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.

Transoral Robotic Surgery (TORS) is utilized for treating various malignancies, such as early-stage oropharyngeal cancer and lymph node metastasis of an unknown primary tumor (CUP), and also benign conditions, like obstructive sleep apnea (OSA) and chronic lingual tonsillitis. However, the success and failure of TORS have not been analyzed to date. In this retrospective observational multicenter cohort study, we evaluated patients treated with TORS using the da Vinci surgical system. Success criteria were defined as identification of the primary tumor for CUP, >2 mm resection margin for malignant conditions, and improvement on respiratory polygraphy and tonsillitis complaints for benign conditions. A total of 220 interventions in 211 patients were included. We identified predictors of success, such as low comorbidity status ACE-27, positive P16 status, and lower age for CUP, and female gender and OSA severity for benign conditions. For other malignancies, no predictors for success were found. Predictors of failure based on postoperative complications included high comorbidity scores (ASA) and anticoagulant use, and for postoperative pain, younger age and female gender were identified. This study provides valuable insights into the outcomes and predictors of success and failure in TORS procedures across various conditions and may also help in patient selection and counseling.

The detection of the primary site in Carcinoma of Unknown Primary (CUP) is a challenging task which can significantly alter the course of management and also prognosis. Various modalities have been assessed with varying sensitivity and specificity. Imaging and cytological diagnosis have formed a key part of the diagnostic algorithm of CUP. Trans Oral Robotic Surgery offers the advantage of being both diagnostic as well as therapeutic with promising sensitivity and specificity and can form an integral part in the management of CUP. A prospective study was carried out at a tertiary care centre over a period of one year. Patients with unilateral neck swelling which was histopathologically proven squamous cell carcinoma neck metastasis were included in the study. They were evaluated with endoscopy and radiology according to the standard algorithm. When these failed to detect the primary, the patients underwent ipsilateral radical tonsillectomy and tongue base mucosal wedge biopsy via TORS. Post-operative histopathological examination was done on the resected specimens to detect the primary site. Transoral Robotic Surgery was able to localise primary in 50% of the patients enrolled in the study. Out of the primary site identified by TORS; 55.56% were located in the tonsil and 44.4% in the tongue base. TORS can offer promising detection rates of the occult primary in CUP and should form an integral part of the diagnostic algorithm.

BACKGROUND: Metastatic carcinoma of unknown primary origin to the head and neck lymph nodes (HNCUP) engenders unique diagnostic considerations. In many cases, the detection of a high-risk human papillomavirus (HR-HPV) unearths an occult oropharyngeal squamous cell carcinoma (SCC). In metastatic HR-HPV-independent carcinomas, other primary sites should be considered, including cutaneous malignancies that can mimic HR-HPV-associated SCC. In this context, ultraviolet (UV) signature mutations, defined as ≥ 60% C→T substitutions with ≥ 5% CC→TT substitutions at dipyrimidine sites, identified in tumors arising on sun exposed areas, are an attractive and underused tool in the setting of metastatic HNCUP.
METHODS: A retrospective review of institutional records focused on cases of HR-HPV negative HNCUP was conducted. All cases were subjected to next generation sequencing analysis to assess UV signature mutations.
RESULTS: We identified 14 HR-HPV negative metastatic HNCUP to either the cervical or parotid gland lymph nodes, of which, 11 (11/14, 79%) had UV signature mutations, including 4 (4/10, 40%) p16 positive cases. All UV signature mutation positive cases had at least one significant TP53 mutation and greater than 20 unique gene mutations.
CONCLUSIONS: The management of metastatic cutaneous carcinomas significantly differs from other HNCUP especially metastatic HR-HPV-associated SCC; therefore, the observation of a high percentage of C→T with CC →TT substitutions should be routinely incorporated in next generation sequencing reports of HNCUP. UV mutational signatures testing is a robust diagnostic tool that can be utilized in daily clinical practice.

Distinguishing primary liver cancer (PLC), namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), from liver metastases is of crucial clinical importance. Histopathology remains the gold standard, but differential diagnosis may be challenging. While absent in most epithelial, the expression of the adherens junction glycoprotein N-cadherin is commonly restricted to neural and mesenchymal cells, or carcinoma cells that undergo the phenomenon of epithelial-to-mesenchymal transition (EMT). However, we recently established N- and E-cadherin expression as hallmarks of normal hepatocytes and cholangiocytes, which are also preserved in HCC and iCCA. Therefore, we hypothesized that E- and/or N-cadherin may distinguish between carcinoma derived from the liver vs carcinoma of other origins. We comprehensively evaluated E- and N-cadherin in 3359 different tumors in a multicenter study using immunohistochemistry and compared our results with previously published 882 cases of PLC, including 570 HCC and 312 iCCA. Most carcinomas showed strong positivity for E-cadherin. Strong N-cadherin positivity was present in HCC and iCCA. However, except for clear cell renal cell carcinoma (23.6% of cases) and thyroid cancer (29.2%), N-cadherin was only in some instances faintly expressed in adenocarcinomas of the gastrointestinal tract (0%-0.5%), lung (7.1%), pancreas (3.9%), gynecological organs (0%-7.4%), breast (2.2%) as well as in urothelial (9.4%) and squamous cell carcinoma (0%-5.6%). As expected, N-cadherin was detected in neuroendocrine tumors (25%-75%), malignant melanoma (46.2%) and malignant mesothelioma (41%). In conclusion, N-cadherin is a useful marker for the distinction of PLC vs liver metastases of extrahepatic carcinomas (P < .01).

BACKGROUND: The term metastatic carcinoma to cervical lymph nodes from an unknown primary includes a small group of tumors that present themselves with metastases to the cervical nodes, and in which diagnostic methods do not reveal the primary source of these metastases. Histologically, in most cases, these are metastases of squamous cell carcinoma. Carcinomas of unknown primary metastatic to cervical nodes account for < 5% of carcinomas of unknown primary and < 5% of head and neck cancers. The optimal treatment has not yet been defined. In the absence of distant metastases, the intention of treatment is curative. Patients are treated mostly with combined approaches including surgery, radiotherapy, or concomitant chemoradiotherapy. Radiotherapy is part of the treatment algorithm in most of the referenced works and includes irradiation of the mucosal sites of the pharyngeal axis as a potential localization of the primary tumor and unilateral or, more often, bilateral irradiation of the neck. Due to the higher risk of late toxicities observed, individualization of irradiated volumes based on the extent of the disease or other clinical parameters is a rational way to reduce these risks.  Purpose: The presented work discusses the treatment options for patients with metastatic carcinoma to cervical lymph nodes from an unknown primary. Furthermore, the work reports on the high effectiveness of curative radiotherapy in this group of tumors.

Primary retroperitoneal carcinomas are very rare tumors. Their pathogenesis remains unknown but may be associated with that of ovarian carcinomas, considering the similarity in morphology and gender preference. Although metaplasia of coelomic epithelium is the most widely accepted theory, the pathogenesis of retroperitoneal carcinomas may differ by histologic subtype, like ovarian carcinomas. Mucinous carcinoma, which develops in both women and men, may originate in both primordial germ cells and Walthard cell nests that may be derived from the fallopian tube. Serous carcinomas may be associated with endosalpingiosis, the presence of fallopian tube-like epithelium outside the fallopian tube, and a remnant Müllerian tract. Endometrioid and clear cell carcinomas appear to be associated with extraovarian endometriosis. Additionally, both carcinomas in the retroperitoneal lymph nodes may be metastatic diseases from endometrial and/or renal cell cancer that regress spontaneously (carcinoma of unknown primary). Retroperitoneal carcinomas are difficult to diagnose, as they have no characteristic symptoms and signs. Surgery is the cornerstone of treatment, but the necessity of chemotherapy may depend on histological subtype. Further studies are necessary, in particular studies on endosalpingiosis, as endosalpingiosis is a poorly understood condition, although it is associated with the development of both serous and mucinous carcinomas.

OBJECTIVE: Carcinoma of unknown primary (CUP) poses a formidable diagnostic challenge, characterised by high mortality rates and an elusive primary tumour site. While Positron emission tomography (PET) scans are routinely employed in the initial evaluation of CUP patients, identifying the primary tumour remains an ongoing struggle. In light of this, the aim of this case report is to introduce a novel radiological description, termed the \'Starburst\' sign, derived from distinctive PET scan appearances associated with CUP.
METHODS: In this report, we present the case of a 47-year-old female patient who presented with abdominal symptoms. Upon investigation, extensive peritoneal disease was observed, yet the primary tumour source remained unidentified. Despite further diagnostic efforts, including a normal gastroscopy, a PET scan was able to confirm the presence of high-volume metastatic disease, without an identifiable primary tumour. Palliative treatment was initiated, but unfortunately, the patient\'s condition deteriorated rapidly, leading to her demise.
CONCLUSIONS: The \'Starburst\' sign, a unique radiological description of CUP in PET scans, has significant potential in advancing our understanding of the disease. It provides a visual analogy to a dying star, aiding comprehension of complex pathophysiology and implications of metastatic lesions. The introduction of the \'Starburst\' sign benefits patients and healthcare professionals, enhancing education, assessment, and treatment of CUP. This novel description contributes to knowledge in the field and can impact clinical management.

Carcinoma of unknown primary (CUP) is a heterogeneous group of metastatic cancers in which the site of origin is not identifiable. These carcinomas have a poor outcome due to their late presentation with metastatic disease, difficulty in identifying the origin and delay in treatment. The aim of the pathologist is to broadly classify and subtype the cancer and, where possible, to confirm the likely primary site as this information best predicts patient outcome and guides treatment. In this review, we provide histopathologists with diagnostic practice points which contribute to identifying the primary origin in such cases. We present the current clinical evaluation and management from the point of view of the oncologist. We discuss the role of the pathologist in the diagnostic pathway including the control of pre-analytical conditions, assessment of sample adequacy, diagnosis of cancer including diagnostic pitfalls, and evaluation of prognostic and predictive markers. An integrated diagnostic report is ideal in cases of CUP, with results discussed at a forum such as a molecular tumour board and matched with targeted treatment. This highly specialized evolving area ultimately leads to personalized oncology and potentially improved outcomes for patients.

Bone marrow (BM) is one of the rare but important site of metastasis of solid tumors. The key steps of metastasis include invasion, intravasation, circulation, extravasation, and colonization. Tumor cells may express some adhesion molecules that promote the transmigration to the marrow space and link them to the marrow stroma with subsequent engraftment. It is important to detect the bone marrow metastasis for initial clinical staging, therapeutic selection, prognostic risk stratification, assessment of response to therapy and predicting relapse. Prognosis of non-hematopoietic malignancies with BM metastasis is dismal. Due to occulting and atypical clinical manifestations, bone marrow metastases can be easily missed or misdiagnosed, leading to higher mortality rates. The important factors on which the prognosis of patients with bone marrow metastases depends are primary tumor site, performance status, platelet count, and therapeutic regimens (systemic chemotherapy or palliative/supportive care). Further, in cases with BM metastasis with unknown primary sites, misdiagnosis can lead to delayed initiation of therapy and increased mortality. BM metastasis is seen in less than 10% of patients with metastatic cancer and is common in lung, breast or prostate carcinoma. Bone marrow metastasis can be presented as the initial presentation with hematological changes and may be misdiagnosed as a primary haematopoietic disorder. Leucoerythoblastic blood picture is the most common peripheral blood smear finding indicating BM metastasis, may be an indicator of associated BM fibrosis. Bone marrow aspiration and biopsy with immunohistochemistry (IHC) is an easy, cost effective and gold standard method of detection of BM metastasis. BM biopsy is superior to bone marrow aspirate for detection of metastasis. Morphology of metastatic cells is as per the primary site of tumor. Immunohistochemistry is a useful adjunct to morphology in reaching a definitive diagnosis even in case with carcinoma unknown primary (CUP) and also in diagnosing case of unsuspected malignancies. Though bone marrow is not among the most common site of involvement in CUP, which are liver, bone, lymph nodes and lung. But BM, if involved, the site of origin is determined using the immunohistochemistry panel applied to the metastatic deposits based on the morphology The aim of the review is to discuss the hematological findings of non-haematopoietic malignancies metastasizing to the bone marrow, emphasizing on histomorphology with IHC and its significance in establishing primary diagnosis in clinically unsuspected cases.