| | Two cases of unusual acral melanocytic tumors: Illustration of molecular cytogenetics as a diagnostic tool☆☆☆Abstract The differential diagnosis between benign Spitz nevus and malignant melanoma may present considerable difficulties in some cases. Here we report 2 unusual melanocytic tumors with spitzoid features developing in acral sites of Japanese patients to illustrate the use of comparative genomic hybridization (CGH) to classify these lesions. Case 1 was a 12-mm-thick, >2 cm-diameter nodule on the sole of a 37-year-old man. Case 2 was a subungual tumor of the left index finger in a 13-year-old boy. CGH showed absence of chromosomal aberrations in case 1 and multiple aberrations in case 2, including focused amplification as previously described in acral melanomas. Case 1 was free of disease after 2.5 years of follow-up, whereas case 2 developed lymph node metastasis. We conclude that molecular techniques such as CGH can be of diagnostic help in the classification of histologically ambiguous lesions. HUM PATHOL 34:89-92. Copyright 2003, Elsevier Science (USA). All rights reserved.
Differentiation of a melanoma from a Spitz nevus can be among the most daunting tasks for a dermatopathologist. Although the diagnosis of most Spitz nevi can be made by conventional histopathologic criteria, a subset of cases is difficult or impossible to distinguish from melanoma. There are no objective histopathologic criteria for distinguishing such ambiguous cases from melanoma and for gauging their malignant potential.1, 2
Recent molecular genetic analyses of melanomas3 and Spitz nevi4 have shown a distinct pattern of genetic defects in different subsets of tumors. Using comparative genomic hybridization (CGH) as a whole-genome scanning approach, we have shown clear differences between Spitz nevi and melanomas. Whereas most melanomas show multiple aberrations of particular chromosomal regions, Spitz nevi have a normal chromosomal complement or only a very restricted set of aberrations.3, 4 Such a clear difference in aberration patterns between benign and malignant melanocytic tumors suggests that molecular genetic analyses can be of diagnostic use in equivocal cases.5 Here we illustrate the potential of CGH with 2 unusual spitzoid lesions arising on acral sites.
Case reports  Case 1 A 37-year-old Japanese man presented with a nodular lesion on his left sole, which had appeared 2 years previously and gradually enlarged without any symptoms. The tumor was 26×25×10 mm in size, dome-shaped, nonpigmented, and nonulcerated. No enlarged lymph nodes were noted. The patient's past and family histories were not contributory. Histologic examination of the excision biopsy specimen showed a well-circumscribed, symmetrical, nonpigmented tumor. The tumor was 11 mm thick and wholly intradermal, consisting of spindle-shaped cells and large epithelioid cells with large nucleoli within desmoplastic stroma. Mitotic figures were scattered throughout the neoplasm, including deeper areas. No significant maturation was noted. There were no lymphocyte infiltrates surrounding the tumor (Fig 1A through D).
Immunohistochemistry revealed that tumor cells expressed S100 protein. Focal staining with HMB-45 and MART1 was also observed. Reexcision of the primary lesion was done, followed by a sentinel lymph node biopsy. No metastasis was found in the sentinel node. The patient has remained free of disease for 2 years. This case was presented at the 16th annual meeting of the Japanese Dermatopathology Association. Some 60% of the participants regarded the lesion as melanoma, whereas the remaining 40% made a diagnosis of desmoplastic Spitz nevus. Case 2 A 13-year-old Japanese boy presented with a painful pigmented subungual tumor of the left index finger in July 1993. The overlying nail plate was intact with a 2-mm-wide pigmented streak, which had developed at age 6 soon after the patient had caught the finger in a car door. Hutchinson's sign was not observed. The nail plate was removed, and an excisional biopsy was performed. The histologic specimen showed a 1-mm-thick, relatively well-circumscribed, mostly nested proliferation of melanocytes with enlarged nuclei, prominent nucleoli, and abundant cytoplasm (Fig 1E through H). The nests showed some confluence, and no maturation was seen. Increased vascularity and a sparse lymphocytic infiltrate were noted. Mitoses were sparse. The lesion was diagnosed as atypical Spitz nevus and was reexcised. Two years later, the patient developed a left axillary mass and underwent radical lymph node dissection. Histologicexamination revealed metastasis in 1 of 7 resected lymph nodes. The involved lymph node was 6 cm in diameter and completely replaced with heavily pigmented epithelioid cells with a large necrotic focus and numerous mitoses. The patient received 5 courses of adjuvant therapy consisting of dacarbazine (DTIC), nimustine hydrochloride, and vincristine, followed by intradermal perilesional injection of human fibroblast interferon-β. To date, 7 years after the lymph node dissection, he has remained free of disease. This case was presented at the CPC session of the 98th annual meeting of the Japanese Dermatology Association. Six expert dermatopathology panelists, who were uninformed of the clinical information of lymph node metastasis, were split on the diagnosis between Spitz nevus and melanoma. Materials and methods DNA extraction Paraffin-embedded tissue blocks were used for analysis after informed consent was obtained from the patient (case 1) and the parents (case 2). Tumor-bearing tissue was microdissected from 30-μm sections (2 to 20 per tumor) using hematoxylin and eosin–stained sections as guidance. DNA extraction and labeling were performed as previously described.3 Comparative genomic hybridization All measurements were performed in duplicate, once with 1 μg tumor DNA labeled with fluorescein-12-deoxyuridine triphosphate (dUTP) (Dupont/NEN, Boston, MA) and 200 ng Texas red–5-dUTP– labeled reference DNA (“standard” labeling), and a second time with the labeling reversed. Controls and threshold definitions Normal DNA and DNA from tumor cell lines with known aberrations were used as negative and positive controls for CGH, respectively. A region was considered aberrant when (1) either the standard labeling or the reverse labeling resulted in a tumor/reference fluorescent ratio <0.80 or >1.2 or (2) both the standard and the reverse labeling resulted in a tumor/reference fluorescent ratio <0.85 or >1.15.3 Results As shown in Table 1 and Figure 2, the primary tumor from case 2 had multiple chromosome aberrations, including losses of chromosomes 9 and 10 and amplification of chromosomes 5p and 11q.
| | |  | Tumor | CGH Results | |
|---|
| Case 1, primary tumor | Normal copy number | |
| Case 2, primary tumor | dim (1p22.3, 1cen, 9pter, 9qter, 10pter, 10qter), enh (1cen, 1p31.1), amp (5pter, 5p14, 11q13.1, 11q13.3) | |
| | | | | |
Amplification of these regions commonly occur in acral melanomas. 6 In contrast, the tumor from case 1 showed no aberrations. Discussion Here we have presented 2 tumors that show overlapping histologic findings between Spitz nevus and melanoma. A benign melanocytic neoplasm commonly seen in children and young adults, Spitz nevus typically presents as a firm, dome-shaped nodule <1 cm in diameter. Spitz nevi are rare in acral sites7 except in Japanese persons, in whom about 50% of melanomas occur in acral sites.8 Expert dermatopathologists are unable to reach agreement as to the classification of these lesions as either Spitz nevi or melanomas. Our CGH analysis of more than 150 melanomas found that more than 5% show no chromosomal aberrations (Bastian et al, manuscript in preparation). This percentage would probably be greater if cases with excessive contaminating normal cells, which can lead to false-negative results, were excluded. Case 1 did not exhibit significant amounts of normal cells, and the fact that CGH analysis demonstrated normal chromosome copy numbers argues against the diagnosis of melanoma. We have analyzed more than 30 Spitz nevi by CGH and found that they either do not show chromosomal aberrations or have only isolated gains of chromosome 11p.4, 9 Although the CGH finding in case 1 does not completely rule out melanoma, the negative sentinel lymph node biopsy and eventless follow-up supports the finding that this lesion is benign. A 12-mm-thick melanoma most likely would have metastasized by now. In contrast, case 2 revealed several losses and gains of chromosome regions, including amplifications involving 11q and 5p. Our previous studies showed that acral melanomas are distinct from other melanomas in that they invariably show amplifications of small chromosome fragments. These amplifications already occur at the in situ stage.6 For these reasons, case 2 is best classified as acral melanoma. We note that acral melanoma occurs extremely rarely in children, and so far only noninvasive subungual melanomas have been described.10, 11 The results of the CGH analyses described here suggest that this type of molecular genetic approach may more clearly define the subsets and biological nature of controversial childhood melanomas and atypical Spitz tumors.1, 2, 10 Further molecular studies are warranted to assess genetic alterations of such controversial cases. References 1.
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J Dermatol. 1998;25:41–44. MEDLINE Department of Dermatology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan; Department of Dermatology, Kumamoto University School of Medicine, Kumamoto, Japan; and Cancer Center, Department of Pathology, University of California, San Francisco, CA. ☆ Supported by the Marvin and Roma Auerback Melanoma Fund and a Grant-in Aid for Scientific Research (C2-12670812) from the Japan Society for the Promotion of Science. ☆☆ Address correspondence and reprint requests to Fumiaki Shirasaki, MD, PhD, Department of Dermatology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8641, Japan. PII: S0046-8177(03)00004-2 doi:10.1053/hupa.2003.49 © 2003 Elsevier Science (USA). All rights reserved. | |
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