A practical approach to borderline melanocytic neoplasms

 

The next case is that of a 64-year-old male with a lesion on his right forehead. In Fig. 12 is the diffuse melanocytic lesion with hypo- and hypercellular area. Three cytomorphology features (epithelioid, nevoid, and balloon cells) are seen on high power (Fig. 13). “And the lesions also show associated lymphoid aggregates—one of the features of this type of lesion,” Dr. Aung said. Some of the epithelioid cells show cytologic atypia. “However, buffer MART-1/Ki67 showed low or absent proliferative index,” she said (Fig. 14). The dermal melanocytes showed loss of BAP1 nuclear expression (Fig. 15, compared with positive control showing nuclear BAP1 expression in the keratinocytes within epidermis [inset]). “And BRAF V600E immunohistochemical studies showed positive staining pattern, indicating mutation in these melanocytes” (Fig. 16).

The differential, Dr. Aung said, is melanocytic nevus with BAP1 loss, melanoma with BAP1 loss, or melanoma arising in association with nevus and BAP1 loss. “The diagnosis is melanocytic nevus with BAP1 loss due to the lack of prominent cytology atypia, lack of mitotic figures, low or absent Ki67 proliferative rate, and typical features of BAP1-associated melanocytic lesion, including diffuse dermal melanocytic proliferation with variable morphology, and associated lymphoid aggregates.”

The final diagnosis: melanocytic nevus, predominantly intradermal type with focal balloon-cell changes and associated loss of BAP1 expression and presence of BRAF V600E mutation. “Some people call this lesion a BAP-oma,” Dr. Aung added.

BAP1 (BRCA1-associated protein 1) is a deubiquitinating enzyme whose gene is located on chromosome region 3p12. “It’s a tumor suppressor gene with an important role in cell proliferation, differentiation, and growth inhibition,” she said.

BAP1 tumor predisposition syndrome, Dr. Aung said, has usually been due to the loss of expression of BAP1 owing to germline or sporadic mutations. The histologic features are similar in both types of mutated lesions, “so it’s not useful to differentiate germline from sporadic.”

BAP1 tumor predisposition syndrome is an autosomal dominant inherited disorder with germline mutation that increases the risk of various types of malignant and benign tumors, including malignant mesothelioma, renal cell carcinoma, uveal melanoma, and other skin melanocytic lesions with Spitzoid morphology, usually present with multiple lesions on the skin, Dr. Aung said. Affected individuals can develop one or more types of tumor, and affected members of the same family can have different tumor types.

BAP1-associated melanocytic lesions can be divided into two groups: nevus with BAP1 loss (BAP-oma) (most common) and melanoma arising in association with nevus and BAP1 loss, which is rare.

“In terms of histomorphology, BAP1-mutated melanocytic lesions usually show one of two common growth patterns,” Dr. Aung said: a single, well-demarcated dermal nodule comprising epithelioid melanocytes or multiple nests of epithelioid melanocytes in a background of a diffuse dermal melanocytic nevus, often with features of congenital onset (Piris A, et al. Hum Pathol. 2015;46[2]:239–245).

BAP1-mutated melanocytic lesions usually pre­sent as multiple benign-appearing, dome-shaped, skin-colored or pink papules, she said. In rare cases with overt cytologic atypia and mitotic figures, “as pathologists, we have to pay extra attention to exclude the possibility of melanoma” (Busam KJ, et al. Am J Surg Pathol. 2013;37[2]:193–199). In an article published in 2019, Dr. Aung and colleagues reported the histomorphologic and clinical characteristics of cutaneous melanomas with loss of BAP1 expression in patients with no known family history of BAP1-associated cancer susceptibility syndrome (Aung PP, et al. Am J Dermatopathol. 2019;41[3]:167–179).

BAP1-associated melanocytic lesions “can be the first clinical manifestation of BAP1 cancer syndrome,” she said. Suspicious lesions should be excised and evaluated by a pathologist, and pathologists must be aware of the atypical histological characteristics. If any are seen, Dr. Aung said, “make sure to evaluate the possibility of melanoma.” Evaluate for BAP1 and BRAF mutations. “If we see individuals or families with this BAP1 cancer syndrome, we can offer genetic counseling or even consider performing germline DNA testing for BAP1 mutations.”

 

Blue nevus-like melanocytic lesions can be subdivided into four histophenotypic groups: benign blue nevus, cellular blue nevus, cellular blue nevus with atypical features, and blue nevus-like melanoma, Dr. Aung said.

 

A study published in 2011 evaluated the ability of a FISH assay targeting 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1), and the centromere of chromosome 6 to distinguish between cellular blue nevus and blue nevus-like melanoma (Gammon B, et al. J Cutan Pathol. 2011;38[4]:335–341). The assay was reported to be sensitive and specific to distinguish between the two in some cases. “They found no FISH positivity in any of the cellular blue nevus cases, but they found three to five cases of blue nevus-like melanoma with abnormalities detected by FISH,” Dr. Aung said.

 

She presented the case of a 19-year-old male with a pigmented nodule on his scalp. Large hypercellular melanocytic proliferation with uniform pigmentation is seen in Fig. 17 and elongation of rete ridges and small junctional component of the melanocytic proliferations in Fig. 18. “We found some of the cells showed very small nucleoli,” Dr. Aung said (Fig. 19). Ki67 staining showed a low to absent proliferative rate. HMB-45 showed diffuse positivity.

“The best diagnosis for this case is cellular blue nevus,” she said, because even though cellularity was high, there was no cytologic atypia or mitotic activity, with normal HMB-45 and low Ki67 expression.

Another case—a 69-year-old with a pigmented lesion on the left scapula—had a diagnosis of blue nevus-like melanoma arising in association with blue nevus (Figs. 20–22). MART-1/Ki67 showed high proliferative rate in large epithelioid melanocytes and low to absent proliferative rate in spindle-shaped melanocytes. HMB-45 showed diffuse expression in epithelioid and spindle cells.

“The best diagnosis for this case is blue nevus-like melanoma arising in association with blue nevus due to the presence of irregular pigmentation, asymmetry, infiltrative border, biphenotypic features, cytologic atypia, atypical mitotic figures, and high proliferative rate,” Dr. Aung said. “And the patient’s sentinel lymph node also showed positive metastatic melanoma highlighted with pan-melanoma cocktail.”

 

In closing, Dr. Aung presented the case of a 20-year-old female with a brown lesion on the thigh that was enlarging and becoming darker. Asymmetrical compound melanocytic proliferation is seen in Fig. 23. In high power the cytologic atypia with Spitzoid features, lack of maturation with dermal descent, and irregularly dispersed deposits of melanin pigment are seen (Fig. 24). In Fig. 25: marked cytologic atypia, showing some of the cells with prominent nucleoli, and mitotic activity at the deeper portion of the lesion. MART-1/Ki67 showed scattered proliferative cells in the dermis and there was patchy expression with HMB-45. “We also performed FISH, which was negative,” she said.

The consensus diagnosis (five to two) among Dr. Aung’s group favored the diagnosis of melanoma with Spitzoid features, she said, primarily based on prominent cytomorphologic atypia, lack of maturation, and presence of a deep dermal mitosis (close to the base of the lesion), despite the negative FISH result.

Amy Carpenter Aquino is CAP TODAY senior editor.