Melanoma Arising in Association with Blue Nevus
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Modern Pathology (2014) 27, 1468–1478 1468 & 2014 USCAP, Inc All rights reserved 0893-3952/14 $32.00 Melanoma arising in association with blue nevus: a clinical and pathologic study of 24 cases and comprehensive review of the literature Sanam Loghavi1, Jonathan L Curry1, Carlos A Torres-Cabala1, Doina Ivan1, Keyur P Patel2, Meenakshi Mehrotra2, Roland Bassett3, Victor G Prieto1 and Michael T Tetzlaff1 1Department of Pathology, Section of Dermatopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; 2Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA and 3Department of Biostatistics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA Melanomas arising in association with blue nevi or mimicking cellular blue nevi comprise a relatively rare and heterogeneous group of melanomas. It remains controversial which prognostic indicators predictive of outcome in conventional cutaneous melanomas are applicable to this type of melanoma. Here, we describe the clinical and histopathologic features of 24 melanomas arising in association with blue nevi and correlate these with clinical outcome. The mean patient age was 49 years (range: 23–85) with a slight female predominance (15 females:9 males). The most common anatomic locations included the head and neck region (50%), the trunk (21%), and the buttock/sacrococcygeum (17%). Histologically, the tumors were typically situated in the mid to deep dermis with variable involvement of the subcutis, but uniformly lacked a prominent intraepithelial component. The mean tumor thickness (defined as either the standard Breslow thickness or, if not available due to the lack of orientation or lack of epidermis, the largest tumor dimension) was 20.9 mm (range: 0.6–130 mm). The mean mitotic figure count was 6.5/mm2 (range: 1–30/mm2). Perineural invasion was common (38%). Follow- up was available for 21 cases (median 2.1 years). The median overall survival, recurrence-free survival, time to local recurrence, and time to distant recurrence were 5.2, 0.7, 2.6, and 1.6 years, respectively. Logistic regression analyses demonstrated a significant association between tumor thickness and recurrence-free survival (hazard ratio ¼ 1.02 per mm; P ¼ 0.04) and reduced time to distant metastasis (hazard ratio ¼ 1.03 per mm; P ¼ 0.02) with a similar trend toward reduced time to local recurrence (hazard ratio ¼ 1.02 per mm; P ¼ 0.07). No other parameters (age, anatomic location, mitotic figures, lymphovascular or perineural invasion, or type of associated blue nevus) emerged as significant. In addition, we provide a comprehensive review of 109 cases of melanoma blue nevus type described in the English literature and summarize our findings in this context. Modern Pathology (2014) 27, 1468–1478; doi:10.1038/modpathol.2014.62; published online 18 April 2014 Keywords: blue nevus; cellular blue nevus; melanoma Blue nevi represent a broad spectrum of melanocytic cteristic blue–black-grey–black clinical discolora- proliferations with distinctive clinical and histo- tion of variable sizes.2,3 Histopathologically, pathologic features. Common blue nevi were first common blue nevi are characterized by a wedge- described by Jadassohn-Tieche.1 These nevi typi- shaped, variably cellular dermal proliferation of cally develop congenitally or de novo on the distinctive spindled, dendritic melanocytes with extremities, scalp, and buttocks and exhibit a chara- elongated, hyperchromatic nuclei and variable amounts of coarse intracytoplasmic pigment. An associated desmoplastic stromal reaction and 2,3 Correspondence: Dr MT Tetzlaff, MD, PhD, Department of melanophages are typical. Cellular blue nevi Pathology, Section of Dermatopathology, The University of Texas most commonly arise on the buttock/sacrococcy- MD Anderson Cancer Center, Unit 0085, 1515 Holcomb Boule- geal area and less commonly, the scalp and extre- vard, Houston, TX 77030, USA. mities. They typically grow as larger, multilobulated E-mail: [email protected] Received 30 November 2013; revised 27 February 2014; accepted masses (often with a characteristic ‘dumbbell 6 March 2014; published online 18 April 2014 shape’) and consist of a biphenotypic proliferation www.modernpathology.org Melanoma blue nevus type S Loghavi et al 1469 of dendritic melanocytes reminiscent of classic blue Materials and methods nevus admixed with cellular nodules of spindled oval-shaped melanocytes with a variable admixture Patient Specimens 2–4 of pigmented macrophages. The term melanoma With approval from the Institutional review Board at blue nevus type designates a heterogeneous group of the University of Texas, MD Anderson Cancer Center, malignant melanocytic proliferations (melanomas) the files of the Department of Pathology at University that either (A) arise in association with common or of Texas, MD Anderson Cancer Center were searched cellular blue nevi or (B) develop de novo but for cases of melanoma described as arising in associa- architecturally or cytologically mimic cellular blue tion with a common or cellular blue nevus. Twenty- 3–5 nevus. Diagnostic histopathologic features include four cases of primary lesions in patients without prior a proliferation of melanocytes with malignant history of invasive melanoma were identified from cytology (nuclear pleomorphism, coarse chromatin, the past 9 years. In each case, either hematoxylin and prominent nucleoli), increased and/or atypical eosin-stained slides or whole slide scanned images mitotic figures, tumor necrosis, and invasive and/or were reviewed to confirm the diagnosis and record destructive pattern of growth and occasionally, an the histopathologic features including tumor thick- adjacent/associated proliferation of distinctly benign ness, tumor cytology, number of mitotic figures, type 6 blue nevus dendritic melanocytes. of associated benign nevus, and the presence of an Although melanoma blue nevus type have been intraepidermal component, ulceration, regression, shown to exhibit outcomes similar to conventional lymphovascular invasion, perineural invasion, satel- melanoma when matched for Breslow thickness, age, litosis, and tumor necrosis. The criteria to distinguish 7 Clark level, and ulceration, it remains controversial between melanoma and an associated nevus compo- which—if any—of the discrete clinical and patholo- nent included distinctly biphenotypic foci with gic indicators (like age, gender, Breslow thickness, increased cellularity, prominent nuclear pleomorph- mitotic figures, and ulceration) predictive of clinical ism and nucleoli, increased mitotic figures, and the outcome in conventional cutaneous melanomas presence of coagulative tumor necrosis.6 ‘Tumor might apply to this group of melanomas. This is thickness’ was defined as the standard Breslow especially contentious considering the typical re- thickness when the lesion abutted or came in close striction of melanoma blue nevus type to the dermis proximity to the epidermis or the largest tumor and/or subcutaneous tissue without an associated dimension available for a given lesion (when the intraepidermal component, which has been sug- lesion grew as a nodule at a location distant from the gested to undermine the biological relevance of epidermis and/or there was no epidermis available for Breslow thickness and tumor ulceration as predictors evaluation in the specimen). Only the malignant 5 of outcome. Further complicating this issue, the component was measured when assessing maximum constellation of distinctive diagnostic features tumor thickness. Using this definition, clinical described above is not apparent in every case; thus, attributes and follow-up information for each case the unequivocal distinction of melanoma (arising were obtained from electronic medical records, when with or resembling blue nevus) from benign cellular available. blue nevus or atypical cellular blue nevus8,9 also remains controversial—even among experienced der- Mutation Analysis matopathologists.10 It is therefore not surprising that there are only B100 cases described in the literature BRAF mutation analysis was performed using to date4,5,7,11–54 and the majority of these are indivi- targeted next generation sequencing or pyrosequen- dual case reports or small case series—too few to cing as previously described.55,56 GNAQ mutation achieve statistical significance in correlating histo- analysis was performed using DNA extracted from pathologic features with clinical behavior. unstained formalin fixed, paraffin-embedded tissue Here, we describe the clinical and histopathologic sections. We tested for mutations in exon 5, codon features of 24 melanomas arising in association with 209 of the GNAQ gene using Sanger sequencing. common or cellular blue nevi. We further correlate Polymerase chain reaction amplification analyses of the clinical and histopathologic features of these six samples were performed in duplicate. Polyme- lesions with annotated clinical follow-up informa- rase chain reaction was performed in a 96-well plate tion. We demonstrate a statistically significant with a 50 ml volume including 100 ng DNA, 10 mMof association between tumor thickness (defined as M13 tagged GNAQ Exon 5 forward and reverse either the standard Breslow thickness or, if not primers, 25 mM MgCl2,5ml10Â GoTaq buffer, 5 ml available due to lack of orientation or lack of 10 mM dNTP mix, and 0.3 ml of 5 units/ml of GoTaq epidermis, the largest tumor dimension) and both enzyme. The reaction mix was subjected