A 29-year-old male presented with progressively increasing right inguinal, cervical, and left axillary swellings over two and a half months, which measured 20 x 10 cm, 10 x 5 cm, and 7 x 5 cm respectively on clinical examination, along with mild fever. There was no history of night sweats or weight loss. He had consumed homeopathic therapy for 10 days, followed by therapy for tuberculosis for the last 1.5 months. On examination, the liver and spleen were non-palpable. Positron emission tomography (PET) scan revealed an FDG avid (SUV max 23.97) conglomerate nodal mass in the (i) left cervical regions (level II-V), (ii) left axillary region, (iii) retroperitoneal nodal mass extending from the pelvic region to the right external iliac region, and (iv) bilateral inguinal nodes; measuring up to 7.7 x 5.5 cm. Erosion of the left third rib and left pleural infiltration were also identified. The working diagnosis was lymphoma.
The cervical lymph node's core biopsy histopathologic examination (HPE) showed multiple tissue cores infiltrated by medium to large-sized pleomorphic atypical cells with variable morphology admixed with small lymphocytes, histiocytes, and few plasma cells, neutrophils, occasional eosinophils and foamy macrophages. The cells demonstrated moderate atypia and ovoid folded to indented nuclei, fine chromatin, inconspicuous nucleoli and moderate cytoplasm. A fair number of the cells were large-sized with wreath-like nuclei and plasmacytoid appearance (Figures 1A, 1B, and 1C). Mitotic index was high (approximately 10-12/10HPF), including atypical mitosis. The differential diagnosis initially considered on HPE included anaplastic large cell lymphoma, diffuse large B cell lymphoma, metastatic carcinoma, myeloid sarcoma and blastic plasmacytoid dendritic cell neoplasm (BPDCN). On immunohistochemistry, the atypical cells were positive for LCA (weak) and negative for PanCK (AE1/AE3), CD20, CD3, CD5, CD8, CD30, ALK-1, CD43, CD2, CD7, CD68, SOX10 and PAX-5. CD4 staining in the atypical cells was diffuse and of strong intensity. At the same time, Ki-67 proliferative index revealed heterogeneous staining, being approximately 65-70% in the highest proliferative zone. LCA stained the remnant lymphocytes, CD20 and CD3 the B and T-lymphocytes among them, respectively, and CD68 the histiocytes. An unequivocal diagnosis could not be rendered at this moment and the possibilities proffered were BPDCN and myeloid sarcoma. The same was communicated to the attending clinician, and the case was discussed in the multidisciplinary tumor board. The moot point was the lack of handy markers such as CD123 and MPO (myeloperoxidase) on IHC, but fortunately, it was available on flow cytometry. A decision was taken to attempt flow cytometry on the material aspirated by fine-needle cytology from the suspicious lymph nodes.
Thus, fine needle aspiration cytology was performed from the left cervical lymph node mass, and smears were also prepared while subjecting the material to flow cytometry. The cellular smears revealed singly scattered and a few cohesive clusters of pleomorphic neoplastic cells, which were medium to large-sized, with a round to oval irregularly folded subcentric to eccentric vesicular nuclei and moderate to abundant cytoplasm, vacuolated at places. Prominent nuclear grooves were discerned in some of the cells. Many multinucleated giant cells containing wreath-like nuclei were evident, accompanied by increased phagocytic activity and marked cytologic atypia, especially in the cells seen in the clusters (Figure 1D). Cytologic diagnosis suggested neoplasm of histiocytic origin.
The histopathology slides were reviewed along with the IHC analysis. Careful and meticulous appraisal evinced nuclear grooves in the atypical cells and variable positivity of CD68 in the atypical cells, thus prompting the consideration of a histiocytic neoplasm, probably of Langerhans cell origin. Additional IHC was resorted to, which illustrated diffuse and strong positivity of the atypical cells for CD1a, S100, and langerin (CD207) and negativity for CD21 and CD23, thus confirming a Langerhans cell neoplasm (Figure 2, 3, and 4). Providing succor was also the flowcytometric finding of negativity of the atypical cells for CD123 and MPO.
However, the dilemma flummoxing the pathologist now was whether the lesion was a Langerhans cell sarcoma or Langerhans cell histiocytosis. In conjunction with the cytopathologic observations and in view of the moderate atypia, high mitotic, and proliferative indices, a final diagnosis of Langerhans cell histiocytosis progressing to Langerhans cell sarcoma was rendered. Molecular analysis, especially for BRAF V600E mutation, was not feasible. Chemotherapy was instituted, and the patient was treated with a combined regimen comprising ifosfamide, carboplatin, and etoposide. After 3 cycles of chemotherapy, the PET-CT scan showed decreased metabolic activity of the retroperitoneal and right inguinofemoral lymph nodes; however, new lesions were detected in the left pleural and right thigh region. Biopsy of the pleural lesion was performed, HPE of which revealed similar histopathologic features as mentioned above and IHC positivity for CD1a, thus reiterating the diagnosis of LCS. The chemotherapy was continued and, until the last follow-up, after having completed 6 cycles of the chemotherapy regimen, a significant reduction in disease activity has been documented.