64 MELANOMA
Mark D. Walsh Jr. M.D., William R. Nelson M.D., Joyesh K. Raj M.D.

1. What is melanoma?

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The term melanoma implies a malignant tumor; malignant melanoma is redundant. The most malignant of all skin cancers, melanoma usually forms from a preexisting nevus or mole but may develop de novo.

2. What is the incidence of melanoma?

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It is the sixth most common cancer in the United States and the fastest rising cancer in men. The lifetime risk in the year 2000 was 1 in 75 versus 1 in 150 in 1985. Over 51,000 new cases of melanoma are reported each year.

3. What are the types of moles? Which are most prone to malignant change?

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* Intradermal: the most benign form
* Junctional: the junctional component may be the site of melanoma formation
* Compound: intradermal and junctional together; intermediate activity
* Spitz: once called juvenile melanoma, it is actually a spindle cell epithelioid nevus that is quite benign
* Dysplastic: the most likely to turn malignant (especially in dysplastic nevus syndrome)

4. What are the risk factors in melanoma formation?

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* Large number of moles (> 50 moles > 2 mm in diameter)
* Changing nevi
* Family history of melanoma
* Light, poorly tanning skin; blonde or reddish-brown hair
* History of episodic, acute, severe sunburns
* Dysplastic nevus syndrome, or familial atypical multiple mole melanoma syndrome (FAMMM)
* History of melanoma

5. Which skin lesions often mimic a primary melanoma?

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* Spitz nevus (spindle cell epithelioid nevus)
* Atypical benign nevus
* Halo nevus
* Recurrent benign nevus after inadequate excision
* Metastatic melanoma to skin
* Mycosis fungoides
* Extramammary Paget’s disease
* Bowen’s disease
* Dark sebaceous keratoses
* Kaposi’s sarcoma
* Pigmented basal cell carcinoma

6. What is the familial melanoma syndrome?

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The inherited FAMMM syndrome has been defined as the occurrence of melanoma in one or more first- or second-degree relatives and the presence of > 50 moles of variable size, some of which are atypical histologically. The risk of melanoma in this syndrome runs as high as 100% in the person’s lifetime.

7. Is a specific gene involved in melanoma development in the FAMMM syndrome?

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Genetic studies have revealed a specific gene (i.e., p16 mapped to chromosome 9) in many people with the FAMMM syndrome.

8. Are any groups at low risk for melanoma formation?

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Children younger than 10 years, African Americans, Asians, Native Americans, and dark-complected whites are at low risk.

9. What are common sites of melanoma development?

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The most common sites are the posterior trunk in men and lower extremities in women. All sun-exposed areas are possible sites. Uncommon sites for melanoma formation are the soles of the feet, palms, and genitalia. Unusual noncutaneous sites for melanoma formation are the eye, anus, and gastrointestinal tract.

10. Where is melanoma most common?

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Melanoma is most common in Australia, especially the northern part of the continent, where light-skinned descendants of the original settlers are exposed to tropical sun.

11. What are the warning signs of melanoma?

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Skin lesions that display:

* A = Asymmetry
* B = Irregular border
* C = -Color: variable; spotted; often very black with irregular tan areas; red or pink spots; ulcerated when advanced (bleeds easily)
* D = Diameter (> 5-6 mm)
* E = Enlargement or Elevation

12. What are the types of melanoma and their incidence?

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* Superficial spreading: 75% of all cases; most common
* Nodular: 15% of cases; most malignant; well circumscribed; deeply invasive
* Lentigo maligna melanoma: 5% of cases; relatively good prognosis
* Acral lentiginous: 5% of cases; most common type in people of color; appears on the soles, palms, subungual sites

13. Which moles should be considered for removal?

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Growing and darkening nevi should be excised, especially in sun-sensitive patients. Itching is a sign of early malignant change. Ulceration is a late sign. Because melanoma may be familial in origin, children of patients with melanoma should be carefully screened for very dark nevi.

14. How should suspicious nevi be biopsied?

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Total excision of the lesion with a narrow (1-mm) margin of normal skin plus primary repair should be done. Partial incisional biopsy is acceptable if the lesion is large or if total excision would require reconstructive surgery. Punch biopsy, incisional biopsy, or saucerization are all appropriate as long as a full-thickness specimen is obtained. Thorough pathologic study is essential.

15. Do melanomas spontaneously regress or even disappear?

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Rarely melanomas can regress or even disappear. Remarkably, such patients have a poor prognosis despite the fact that the primary lesion has regressed or even sloughed off because metastatic disease to the lymph nodes and viscera may have already occurred.

16. What are the Breslow and Clark classifications of melanoma invasion?

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Clark selected five levels of melanoma thickness in the skin:

* Level I-intradermal melanoma that does not metastasize; may be better termed atypical melanotic hyperplasia: a benign lesion
* Level II-melanoma that penetrates the basement membrane into the papillary dermis
* Level III-melanoma that fills the papillary dermis and encroaches on the reticular dermis in a pushing fashion
* Level IV-melanoma that invades the reticular dermis
* Level V-melanoma that works its way into the subcutaneous fat

The Breslow method requires an optical micrometer fitted to the ocular position of a standard microscope. This technique is a more exact determination of tumor invasion. Lesions are classified as follows:

* ≤ 0.75 mm
* 0.76-1.5 mm
* 1.51-3.99 mm
* ≥ 4.0 mm

Lesions < 1 mm include melanoma in situ and thin invasive tumors. The cure rate in the latter is over 95% with excision. Tumors of 1.0-4.0 mm are called intermediate but involve risk of metastasis. Lesions > 4.0 mm are high-risk lesions with a poor cure rate.
All melanomas should be checked by both methods because some tumors may show a low Breslow measurement with a deeper Clark level, indicating a great risk of recurrence and spread. Measurement of thickness is important, and the tumor should be measured from the total height of the lesion vertically at the point of maximal thickness. In addition, if ulceration is present, the measurement should be from the bottom of the ulcer crater down to the deepest margin of the lesion. (See Figure 64-1.)

Figure 64-1 The Clark and Breslow classifications of melanoma invasion. (From Young OM, Mathes ST: In Schwartz SI (ed): Principles of Surgery, 6th ed. New York, McGraw-Hill, 1994, with permission.)

17. What is the TNM staging system for melamoma?

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The TNM (primary tumor, regional nodes, metastasis) staging system is the most comprehensive classification of melanoma. Using established risk factors for advanced disease, it stratifies patients based on the thickness of the melanoma, ulceration, micrometastases or nodal metastastes, and distant metastatic disease. Recently revised, it more accurately predicts prognosis and the need for further treatment.

18. What are the chances of nodal and systemic spread of the various degrees of melanoma invasion?

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Regional node metastases occur in about 2% of melanomas < 0.76 mm in depth; the distant spread approaches 0%. In tumors 0.76-1.5 mm thick, nodes are cancerous in 25% and distant spread is 8%. In tumors 1.5-4.0 mm thick, node metastasis occurs in 57% and distant spread in 15%. In tumors > 4 mm, node metastasis occurs in ≤ 62% and distant spread is about 72%.

19. What are the characteristics of a subungual melanoma?

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Subungual lesions are often mistaken for a chronic inflammatory process; therefore, most patients present quite late. They are usually older than patients with other forms of cutaneous melanoma. The great toe is the most common site of origin. Amputation at or proximal to the metatarsal phalangeal joint and regional sentinel lymph node biopsy are advised by most authors. The primary lesions are usually deeply invasive, and the lymph nodes are positive for cancer in the majority of cases, either at the time of the original diagnosis or at subsequent follow-up.

20. Describe the technique of sentinal lymph node (SLN) biopsy.

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The SLN biopsy is based on the theory that lymph from a solid neoplasm initially drains to a central, culprit sentinel node (SN). These SNs are the first nodes at risk for metastatic disease. The nodes can be biopsied and examined with serial sectioning and immunohistochemical staining. The SLN identification technique requires the cooperation of a surgeon, radiologist, and pathologist. Lymphoscintigraphy with the injection of radioactive technetium sulfur colloid (99mTeSC) is performed around the site of the primary melanoma. Scans are then performed in 15 minutes. The SLN is located and the overlying skin is marked. Four hours later, the patient is taken to the operating room for intradermal injection of blue contrast dye (lymphazurin 1%) around the primary site. A hand-held gamma probe identifies the hot spot, and a small incision is made over this area for removal of the SLN. A combination of blue contrast dye and radiocolloid provides the highest yield of SN identification
KEY POINTS: MELANOMA

1. The term melanoma implies a malignant tumor.
2. Melanoma is the sixth most common cancer in the United States and the fastest rising cancer in men.
3. The warning signs of melanoma are skin lesions that display asymmetry, irregular borders, color changes, diameter > 5-6 cm, and enlargement or elevation.

21. How is SLN biopsy changing the treatment of melanoma?

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An SN is now recognized as an independent predictor of survival. SLN biopsy also selctively, with minimal morbidity, identifies patients who might benefit from complete lymphadenectomy or who might benefit from biochemotherapy (see question 32). There may also be a significant psychological benefit for patients whose biopsies are found to be benign.

22. Does elective lymph node dissection (ELND) improve cure rates in patients with melanoma?

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The Mayo Clinic trial and World Health Organization melanoma group trial have not shown a benefit for ELND for stage I and II melanoma involving the extremities and trunk. The Intergroup Melanoma Trial demonstrated that for patients younger than 60 years with tumors 1.1-2.0 mm thick, there was a significant improvement in 5-year survival (96% versus 84%). However, beginning with the work of Morton et al., who used lymphoscintigraphy to identify routes of lymph drainage and SLN identification, SLN biopsy has come to the fore. In this approach, the first-echelon node is removed. If it is negative for metastasis, further node dissection is not performed. (If the SLN is positive for metastasis, surgical lymph node dissection is completed at a separate time.)

23. Do routine histologic studies miss micrometastases? What newer methods help to identify such spread?

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Routine sectioning of a lymph node exposes only 1% of the total volume of tissue. Cell cultures were originally used to identify micrometastases. This technique has been abandoned in favor of an assay with a combination of reverse transcriptase (RT) plus polymerase chain reaction (PCR). In one study, histologically and RT/PCR-positive patients had a recurrence rate of 42% at 3 years. If both assays were negative for cancer, the rate was 6.6% at 3 years. Histologically negative and RT/PCR-positive patients had a 3-year recurrence rate of 22%.

24. What are the results of lymph node studies in patients undergoing SLN biopsy and node dissection?

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Brobeil and associates found 13.9% micrometastases in SLNs. In lesions > 4.0 mm, 30% of nodes were cancerous. From 1.5-4.0 mm, 18% of nodes were cancerous, and in lesions of 1.0-1.5 mm, 7% of nodes contained melanoma. In lesions < 0.76 mm, no melanoma was found. In patients who underwent node dissection after the SLN-positive report, 8% had further positive nodes. All patients with cancerous lymph nodes in the dissections had tumors > 3.0 mm.

25. What features of melanoma are unfavorable for prognosis and metastatic risk?

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Tumor thickness (Breslow), anatomic invasion of dermis (Clark), nodal status, angiolymphatic invasion, regression, microsatellitosis, neurotropism, mitotic index (> 6/mm2), trunk versus extremities, ulceration, and male gender are unfavorable.

26. Does ulceration of a melanoma make a difference in outcome?

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Yes, it is worse. In the new American Joint Committee on Cancer (AJCC) staging system, ulceration decreases survival in every stage.

27. If indicated, which types of node dissection should be performed?

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If there is no evidence of gross involvement of nodes except for the histologically positive SLN, a functional type dissection is preferred by most authorities because it preserves vital nerves and vessels.

28. Is in-continuity removal of primary site and nodes ever indicated?

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Only if the primary lesion is near the regional lymph node areas and if the SLNs are positive.

29. How much normal skin should be removed around a melanoma?

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Whereas melanoma in situ can be cured with an excisional margin of 0.5 mm, a thin melanoma of < 1.0 mm can be excised with a 1.0-cm margin of normal skin and underlying subcutaneous tissue (down to the fascia). For thicker lesions, a 2-cm margin is now advised.

30. Does pregnancy worsen the prognosis of melanoma?

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No.

31. Does melanoma respond to chemotherapy?

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Dacarbazine (DTIC) is the most active single agent cytotoxic drug against metastatic melanoma. The response rate is 20%, and the average duration of response is a 6-month period free of disease. Multidrug regimens are not much more effective.

32. What is biochemotherapy?

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This term refers to a combination of cytotoxic therapy and immunotherapy with interleukin-2 (IL-2) and interferon alpha (IFN). The Eastern Cooperative Oncology Group (ECOG) trial 1684 has shown increased disease-free and overall survival rates with high-dose interferon therapy for patients with melanomas > 4 mm and surgically resected nodal metastases.

33. Can radiotherapy be helpful in melanoma treatment?

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Radiotherapy is quite helpful as palliative treatment of metastatic disease.

34. Should amputation be used in the management of locally advanced melanoma?

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With the development of isolation perfusion, the indications for major limb amputation are rare. Patients who might benefit from amputation are those who have experienced recurrences after isolation limb perfusion and those with severe comorbidities who are not candidates for limb perfusion. Partial digital amputation is the recommended therapy for subungual melanoma.

35. What is isolation perfusion? How is it used in melanoma?

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Although studies have not shown that isolation perfusion conveys a survival advantage in primary melanoma, this technique is often used in setting of multiple or recurrent intransit metastases of an extremity. Melphalan (commonly used) or other chemotherapy preparations (e.g., interferon, tumor necrosis factor) are circulated through an isolated extremity using a pump oxygenator at mild hyperthermic temperatures. Successful isolation perfusion preserves a functional extremity, has a superior response rate, and incurs less morbidity than systemic therapy.

36. What is the treatment of a patient with metastatic nodes confined to a single area when the primary site is unknown?

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If careful workup reveals no other foci of melanoma, radical lymph node dissection should be carried out. Cure rates as high as 15% have been reported in these unusual situations.

37. How do you manage postlymphadenectomy edema of an extremity, especially the leg?

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Custom-made support stockings should be placed immediately after surgery.

38. What should you do in the follow-up care of patients undergoing curative surgery for melanoma?

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Besides frequent physical examinations, chest radiographs and liver function tests are important.

39. Is cure possible in a patient with a single, isolated, distant metastasis of melanoma?

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Absolutely yes. In a series reported by Overett and Shiu, a survival rate of 33% was achieved in a large series of patients undergoing resection of single, isolated, distant metastases. Such patients, of course, must be carefully studied to rule out other evidence of spread.

References
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