Final Diagnosis -- Atypical melanocytic neoplasms of uncertain malignant potential

FINAL DIAGNOSIS:

Specimen	At our institution	At a consulted outside institution
#1	Atypical melanocytic neoplasm, strongly favor malignant melanoma. Note: … "Favor primary melanoma arising in a Spitz or deep penetrating nevus-like lesion. …not sure whether Clark' s and/or Breslow' s prognostic parameters would apply , but it extends to the depth of 4.0 mm, and involves deep reticular dermis (subcutis is not involved by multiple deeper levels)	Markedly atypical melanocytic tumor composed of an amelanotic epithelioid cell and pigmented deep penetrating nevus-like components; Note: I need to acknowledge some uncertainty of its biologic potential in light of some unusual features. … Consideration may also be given to sentinel lymph node biopsy as an adjunct in the evaluation of such an unusual melanocytic tumor.
#2	Highly atypical melanocytic neoplasm. Note: This neoplasm could be interpreted as severely atypical Spitz-like dermal neoplasm, but I cannot rule out malignancy.	Markedly atypical epithelioid melanocytic tumor of uncertain malignant potential arising in a congenital nevus. Note: I would classify this as a combined lesion with an atypical Spitz tumor of uncertain malignant potential arising in a background of a nevus. Some might designate this tumor as minimal deviation melanoma or borderline Spitz tumor.
#3	Compound melanocytic neoplasm with severe cytologic atypia and features of spitzoid neoplasm. Note: Neoplasm is of concern and we cannot rule out malignancy.	Malignant melanoma, in-situ and invasive arising in association with a nevus. Breslow thickness ~ 0.6 cm.
#4	Malignant melanoma, in-situ, with focal possible early invasion, Clark level II, Breslow thickness less than 0.1 mm arising in a compound nevus with features of dysplastic nevus.

DISCUSSION:

The neoplasms described above belong to a subset of problematic and diagnostically challenging melanocytic neoplasms variably labeled as: as atypical Spitz tumor, atypical Spitz nevus, Spitz-like lesion in the borderline category of indeterminate malignant potential, and diagnostically controversial spitzoid melanocytic tumors [1], as well as atypical Spitzoid neoplasms, severely atypical melanocytic neoplasms (tumors), and would also be classifiable under the category of "minimal deviation" or "nevoid" melanoma.. These lesions simultaneously exhibit some features of Spitz nevus and Spitz-like melanoma.

The cases discussed above have some features of Spitz nevus:

• Proliferation of spindle and/or epithelioid cells.
• Symmetric growth.
• Epidermal hyperplasia (except for specimen#1 which shows somewhat flattened epidermis with loss of rete ridges in addition to a lymphocytic infiltrate and fibrosis in the papillary dermis suggestive of regression)
• Well circumscribed margins.
• Maturation of the deep dermal component (except for specimen #1 which shows a pigmented deep penetrating nevus-like component): The cell cytoplasm and cell nuclei become smaller and dispersed among reticular dermal fibers with progressive descent into the dermis.
• Pagetoid (upward) spread is only focal and limited to the lower portions of the epidermis.

The same neoplasms also have some atypical features:

• Lack of the typical vertically oriented fascicles of nevus cells in nests at the dermo-epidermal junction and in the papillary dermis in a "raining down" or "bunch of bananas" pattern
• Increased mitotic activity in the lower one third of the neoplasms and increased percentage of melanocytes staining with Ki-67 (Specimen #1 and 2)
• Higher degree of pleomorphism with variability in nuclear size and shape.
• The presence of two distinct dermal components in all four lesions: Markedly atypical melanocytic component higher in the dermis (overgrowing the less atypical component) and a deeper nevus-like component with congenital features.

The biologic behavior of these atypical spitzoid melanocytic neoplasms has not been clearly elucidated. Experts often regard these lesions as having an indeterminate malignant potential. Therefore most dermatologists would recommend treating these neoplasms in a similar fashion to melanomas advising wide re-excision and SLNB depending on the measured depth of "possible" invasion (from the surface of epidermis to the bottom of the atypical melanocyte component). However, this is the problematic area, as the accepted prognostic markers (namely: Breslow's and Clark's depths and surface ulceration) do not apply well with the neoplasms that do NOT arise at the dermo-epidermal junction [8]).

Many ancillary diagnostic techniques have been used to try to discriminate benign lesions from malignant melanocytic.

• Immunohistochemistry: Ki-67, [2] is used to discriminate melanoma from benign nevi, including Spitz nevi; however, there is a significant overlap.
• In situ hybridization to detect expression of melastatin, a melanocyte specific gene that is expressed in melanoma at levels inversely proportional to metastatic rates [3]
• DNA in situ hybridization using a chromosome-1 centromere probe on routinely processed paraffin sections reportedly showed a clear difference in the number of aberrant (aneuploid) nuclei between most of the Spitz nevi and melanoma.[4]
• Comparative genomic hybridization, shows no chromosomal aberrations in most Spitz nevi, whereas melanoma shows frequent deletions of chromosomes 9p, 10q, 6q, 8p and gains of chromosomes 7, 8, 6p, and 1q. [5]

However, currently, there is no single technique that unequivocally discriminates among these borderline lesions.

Because the status of the regional lymph nodes is a powerful predictor of overall survival for melanoma, SLNB is a useful adjunct in the management of histologically difficult melanocytic lesions.[6] In one recent study, 8 of 18 patients (44%) with atypical spitzoid melanocytic lesions were reclassified as melanoma based on positive SLNB results [1]. In another study 5 of 10 (50%) of diagnostically controversial spitzoid tumors metastasized to SLNs [7].

Our patient underwent SLNB of axillary and groin lymph nodes and there was no metastatic disease identified in any of the specimens. In addition to the wide re-excisions, he also received Interferon alpha2b therapy. The last three neoplasms described above were excised while the patient was receiving this therapy.

REFERENCES:

1. Su LD, Fullen DR, Sondak VK, Johnson TM, Lowe L. Sentinel lymph node biopsy for patients with problematic spitzoid melanocytic lesions: a report on 18 patients. Cancer 2003 Jan 15;97(2):499-507.
2. Li LX, Crotty KA, McCarthy SW, Palmer AA, Kril JJ. A zonal comparison of MIB1-Ki67 immunoreactivity in benign and malignant melanocytic lesions. Am J Dermatopathol. 2000; 22: 489-495.
3. Duncan LM, Deeds J, Cronin FE, et al. Melastatin expression and prognosis in cutaneous malignant melanoma. J Clin Oncol. 2001; 19: 568-576.
4. De Wit PE, Kerstens HM, Poddighe PJ, Van Muijen GN, Ruiter DJ. DNA in situ hybridization as a diagnostic tool in the discrimination of melanoma and Spitz naevus. J Pathol. 1994; 173: 227-233.
5. Bastian BC, Wesselmann U, Pinkel D, LeBoit PE. Molecular cytogenetic analysis of Spitz nevi shows clear differences to melanoma. J Invest Dermatol. 1999; 113: 1065-1069.
6. Kelley SW, Cockerell CJ. Sentinel lymph node biopsy as an adjunct to management of histologically difficult to diagnose melanocytic lesions: a proposal. J Am Acad Dermatol. 2000
7. Lohmann CM, Coit DG, Brady MS, Berwick M, Busam KJ. Sentinel lymph node biopsy in patients with diagnostically controversial spitzoid melanocytic tumors. Am J Surg Pathol. 2002; 26: 47-55.
8. Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS, Cascinelli N, Urist M, McMasters KM, Ross MI, Kirkwood JM, Atkins MB, Thompson JA, Coit DG, Byrd D, Desmond R, Zhang Y, Liu PY, Lyman GH, Morabito A.: Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001 Aug 15;19(16):3622-34.

Contributed by Muammar Arida, MD and Drazen M. Jukic, MD, PHD.