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.

BACKGROUND: Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care. OBJECTIVE: We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions. METHODS: Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated. RESULTS: Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91. LIMITATIONS: This was a small sample size of experienced pathologists in a testing situation. CONCLUSION: Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care.

Cellular Blue Nevomelanocytic Lesions: Analysis of Clinical, Histological, and Outcome Data in 37 Cases.

Cellular blue nevomelanocytic lesions (CBNLs) frequently pose diagnostic problems to pathologists, and their biological potential may be difficult to establish. In this study, the authors have analyzed the clinical, histological, and outcome data of 37 cellular blue nevomelanocytic lesions and the molecular characteristics of 4 lesions. The cohort of cases comprised 8 cellular blue nevi (CBNs), 17 atypical cellular blue nevi (ACBNs), and 12 blue-nevus-like melanomas (BNLMs) with a mean follow-up of 5 years. The average age at diagnosis was 25.9 years for patients with ACBN, versus 30.4 years for CBN, and 44.6 years for BNLM. Both CBN and ACBN occurred most frequently on the trunk or extremities, whereas BNLM primarily involved the scalp. Histologically, CBN and ACBN were characterized by a mean diameter of <1 cm, absence of necrosis, low mitotic rate (mean: 1-2 mitotic figures/mm), little or no infiltrative properties, and usually low-grade cytologic atypia. In contrast, BNLM had a mean diameter of 1.6 cm, necrosis, tissue infiltration, greater mitotic activity (mean: 6 mitotic figures/mm), and high-grade cytologic atypia. ACBNs often were larger, more densely cellular, exhibited higher mitotic counts, and were cytologically more atypical than CBN. Seven CBN cases with follow-up had a benign clinical course (average follow-up of 4.7 years). Among 6 patients with ACBN who underwent sentinel lymph node (SLN) biopsy, 3 were positive, and a single additional case had 1 positive non-SLN (this patient did not have a SLN biopsy performed). All 14 cases of ACBN with follow-up were alive and without recurrence with mean follow-up of 5 years. Of the 9 melanoma cases with follow-up, 3 patients with SLN and non-SLN involvement died from their disease (average follow-up of 4.8 years). Array comparative genomic hybridization was performed on 2 ACBNs and 1 BNLM: One of the 2 ACBNs showed chromosomal aberrations and 1 BNLM showed multiple chromosomal gains and losses. Multiplex polymerase chain reaction was performed on 1 ACBN, and no mutations were found. From these results, the authors conclude that ACBN occupy an intermediate position within the spectrum of CBN and BNLM, yet many lesions cannot be reliably distinguished from either CBN or BNLM because of overlapping histologic features. However, in general, ACBNs seem to aggregate more closely with CBN in terms of clinical, histological, molecular profile (limited data), and biological behavior.

Granular cell variant of epithelioid cell histiocytoma.

Classic granular cell tumors (GCTs) stain strongly and uniformly positive for S100 protein and are believed to show Schwann cell derivation. Polypoid cutaneous tumors composed of cells with large nuclei and abundant granular cytoplasm that do not stain for S100 protein or show apparent Schwannian differentiation have been reported by several groups under names including "primitive polypoid granular cell tumors," "dermal nonneural granular cell tumor," and "primitive nonneural granular cell tumors of skin." We report a polypoid tumor composed of S100-negative epithelioid cells with abundant eosinophilic granular cytoplasm that meets diagnostic criteria for (primitive polypoid dermal) nonneural GCT but also meets criteria for a granular cell variant of epithelioid cell histiocytoma. We have identified a single previous report of a similar lesion. We report the immunohistochemical characteristics of these lesions and address how they are best classified.

Atypical cellular blue nevi (cellular blue nevi with atypical features): lack of consensus for diagnosis and distinction from cellular blue nevi and malignant melanoma ("malignant blue nevus").

The distinction of cellular blue nevi (CBN) with atypical features ["atypical" CBN (ACBN)] from conventional CBN and malignant melanomas related to or derived from CBN remains a difficult problem. Here, we report on the diagnosis of various cellular blue melanocytic neoplasms by 14 dermatopathologists who routinely examine melanocytic lesions. Three parameters were assessed: (1) for between rater analyses, we calculated interobserver agreement by the kappa statistic (regardless of whether the diagnosis was correct). (2) For each individual lesion, we reported whether a majority agreement (>50%) was reached and, if so, whether the majority agreed with the gold standard diagnosis, derived from standardized histopathologic criteria for melanoma, definitive outcome such as metastatic event or death of disease, or disease-free follow-up for > or =4 years. (3) For the individual pathologists, we calculated sensitivity and specificity for each type of lesion. The study set included 26 melanocytic lesions: (1) 6 malignant melanomas developing in or with attributes of CBN; (2) 11 CBN with atypical features and indeterminate biologic potential (ACBN); (3) 8 conventional CBN; and (4) 1 common BN. The kappa values for interrater agreement varied from 0.52 (95% confidence interval 0.45, 0.58) for melanoma to 0.02 (0.05, 0.08) for ACBN and 0.20 (0.13, 0.28) for CBN. The kappa for all lesions was 0.25 (0.22, 0.28). The pathologists' sensitivities were 68.6% (61.0%, 76.1%) for melanoma, 33.1% (21.0%, 45.2%) for ACBN, and 44.6% (29.0%, 60.3%) for CBN. The specificities were 65.7% (55.8%, 75.6%) for melanoma, 84.7% (77.3%, 92.2%) for ACBN, and 89.9% (82.7%, 97.1%) for CBN. Overall, greater than 50% of the pathologists agreed and were correct in their diagnosis 38.5% (10 lesions) of the time. There was a majority agreement, but with an incorrect diagnosis, another 26.9% (7 lesions) of the time. Six of the 7 majority agreements with an incorrect diagnosis were for ACBN lesions. In summary, the results of our study indicate that there is substantial confusion and disagreement among experienced histopathologists about the definitions and biologic nature of cellular blue melanocytic neoplasms particularly those thought to have atypical features ("atypical" CBN).

The limited specificity of histological examination in the diagnosis of dysplastic nevi.

Dysplastic nevi were originally described as a distinct entity with specific clinical and histological features of importance as direct precursors of malignant melanoma and as markers of patients at increased risk of developing melanoma in the setting of familial melanoma. Nevi with the clinical and histological features described first as 'B-K moles' and later as 'dysplastic nevi' clearly do exist and do sometimes represent melanoma precursors or melanoma risk markers, but it is now recognized that most dysplastic nevi never progress to melanoma, that the histological features originally described in nevi in familial melanoma patients are poorly correlated with dysplastic nevi as they are defined clinically, and that overlapping or identical histological features are found in a variety of other melanocytic lesions including small (< 5 mm) melanocytic nevi, lentiginous nevi, atypical (dysplastic) lentiginous nevi, lentiginous melanoma, lentigo maligna and nevi in an ever-growing number of 'special sites'. This article will briefly review the evolution of our understanding of the histological range of nevi and the histological differential diagnosis of dysplastic nevi.

Smooth muscle hamartoma associated with a congenital pattern melanocytic nevus, a case report and review of the literature.

Smooth muscle hamartoma (SMH) is a rare benign congenital or acquired lesion sometimes associated with Becker's nevus (Becker's melanosis). We report an unusual lesion with combined features of SMH and melanocytic nevus. The patient is a 49-year-old male with a history of a changing 'mole' on the left upper back. Clinical examination showed a solitary 1.2-cm nodule with central gray pigmentation. Histological examination showed a relatively well-circumscribed intradermal lesion. The superficial portion of the lesion consisted of melanocytes with nevoid morphology. The melanocytes had congenital pattern of distribution. Lesional melanocytes acquired a spindled morphology in the deeper dermis. The base of the lesion consisted of intersecting smooth muscle fascicles focally admixed with spindled melanocytes. The melanocytic component strongly expressed melanoma antigen recognized by T-cells-1 (MART-1) and HMB-45. The smooth muscle component was strongly positive for smooth muscle actin and h-caldesmon. Neither components showed significant cytological atypia or mitotic activity. Unlike a recently reported case of SMH combined with a melanocytic nevus and basal cell carcinoma, the current lesion did not occur in association with a Becker's nevus.

Clinicopathologic, immunophenotypic, and molecular cytogenetic fluorescence in situ hybridization analysis of primary and secondary cutaneous follicular lymphomas.

Although primary cutaneous follicular lymphoma (FL) is considered a distinct variant of FL in the World Health Organization classification ("cutaneous follicle center lymphoma"), its biologic relationship to nodal FL remains controversial. The clinical, morphologic, immunophenotypic, and molecular cytogenetic features of 17 patients with primary cutaneous FL were studied and compared with 16 patients with secondary cutaneous FL. The head and neck region was the most frequent site at initial skin presentation in both the primary and secondary cases. Among the primary cases, 29% of the 31 biopsies were grade 1, 48% grade 2, 13% grade 3, and 10% grade 3 with diffuse large B-cell (DLBCL) areas. Among the secondary cases, 38% of the 29 skin biopsies were grade 1, 45% grade 2, 3% grade 3, and 7% grade 3 with DLBCL areas with two not evaluable. A floral-like pattern was observed in 32% of primary FL but only 5% of secondary cases. Histologic progression was found in 21% of patients. CD10 expression was demonstrated in 90% (27 of 30) of primary cases and 96% (22 of 23) of secondary cases. Bcl-6 was expressed in all cases tested. Bcl-2 expression was detected in 57% (17 of 30) of the primary cases (100% of grade 1, 43% of grade 2, 40% of grade 3), whereas all secondary cases were bcl-2 positive (P=0.0002). The t(14;18) translocation was identified by interphase fluorescence in situ hybridization (FISH) in biopsies from 31% (4 of 13) of the patients with primary FL compared with 77% (10 of 13) of those with secondary lymphoma (P <0.05). Seven of the 17 (41%) patients with primary disease had cutaneous relapse, including 1 who also developed nodal disease. Bcl-2 positivity was seen in 4 of these 7 patients. Eight of the 16 (50%) patients with secondary FL had cutaneous relapse. Primary and secondary cutaneous FL share many clinical and phenotypic features, but primary cases may have some distinctive morphologic features, more frequently lack bcl-2 protein, and often lack the t(14;18) translocation. These findings suggest that primary cutaneous FL are distinctive and often but not always have a pathogenesis different from most of nodal and secondary cutaneous FL.

Are en face frozen sections accurate for diagnosing margin status in melanocytic lesions?

To assess the diagnostic accuracy of margin evaluation of melanocytic lesions using en face frozen sections compared with standard paraffin-embedded sections, we studied 2 sets of lesions in which en face frozen sections were used for analysis of surgical margins (13 from malignant melanomas [MMs] and 10 from nonmelanocytic lesions [NMLs]). Routine permanent sections were cut after routine processing. The slides were mixed and coded randomly. Fifteen dermatopathologists examined the cases separately. Margin status was categorized as positive, negative, or indeterminate. Kappa statistics were calculated per dermatopathologist and per case. One case from each group was excluded because epidermis was not available in the routine sections. Of 330 evaluations (22 cases, 15 dermatopathologists), there were 132 diagnostic discrepancies (40.0%): 66 each for MM and NML (mean per case for both diagnoses, 6). In 9 instances (6.8%), the change was from positive (frozen) to negative (permanent) and in 43 (32.6%), from negative (frozen) to positive (permanent). There was poor agreement between frozen and permanent sections (kappa range per dermatopathologist, -0.1282 to 0.6615). If permanent histology is considered the "gold standard" for histologic evaluation, en face frozen sections are not suitable for accurate surgical margin assessment of melanocytic lesions.

Histological characteristics of metastasizing thin melanomas: a case-control study of 43 cases.

OBJECTIVE: To study clinical and histological features associated with metastasizing thin melanomas (MTMs). DESIGN: Case-control study of clinicopathological features of patients with MTMs by a panel of 10 dermatopathologists. SETTING: Members of the North American Melanoma Pathology Study Group selected the cases from the melanoma databases at 8 academic institutions. PATIENTS: Forty-three patients with MTMs (<1 mm thick) and 42 control subjects without metastasis matched for age, sex, tumor site, and Breslow thickness. INTERVENTION: None. MAIN OUTCOME MEASURES: Clinical (age, sex, site of lesion, stage at diagnosis, metastasis site, disease-free survival, and outcome) and histological (Breslow thickness, Clark level, growth phase, regression, and inflammatory response) features of patients with MTMs vs controls. RESULTS: There was an overrepresentation of axial tumors among patients with MTMs. Extensive regression was present in 18 patients (42%) with MTM vs 2 matched control subjects (5%) (95% confidence interval, 21%-53%; P =.001). Other histological variables were not significantly different. Two patients had melanomas in situ with subsequent metastasis. CONCLUSIONS: Thin melanomas with extensive regression represent a group at higher risk for the development of metastasis. Furthermore, the risk of metastasis cannot be dismissed in cases of melanoma in situ.

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 (κ=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.

Multiple hybrid granular cell tumor-perineuriomas.

Hybrid peripheral nerve sheath tumors (PNSTs) are recently recognized, rarely reported entities. Very few hybrid PNSTs with elements of perineurioma have been reported. We report a case of a 47-year-old man who presented with multiple (>20) cutaneous nodules on all 4 extremities, present since childhood. The patient and his family had no history of other PNSTs, other neural-origin tumors, or genetic disorders, including neurofibromatosis. Five excised lesions are well circumscribed but unencapsulated nodular tumors composed of cytologically bland spindled cells with tapering nuclei and indistinct cytoplasm arranged in a storiform pattern in a collagenous matrix. Scattered among these cells are large granular eosinophilic cells. The spindled cells are epithelial membrane antigen-positive and S-100 protein negative. The cytoplasm of the granular cells contains abundant S-100 protein, NK1/C3, and CD68-positive granules. Sparse nerve fascicles contain neurofilament-positive axons. Each tumor also contains poorly marginated areas that histologically resemble pure granular cell tumor, and superficial biopsies of these tumors can histologically resemble pure granular cell tumors. Considering a Schwannian origin for both perineurial and granular cells can provide a logical explanation for the pathogenesis of this case. To the best of our knowledge, our case is the first report of multiple hybrid granular cell tumor-perineurioma.

Mohs micrographic surgery for the eradication of phaeohyphomycosis of the hand.

BACKGROUND: Phaeohyphomycosis is a rare mycotic infection that is caused by dematiaceous fungi requiring surgical excision or long-term use of oral antifungal agents for treatment. OBJECTIVE: To report a case of phaeohyphomycosis of the dorsal hand successfully cleared with Mohs micrographic surgery. METHODS: We performed Mohs micrographic surgery on phaeohyphomycosis of the dorsal hand. The fungus was cleared in three stages of surgery. Permanent processing and special stains of the final stage confirmed eradication of the infection. RESULTS: The patient remained free of the phaeohyphomycosis, without complications, at the 6-month follow-up. CONCLUSION: Mohs micrographic surgery is an effective, tissue-sparing technique for the eradication of phaeohyphomycosis, potentially eliminating the need for costly long-term antifungal therapy.