UNASSIGNED: Neuroendocrine transdifferentiation refers to the progressive transformation of a nonneuroendocrine tumor to the one showing evidence of neuroendocrine differentiation on morphological and immunohistochemical grounds. Although this phenomenon has been well-documented in certain malignancies, particularly prostatic adenocarcinoma after androgen deprivation, cases of neuroendocrine transdifferentiation in melanomas are exceptionally rare. Herein, we report a case of a conventional superficial spreading melanoma occurring on the skin of the leg in a young male which showed progressive neuroendocrine transdifferentiation as it progressed through 2 in-transit metastases and a nodal metastatic deposit over a 4-year period. The tumor retained the BRAF V600E mutation throughout the disease process, and disease control was achieved through dual BRAF inhibition therapy. The possibility of melanoma masquerading as a high-grade neuroendocrine malignancy when investigating tumors of unknown primary should be kept in the mind of clinicians and histopathologist alike as a potential diagnostic pitfall, thus helping avoid misdiagnosis and guide appropriate treatment strategies.

Transdifferentiation of follicular lymphoma to a Langerhans cell neoplasm is rarely reported and not well understood. Here we present a case, review the literature and discuss some of the biological underpinnings of lineage switch of B cells to histiocytes/Langerhans cells. A 31-year-old woman had follicular lymphoma (FL) and Langerhans cell sarcoma (LCS) co-localized above and below diaphragm. The FL was low-grade, had typical morphologic features, and was positive for CD10, BCL-2, and BCL-6. The LCS was cytologically atypical with necrosis and a high mitotic rate, and the immunophenotype supported Langerhans cell lineage positive for CD1a, CD207/langerin, and S-100 protein. Both tumors carried IGH-BCL2 and the LCS cells had immunophenotypic evidence of a residual B cell program, supporting the notion that these neoplasms are clonally related. The case reported is unusual because the patient was young and both diseases presented simultaneously, before any therapy. In addition, immunohistochemical analysis showed that the LCS was negative for BRAF V600E and phospho-ERK, suggesting that the LCS belongs to the known subset of Langerhans cell tumors lacking BRAF V600E and MAP2K1 mutations. Concurrent occurrence of FL and Langerhans cell neoplasm is an unusual phenomenon, with 10 cases reported previously: 4 Langerhans cell histiocytosis and 6 Langerhans cell sarcoma, including this case.

Here, we report the case of a 54-year-old man with a history of squamous cell carcinoma (SCC) of the lung, who developed bilateral neuroendocrine carcinoma (NEC) of the palatine tonsils. Faced with this atypical situation, another biopsy of the lung lesion was performed, revealing NEC histology patterns. This article describes the first case of metastasis to the bilateral palatine tonsils from the NEC component of a mixed NEC/SCC of the lung, highlighting the importance of reconsidering the diagnosis of the primary tumor histology, particularly in lung cancer with the possible presence of mixed tumor after phenotype transdifferentiation of the primary tumor. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Mixed lung carcinoma can be revealed after the presence of neuroendocrine carcinoma metastasis. WHAT THIS STUDY ADDS: Bilateral neuroendocrine carcinoma of the palatine tonsils should be considered as metastases, particularly in the presence of lung cancer with a poor response to treatment.

Histiocytic sarcoma (HS) is a rare aggressive hematologic neoplasm that can be associated with low-grade B cell lymphoma. The development of both neoplasms is currently being considered a transdifferentiation mechanism but remains elusive. We report the case of a 65-year-old patient with synchronous development of peritoneal/abdominal HS and grade 1-2 follicular lymphoma (FL). Cytogenetic analysis and targeted next-generation sequencing of both FL and HS tumors identified common genomic alterations such as IGH-BCL2 rearrangement, CREBBP and KMT2D, and aberrations of chromosomes 9q and 19q. However, only the HS tumor had a KRAS mutation while the lymph node involved by FL harbored a TNFAIP3 mutation and both tumors also showed distinct chromosomal alterations. This report strengthens the hypothesis of a common lymphoid progenitor which accumulates genetic alterations leading to two different hematologic malignant diseases with significantly distinct prognoses.

Malignant melanoma is notorious for its remarkable morphological variation and aberrant histopathological patterns. However, melanoma with prominent cartilaginous transdifferentiation simulating chondrosarcoma is extremely rare. A 75-year-old male developed a swelling in his left inguinal region and was diagnosed with a metastatic melanoma, which was found to harbor a BRAF V600E mutation. Later on, the left inguinal lymph node was excised and immunohistochemistry done on the specimen revealed an undifferentiated component negative for S-100 protein, HMB-45 and Melan-A and a cartilaginous component positive for S-100 protein and diffusely positive for BRAF V600E mutation. To our knowledge, there are around 14 cases reported in the literature of malignant melanoma with pure cartilaginous transdifferentiation. In all cases, immunohistochemistry of the cartilaginous component was positive for S-100, which is not an indicator of melanoma because cartilage expresses S-100. BRAF mutational studies support that the tumor arose from a common melanoma cell that harbored the mutation and subsequently transdifferentiated. This case illustrates the importance of an accurate and thorough clinical assessment when it comes to the diagnosis of melanomas as they are notable for their impressive degree of morphologic variability. Moreover, this report helps shed light on the use of immunohistochemical analysis to reach a definitive diagnosis.

Transdifferentiation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) has been reported mostly in adenocarcinomas and has been described as a cause of acquired tyrosine kinase inhibitor (TKI) resistance. However, transdifferentiation has also been described in patients with different histologic characteristics and patients not exposed to TKIs and with no epidermal growth factor receptor (EGFR) mutation (the target of TKIs). To this date transdifferentiation remains poorly understood. We conducted a retrospective case series of patients who had biopsy-proven SCLC within 2 years after a diagnosis of NSCLC or in the same location as the known primary NSCLC. We found that 0.2% of lung cancer patients at our institution experienced transdifferentiation. Among these, 30 had adenocarcinoma and 16 had squamous cell carcinoma. In 27 of the 30 patients with adenocarcinoma (90%), SCLC was found in the same location as the known primary. In 14 of the 30 patients (47%), SCLC occurred within 2 years after the NSCLC diagnosis. In 12 of the 16 patients with squamous cell carcinoma (75%), SCLC was found in the same location as the known primary. In 8 of these 16 patients (50%), SCLC occurred within 2 years after the NSCLC diagnosis. Few patients with adenocarcinoma and none with squamous cell carcinoma were treated with TKIs or had an EGFR mutation. In conclusion the findings in the current study suggest that the discovery of SCLC histology after treatment of NSCLC may be more common than thought suggesting that further study is warranted to evaluate the phenomenon of transdifferentiation.

Chronic injury and inflammation in the esophagus can cause a change in cellular differentiation known as metaplasia. Most commonly, the differentiation changes manifest as Barrett\'s esophagus (BE), characterized by the normal stratified squamous epithelium converting into a cuboidal-columnar, glandular morphology. BE cells can phenotypically resemble specific normal cell types of the stomach or intestine, or they can have overlapping phenotypes in disorganized admixtures. The stomach can also undergo metaplasia characterized by aberrant gastric or intestinal differentiation patterns. In both organs, it has been argued that metaplasia may represent a recapitulation of the embryonic or juvenile gastrointestinal tract, as cells access a developmental progenitor genetic program that can help repair damaged tissue. Here, we review the normal development of esophagus and stomach, and describe how BE represents an intermixing of cells resembling gastric pseudopyloric (SPEM) and intestinal metaplasia. We discuss a cellular process recently termed \"paligenosis\" that governs how mature, differentiated cells can revert to a proliferating progenitor state in metaplasia. We discuss the \"Cyclical Hit\" theory in which paligenosis might be involved in the increased risk of metaplasia for progression to cancer. However, somatic mutations might occur in proliferative phases and then be warehoused upon redifferentiation. Through years of chronic injury and many rounds of paligenosis and dedifferentiation, eventually a cell with a mutation that prevents dedifferentiation may arise and clonally expand fueling stable metaplasia and potentially thereafter acquiring additional mutations and progressing to dysplasia and cancer.

Primary pancreatic leiomyosarcoma is a rare pancreatic malignancy; the clinical presentation and treatment is not well-characterized. Further, the molecular mechanisms underlying its pathogenesis are not known. We report a patient with pancreatic stromal tumor that progressed to primary pancreatic leiomyosarcoma with hepatic and peritoneal metastases.
A 54-year-old woman was found to have pancreatic and hepatic tumor masses on routine health checkup. Owing to the difficulty in performing biopsy, this patient underwent open operation. Histopathological examination of pancreatic and liver biopsy specimen demonstrated spindle cells with nuclear mitoses. Immunohistochemical examination showed positive staining for Cluster of Differentiation117 (+) and negative staining for S-100 (-) and Smooth Muscle Actin (-). Thus, the patient was diagnosed as a case of advanced pancreatic stromal tumor with liver metastases. After surgery, treatment with oral imatinib mesylate combined with thymosin injection therapy was prescribed. Follow-up examination at 13-months revealed multiple nodular masses in liver and right peritoneum. The patient underwent a second surgery. Liver biopsy and the resected peritoneal specimen showed positive staining for Discovered On Gastrointestinal tumor-1(weak +), Actin (+), Smooth Muscle Actin (+) and negative staining for Cluster of Differentiation117 (-) Cluster of Differentiation34 (-) and S-100 (-). Histopathological examination showed spindle cells with nuclear mitoses. The final diagnosis was primary pancreatic leiomyosarcoma, transdifferentiating from pancreatic stromal tumor, with liver and peritoneal metastases.
Surgery is the first line treatment for primary pancreatic leiomyosarcoma and extra-gastrointestinal stromal tumors. In the present case, radical resection was not performed owing to hepatic metastases. Palliative treatment with radioactive 125I ion implantation and microwave coagulation therapy was administered. However, the long-term therapeutic effect needs to be assessed in future.

Histiocytic sarcoma (HS) is a rare malignant tumor, and in extraordinary circumstances it can be transdifferentiated from a low-grade B-cell lymphoma. In our report, a 62-year-old female was initially diagnosed with a low-grade follicular lymphoma, and 2 years later she presented with bilateral lung masses and lymphadenopathy. Fine needle aspiration (FNA) of the lung masses revealed solid nests of large pleomorphic epithelioid cells. By immunohistochemical studies, the tumor cells were positive for histiocytic markers (CD68 and CD163) and S100, supporting a diagnosis of HS with dendritic cell differentiation. Further fluorescence in situ hybridization (FISH) analyses detected IGH@/BCL2 rearrangement in both the previous follicular lymphoma and the current HS, which was highly suggestive of the clonal relationship between these two tumors. To the best of our knowledge, this is the first case of transformation of follicular lymphoma into HS diagnosed by FNA of lung masses.

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