The clinical presentations of BCMM are variable. BCMM have been characterized as nodular, ulcerated, pedunculated, polypoid, and papillomatous, with clinical differential diagnoses of halo nevus, fibromatous lesions, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, and cutaneous adnexal tumors [1
]. The primary lesion in our case appeared as an erythematous papule, and given the patient's history of multiple basal cell carcinomas, basal cell carcinoma had been clinically suspected.
In the absence of prior clinical and pathological history, numerous differential diagnoses were posed in this lesion composed exclusively of foamy to clear balloon cells, including renal cell carcinoma, adrenal tumors, malignant granular cell tumor, clear cell sarcoma, alveolar soft part sarcoma, perivascular epithelioid cell tumors (PECOMAS), liposarcoma, xanthomatous lesions, sebaceous lesions, hibernoma, and clear cell hidradenoma. The first case of balloon cell melanoma was reported in 1970 by Gardner [3
]. As with several subsequent reports, the metastatic lesion was misinterpreted. In the case by Gardner, the lymph node metastasis was initially diagnosed as clear cell sarcoma. Ranchod reported a case in which a diagnosis of round cell liposarcoma was made on a lymph node metastasis [4
]. Akslen reported a case in which the metastatic tumor mimicked clear cell renal carcinoma [5
]. These cases, as well as our case, illustrate the importance of clinical investigation and correlation in reaching a diagnosis of BCMM.
Balloon cells have been reported in nevi, including intradermal, halo and combined nevi, but remain rare in melanoma[6
]. BMC are cytologically distinct from balloon nevus cells. BMC show mild pleomorphism and may show mitotic figures. Focal areas of high mitotic count and nuclear pleomorphism can be identified (). Though rare, tumor necrosis, when seen, is supportive of melanoma. Balloon cell nevi have centrally located nuclei with no nuclear pleomorphism and no mitotic activity. Schrader suggested that the presence of multi-nucleated giant balloon cells was a feature of balloon cell nevi, but these were later found to be identified in BCMM as well [1
]. Maturation in balloon cell nevi is also an important clue to their benignity. Although intraepidermal pagetoid spread and a confluent junctional proliferation of BMC may be identified in BCMM, it is interesting to note that there are no reports of balloon cell melanoma in situ.
In BCMM, balloon cells are usually sparse in the primary melanoma, but have a potential of constituting the entire metastasis. In at least three cases, the primary melanoma did not exhibit any balloon cells and the tumor predominantly consisted of spindle-shaped and epithelioid cells [4
]. When balloon cells were present in the primary lesion, they were a minor component. Sondergaard reported a case of a 20-year-old man with a primary melanoma that was composed of spindle-shaped and epithelioid cells and only upon step-sectioning of the lesion did a small area of large nonpigmented clear cells with vesicular cytoplasm appear [11
]. This discovery reiterates the importance of thorough examination of the entire tissue. When BMC are a minimal component of the primary lesion, a diagnosis of malignant melanoma with balloon cells is made, rather than BCMM. Kao has defined cutaneous balloon cell melanoma as a tumor composed of more than 50% foamy cells [1
The main reason BCMM can be mistaken for a benign clear cell neoplasm is its bland cytology (). Another reason for the diagnostic difficulty is the general lack of melanin in BMC, in contrast to balloon nevus cells. In several case reports, the BMC contained no melanin pigment and stained negatively for Fontana-Masson [2
]. Melanin granules were found in sparse amounts in only nine of the 34 reported by Kao [1
]. This characteristic is further exacerbated by the fact that when balloon cell melanoma metastasizes, the metastases are often composed entirely of balloon cells with no residual spindle-shaped or epithelioid component. However, if spindle-shaped and epithelioid cells are present in metastases, they are a supportive tool in the diagnosis of metastatic melanoma as these are the cells which may be pigmented and stain positively for melanin.
Immunohistochemistry is helpful in the diagnosis of BCMM, in conjunction with clinical history and other diagnostic modalities. Histological and IHC stains alone have limitations due to the wide differential diagnoses for BCMM. Notably, clear cell sarcoma also stains positively for S-100, HMB-45, Fontana-Masson, and PAS. However, whereas the tumor in our case is composed of nests of balloon cells divided by fibrous septae illustrated best by reticulin stain, clear cell sarcoma is composed of nests which are more packeted and contain fusiform cells with scattered wreath-like or syncytial giant cells. The nuclei in clear cell sarcoma are also uniform, lacking pleomorphism, and contain prominent central nucleoli. In addition, molecular analysis of clear cell sarcoma shows EWS-AFT1 fusion. Another possible diagnosis is perivascular epithelioid cell tumor (PECOMA) which stains positively for HMB-45, melan-A, tyrosinase, and in 30% of cases, positively for S-100. They also stain positively for smooth muscle actin, which may assist in differentiating the tumors from BCMM. Granular cell tumors have granular cytoplasm with abundant PAS-positive, diastase-resistant lysosomes. Granular cell tumors and xanthomatous lesions may be distinguished from BCMM by negative melan-A staining. S-100 is also negative in xanthomatous lesions. Sebaceous lesions have “bubbly” cytoplasm and the nucleus is crenated, showing a scalloped border. They are distinctly S-100 and HMB-45 negative and stain positively for epithelial membrane antigen. Renal clear cell carcinoma often shows prominent vascular stroma, hemorrhage, and tumor necrosis. It can be differentiated with positive staining for cytokeratin and CD10.
Electron microscopy of BMC shows abundant cytoplasmic membrane-bound vacuoles, scattered glycogen granules, along with mitochondria, ribosomes, and Golgi apparatus. While abnormal melanosomes may appear in the spindle-shaped and epithelioid cells, the balloon melanoma cell is often completely devoid of melanosomes or show only infrequent abnormal premelanosomes [4
]. Rarely, small clusters of melanosomes and premelanosomes are identified [1
Ranchod and Friedman both reported cases of patients surviving more than 10 and 20 years after the diagnosis of primary BCMM [4
]. The patient reported by Gardner lived 3 years after primary diagnosis [3
]. In the case series reported by Kao, 78.9% of patients with tumors greater than 2.0 mm thick died of widespread metastasis [1
]. Importantly, the prognosis of BCMM does not depend on the degree of balloon cell change, tumor size, nuclear atypia, or mitotic activity, but instead follows the prognosis patterns of conventional malignant melanoma correlating with tumor thickness. Kao reports a 37.5% overall 5-year survival rate in BCMM [1