5): 275-81, 2005. [PUBMED Abstract]
28. Jabbour J, Cumming R, Scolyer RA, et al.: Merkel cell carcinoma: assessing the effect of wide local excision, lymph node dissection, and radiotherapy on recurrence and survival in early-stage disease–results from a review of 82 consecutive cases diagnosed between 1992 and 2004. Ann Surg Oncol 14 (6): 1943-52, 2007. [PUBMED Abstract]
29. Veness M, Foote M, Gebski V, et al.: The role of radiotherapy alone in patients with merkel cell carcinoma: reporting the Australian experience of 43 patients. Int J Radiat Oncol Biol Phys 78 (3): 703-9, 2010. [PUBMED Abstract]
30. Meeuwissen JA, Bourne RG, Kearsley JH: The importance of postoperative radiation therapy in the treatment of Merkel cell carcinoma. Int J Radiat Oncol Biol Phys 31 (2): 325-31, 1995. [PUBMED Abstract]
31. Marks ME, Kim RY, Salter MM: Radiotherapy as an adjunct in the management of Merkel cell carcinoma. Cancer 65 (1): 60-4, 1990. [PUBMED Abstract]
32. Mojica P, Smith D, Ellenhorn JD: Adjuvant radiation therapy is associated with improved survival in Merkel cell carcinoma of the skin. J Clin Oncol 25 (9): 1043-7, 2007. [PUBMED Abstract]
33. Housman DM, Decker RH, Wilson LD: Regarding adjuvant radiation therapy in merkel cell carcinoma: selection bias and its affect on overall survival. J Clin Oncol 25 (28): 4503-4; author reply 4504-5, 2007. [PUBMED Abstract]
34. Garneski KM, Nghiem P: Merkel cell carcinoma adjuvant therapy: current data support radiation but not chemotherapy. J Am Acad Dermatol 57 (1): 166-9, 2007. [PUBMED Abstract]
35. Foote M, Harvey J, Porceddu S, et al.: Effect of radiotherapy dose and volume on relapse in Merkel cell cancer of the skin. Int J Radiat Oncol Biol Phys 77 (3): 677-84, 2010. [PUBMED Abstract]
36. Fang LC, Lemos B, Douglas J, et al.: Radiation monotherapy as regional treatment for lymph node-positive Merkel cell carcinoma. Cancer 116 (7): 1783-90, 2010. [PUBMED Abstract]
37. Kaufman HL, Russell JS, Hamid O, et al.: Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer 6 (1): 7, 2018. [PUBMED Abstract]
38. Becker JC, Lorenz E, Ugurel S, et al.: Evaluation of real-world treatment outcomes in patients with distant metastatic Merkel cell carcinoma following second-line chemotherapy in Europe. Oncotarget 8 (45): 79731-79741, 2017. [PUBMED Abstract]
39. Cowey CL, Mahnke L, Espirito J, et al.: Real-world treatment outcomes in patients with metastatic Merkel cell carcinoma treated with chemotherapy in the USA. Future Oncol 13 (19): 1699-1710, 2017. [PUBMED Abstract]
40. D’Angelo SP, Lebbé C, Mortier L, et al.: First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study. J Immunother Cancer 9 (7): , 2021. [PUBMED Abstract]
41. Nghiem PT, Bhatia S, Lipson EJ, et al.: PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 374 (26): 2542-52, 2016. [PUBMED Abstract]
42. Grignani G, Rutkowski P, Lebbe C, et al.: Updated results from POD1UM-201: A phase II study of retifanlimab in patients with advanced or metastatic Merkel cell carcinoma (MCC). [Abstract] Ann Oncol 34 (Suppl 2): A-1146P, S686, 2023.
43. Grignani G, Rutkowski P, Lebbé C, et al.: Updated results from POD1UM-201: A phase 2 study of retifanlimab in patients with advanced or metastatic Merkel cell carcinoma. In: Grignani G, Rutkowski P, Lebbe C, et al.: Updated results from POD1UM-201: A phase II study of retifanlimab in patients with advanced or metastatic Merkel cell carcinoma (MCC). 34 (Suppl 2): A-1146P, S686, 2023, Poster. Available online. Last accessed May 9, 2025.
44. Bhatia S, Topalian SL, Sharfman WH, et al.: Non-comparative, open-label, international, multicenter phase I/II study of nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with recurrent/metastatic merkel cell carcinoma (MCC) (CheckMate 358). [Abstract] J Clin Oncol 41 (Suppl 16): A-9506, 2023.
45. Topalian SL, Bhatia S, Hollebecque A, et al.: Abstract CT074: Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): efficacy and safety in Merkel cell carcinoma (MCC). [Abstract] Cancer Res 77 (13 Suppl): A-CT074, 2017.
46. Tai PT, Yu E, Winquist E, et al.: Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 18 (12): 2493-9, 2000. [PUBMED Abstract]
47. Henness S, Vereecken P: Management of Merkel tumours: an evidence-based review. Curr Opin Oncol 20 (3): 280-6, 2008. [PUBMED Abstract]
48. Poulsen M, Rischin D, Walpole E, et al.: High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study–TROG 96:07. J Clin Oncol 21 (23): 4371-6, 2003. [PUBMED Abstract]
49. Poulsen MG, Rischin D, Porter I, et al.: Does chemotherapy improve survival in high-risk stage I and II Merkel cell carcinoma of the skin? Int J Radiat Oncol Biol Phys 64 (1): 114-9, 2006. [PUBMED Abstract]
50. Poulsen M, Walpole E, Harvey J, et al.: Weekly carboplatin reduces toxicity during synchronous chemoradiotherapy for Merkel cell carcinoma of skin. Int J Radiat Oncol Biol Phys 72 (4): 1070-4, 2008. [PUBMED Abstract]
51. Voog E, Biron P, Martin JP, et al.: Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer 85 (12): 2589-95, 1999. [PUBMED Abstract]

Stage I and II Merkel cell carcinoma (MCC) include patients with local disease only.

Excision with 1 cm to 2 cm margins and radiation therapy are the mainstays of management for primary MCC tumors. Adjuvant radiation therapy to the primary tumor site is often recommended. However, the morbidity of radiation may be avoided and low local recurrence rates maintained, as shown in a subset of patients with small low-risk lesions (i.e., tumors <2 cm without other adverse prognostic factors).[1]

Because of the risk of occult nodal disease, sentinel lymph node (SLN) biopsy is recommended for patients without clinically detectable metastatic disease.[2] Any size of metastatic deposit is currently considered positive with regard to regional lymph node (N) staging; therefore, immunohistochemistry is routinely used to improve detection of micrometastases in SLN.[3,4]

References

1. Frohm ML, Griffith KA, Harms KL, et al.: Recurrence and Survival in Patients With Merkel Cell Carcinoma Undergoing Surgery Without Adjuvant Radiation Therapy to the Primary Site. JAMA Dermatol 152 (9): 1001-7, 2016. [PUBMED Abstract]
2. Cassler NM, Merrill D, Bichakjian CK, et al.: Merkel Cell Carcinoma Therapeutic Update. Curr Treat Options Oncol 17 (7): 36, 2016. [PUBMED Abstract]
3. Harms PW: Update on Merkel Cell Carcinoma. Clin Lab Med 37 (3): 485-501, 2017. [PUBMED Abstract]
4. Su LD, Lowe L, Bradford CR, et al.: Immunostaining for cytokeratin 20 improves detection of micrometastatic Merkel cell carcinoma in sentinel lymph nodes. J Am Acad Dermatol 46 (5): 661-6, 2002. [PUBMED Abstract]

Stage III Merkel cell carcinoma (MCC) includes patients with nodal disease.

Stage IV Merkel cell carcinoma (MCC) includes patients with distant metastases.

Single-agent immunotherapy is the preferred initial systemic therapy for patients with metastatic disease. Chemotherapy may be considered for patients with stage IV disease who have a good performance status and are either ineligible for or have disease progression while receiving immunotherapy. Although responses have been seen with various regimens, evidence is lacking that chemotherapy results in permanent disease control or long-term survival.

If chemotherapy is not considered an appropriate option, patients with stage IV disease may consider surgery and/or radiation therapy for local or regional palliation.

Merkel cell carcinoma (MCC) is a rare tumor. Recommendations and outcomes of various treatments for patients with MCC are included in many large case series [1–3][Level of evidence C2] and several single-arm phase II clinical trials.[4][Level of evidence C1] Treatment is usually individualized based on patient preference and the specifics of each case. Patients should strongly consider enrolling in clinical trials.

References

1. Goessling W, McKee PH, Mayer RJ: Merkel cell carcinoma. J Clin Oncol 20 (2): 588-98, 2002. [PUBMED Abstract]
2. Henness S, Vereecken P: Management of Merkel tumours: an evidence-based review. Curr Opin Oncol 20 (3): 280-6, 2008. [PUBMED Abstract]
3. Voog E, Biron P, Martin JP, et al.: Chemotherapy for patients with locally advanced or metastatic Merkel cell carcinoma. Cancer 85 (12): 2589-95, 1999. [PUBMED Abstract]
4. Poulsen M, Rischin D, Walpole E, et al.: High-risk Merkel cell carcinoma of the skin treated with synchronous carboplatin/etoposide and radiation: a Trans-Tasman Radiation Oncology Group Study–TROG 96:07. J Clin Oncol 21 (23): 4371-6, 2003. [PUBMED Abstract]
5. Kaufman HL, Russell JS, Hamid O, et al.: Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial. J Immunother Cancer 6 (1): 7, 2018. [PUBMED Abstract]
6. D’Angelo SP, Lebbé C, Mortier L, et al.: First-line avelumab in a cohort of 116 patients with metastatic Merkel cell carcinoma (JAVELIN Merkel 200): primary and biomarker analyses of a phase II study. J Immunother Cancer 9 (7): , 2021. [PUBMED Abstract]
7. Nghiem PT, Bhatia S, Lipson EJ, et al.: PD-1 Blockade with Pembrolizumab in Advanced Merkel-Cell Carcinoma. N Engl J Med 374 (26): 2542-52, 2016. [PUBMED Abstract]
8. Grignani G, Rutkowski P, Lebbe C, et al.: Updated results from POD1UM-201: A phase II study of retifanlimab in patients with advanced or metastatic Merkel cell carcinoma (MCC). [Abstract] Ann Oncol 34 (Suppl 2): A-1146P, S686, 2023.
9. Eng TY, Boersma MG, Fuller CD, et al.: A comprehensive review of the treatment of Merkel cell carcinoma. Am J Clin Oncol 30 (6): 624-36, 2007. [PUBMED Abstract]
10. Tai PT, Yu E, Winquist E, et al.: Chemotherapy in neuroendocrine/Merkel cell carcinoma of the skin: case series and review of 204 cases. J Clin Oncol 18 (12): 2493-9, 2000. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

References

1. Degnan AJ, Tocchio S, Kurtom W, et al.: Pediatric neuroendocrine carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center. Pediatr Blood Cancer 64 (9): , 2017. [PUBMED Abstract]
2. Pelizzo G, La Riccia A, Bouvier R, et al.: Carcinoid tumors of the appendix in children. Pediatr Surg Int 17 (5-6): 399-402, 2001. [PUBMED Abstract]
3. Hatzipantelis E, Panagopoulou P, Sidi-Fragandrea V, et al.: Carcinoid tumors of the appendix in children: experience from a tertiary center in northern Greece. J Pediatr Gastroenterol Nutr 51 (5): 622-5, 2010. [PUBMED Abstract]
4. Henderson L, Fehily C, Folaranmi S, et al.: Management and outcome of neuroendocrine tumours of the appendix-a two centre UK experience. J Pediatr Surg 49 (10): 1513-7, 2014. [PUBMED Abstract]
5. Dall’Igna P, Ferrari A, Luzzatto C, et al.: Carcinoid tumor of the appendix in childhood: the experience of two Italian institutions. J Pediatr Gastroenterol Nutr 40 (2): 216-9, 2005. [PUBMED Abstract]
6. Wu H, Chintagumpala M, Hicks J, et al.: Neuroendocrine Tumor of the Appendix in Children. J Pediatr Hematol Oncol 39 (2): 97-102, 2017. [PUBMED Abstract]
7. Boxberger N, Redlich A, Böger C, et al.: Neuroendocrine tumors of the appendix in children and adolescents. Pediatr Blood Cancer 60 (1): 65-70, 2013. [PUBMED Abstract]
8. Njere I, Smith LL, Thurairasa D, et al.: Systematic review and meta-analysis of appendiceal carcinoid tumors in children. Pediatr Blood Cancer 65 (8): e27069, 2018. [PUBMED Abstract]
9. Virgone C, Cecchetto G, Alaggio R, et al.: Appendiceal neuroendocrine tumours in childhood: Italian TREP project. J Pediatr Gastroenterol Nutr 58 (3): 333-8, 2014. [PUBMED Abstract]
10. de Lambert G, Lardy H, Martelli H, et al.: Surgical Management of Neuroendocrine Tumors of the Appendix in Children and Adolescents: A Retrospective French Multicenter Study of 114 Cases. Pediatr Blood Cancer 63 (4): 598-603, 2016. [PUBMED Abstract]

References

1. Degnan AJ, Tocchio S, Kurtom W, et al.: Pediatric neuroendocrine carcinoid tumors: Management, pathology, and imaging findings in a pediatric referral center. Pediatr Blood Cancer 64 (9): , 2017. [PUBMED Abstract]
2. Virgone C, Ferrari A, Chiaravalli S, et al.: Extra-appendicular neuroendocrine tumors: A report from the TREP project (2000-2020). Pediatr Blood Cancer 68 (4): e28880, 2021. [PUBMED Abstract]
3. Boston CH, Phan A, Munsell MF, et al.: A Comparison Between Appendiceal and Nonappendiceal Neuroendocrine Tumors in Children and Young Adults: A Single-institution Experience. J Pediatr Hematol Oncol 37 (6): 438-42, 2015. [PUBMED Abstract]
4. Tormey WP, FitzGerald RJ: The clinical and laboratory correlates of an increased urinary 5-hydroxyindoleacetic acid. Postgrad Med J 71 (839): 542-5, 1995. [PUBMED Abstract]
5. Delaunoit T, Rubin J, Neczyporenko F, et al.: Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors. Mayo Clin Proc 80 (4): 502-6, 2005. [PUBMED Abstract]
6. Enzler T, Fojo T: Long-acting somatostatin analogues in the treatment of unresectable/metastatic neuroendocrine tumors. Semin Oncol 44 (2): 141-156, 2017. [PUBMED Abstract]
7. Courtel T, Orbach D, Lacour B, et al.: Childhood pancreatic neuroendocrine neoplasms: A national experience. Pediatr Blood Cancer 72 (2): e31258, 2025. [PUBMED Abstract]
8. Ambe CM, Nguyen P, Centeno BA, et al.: Multimodality Management of “Borderline Resectable” Pancreatic Neuroendocrine Tumors: Report of a Single-Institution Experience. Cancer Control 24 (5): 1073274817729076, 2017 Oct-Dec. [PUBMED Abstract]
9. Elf AK, Andersson M, Henrikson O, et al.: Radioembolization Versus Bland Embolization for Hepatic Metastases from Small Intestinal Neuroendocrine Tumors: Short-Term Results of a Randomized Clinical Trial. World J Surg 42 (2): 506-513, 2018. [PUBMED Abstract]
10. Rinke A, Wittenberg M, Schade-Brittinger C, et al.: Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients with Metastatic Neuroendocrine Midgut Tumors (PROMID): Results of Long-Term Survival. Neuroendocrinology 104 (1): 26-32, 2017. [PUBMED Abstract]
11. Caplin ME, Pavel M, Ćwikła JB, et al.: Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371 (3): 224-33, 2014. [PUBMED Abstract]
12. Brabander T, Teunissen JJ, Van Eijck CH, et al.: Peptide receptor radionuclide therapy of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 30 (1): 103-14, 2016. [PUBMED Abstract]
13. Gajate P, Martínez-Sáez O, Alonso-Gordoa T, et al.: Emerging use of everolimus in the treatment of neuroendocrine tumors. Cancer Manag Res 9: 215-224, 2017. [PUBMED Abstract]
14. Liu IH, Kunz PL: Biologics in gastrointestinal and pancreatic neuroendocrine tumors. J Gastrointest Oncol 8 (3): 457-465, 2017. [PUBMED Abstract]
15. Vellani SD, Nigro A, Varatharajan S, et al.: Emerging Immunotherapeutic and Diagnostic Modalities in Carcinoid Tumors. Molecules 28 (5): , 2023. [PUBMED Abstract]
16. Strosberg JR, Caplin ME, Kunz PL, et al.: 177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial. Lancet Oncol 22 (12): 1752-1763, 2021. [PUBMED Abstract]

Treatment of metastatic neuroendocrine tumors of the large bowel, pancreas, or stomach is complicated and requires treatment similar to that given for adult high-grade neuroendocrine tumors. For more information about treatment options for patients with malignant carcinoid tumors, see Gastrointestinal Neuroendocrine Tumors Treatment.

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.

Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following pediatric specialists and others to ensure that children receive treatment, supportive care, and rehabilitation to achieve optimal survival and quality of life:

For specific information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.

The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[2] At these centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Other types of clinical trials test novel therapies when there is no standard therapy for a cancer diagnosis. Most of the progress in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[3–5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.

Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people in the United States. Therefore, all pediatric cancers are considered rare.

The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[7,8] In children and adolescents, the designation of a rare tumor is not uniform among international groups, as follows:

These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the small number of clinical trials for adolescents with rare cancers.

Information about these tumors may also be found in sources relevant to adults with cancer, such as Gastrointestinal Neuroendocrine Tumors Treatment.

References

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010. [PUBMED Abstract]
2. American Academy of Pediatrics: Standards for pediatric cancer centers. Pediatrics 134 (2): 410-4, 2014. Also available online. Last accessed February 25, 2025.
3. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
4. National Cancer Institute: NCCR*Explorer: An interactive website for NCCR cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed February 25, 2025.
5. Surveillance Research Program, National Cancer Institute: SEER*Explorer: An interactive website for SEER cancer statistics. Bethesda, MD: National Cancer Institute. Available online. Last accessed December 30, 2024.
6. Ward E, DeSantis C, Robbins A, et al.: Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin 64 (2): 83-103, 2014 Mar-Apr. [PUBMED Abstract]
7. Gatta G, Capocaccia R, Botta L, et al.: Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet-a population-based study. Lancet Oncol 18 (8): 1022-1039, 2017. [PUBMED Abstract]
8. DeSantis CE, Kramer JL, Jemal A: The burden of rare cancers in the United States. CA Cancer J Clin 67 (4): 261-272, 2017. [PUBMED Abstract]
9. Ferrari A, Brecht IB, Gatta G, et al.: Defining and listing very rare cancers of paediatric age: consensus of the Joint Action on Rare Cancers in cooperation with the European Cooperative Study Group for Pediatric Rare Tumors. Eur J Cancer 110: 120-126, 2019. [PUBMED Abstract]
10. Pappo AS, Krailo M, Chen Z, et al.: Infrequent tumor initiative of the Children’s Oncology Group: initial lessons learned and their impact on future plans. J Clin Oncol 28 (33): 5011-6, 2010. [PUBMED Abstract]

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This summary was reformatted.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.