BACKGROUND: SMARCA4 is a component gene of the SWI/SNF (SWItch/Sucrose NonFermentable) chromatin remodeling complex; undifferentiated tumors associated with its functional deletion have been described in several organs. However, no established treatment for these tumors currently exists.
METHODS: In this study, we report a case of a SMARCA4-deficient undifferentiated urothelial carcinoma with high PD-L1 expression that was effectively treated with nivolumab after early relapse following treatment for non-invasive bladder cancer. The histological morphology of the rhabdoid-like undifferentiated tumor of unknown primary led us to suspect a SWI/SNF-deficient tumor, and subsequent immunostaining led to the diagnosis of a SMARCA4-deficient undifferentiated tumor. This effort also led to the identification of the developmental origin of this SMARCA4-deficient undifferentiated tumor as a non-invasive bladder cancer. We also carried out a detailed immune phenotypic assay on peripheral T cells. In brief, a phenotypic change of CD8+T cells from naive to terminally differentiated effector memory cells was observed.
CONCLUSIONS: Regardless of the organ of cancer origin or cancer type, SWI/SNF-deficient tumors should be suspected in undifferentiated and dedifferentiated tumors, and immune checkpoint inhibitors may be considered as a promising treatment option for this type of tumor. The pathogenesis of SMARCA4-deficient anaplastic tumors awaits further elucidation for therapeutic development.

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BACKGROUND: Cancer-related thrombotic microangiopathy (CR-TMA) is a rare type of Coombs-negative hemolytic anemia, which is caused by malignancy and has a poor prognosis.
METHODS: A 76-year-old female was referred to our hospital due to Coombs-negative hemolytic anemia, which was causing fatigue and dyspnea on exertion, accompanied by schistocytosis. A bone marrow examination demonstrated bone marrow carcinomatosis, and the tumor cells were morphologically suspected to be signet-ring cell carcinoma cells. As we failed to find the primary tumor site before the patient died, she was diagnosed with CR-TMA due to bone marrow carcinomatosis of unknown primary origin. Thrombotic thrombocytopenic purpura (TTP) was rapidly ruled out based on her PLASMIC score. In addition, immunohistochemical staining of a clot section of the bone marrow and tumor marker data were useful for narrowing down the likely primary tumor site.
CONCLUSIONS: Although CR-TMA is an extremely rare phenomenon, clinicians who suspect CR-TMA should quickly rule out TTP and decide whether to provide appropriate chemotherapy or plan for palliative care.

Intrahepatic cholangiocarcinoma (iCCA) with regional lymph node metastases, which lacks a well-delineated liver mass, may be misdiagnosed as a carcinoma of unknown primary (CUP) origin. The present study reports the case of a 69-year-old man initially diagnosed with CUP, who was incidentally found to have abdominal lymphadenopathy during ultrasonography (US). The clinical course from the time of lymphadenectomy and CUP diagnosis to iCCA detection after long-term follow-up is reported. A patient with a history of hypertensive renal disease presented with an incidental finding of enlarged abdominal lymph nodes in the perihepatic region on US. Abdominal contrast-enhanced computed tomography (CT) scan and magnetic resonance imaging (MRI) revealed two enlarged lymph nodes in the hepatoduodenal ligament. Exploratory laparotomy and lymphadenectomy were performed for diagnostic and therapeutic purposes, respectively. Poorly differentiated metastatic adenocarcinoma positive for cytokeratin 7 and negative for cytokeratin 20 was identified in two of the 22 lymph nodes. Postoperatively, a positron emission tomography/CT (PET/CT) scan was performed, which failed to locate the primary site. The diagnosis of CUP was confirmed based on clinical, radiological and histopathological characteristics. A sequential abdominal CT scan 48 months after lymphadenectomy revealed a faintly enhancing, intraductal polypoid mass with localized ductal dilatation in liver segment 3. MRI and PET/CT confirmed a mass in the left lobe of the liver. US-guided percutaneous needle biopsy confirmed the presence of moderately differentiated adenocarcinoma. The patient refused surgical treatment because of general weakness caused by Coronavirus disease 2019 infection. The patient received radical radiotherapy and underwent left hepatectomy after recovery of their performance status. Histopathological examination of the surgical specimen demonstrated prevailing fibrosis and mucin accumulation, with scattered cancer cells observed focally in the resected liver specimen owing to the effect of the radiotherapy. Consequently, a definitive diagnosis of primary adenocarcinoma of the intrahepatic bile duct was confirmed. The present report may improve understanding of the pathophysiology and clinical progression of iCCA, with a specific focus on the intraductal growth subtype.

We present a very rare case of spontaneous hemothorax which was caused by carcinoma of unknown primary. To the best of our knowledge, there are no other such cases reported worldwide. The patient was 72-year-old male who was referred to our department for massive hemothorax. We undertook surgical treatment for haemostasis, and found multiple tumours which led to the diagnosis of carcinoma of unknown primary as the cause of haemorrhage. The tumours increased and grew rapidly after surgery and hemothorax progressed despite our treatment. The patient died from disseminated intravascular coagulation caused by continuous bleeding on postoperative day 19.

We reported a female presented with an initial diagnosis of metastatic axillary lymph-node carcinoma that comprehensive assessments revealed a definitive diagnosis of high-grade serous ovarian carcinoma as the primary tumor.

BACKGROUND: Accessory breast (AB) is extra and ectopic breast tissue. Fibroadenoma (FA) in AB is a rare finding. This study aims to present a case of FA in axillary AB mimicking carcinoma of unknown primary (CUP).
METHODS: A 38-year-old female presented with a mass in her right axilla. She had a mass in her right breast for 5 years. She previously had a left breast lumpectomy for a benign condition. The lump in her axilla was palpable and hard. Ultrasound showed an oval lymph node in the level I axilla (12*6mm) with blurred and unclear fatty hilum, suspicious for malignancy. Magnetic resonance imaging revealed an oval lesion (12*7mm) in the level I axilla with no fatty hilum and with heterogeneous enhancements, suggesting abnormal nodes. Fine needle aspiration of the axillary mass suspected CUP. But core biopsy resembled FA. Both masses in the right axilla and breast were surgically excised. Histopathology confirmed FA in both masses.
CONCLUSIONS: Although pathologies in AB are uncommon, it is still susceptible to the same malignant and benign transformations that are found in normal breasts. The axilla is the most frequent location for FA in AB and often affects young women. Imaging techniques can be inconclusive and only histopathology can conclude a definitive diagnosis.
CONCLUSIONS: FA in axillary AB is a rare condition that causes a diagnostic dilemma as it can be mistaken for other benign or malignant pathologies.

Gene alteration in anaplastic lymphoma kinase (ALK) is rare, and the efficacy of ALK inhibitors in the treatment of carcinoma of unknown primary (CUP) with ALK alteration remains unclear. The patient was a 56-year-old woman who presented with cervical lymph node swelling. Computed tomography revealed paraaortic, perigastric, and cervical lymph node swelling; ascites; a liver lesion; and a left adrenal mass. A cervical lymph node biopsy was performed, and pathological diagnosis of an undifferentiated malignant tumor was conducted. Finally, the patient was diagnosed with CUP and treated with chemotherapy. To evaluate actionable mutations, we performed a multigene analysis, using a next-generation sequencer (FoundationOne® CDx). It revealed that the tumor harbored an echinoderm microtubule-associated protein-like 4 (EML4) and ALK fusion gene. Additionally, immunohistochemistry confirmed ALK protein expression. Alectinib, a potent ALK inhibitor, was recommended for the patient at a molecular oncology conference at our institution. Accordingly, alectinib (600 mg/day) was administered, and the multiple lesions and symptoms rapidly diminished without apparent toxicity. The administration of alectinib continued for a period of 10 months without disease progression. Thus, ALK-tyrosine kinase inhibitors should be considered in patients with CUP harboring the EML4-ALK fusion gene.

We report a case of synchronous high-grade cervical intraepithelial neoplasia (CIN) and metastatic squamous cell carcinomas (SCCs) of unknown primary in the rectum. A 74-year-old woman was diagnosed with CIN3 by biopsy of the uterine cervix. Magnetic resonance imaging showed two masses in the outer rectal wall. They were diagnosed as SCCs by transrectal biopsy from one mass. On surgical treatment, CIN3 and SCCs in the rectum were identified, respectively. Pathological analysis revealed that SCCs were observed in serosa of the rectum, not mucosa, indicating that these tumors were metastatic SCCs. Gene analysis showed HPV31-positive and TP53 mutation in CIN3, and HPV16-positive in rectal SCCs. Pretreatment examination did not detect the primary site of metastatic SCCs in the rectum. We diagnosed the patient with synchronous CIN3 and metastatic SCCs of unknown primary in the rectum. In this case, gene analysis was useful to clarify the relationship between CIN3 and SCCs.

The term carcinoma of unknown primary (CUP) refers to a malignant tumor whose histology suggests strongly that it is a metastasis, yet the primary lesion is unknown despite sufficient whole body evaluation at the time of examination. CUP has similar incidences in men and women and the average age at diagnosis is 60 years. While its overall incidence varies depending on the report, it generally accounts for 1-5% of all cancers. Thus, it is rare. We encountered a case of squamous cell carcinoma of the inguinal region that seemed to be a metastasis and for which we could not find the primary lesion. This case is reported here along with a literature review on CUP to increase awareness of this rare lesion.