Balloon cells in metastatic melanoma

A 42-year-old male patient presented to an outside hospital for right pleuritic chest pain. Physical examination revealed left supracervical, axillary, and bilateral inguinal lymphadenopathy and a 1-cm irregularly shaped hyperpigmented lesion over his left scapula, of which the patient had known for at least 2 years without previously seeking medical attention. Imaging additionally revealed an expansile lytic lesion of the anterior 4th rib and a 0.4 cm nodule in the right lung base. A fine needle aspiration (FNA) with subsequent core needle biopsy of the enlarged axillary lymph node was performed. The Diff-Quik and Papanicolaou stained smears were composed predominantly of large cells with low nucleocytoplasmic ratios admixed with lymphocytes, occasional smaller neoplastic cells, and naked nuclei in a foamy (“bubbly”) background without necrotic debris (Figures 1AD and 2A-D). The large ovoid/polygonal neoplastic cells (60–120 mm) showed ill-defined cytoplasmic borders and were present both singly and in small syncytial sheets. Cells were both uninucleated and multinucleated with centrally or eccentrically located round to ovoid large nuclei (10–16 mm) demonstrating finely granular chromatin, central macronucleoli (3–8 mm), and occasional nuclear pseudoinclusions. No mitoses were identified. The large cells had abundant pale nonpigmented finely granular cytoplasm showing delicate condensations and wrinkled paper-like creases imparting it a honeycomb or waffle-like appearance. Occasional cells showed peripheral cytoplasmic vacuoles or blebs (4–10 mm) seen with both Romanowsky and Papanicolaou stains. Rarely, larger vacuoles (>20 mm) occupied most of the cytoplasm of the tumor cells. In addition to these large cells, smaller cells (20–25 mm) and “intermediate” cells (40–50 mm) with scant to moderate amounts of ill-defined to dense cytoplasm and large nuclei with prominent macronucleoli were also present. On core needle biopsy (H&E stained), sections showed the large pale cells with finely granular cytoplasm as seen on fine needle aspiration along with a minority of cells with similar nuclei but smaller amounts of eosinophilic cytoplasm, lipoblast-like cells with large vacuoles indenting the nucleus, and sebocyte-like cells with numerous small vacuoles occupying the entire cytoplasm (Figure 3A-D). Immunohistochemical stains performed on the cell block and core biopsy showed no reactivity for epithelial markers (cytokeratins 8/18 and AE1/AE3, EMA) and histiocytic markers (CD68) and showed positivity for melanocytic markers (S100, MITF, HMB45, MART1, Figure 4A-D), confirming the diagnosis of metastatic balloon cell melanoma (BCM). Interestingly, both HMB45 andMART1 showed a checkerboard-like alternating dark and pale staining. The MART1/Ki67 cocktail showed that the large pale “balloon” cells were largely negative for Ki67 while the smaller cells were almost uniformly positive, suggesting that the balloon cells are not mitotically active and may represent a degenerative change in melanoma cells. Molecular testing showed no BRAF mutations. Subsequently, the patient was started on dual checkpoint blockade with ipilimumab (a monoclonal antibody targeting CTLA-4) and nivolumab (a human IgG4 anti-PD-1 monoclonal antibody). Malignant melanoma metastases are frequently diagnosed by FNA cytology. The diagnosis is usually relatively straightforward when the aspirates show abundant cellularity with predominance of single tumor cells with obvious cytologic features of malignancy, prominent macronucleoli, binucleation, nuclear eccentricity, and nuclear pseudoinclusions. If melanin pigment is present, the diagnosis is even clearer. However, melanin pigment is only identified in a minority of cases, and metastatic melanomas can show a bewildering variety of cytomorphologic patterns. Malignant melanoma has gained a well-deserved reputation as a “great imitator” as it can mimic many other neoplastic conditions. Melanoma cells can vary in size from small, lymphocyte-like cells to very large multinucleated giant cells, in shape from round/oval or polygonal epithelioid cells to spindle cells, and in appearance with occasional resemblance to plasma cells, lipoblasts, or rhabdomyoblasts. Amongst the rarest cytomorphologic variants of melanomas are those characterized by a predominance of clear cells, sebocyte-like cells, or balloon cells, which appear to represent a spectrum of