Pedram Yazdan

Risk Assessment for Atypical Spitzoid Melanocytic Neoplasms Using FISH to Identify Chromosomal Copy Number Aberrations

Risk assessment for atypical Spitz tumors remains an enigma for physicians. Many prognosticators including sentinel lymph node biopsy fail to show the same prognostic significance in these tumors as seen in conventional melanoma. We conducted a case-controlled collaborative study involving multiple major melanoma treatment centers in the United States and Australia. Sixty-four atypical Spitz tumors with 5 years of uneventful follow-up and 11 atypical Spitz tumors resulting in advanced locoregional disease, distant metastasis, or death were evaluated by fluorescence in situ hybridization using 2 probe sets targeting 6 chromosomal loci. Predetermined criteria were utilized to detect the presence or absence of copy number aberrations for each locus. Logistic regression analysis, Fisher exact test, and multivariate analysis were performed to determine chromosomal copy number aberrations with statistically significant association with aggressive clinical behavior. Gains in 6p25 or 11q13 and homozygous deletions in 9p21 had statistically significant association with aggressive clinical behavior with P-values of 0.02, 0.02, and <0.0001, respectively. In multivariate analysis, homozygous 9p21 deletion was highly associated with clinically aggressive behavior (P<0.0001) and death due to disease (P=0.003). Fluorescence in situ hybridization detecting a limited number of chromosomal copy number aberrations can provide clinically useful and statistically significant risk assessment for atypical Spitz tumors. Cases with homozygous 9p21 deletions have the greatest risk. Cases with 6p25 or 11q13 gains also have higher risk for aggressive clinical behavior than FISH-negative atypical Spitz tumors or cases with 6q23 deletions.

Histomorphologic assessment and interobserver diagnostic reproducibility of atypical spitzoid melanocytic neoplasms with long-term follow-up

Predicting clinical behavior of atypical Spitz tumors remains problematic. In this study, we assessed interobserver agreement of diagnosis by 13 expert dermatopathologists for atypical Spitz tumors (n=75). We determined which histomorphologic features were most heavily weighted for their diagnostic significance by the experts and also which histomorphologic features had a statistically significant correlation with clinical outcome. There was a low interobserver agreement among the experts in categorizing lesions as malignant versus nonmalignant (&kgr;=0.30). The histomorphologic features that were given the most diagnostic significance by the experts were: consumption of the epidermis, atypical mitoses, high-grade cytologic atypia, and mitotic rate. Conversely, the histomorphologic features that most correlated with disease progression were: frequent mitoses, deep mitoses, asymmetry, high-grade cytologic atypia, and ulceration. The presence and/or pattern of pagetoid spread, consumption of the epidermis, and lymphoid aggregates demonstrated no association with clinical behavior. The results support the assertion that there is a lack of consensus in the assessment of atypical Spitz tumors by expert dermatopathologists. Importantly, many features used to distinguish conventional melanoma from nevi were not useful in predicting the behavior of atypical Spitz tumors. This study may provide some guidance regarding histologic assessment of these enigmatic tumors.

Comparative analysis of atypical Spitz tumors with heterozygous versus homozygous 9p21 deletions for clinical outcomes, histomorphology, BRAF mutation, and p16 expression

Studies have shown that atypical Spitz tumors (ASTs) with homozygous deletions in 9p21 have worse prognosis than those without this finding. Conversely, numerous studies have shown that a range of other copy number aberrations including isolated 6q23 or 3p21 loss may be seen in ASTs without conferring higher risk for aggressive behavior. We studied 31 cases of ASTs with heterozygous 9p21 loss and hypothesize that heterozygous 9p21 loss in ASTs does not confer an increased risk for aggressive behavior. We compared clinical, histopathologic, and immunohistochemical features of 31 ASTs with heterozygous 9p21 deletions with 30 ASTs with homozygous 9p21 deletions. No ASTs with heterozygous 9p21 deletions resulted in distant metastasis. Severe cytologic atypia, a predominance of epithelioid cytomorphology and increased dermal mitotic activity were more frequent in ASTs with homozygous deletions versus ASTs with heterozygous deletions (P=0.0003, 0.0004, and 0.042, respectively). Expression of p16 and mutated BRAFV600E proteins was also evaluated in 17 conventional (nonspitzoid) melanomas with homozygous 9p21 loss and the 2 groups of ASTs. Expression of p16 was retained in 67% of ASTs with heterozygous loss, whereas among ASTs with homozygous loss, 100% of cases had areas with complete loss of staining. Mutated BRAFV600E protein expression was detected in 53% of conventional melanomas, in none of the ASTs with heterozygous loss, and in 1 AST with homozygous loss (P=0.0007 between homozygous ASTs and the conventional melanomas). Coexisting BRAF mutation and 9p21 deletion was more common in conventional melanomas than in ASTs with heterozygous or homozygous 9p21 deletion. BRAF mutation was highly uncommon among the ASTs.

A comparative study of proliferative nodules and lethal melanomas in congenital nevi from children.

Differentiating proliferative nodules (PNs) from melanomas arising in congenital nevi (CN) is a considerable challenge for dermatopathologists. Most of the specimens dermatopathologists assess that deal with this differential diagnosis involve proliferations of melanocytes arising in the dermis. In this study, we compare the clinical, histologic, and molecular findings of these 2 conditions. In our database, we found 22 examples of PNs arising in the dermis of CN and 2 cases of lethal melanomas arising from the dermis/epidermis of CN of children. Importantly, we found that among dermal melanocytic proliferations arising from CN in children, PNs are far more common than lethal melanomas. Clinically, multiplicity of lesions favored a diagnosis of PNs, whereas ulceration was infrequent in PNs compared with lethal melanomas. Histologically, PNs showed several distinct patterns including expansile nodules of epithelioid melanocytes with mitotic counts lower than that seen in the melanomas (1.67 vs. 12.5 mitoses/mm2), a small round blue cell pattern often highly mitotically active, neurocristic-like, blue nevus-like, a nevoid melanoma-like pattern, or an undifferentiated spindle cell pattern. The lethal melanomas both featured expansile nodules of epithelioid melanocytes with high mitotic counts (range, 5 to 20 mitoses/mm2) and an ulcerated overlying epidermis. At the molecular level, the PNs showed mostly whole chromosomal copy number aberrations, which in some cases were accompanied by rare partial chromosomal aberrations, whereas both lethal melanomas showed highly elevated copy number aberrations involving 6p25 without gains of the long arm of chromosome 6.

Nonoverlapping Clinical and Mutational Patterns in Melanomas from the Female Genital Tract and Atypical Genital Nevi

Genital melanomas (GM) are the second most common cancer of the female external genitalia and may be confused with atypical genital nevi (AGN), which exhibit atypical histological features but have benign behavior. In this study, we compared the clinical, histological, and molecular features of 19 GM and 25 AGN. We described chromosomal copy number aberrations and the mutational status of 50 oncogenes and tumor suppressor genes in both groups. Our study showed that a pigmented lesion occurring in mucosal tissue, particularly in postmenopausal women, was more likely to be a melanoma than a nevus. GM had high levels of chromosomal instability, with many copy number aberrations. Furthermore, we found a completely nonoverlapping pattern of oncogenic mutations when comparing GM and AGN. In GM, we report somatic mutations in KIT and TP53. Conversely, AGN had frequent BRAF V600E mutations, which were not seen in any of the GM. Our results show that GM and AGN have distinct clinical and molecular changes and that GM have a different mutational pattern compared with AGN.

Multiple Cutaneous Melanomas and Clinically Atypical Moles in a Patient With a Novel Germline BAP1 Mutation

IMPORTANCE Several kindreds having germline BAP1 mutations with a propensity for uveal and cutaneous melanomas and other internal malignancies have been described in an autosomal dominant tumor predisposition syndrome. However, clinically atypical moles have not been previously recognized as a component of this syndrome, to our knowledge. We describe the first kindred to date with a germline mutation in BAP1 associated with multiple cutaneous melanomas and classic dysplastic nevus syndrome. OBSERVATIONS We describe a 53-year-old man who was initially seen in 2003 with dysplastic nevus syndrome, multiple atypical melanocytic proliferations showing loss of immunostaining for BAP1, and 7 cutaneous melanomas. Germline testing was performed in the proband, his 16-year-old son, and his 13-year-old daughter, revealing a germline mutation in the BAP1 gene (c.592G>T, p.Glu198X) in the proband and in his 16-year-old son. CDKN2A and CDK4 genes were wild type. No members of this kindred reported a history of uveal melanoma. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report of a patient with multiple melanomas, dysplastic nevus syndrome, and an inactivating germline BAP1 mutation. The coexistence of dysplastic nevus syndrome and a BAP1 germline mutation extends the spectrum of the BAP1 tumor predisposition syndrome and may confer a greater risk for cutaneous melanomas.

Epithelioid and fusiform blue nevus of chronically sun-damaged skin, an entity distinct from the epithelioid blue nevus of the Carney complex.

Epithelioid blue nevus (EBN) was first described in patients with Carney complex (CNC) and subsequently shown to also occur sporadically. Over 50% of patients with CNC harbor mutations in the gene PRKAR1A, which codes for protein kinase A regulatory subunit 1&agr; (R1&agr;) involved in the signaling pathway regulating melanogenesis and melanocytic proliferation. Immunohistochemical expression of R1&agr; has been shown to be absent in the majority of pigmented epithelioid melanocytomas and all CNC-associated EBNs but present in melanomas and other melanocytic nevi. We have observed several examples of EBN occurring in chronically sun-damaged (CSD) skin with a predominance of epithelioid morphology but also containing a component of fusiform and conventional blue nevus cells, which we have termed epithelioid and fusiform blue nevus of CSD skin. Several of these cases demonstrated notable pleomorphism and nuclear atypia with rare mitotic activity raising concern for the possibility of melanoma; however, the clinical outcomes, detailed histologic review, and molecular results were most consistent with a benign melanocytic neoplasm. We report our clinical, histopathologic, immunohistochemistry, and fluorescence in situ hybridization experience with this distinct entity of epithelioid and fusiform blue nevus and demonstrate that it is a unique subtype of blue nevus occurring on CSD skin with a higher frequency of an associated conventional blue nevus component compared with EBN and without association with CNC or loss of R1&agr; expression typically found in pigmented epithelioid melanocytoma and CNC-associated EBN. We also postulate that the epithelioid pattern may represent a subclone of the conventional blue nevus component induced by chronic UV damage.

CD8+ mycosis fungoides clinically masquerading as alopecia areata

A 33‐year‐old female with a 7‐year history of CD8‐positive hypopigmented mycosis fungoides (MF) involving the trunk and extremities presented with a large well‐defined alopecic patch on her frontal scalp. Clinically, this area resembled alopecia areata (AA) and was without hypopigmentation or erythema. A scalp biopsy revealed a non‐scarring inflammatory alopecia and a superficial band‐like atypical lymphoid infiltrate with prominent epidermotropism. Atypical, predominately CD8‐positive lymphocytes were seen surrounding and infiltrating the bulb portion of several hair follicles. Treatments for her MF lesions have included topical bexarotene, topical corticosteroids and phototherapy. Her alopecia has been treated with high potency topical corticosteroids and multiple intralesional triamcinolone injections with very minimal hair regrowth to date. Alopecia due to cutaneous lymphoma is an uncommon phenomenon but can occur in erythrodermic MF or Sezary syndrome. AA‐like changes have most often been reported in conventional patch/plaque stage MF and folliculotropic MF. In these cases, the atypical lymphoid infiltrate is comprised predominately of CD4‐positive lymphocytes. This is a rare report of a CD8‐positive MF causing AA‐like changes. This case highlights the importance of a scalp biopsy in patients with a history of cutaneous lymphoma presenting with alopecia in order to evaluate the nature of their hair loss.

Eccrine Duct Dilation as a Marker of Cicatricial Alopecia.

Background: Eccrine duct dilation (EDD) and syringoma-like sweat duct proliferation have been described as reactive changes occurring in a variety of skin conditions. However, extensive evaluation of EDD in scalp biopsies performed for alopecia has not been performed. Methods: We retrospectively examined 129 cases of cicatricial alopecia (lichen planopilaris, central centrifugal cicatricial alopecia, and discoid lupus erythematosus) and 130 cases of noncicatricial alopecias (androgenetic alopecia, telogen effluvium, and alopecia areata) for the presence of EDD. Results: Overall, EDD occurred in 4% (5/130) of noncicatricial alopecia (2/43 of androgenetic alopecia, 0/15 of telogen effluvium, 3/72 of alopecia areata) and 35% (45/129) of cicatricial alopecia (10/31 of lichen planopilaris, 17/36 central centrifugal cicatricial alopecia, and 18/62 of discoid lupus erythematosus; P < 0.0001) cases. Conclusions: EDD can infrequently occur in noncicatricial alopecias; however, the frequency of dilation is significantly increased in cicatricial alopecias. This alteration may be due to compressive or inflammatory effects inherent to the scarring process. The presence of EDD may be a useful adjunctive histopathologic feature in the diagnosis of cicatricial alopecias.

The role of TERT promoter mutations in differentiating recurrent nevi from recurrent melanomas: a retrospective, case-control study

Background: Repigmentation at previous biopsy sites pose a significant diagnostic dilemma given clinical and histologic similarities between recurrent nevi and locally recurrent melanoma. Though common in melanoma, the role of TERT promoter mutations (TPMs) in recurrent nevi is unknown. Objective: We investigated the role of TPMs in recurrent nevi and whether the presence of hotspot TPM distinguishes recurrent nevi from locally recurrent melanoma. We also characterized clinical and histologic features differentiating these lesions. Methods: We analyzed 11 locally recurrent melanomas, 17 recurrent nevi, and melanoma and nevus controls to determine TPM status. We also assessed clinical and histologic features of the recurrent groups. Results: Hotspot TPMs were more common in recurrent melanomas than recurrent nevi (P = .008). Recurrent melanomas were more likely to have solar elastosis (P = .0047), multilayering of melanocytes in the epidermis (P = .0221), adnexal involvement (P = .0069), and epidermal consumption (P = .0204). Recurrent nevi had intra‐epidermal atypia limited to the area above the scar (P < .0001) and occurred earlier after the original biopsy (P < .0008). Solar elastosis, months to recurrence, and hotspot TPMs were independently associated with recurrent melanoma in multivariate analysis. Limitations: This was a retrospective study. Conclusion: Hotspot TPMs are significantly more frequent in recurrent melanomas and could serve as a diagnostic clue in histologically ambiguous cases.