Aberrant SWI/SNF Complex Members Are Predominant in Rare Ovarian Malignancies-Therapeutic Vulnerabilities in Treatment-Resistant Subtypes.

SWI/SNF (SWItch/Sucrose Non-Fermentable) is the most frequently mutated chromatin-remodelling complex in human malignancy, with over 20% of tumours having a mutation in a SWI/SNF complex member. Mutations in specific SWI/SNF complex members are characteristic of rare chemoresistant ovarian cancer histopathological subtypes. Somatic mutations in ARID1A, encoding one of the mutually exclusive DNA-binding subunits of SWI/SNF, occur in 42-67% of ovarian clear cell carcinomas (OCCC). The concomitant somatic or germline mutation and epigenetic silencing of the mutually exclusive ATPase subunits SMARCA4 and SMARCA2, respectively, occurs in Small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), with SMARCA4 mutation reported in 69-100% of SCCOHT cases and SMARCA2 silencing seen 86-100% of the time. Somatic ARID1A mutations also occur in endometrioid ovarian cancer (EnOC), as well as in the chronic benign condition endometriosis, possibly as precursors to the development of the endometriosis-associated cancers OCCC and EnOC. Mutation of the ARID1A paralogue ARID1B can also occur in both OCCC and SCCOHT. Mutations in other SWI/SNF complex members, including SMARCA2, SMARCB1 and SMARCC1, occur rarely in either OCCC or SCCOHT. Abrogated SWI/SNF raises opportunities for pharmacological inhibition, including the use of DNA damage repair inhibitors, kinase and epigenetic inhibitors, as well as immune checkpoint blockade.

The expression of YAP1 and other transcription factors contributes to lineage plasticity in combined small cell lung carcinoma.

Lineage plasticity in small cell lung carcinoma (SCLC) causes therapeutic difficulties. This study aimed to investigate the pathological findings of plasticity in SCLC, focusing on combined SCLC, and elucidate the involvement of YAP1 and other transcription factors. We analysed 100 surgically resected SCLCs through detailed morphological observations and immunohistochemistry for YAP1 and other transcription factors. Component-by-component next-generation sequencing (n = 15 pairs) and immunohistochemistry (n = 35 pairs) were performed on the combined SCLCs. Compared with pure SCLCs (n = 65), combined SCLCs (n = 35) showed a significantly larger size, higher expression of NEUROD1, and higher frequency of double-positive transcription factors (p = 0.0009, 0.04, and 0.019, respectively). Notably, 34% of the combined SCLCs showed morphological mosaic patterns with unclear boundaries between the SCLC and its partner. Combined SCLCs not only had unique histotypes as partners but also represented different lineage plasticity within the partner. NEUROD1-dominant combined SCLCs had a significantly higher proportion of adenocarcinomas as partners, whereas POU2F3-dominant combined SCLCs had a significantly higher proportion of squamous cell carcinomas as partners (p = 0.006 and p = 0.0006, respectively). YAP1 expression in SCLC components was found in 80% of combined SCLCs and 62% of pure SCLCs, often showing mosaic-like expression. Among the combined SCLCs with component-specific analysis, the identical TP53 mutation was found in 10 pairs, and the identical Rb1 abnormality was found in 2 pairs. On immunohistochemistry, the same abnormal p53 pattern was found in 34 pairs, and Rb1 loss was found in 24 pairs. In conclusion, combined SCLC shows a variety of pathological plasticity. Although combined SCLC is more plastic than pure SCLC, pure SCLC is also a phenotypically plastic tumour. The morphological mosaic pattern and YAP1 mosaic-like expression may represent ongoing lineage plasticity. This study also identified the relationship between transcription factors and partners in combined SCLC. Transcription factors may be involved in differentiating specific cell lineages beyond just 'neuroendocrine'.

The rare case of synchronous bilateral breast metastasis from a lung neuroendocrine tumor (small cell lung carcinoma): a case report and literature review.

BACKGROUND: Breast metastasis from small cell neuroendocrine carcinoma (SNEC) is very rare. In the present report, we describe a case of a female patient who was initially diagnosed with triple negative primary bilateral breast cancer, but during systemic examination, the diagnosis was bilateral breast metastasis from SNEC. CASE PRESENTATION: A 62-year-old woman with no history of smoking presented to the Department of General Medicine with left-sided chest pain, and computed tomography revealed masses in both breasts and left pleural thickening that was further confirmed by mammography and ultrasound of the breasts. A needle biopsy was performed, and triple negative primary bilateral breast cancer was diagnosed. Because progastrin-releasing peptide (ProGRP) 37,300 pg/ml (normal range, 0-81.0 pg/ml) and neuron-specific enolase 35.0 ng/ml (normal range, 0-16.3 ng/ml) levels were elevated, thoracoscopic biopsy was performed, and SNEC was diagnosed. Pathological examinations showed that the bilateral breast masses were also positive for immunohistochemical staining of chromogranin A, synaptophysin, and CD56, leading to a diagnosis of bilateral breast metastasis of neuroendocrine tumor. CONCLUSION: Although very rare, the possibility of breast metastasis should be considered when malignancy is suspected in other organs.

Unusual coexistence: A case of mixed small and large cell neuroendocrine tumor in a bladder previously affected by bilharzial cystitis.

Neuroendocrine tumors of the bladder are rare, accounting for less than 1% of all bladder tumors. Among these, large cell neuroendocrine carcinoma is an extremely uncommon subtype. We report on a histologically confirmed case of mixed both large and small cells neuroendocrine tumor of the bladder in a 64-year-old male with a history of bilharzial cystitis. The diagnosis was made after radical cystectomy with Immunohistochemical staining revealing positivity for synaptophysin, CD56, and AE1/3. While bilharzia is commonly linked to squamous cell carcinoma in the bladder, the potential relationship with neuroendocrine tumors is still relatively unexplored in this context. This case marks the first reported instance of the atypical coexistence of bilharzial cystitis and mixed large and small cell neuroendocrine carcinoma of the bladder. This unique case of coexisting highlights a rare phenomenon warranting further study. Similar associations have been documented in other organs, emphasizing the importance of exploring underlying mechanisms and clinical implications for improved patient care and outcomes.

First reported case of primary small cell cancer of the pancreas with positive TTF-1 tumor marker.

Small cell carcinomas are very aggressive malignancies that are most often linked with lung cancer, although they may also develop in the pancreas, colon, rectum, skin, and cervix. SCC of the pancreas accounts for about 1% of these neoplasms. An 88-year-old male with several comorbidities who presented with significant weight loss was diagnosed with metastatic pancreatic neuroendocrine carcinoma after complaining of persistent epistaxis and back pain. This case underscores the significance of using atypical tumor markers, such as thyroid transcription factor 1, to diagnose small-cell pancreatic cancer. It also emphasizes the importance of a multidisciplinary, patient-centered approach to managing these aggressive tumors.

Neuroendocrine neoplasms of the thymus.

Neuroendocrine neoplasms of the thymus (tNENs), including typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma, are rare tumors with scarce clinical and pathological data available in the literature. They share many common features with neuroendocrine neoplasms in other organs, such as those in the lungs, while demonstrating some distinct clinical and pathological features. This review aims to give an updated overview of each category of tNENs, focusing primarily on the pathologic diagnosis and differential diagnosis of these tumors.

Prognostic factors and treatment strategies of limited-stage primary esophageal small-cell carcinoma-a SEER database analysis.

Background: Primary esophageal small-cell carcinoma (PESC) is a rare tumor with poor efficacy, and there is currently no standardized treatment method. Our aim is to explore the prognostic factors and possible optimal treatment modalities for limited-stage PESC. Methods: We retrospectively searched the Surveillance, Epidemiology, and End Results (SEER) database from 1975 to 2019 for data of patients with limited-stage PESC. Kaplan-Meier method was used to plot survival curves, calculate survival rates, and Log-rank was used to test the differences among survival curves. Prognostic factors were explored through univariate and multivariate Cox regression survival analyses; Cox regression survival analysis was also conducted to analyze the risk of death among treatment groups and compare the survival differences among each treatment group. The non-single treatment (ST) group was defined as the comprehensive treatment (CT) group and it was compared against the ST group. Results: A total of 186 cases of limited-stage PESC were included in the study, there were differences in survival time among different groups due to differences in age, year, median household income, and N stage (P<0.001, P=0.041, P=0.002, P=0.001). The median overall survival (mOS) of the surgical group (19 months) was longer than that of the nonsurgical group (11 months) (P=0.01). The mOS of the chemotherapy group (16 months) was longer than that of the non-chemotherapy group (4 months) (P<0.001). The mOS of the radiotherapy group (16 months) was longer than that of the non-radiotherapy group (8 months) (P<0.001). Univariate analysis showed that age ≥80 years (P=0.006), year (1997-2007) (P=0.01), year (2008-2019) (P=0.01), N2 (P=0.003), surgery (P=0.02), radiotherapy (P<0.001), and chemotherapy (P<0.001) were prognostic factors affecting overall survival (OS) in limited-stage PESC patients. Multivariate analysis showed that SEER stage (P=0.02), age (P=0.007), radiotherapy (P<0.001), surgery (P=0.006), and chemotherapy (P<0.001) were independent prognostic factors affecting OS in patients of limited-stage PESC. Prognosis was better in the non-monotherapy group than in each monotherapy group. The CT group is superior to the ST group (P<0.001). The surgery combined with chemotherapy (SC) group had the longest mOS and the highest reduced risk of death, but there was no statistical difference. Conclusions: SEER stage, age, radiotherapy, chemotherapy, and surgery were independent prognostic factors in limited-stage patients; CT outperformed ST; the SC group had the longest median survival, but showed no statistical difference.

Assessing treatment effects with adjusted restricted mean time lost in observational competing risks data.

BACKGROUND: According to long-term follow-up data of malignant tumor patients, assessing treatment effects requires careful consideration of competing risks. The commonly used cause-specific hazard ratio (CHR) and sub-distribution hazard ratio (SHR) are relative indicators and may present challenges in terms of proportional hazards assumption and clinical interpretation. Recently, the restricted mean time lost (RMTL) has been recommended as a supplementary measure for better clinical interpretation. Moreover, for observational study data in epidemiological and clinical settings, due to the influence of confounding factors, covariate adjustment is crucial for determining the causal effect of treatment. METHODS: We construct an RMTL estimator after adjusting for covariates based on the inverse probability weighting method, and derive the variance to construct interval estimates based on the large sample properties. We use simulation studies to study the statistical performance of this estimator in various scenarios. In addition, we further consider the changes in treatment effects over time, constructing a dynamic RMTL difference curve and corresponding confidence bands for the curve. RESULTS: The simulation results demonstrate that the adjusted RMTL estimator exhibits smaller biases compared with unadjusted RMTL and provides robust interval estimates in all scenarios. This method was applied to a real-world cervical cancer patient data, revealing improvements in the prognosis of patients with small cell carcinoma of the cervix. The results showed that the protective effect of surgery was significant only in the first 20 months, but the long-term effect was not obvious. Radiotherapy significantly improved patient outcomes during the follow-up period from 17 to 57 months, while radiotherapy combined with chemotherapy significantly improved patient outcomes throughout the entire period. CONCLUSIONS: We propose the approach that is easy to interpret and implement for assessing treatment effects in observational competing risk data.

An autopsy case of lung adenocarcinoma with immune checkpoint inhibitor-induced pneumonia and fulminant myocarditis following pembrolizumab administration: a case report.

Immune checkpoint inhibitors (ICIs) are the current standard of care for non-small-cell lung cancer (NSCLC). Myocarditis is a rare but serious immune-related adverse event (irAE) associated with ICI therapy. We present a patient who received a single dose of pembrolizumab for NSCLC and developed ICI-associated pneumonia. Although pneumonia improved with corticosteroid therapy, the patient subsequently developed ICI-associated fulminant myocarditis. Despite high-dose corticosteroid therapy, the patient died on day 30 after pembrolizumab initiation. Even if an observed irAE was effectively treated, clinicians should remain vigilant for other irAEs, especially those that are difficult to control with low-dose corticosteroids.

Neoadjuvant chemoimmunotherapy for small cell carcinoma of the esophagus: Clinical efficacy and biomarker exploration.

Small cell carcinoma of the esophagus (SCCE) is a rare and highly malignant type of esophageal cancer with no standard treatment, facing challenges of resistance to conventional therapies. This study presents the cases of one extensive-stage and two limited-stage SCCE patients treated with chemoimmunotherapy. The two limited-stage patients underwent surgery post-treatment and experienced notable and enduring positive responses. This represents the first documented application of neoadjuvant chemoimmunotherapy in limited-stage SCCE patients. Additionally, comprehensive immunohistochemical analysis and whole exome sequencing were performed on the case patients. The findings revealed that infiltration of CD8+ T cells and PD-L1 expression in the SCCE tumor were key factors for favorable responses in SCCE patients receiving chemoimmunotherapy.

Gastrointestinal stromal tumor with small cell carcinoma infiltration: a case report.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive system. They usually occur in the gastrointestinal tract. However, we discovered a rare phenomenon in which small cell carcinoma infiltrated the GIST of a patient. The patient came to the hospital and presented with chest tightness and shortness of breath for 2 months and a dry cough for half a month. As the ancillary tests were refined, it was discovered that he also had a lesion in the pelvic cavity. After pathological examination of the core needle biopsy (CNB) samples from the pelvic cavity lesion, the patient was diagnosed with GIST with small cell carcinoma infiltration. The patient is currently receiving a chemotherapy regimen of etoposide combined with cisplatin.

ALK fusion small cell transformation of lung adenocarcinoma: A case report and literature review. / ALKèžåˆè‚ºè ºç™Œå°ç»†èƒžè½¬åŒ–1ä¾‹å¹¶æ–‡çŒ®å¤ä¹ .

Patients with anaplastic lymphoma kinase (ALK) fusion lung adenocarcinoma may develop drug resistance after treatment with ALK-tyrosine kinase inhibitor (ALK-TKI), and the mechanisms of this resistance are not yet fully defined. The Affiliated Hospital of Zunyi Medical University admitted a patient who was resistant to ALK fusion after ALK-TKI treatment, leading to disease progression and subsequent biopsy indicating a transformation to small cell lung cancer in September 2021. The patient, a 54-year-old female, initially presented with symptoms of cough, sputum production, and chest pain for 4 months. Chest CT showed a neoplastic lesion in the posterior segment of the right upper lobe to right lower lobe with obstructive pneumonia, metastasis in the right lower lobe, increased and enlarged mediastinal and right hilar lymph nodes, and thickening of the right hilar soft tissue. Bronchoscopy and pathological biopsy confirmed the diagnosis of lung adenocarcinoma. The results of next-generation sequencing indicated that echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) fusion is associated with tumor protein 53 (TP53) and retinoblastoma 1 (RB1) gene mutations. The patient received second-generation ALK-TKI aletinib, achieving a progression-free survival of 11 months before disease progression suggested aletinib resistance. Subsequently, the third-generation ALK-TKI lorlatinib administered for one month without efficacy, resulting in rapid systemic disease progression. The neuron specific enolase (NSE) was significantly increased, and the patient developed new pleural, pericardial, intracranial, liver, and multiple bone metastases occurred in a short period. A second biopsy indicated small cell lung cancer. Modification of treatment regimen to chemotherapy combined with immunotherapy proved effective. The mechanisms of drug resistance of ALK-TKI treatment for advanced non-small cell lung cancer with ALK fusion are complex, and small cell transformation of pathological type is one such mechanism, although rare. Concurrent TP53 and RB1 gene mutations may be characteristic of this transformation. Elevated NSE can serve as a predictive serum marker for adenocarcinoma transforming to small cell carcinoma. Timely re-biopsy and selection of subsequent treatments based on different resistance mechanisms are crucial for comprehensive disease management.

[Diagnosis and treatment of small-cell carcinoma of the prostate: A report of 2 cases].

OBJECTIVE: To explore the clinical manifestations, diagnosis, pathological features and treatment of small-cell carcinoma of the prostate (SCCP). METHODS: We conducted a retrospective analysis of the clinical and pathological data of 2 cases of confirmed SCCP treated from November 2017 to March 2018, and reviewed relevant literature. RESULTS: Both the patients had the symptoms of frequent, urgent and difficult urination, with an elevated level of PSA and gradesⅡ－Ⅲ enlargement of the prostate at palpation. One underwent prostate puncture biopsy and the other received transurethral 1470 laser vaporization resection of the tumor. Postoperative pathology indicated prostate adenocarcinoma accompanied by SCCP in both of the cases. One of them was treated by etoposide-platinum (EP) chemotherapy and died of systemic multiple organ failure 20 months after diagnosis, while the other underwent endocrine therapy and has lived with tumor up to the present day. CONCLUSION: The incidence rate of SCCP is low, its malignancy is high, and its prognosis is poor. The average survival of the patient is about 7 to 10 months after diagnosis. Currently there is no effective management of the dissease, except by relying on the experience of the treatment of small-cell lung cancer, with chemotherapy as the main option.

Small Cell Carcinoma Prostate: A Case Report with Findings on 18-F FDG PET/CT.

Small-cell carcinoma of the prostate (SCCP) is a rare and very aggressive malignancy with neuroendocrine differentiation. In contrast to conventional prostate adenocarcinoma, SCCP is an aggressive carcinoma and portends to have a poor prognosis. Around 50% of these patients have metastatic disease at the first clinical presentation. We report the findings of 18-F fluorodeoxyglucose positron emission tomography/computed tomography in a case of histologically proven SCCP with an unusual finding of the left internal mammary lymph node.

Liquid-Based Cytology of Small Cell Carcinoma of the Cervix: A Multicenter Retrospective Study.

Background/Aims: There are currently few reports describing the liquid-based cytological characteristics of small cell neuroendocrine carcinoma of the cervix. This study aimed to retrospectively analyze these features to reduce missed or misdiagnosis. Methods: A total of 11 patients with histologically diagnosed small cell carcinoma of the cervix from three hospitals between 2017 and 2023 were included in this study. The cytological morphology of small cell carcinoma of the cervix and causes of missed or misdiagnosis were analyzed and summarized through a review of clinical data, liquid-based cytology, histology, immunohistochemistry, and human papillomaviruses (HPV) test results. Results: In this study, the positivity rate of preliminary cytological screening was 63.6% (7/11); however, no cases were accurately diagnosed as small cell carcinoma of the cervix. A total of 36.4% (4/11) of small cell carcinoma of the cervix cases were cytologically negative; retrospective cytology found that two of these were false negatives. The main cytological features of small cell carcinoma of the cervix were summarized. Most of the liquid-based cytology smear cells were dense, and almost all cases showed clustered and scattered cytoplasm-scanty tumor cells. The tumor cells were all deeply stained and relatively consistent small cells. Most cases showed typical nuclear molding, chromatin stippling, and no obvious nucleoli. Mild nuclear smears, nuclear fragments, and mitotic figures were seen in most cases. Conclusion: Liquid-based cytology has a high rate of missed diagnosis and misdiagnosis in small cell carcinoma of the cervix. This study confirms that reviewing cytology results can effectively reduce this proportion and that increasing understanding of small cell carcinoma of the cervix morphology is conducive to improving the cytology-based diagnosis rate.

Small cell carcinoma of uterine cervix: A case report.

Background: Small cell carcinoma of cervix (SCCC) is a rare disease. SCCC is highly invasive and prone to distant metastatic spread and lymph node involvement. Here we aim to present a patient and her treatment. Case Presentation: We report 47-year-old patient with history of breast cancer manifesting with abnormal vaginal bleeding diagnosed with SCCC. Patient underwent radical hysterectomy and bilateral salpingo-oophorectomy. Then, she received adjuvant chemoradiation postoperatively. Conclusion: Small cell carcinoma of cervix is an aggressive form of cervical cancer with poor prognosis. Optimal treatment remains unsettled.

Unlocking Precise Lung Cancer Detection Through Minimal Panel Immunostaining in Small Biopsy Samples.

Introduction Lung cancer diagnosis faces challenges due to morphological heterogeneity and limited biopsy tissue. This study evaluates the efficacy of a minimal panel immunostaining technique using immunohistochemical markers like napsin A, thyroid transcription factor 1 (TTF-1), p63, and synaptophysin to improve the precision of lung carcinoma subclassification. Methods A retrospective analytical study was conducted at the Histopathology Laboratory of Saveetha Medical College and Hospital, Chennai, from January 2018 to February 2024. A total of 64 lung carcinoma cases were analyzed. Inclusion criteria included biopsy samples from lung lesions with a confirmed diagnosis of lung carcinoma based on histomorphological examination, covering all age groups and both genders. Non-carcinomatous lung lesions were excluded. Clinical data were obtained from the Medical Information Archiving Software (MIAS) database and histopathological examination request forms. Under a light microscope, tissue samples were examined after being fixed in formalin, processed, and stained with hematoxylin and eosin (H&E). Additionally, a minimal panel of immunohistochemical markers, including napsin A, TTF-1, p63, and synaptophysin, was used to subclassify lung carcinomas. Results The age group older than 50 years was the most affected, with a higher incidence in males. Histologically, 49% of cases were adenocarcinoma, 42% were squamous cell carcinoma, and 9% were small cell carcinoma. Immunohistochemistry (IHC) results adjusted these proportions to 54.6% adenocarcinoma, 31.2% squamous cell carcinoma, and 14% small cell carcinoma, showing a 5.6% increase in adenocarcinoma cases. The most common adenocarcinoma pattern was mixed, followed by acinar. TTF-1 and napsin A were crucial for identifying adenocarcinoma, while p63 was key for squamous cell carcinoma. Synaptophysin confirmed neuroendocrine differentiation in small cell carcinoma. Conclusion Incorporating a minimal panel of IHC markers significantly enhances the accuracy of lung carcinoma subclassification, addressing diagnostic challenges posed by morphological heterogeneity and limited sample size. This approach supports more precise and efficient clinical care for patients with lung cancer. Further validation in diverse clinical settings is recommended.

Differential NEUROD1, ASCL1, and POU2F3 Expression Defines Molecular Subsets of Bladder Small Cell/Neuroendocrine Carcinoma With Prognostic Implications.

Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, and YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and prometastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell NEC (LCNEC) assembled in tissue microarrays. Coexpression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence-free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified 5 distinct molecular subtypes in bladder SMC based on the expression of ASCL1, NEUROD1, and POU2F3: ASCL1+/NEUROD1- (n = 33; 34%), ASCL1- /NEUROD1+ (n = 21; 21%), ASCL1+/NEUROD1+ (n = 17; 17%), POU2F3+ (n = 22, 22%), and ASCL1- /NEUROD1- /POU2F3- (n = 5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (P < .001). DLL3 expression was high in both SMC (n = 72, 82%) and LCNEC (n = 11, 85%). YAP1 expression was enriched in nonneuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (P < .05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, the NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1, and POU2F3. POU2F3-expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter RFS and OS. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.

Oropharyngeal Mixed Neuroendocrine-Nonneuroendocrine Neoplasm (MiNEN): A Case Report and Literature Review.

Mixed neuroendocrine-nonneuroendocrine (MiNEN) neoplasms in the head and neck are exceptionally rare biphasic tumors with unclear pathogenesis and an aggressive clinical behavior. This is the first reported case of an oropharyngeal MiNEN with the nonneuroendocrine component being an HPV-associated adenocarcinoma. The tumor arose in a 56 year-old male with history of long-term cigarette smoking and was composed of an adenocarcinoma intermixed with a small cell neuroendocrine carcinoma. P16 immunohistochemical stain and HPV16/18 in-situ hybridization were strongly and diffusely expressed in both components.

Multiple Somatic Mutations of SMARCA4 in Small Cell Carcinoma of the Ovary, Hypercalcemic Type: A Case Report.

Small-cell carcinoma of the ovary, the hypercalcemic type (SCCOHT) is a rare, aggressive tumor that primarily affects young females. It is a monogenic disorder caused by germline and/or somatic SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 (SMARCA4) mutations. Here, we report a case of SCCOHT harboring multiple previously unreported somatic mutations in SMARCA4 (c.2866_2867delC>T; c.3543del). A 28-year-old breastfeeding Japanese female presented to a previous hospital with nausea and vomiting. She had no family history of relevant malignancies, including ovarian cancer. Based on an evaluation performed at another institution, she was referred to a gynecologist for suspected ovarian cancer. Imaging studies revealed a 16×15 cm heterogenous enhancing mass within the right ovary without lymph node or distant metastasis. She had mild ascites without peritoneal dissemination, but there was an elevation in the serum calcium level (15.1 mg/dL). The patient underwent cytoreductive surgery and was pathologically diagnosed with SCCOHT. Auxiliary immunohistochemical staining confirmed the loss of SMARCA4 protein expression. The patient was diagnosed with the International Federation of Gynecology and Obstetrics (FIGO) 2014 stage IA (pT1a pN0 M0). The serum calcium levels returned to normal post-surgery. Matched-pair analysis using tumor tissue and peripheral blood revealed multiple somatic mutations in SMARCA4, but no deleterious germline mutations were present. Microsatellite instability was not significant, and the patients had a heterozygous mutation of uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1)*6. She underwent six cycles of irinotecan hydrochloride plus cisplatin chemotherapy and achieved complete remission. The patient was finally examined and evaluated 45 months postoperatively; there was no evidence of the disease. Overall, the genetic findings will not aid in the SCCOHT diagnosis and relevant genetic counseling; however, they may have implications for the treatment of this disease in the future.