FNA Cytological Diagnosis of Breast Metastasis From a Plantar Melanoma: Case Report

Benign and primary malignant breast tumors are quite common, but metastatic malignancies are rare and the diagnosis is challenging due to its low incidence. Here, we report a case of metastatic melanoma which was initially diagnosed in breast by ne needle aspiration(FNA). Although the suggestive diagnosis is based on the strong pigmentation of tumor cells in FNA smears, cell block and immunohistochemical melanocyte markers (HMB45 and MART-1) help to conrm the diagnosis. Later, FNAs from lower limb mass and inguinal mass also revealed the same tumor. In addition, a pigmented nevus with the appearance of malignant melanoma was found on the sole of the patient's right foot. Our report illustrates the morphological evaluation on cytology(cid:0)ancillary testing on cell block and meticulous clinical examination play a pivotal role in establishing the correct diagnosis. we report a rare case of a 57-year-old female with metastatic melanoma which was initially diagnosed in breast by ne needle aspiration. If a diagnosis of melanoma is suspected, performing immunohistochemistry is critical for conrming the diagnosis. Any melanoma patient with breast metastasis should be carefully examined for a history of cutaneous malignant melanoma. In summary, morphological evaluation on cytology, ancillary testing on cell block and meticulous clinical examination play a pivotal role in establishing the correct diagnosis.


Abstract Background
Benign and primary malignant breast tumors are quite common, but metastatic malignancies are rare and the diagnosis is challenging due to its low incidence.

Case presentation
Here, we report a case of metastatic melanoma which was initially diagnosed in breast by ne needle aspiration(FNA). Although the suggestive diagnosis is based on the strong pigmentation of tumor cells in FNA smears, cell block and immunohistochemical melanocyte markers (HMB45 and MART-1) help to con rm the diagnosis. Later, FNAs from lower limb mass and inguinal mass also revealed the same tumor. In addition, a pigmented nevus with the appearance of malignant melanoma was found on the sole of the patient's right foot.

Conclusion
Our report illustrates the morphological evaluation on cytology ancillary testing on cell block and meticulous clinical examination play a pivotal role in establishing the correct diagnosis.

Background
The ne needle aspiration(FNA) smear is a robust tool for detection of breast epithelial lesions and primary breast carcinomas.The National Health Service Breast Cancer Screening Programme (NHSBSP) diagnostic categories are universally applied [1,2].The combination of clinical impression by physical examination, mammography, and FNA cytology can maximize the diagnostic accuracy for breast disease [3]. Although the application of core needle biopsy has increased greatly, reports in the literature and guidelines show that FNA is still a useful method for diagnosing breast diseases [4]. All palpable masses are suitable for FNA ,and there are few contraindications to FNA for breast masses [5].After mastectomy and mass resection, especially during and after radiotherapy, there are extensive lesions in the breast and surgical scar area, most of which are benign. FNA smears help to achieve a quick diagnosis and prevent further surgery. The preparation of cell block (CB) and immunohistochemistry (IHC) is increasingly regarded as a useful tool in providing a reliable diagnosis in resource-limited settings [6]. In this article, we report a rare case of melanoma which was initially diagnosed in breast by FNA. In this case report, we review the cytomorphology of melanoma on FNA cytology and highlight the signi cance of uncommon lesions in breast FNA smears.

Case Presentation
A 57-year-old female presented with a painless breast mass. Mammography showed a round and highdensity nodular in right breast with a possibility of malignancy( Figure 1A). On clinical examination, the patient had a suspect palpable mass (1.5 cm in diameter) in the upper outer quadrant of the right breast.
There was no further information available. FNA biopsy was performed by using our patented 21-gauge (0.8 mm) aspirator (Youyi aspirator) as previous report [7]. The sample material was macroscopically dark and therefore highly suggestive of melanocytic pigmentation. Smears were cellular, consisting of tightly cohesive clusters of breast ductal cells and scattered atypical cells, which were of big size with high nuclear to cytoplasmic ratio, round to oval nucleus, and evenly distributed coarse chromatin and conspicuous nucleoli. Some of these atypical cells showed abundant cytoplasm and granular cytoplasmic pigment( Figure 1B). Therefore, a possibility of malignant big cell tumor was considered. The tumor cells are large and mostly lobated or histiocytoid clear nuclei. The cytoplasm is vacuolated or granular. Cytomorphological features and suspicious melanocytes are conducive to the diagnosis of malignant melanoma, which needs to be distinguished from undifferentiated non-epithelial tumors or anaplastic large cell carcinoma. In addition, pigmented melanoma should raise no diagnostic problems except in rare cases of carcinoid tumors that exhibit nuclear polymorphism and melanin production. Cell block and immunohistochemical analysis were performed to obtain the right diagnosis. Melanoma cells were negative for cytokeratin ( Figure 1D) and melanoma markers HMB45 and MART-1 were positive( Figure 1E-F).
Subsequently, through detailed inquiry and physical examination, a mass (2.0 cm in diameter) with slightly dark skin color was found in the right lower limb (Figure 2A). In the past year, the patient had unexplained foot and ankle fractures. In addition, physical examination showed two 2 cm masses in the right groin( Figure 2B). A pigmented nevus was also found on the sole of the patient's right foot. The plantar nevus had a large area (2x0.5cm) and a serrated arc at the edge, which were consistent with the appearance of malignant melanoma (Fig. 2C). FNAs from lower limb mass and groin mass were performed. Smears are cellular and contain singly scattered plasmacytoid cells with brown to black pigment( Figure 2D-E). The melanoma cells are discohesive, containing densely packed yellow-brown stained pigment granules of the cytoplasm. The nuclei are enlarged and eccentrically located and contain macronuclei. Nuclear pseudo-inclusions are common( Figure 2F). Since the patient had a clear history of fracture, MRI showed melanoma involvement of bone. Thus, the overall features were those of melanoma involving breast, lymph node and bone marrow. The patient refused further treatment because she had no serious clinical symptoms. However, the patient succumbed to the disease a few months after she was discharged from the hospital.

Discussion
Benign and primary malignant breast tumors are quite common, but melanoma involvement of breast is only seen in 1.3%-2.7% of all malignant mammary tumors [8]. Melanoma is the most rapidly increasing cancer and 20% of patients diagnosed with melanoma will develop metastasis via hematologic or lymphatic routes [9]. Sometimes it can present many years after the primary diagnosis [10]. Breast metastases may be asymptomatic and/or palpable as well-de ned nodules. On mammography, breast metastases showed clear nodular shadows without calci cation or structural deformation. Therefore, clinical history, cytology and histology are very important for diagnosis.
According to our experience and literature report [10], cytoplasmic melanin pigment allowed a highly suggestive of breast metastases, therefore histological examination was not required. It should be emphasized that melanin must exist in malignant cells because hemosiderin simulates melanin in macrophages to a certain extent. The pigmented epidermotropic form of breast carcinoma can also mimic a melanoma [11]. However, although characteristic, the pigment is often not visible in cytological samples. Metastatic melanoma can also simulate a variety of cellular and architecture phenotypes, including primary breast malignancies [12]. Thus, a panel of biomarkers played a vital role in establishing the melanocytes originate of tumor cells. Immunohistochemistry for S100, HMB45, or Melan-A help to con rm the diagnosis.
Cutaneous melanoma is one of the tumors with a high frequency of dissemination to the breast.The prognosis for a patient with a newly diagnosed cutaneous melanoma depends mainly on the thickness of the primary tumour and the presence or absence of metastasis [13]. Due to the poor prognosis of patients with metastatic melanoma, active surgical treatment should be avoided. With regard to chemotherapy, ipilimumab, vemurafenib, interferon alfa-2b, dacarbazine and interleukin-2 have low response rates and are associated with serious adverse events [14]. Due to the low radio-sensitivity of melanoma cells, radiation therapy plays a limited role in the control of the natural history of metastatic melanoma [15].
However, the treatment of metastatic melanoma has been modi ed by the introduction of targeted therapy and immunotherapy.Treatments by using selected BRAF inhibitors combined with mitogenactivated protein kinase inhibitors have signi cantly improved response and overall survival [16].
Antibodies that block immune checkpoint proteins, including CTLA4, PD-1, and PD-L1 are FDA approved for treating melanoma [17]. While these therapies have limitations, identifying biomarkers to improve patient selection and discovering future therapeutic targets will hopefully lead to further treatment advances.

Conclusion
In conclusion, we report a rare case of a 57-year-old female with metastatic melanoma which was initially diagnosed in breast by ne needle aspiration. If a diagnosis of melanoma is suspected, performing immunohistochemistry is critical for con rming the diagnosis. Any melanoma patient with breast metastasis should be carefully examined for a history of cutaneous malignant melanoma. In summary, morphological evaluation on cytology, ancillary testing on cell block and meticulous clinical examination play a pivotal role in establishing the correct diagnosis.

Consent for publication
Written informed consent was obtained from the patient for publication. All authors are in agreement for the publication of the study.

Availability of data and materials
All data and material were presented in this published article.