bromochloroacetic-acid and Carcinoma--Neuroendocrine

Although the definitions of sinonasal neuroendocrine and neuroectodermal neoplasms did not change substantially in the 5th edition WHO Classification of Head and Neck Tumours, the diagnosis of olfactory neuroblastoma (ONB), small cell neuroendocrine carcinoma, and large cell neuroendocrine carcinoma remains quite challenging in practice. Ambiguities surrounding the amount of keratin expression allowable in ONB and the amount of neuroendocrine differentiation seen in sinonasal undifferentiated carcinoma (SNUC) lead to significant diagnostic discrepancies at the high grade end of this tumor spectrum. Furthermore, a group of problematic neuroepithelial tumors that show overlapping features of ONB and neuroendocrine carcinoma have never been recognized in formal classification schemes. Since publication of the 5th edition WHO, two new tumor entities have been proposed that help resolve these problems. Olfactory carcinoma is defined by high grade keratin-positive neuroectodermal cells with frequent intermixed glands and shows recurrent Wnt pathway, ARID1A, and RUNX1 alterations. IDH2-mutant sinonasal carcinoma is a molecularly-defined category that encompasses tumors with undifferentiated (SNUC), large cell neuroendocrine, and neuroepithelial phenotypes. This review will provide a practical overview of these emerging entities and their application to diagnostic challenges in the post-WHO sinonasal neuroendocrine and neuroectodermal tumor classification.

Topics: Carcinoma, Neuroendocrine; Esthesioneuroblastoma, Olfactory; Humans; Keratins; Maxillary Sinus Neoplasms; Nasal Cavity; New Orleans; Nose Neoplasms; Paranasal Sinus Neoplasms

Ovarian pulmonary-type small cell carcinoma is a rare and extremely aggressive neoplasm. We report the occurrence of an ovarian small cell carcinoma of pulmonary type in a 54-year-old woman. She underwent a total abdominal hysterectomy with a bilateral salpingo-oophorectomy and infracolic omentectomy. A diagnosis of stage IIIA pulmonary-type small cell carcinoma was rendered. The tumor appeared to be composed of a solid growth of small cells arranged in sheets and closely packed nests with insular arrangements separated by a fibrous stroma. The tumor cells had hyperchromatic nuclei with inconspicuous nucleoli and scanty cytoplasm. Rosette and rosette-like structures were scattered. Immunohistochemical staining showed positivity for synaptophysin, neural cell adhesion molecule (NCAM), and focally for chromogranin. Cytokeratin and neuron-specific enolase (NSE) were also positive. Over 80% of the tumor cells showed strong reactivity for MIB-1. Electron microscopy showed neuroendocrine granules. She was effectively treated with paclitaxel plus carboplatin after the surgery.

Topics: Antineoplastic Agents; Carboplatin; Carcinoma, Neuroendocrine; Carcinoma, Ovarian Epithelial; Carcinoma, Small Cell; Carrier Proteins; Female; Humans; Keratins; Lung; Middle Aged; Neoplasms, Glandular and Epithelial; Neural Cell Adhesion Molecules; Ovarian Neoplasms; Paclitaxel; Tomography, X-Ray Computed; Ubiquitin-Protein Ligases

A case of metastatic mixed acinar-neuroendocrine carcinoma (MANEC) of the pancreas to the liver is reported. A diagnostic percutaneous US-guided FNA and core biopsy of a liver nodule was performed. The FNA smears were cellular and showed neoplastic cells in clusters with acinar formation, isolated single cells, and scattered naked nuclei. The cytoplasm was finely granular. The nuclei were relatively uniform, some with speckled chromatin and prominent nucleoli. The immunohistochemistry performed on the cell block showed strong positivity for cytokeratin AE1/AE3, chromogranin, and synaptophysin. Furthermore, the tumor cells were weakly positive for α1-antichymotrypsin. The Ki-67 mitotic index was up to 50%. Based on the morphology and supporting immunohistochemical stains, the final cytopathologic diagnosis rendered was "Positive for malignant cells. Carcinoma with mixed acinar and endocrine features." To our knowledge, this is the first report of a metastatic MANEC to the liver diagnosed based on cytology with confirmatory histology. The difficulties in the cytopathologic diagnosis and differential diagnosis of MANEC are discussed in this article.

Topics: Aged; Carcinoma, Neuroendocrine; Cell Nucleus; Chromogranins; Cytoplasm; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Humans; Keratins; Liver Neoplasms; Male; Mitotic Index; Pancreatic Neoplasms; Synaptophysin

Small cell carcinoma of the urinary bladder is a rare, often fatal, disease. Its presenting symptoms and gross morphology are similar to those of conventional urothelial carcinoma, whereas its prognosis is much poorer with frequent metastasis. Small cell carcinoma of the urinary bladder shares similar histology with its counterparts in other organs; however, its immunoreactivity to conventional neuroendocrine markers is low. Its diagnosis is thus considered permissible on morphologic grounds alone. Multimodal treatments are often employed, although no definite treatment algorithm has been established. For this extremely aggressive malignancy with an as-yet inconclusive etiology, further studies are needed to clarify its molecular pathogenesis to serve as a basis for diagnostic markers and therapeutic targets. The clinical, morphologic, immunoreactive, molecular, and therapeutic features of bladder small cell carcinoma are reviewed, including a detailed discussion on the utility of immunohistochemical markers.

Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cyclin-Dependent Kinase Inhibitor p16; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Male; Molecular Biology; Nuclear Proteins; Prognosis; Thyroid Nuclear Factor 1; Transcription Factors; Urinary Bladder Neoplasms

Topics: Adenocarcinoma; Biomarkers, Tumor; Brain Neoplasms; Breast Neoplasms; Carcinoma, Hepatocellular; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Differentiation; Cytogenetic Analysis; Head and Neck Neoplasms; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Lymphatic Metastasis; Magnetic Resonance Imaging; Mesothelioma; Neoplasm Metastasis; Neoplasms, Unknown Primary; Peritoneal Neoplasms; Positron-Emission Tomography; Prognosis; Rhabdomyosarcoma; Tomography, X-Ray Computed; Urinary Bladder Neoplasms

To review the clinical and pathological picture of laryngeal paragangliomas and compare laryngeal paragangliomas with the three other types of laryngeal neuroendocrine neoplasms.. The study presents a case review of a patient with a subglottic laryngeal paraganglioma treated at our institution, with a literature review of the laryngeal neuroendocrine neoplasms. Included is a review of all four neuroendocrine neoplasms, taking a close look at a comparison between laryngeal paragangliomas and atypical carcinoids tumors. All cases of subglottic laryngeal paragangliomas reported in the literature were also compiled and tabulated.. The patient's record was reviewed for age, symptomatology, workup, and surgical procedures performed.. The patient was disease free 36 months after undergoing a tracheostomy for airway control, followed by a cricoid split for complete excision of the tumor.. It is important to differentiate among the four laryngeal neuroendocrine neoplasms, especially between atypical carcinoids and paragangliomas. Each tumor requires different treatments, with the former requiring a more aggressive approach. Paragangliomas must be completely excised to prevent their recurrence, and this approach should be considered a curative treatment. In addition, the immunohistochemical battery is of paramount importance in obtaining the correct pathological diagnosis.

Topics: Aged; Calcitonin; Carcinoma, Neuroendocrine; Endoscopy; Female; Humans; Immunoenzyme Techniques; Immunohistochemistry; Keratins; Laryngeal Neoplasms; Paraganglioma; Tracheal Neoplasms; Tracheostomy

Three cases of neuroendocrine carcinoma showing skeletal muscle differentiation are presented. The tumors were located in the skin and subcutaneous tissue, the urinary bladder, and the nasal cavity respectively, and were composed by two cell types admixed intimately with each other. One cell type had features identical to those seen in conventional small cell neuroendocrine carcinoma, including scanty cytoplasm, round nuclei with fine granular chromatin, immunohistochemical reactivity for neuron-specific enolase, chromogranin and cytokeratins, and electron-dense granules on ultrastructural examination. The second cell type was either plasmacytoid or elongated and straplike, with abundant eosinophilic cytoplasm and irregular nuclei with prominent nucleoli. These cells showed immunohistochemical positivity for desmin, sarcomeric actin, myoglobin, and myogenin. They also exhibited ultrastructural evidence of rhabdomyoblastic differentiation in the form of contractile filaments with abortive Z-band formation. An origin from a cell capable of dual differentiation toward neuroendocrine and rhabdomyoblastic elements is postulated for these tumors.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Chromogranins; Cytoplasmic Granules; Fatal Outcome; Female; Humans; Immunoenzyme Techniques; Keratins; Male; Muscle, Skeletal; Nose Neoplasms; Phosphopyruvate Hydratase; Rhabdomyosarcoma; Skin Neoplasms; Urinary Bladder Neoplasms

Neuroendocrine bladder tumours are exceptional, and the positive diagnosis is only established when they are already large and advanced. We report an original case in view of its small dimensions. We discuss the differential diagnosis (mainly bladder metastases from lung cancer) and pathological specificities, particularly the value of epithelial immunolabelling allowing exclusion of lymphoma. Because of the similarities with bronchial neuroendocrine tumours, the potential value of serum NSE assay should be emphasized. Combined surgery-cisplatin-based adjuvant chemotherapy is recommended.

Topics: Aged; Antineoplastic Agents; Carcinoembryonic Antigen; Carcinoma, Neuroendocrine; Chemotherapy, Adjuvant; Cisplatin; Diagnosis, Differential; Female; Humans; Keratins; Lung Neoplasms; Lymphoma; Mucin-1; Neoplasm Staging; Phosphopyruvate Hydratase; Synaptophysin; Urinary Bladder Neoplasms

The problems with classification and diagnosis of bronchopulmonary carcinoid and other neuroendocrine tumors are described in this paper. Single neuroendocrine cells and so-called neuroepithelial bodies found in normal bronchial epithelium are currently believed to constitute pulmonary components of an extensive neuroendocrine system. In view these opinions, it has appeared a need for a new, standardized nomenclature. Hence presently suggested classification of neuroendocrine carcinomas taking into account their histological structure, immunohistochemical as well as prognostic features starting from carcinoid tumors to small cell anaplastic carcinomas-includes three types of neoplasms.

Topics: Biomarkers, Tumor; Bronchial Neoplasms; Carcinoid Tumor; Carcinoma, Neuroendocrine; CD57 Antigens; Cell Size; Chromogranin A; Chromogranins; Humans; Keratins; Lung Neoplasms; Neoplasm Proteins; Neuroendocrine Tumors; Neuropeptides; Phosphopyruvate Hydratase; Silver Staining; Somatostatin; Synaptophysin; Terminology as Topic

Aberrant expression of epithelial and neuroendocrine markers is rare in diffuse large B-cell lymphoma (DLBCL) and can lead to erroneous diagnosis with inappropriate treatment. This case report describes a case of DLBCL with a co-expression of cytokeratins and CD56 that was misdiagnosed as metastatic neuroendocrine carcinoma.

Topics: Carcinoma, Neuroendocrine; CD56 Antigen; Humans; Immunophenotyping; Keratins; Lymphoma, Large B-Cell, Diffuse

Small cell lung carcinoma (SCLC), a malignancy of neuroendocrine origin, can show varied morphologies and patterns but is typically positive for at least one neuroendocrine marker and almost always for cytokeratins. It is essential to distinguish this tumour due to its characteristic genetic features, aggressive behaviour, propensity for metastasis and responsiveness to chemotherapy. We hereby present a rare case of a pulmonary mass that showed morphological features of an SCLC but lacked cytokeratin expression on biopsy as well as resection specimens. Various cytokeratins were tested on multiple blocks and at different laboratories. A broad differential diagnosis was considered and ruled out including small round blue cell tumours, non-SCLC and metastasis. After performing an extensive work-up to identify the origin of this tumour, it was finally diagnosed as SCLC with expression of neuroendocrine markers synaptophysin and CD56, and intracytoplasmic electron dense neurosecretory granules (250-350 nm) however lacked cytokeratin expression.

Topics: Biomarkers, Tumor; Biopsy; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Humans; Keratins; Lung Neoplasms; Small Cell Lung Carcinoma

Molecular analysis of poorly differentiated/undifferentiated sinonasal neoplasms has resulted in identification of a growing number of genetically defined tumors. SMARCA4-deficient sinonasal carcinoma is one such recently described entity that emerged from within sinonasal undifferentiated carcinoma (SNUC), neuroendocrine carcinoma (NEC), and teratocarcinosarcoma (TCS).. To identify SMARCA4-deficient sinonasal carcinomas from a large institutional cohort of poorly differentiated/undifferentiated carcinomas and evaluate their clinicopathologic features.. SMARCA4/BRG1 immunohistochemistry was performed on all tumors diagnosed as SNUC, poorly differentiated carcinoma, NEC, and TCS during a 12-year period. SMARCA2/BRM and INSM1 immunostaining was performed in SMARCA4-deficient cases.. Twelve SMARCA4-deficient sinonasal carcinomas were identified among 299 cases. Morphologically, 5 cases were large cell NEC, 2 cases were small cell NEC, and 5 were TCS. SMARCA4 loss was diffuse and complete in 10 cases, while 2 cases showed focal retention. Most cases showed diffuse cytokeratin staining accompanied by weak, usually focal staining for chromogranin and synaptophysin. INSM-1 showed negativity in most cases. All cases showed retained SMARCA2 expression. IDH1/2 mutation was absent in all cases analyzed. Four of 7 patients died of disease, and aggressive multimodality treatment provided better outcome.. SMARCA4-deficient sinonasal carcinomas are morphologically akin to sinonasal poorly differentiated NECs and TCS, display cytokeratin positivity and only focal staining for neuroendocrine markers, and have aggressive biological behavior. Inclusion of SMARCA4 in the immunohistochemical panel for diagnostic workup of all sinonasal NEC and TCS phenotypes will facilitate their early recognition. Comprehensive germline and somatic mutational analyses of these tumors are necessary for further insights into their molecular pathogenesis.

Topics: Biomarkers, Tumor; Carcinoma; Carcinoma, Neuroendocrine; DNA Helicases; Humans; Immunohistochemistry; Keratins; Maxillary Sinus Neoplasms; Nuclear Proteins; Repressor Proteins; Transcription Factors

The sinonasal cavities harbour a variety of rare tumour types. Many carry a poor prognosis while therapeutic options are limited. Histopathological classification can be difficult, especially for poorly differentiated tumours such as olfactory neuroblastoma (ONB), sinonasal neuroendocrine carcinoma (SNEC) and sinonasal undifferentiated carcinoma (SNUC). We analysed Affymetrix OncoScan genome-wide copy number profiles of these three tumour types, both as originally diagnosed and as regrouped by their cytokeratin (Ck) and neuroendocrine (Ne) expression pattern, aiming to find a relation between phenotype and genotype. According to the original histopathological classification our series consisted of 24 ONB, 11 SNEC and 19 SNUC, while immunohistochemistry indicated 11 Ck-Ne+/ONB, 18 Ck+Ne+/SNEC, 24 Ck+Ne-/SNUC, and 1 Ck-Ne-/unclassified. As originally diagnosed, the three tumour types showed similar copy number profiles. However, when regrouped by Ck/Ne immunostaining we found a distinct set of gains and losses; Ck-Ne+/ONB harboured few and predominantly whole chromosomes abnormalities, Ck+Ne+/SNEC carried both gains and losses in high frequency, and Ck+Ne-/SNUC showed mostly gains. In addition, each tumour carried a number of unique chromosomal deletions. Genome-wide copy number profiling supports the value of immunohistochemical CkNe staining of ONB, SNEC and SNUC for tumour classification, which is important for prognosis and therapeutic decision-making.

Topics: Biomarkers, Tumor; Carcinoma; Carcinoma, Neuroendocrine; Cell Differentiation; Esthesioneuroblastoma, Olfactory; Gene Expression Profiling; Genotype; Humans; Keratins; Maxillary Sinus Neoplasms

Intratumoral phenotypic heterogeneity has been described in many tumor types, where it can contribute to drug resistance and disease recurrence. We analyzed ductal and neuroendocrine markers in pancreatic ductal adenocarcinoma, revealing heterogeneous expression of the neuroendocrine marker Synaptophysin within ductal lesions. Higher percentages of Cytokeratin-Synaptophysin dual positive tumor cells correlate with shortened disease-free survival. We observe similar lineage marker heterogeneity in mouse models of pancreatic ductal adenocarcinoma, where lineage tracing indicates that Cytokeratin-Synaptophysin dual positive cells arise from the exocrine compartment. Mechanistically, MYC binding is enriched at neuroendocrine genes in mouse tumor cells and loss of MYC reduces ductal-neuroendocrine lineage heterogeneity, while deregulated MYC expression in KRAS mutant mice increases this phenotype. Neuroendocrine marker expression is associated with chemoresistance and reducing MYC levels decreases gemcitabine-induced neuroendocrine marker expression and increases chemosensitivity. Altogether, we demonstrate that MYC facilitates ductal-neuroendocrine lineage plasticity in pancreatic ductal adenocarcinoma, contributing to poor survival and chemoresistance.

Topics: Animals; Antineoplastic Agents; Carcinoma, Neuroendocrine; Carcinoma, Pancreatic Ductal; Cell Differentiation; Cell Line, Tumor; Cell Lineage; Deoxycytidine; Drug Resistance, Neoplasm; Female; Gemcitabine; Heterografts; Humans; Keratins; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Transplantation; Neuroendocrine Cells; Pancreatic Neoplasms; Prognosis; Proto-Oncogene Proteins c-myc; Synaptophysin

Topics: Adult; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Diagnosis, Differential; Esthesioneuroblastoma, Olfactory; Humans; Keratins; Male; Nasal Cavity; Nose Neoplasms

Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cyclin-Dependent Kinase-Activating Kinase; Cyclin-Dependent Kinases; Diagnosis, Differential; Female; Gene Expression; Humans; Keratins; Membrane Proteins; Middle Aged; Nuclear Proteins; Oropharyngeal Neoplasms; Synaptophysin; Thyroid Nuclear Factor 1; Transcription Factors

Topics: Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Endometrial Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Middle Aged; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1

Patients with small cell lung carcinoma (SCLC) rarely demonstrate long-term survival. We previously reported that gene expression profiling identified a subset of SCLC with good prognosis in surgical cases. To find an easier way to routinely identify SCLC belonging to this subset, we conducted the present study with a hypothesis that neuroendocrine (NE) or basaloid (BA) phenotypes may influence prognosis. To confirm the subset, we used an array platform to analyze fresh samples. Because inoperable cases may differ from surgical cases, we enrolled 51 biopsy cases and 43 resected samples. To evaluate NE and BA phenotypes, we used NE (synaptophysin, chromogranin A, and CD56) and BA (p63 and CK34βE12) markers. To varying extents, expression profiling based on the array platform duplicated the subsets. For NE phenotypes, 77% of surgical cases and 100% of biopsy cases were positive for at least 1 marker. For BA phenotypes, only 19% of surgical cases were positive for at least 1 marker, whereas there were no positive biopsy cases. Cases undergoing surgery were categorized based on NE and BA immunoreactivity; 58% into NE+BA-, 19% into NE+BA+, 23% into NE-BA-, and 0 into NE-BA+ groups. NE- patients (n = 10) demonstrated a significantly better prognosis (P = .0306) than their NE+ counterparts (n = 33), whereas no survival difference was evident between the BA+ and BA- groups. Multivariate analyses showed that NE positivity was an independent prognostic factor. In conclusion, the SCLC subset with good prognosis is identified by low NE marker expression, which was found only in surgical cases.

Topics: Aged; Biomarkers, Tumor; Biopsy; Carcinoma, Neuroendocrine; CD56 Antigen; Chromogranin A; Female; Gene Expression Profiling; Humans; Immunohistochemistry; Keratins; Lung Neoplasms; Male; Membrane Proteins; Middle Aged; Prognosis; Protein Array Analysis; Small Cell Lung Carcinoma; Synaptophysin

To study the clinicopathologic features and histologic differential diagnosis of small cell neuroendocrine carcinoma (SmCC) of kidney.. The clinicopathologic features of 12 cases of SmCC of kidney encountered during the period from 1999 to 2010 were retrospectively reviewed.. Six cases of primary and 6 cases of metastatic SmCC involving kidney were identified. Amongst the primary renal SmCC, 2 were located in renal parenchyma and 4 in renal pelvis. Chest X-ray showed negative findings. Five of them underwent radical nephrectomy. On gross examination, the tumor was located centrally around the renal pelvis in 4 cases and peripherally in renal parenchyma in 1 case. On the other hand, 4 of the 6 cases of metastatic SmCC were discovered during therapy for pulmonary SmCC. Two of these patients presented with abdominal pain and gross hematuria, with lung and renal tumor masses identified simultaneously. The diagnosis of all the 6 cases of metastatic SmCC was confirmed by fine needle aspiration biopsy. Microscopically, pure SmCC was demonstrated in the 2 cases of primary renal parenchymal SmCC and 6 cases of metastatic SmCC. The 4 primary renal pelvic SmCC coexisted with urothelial carcinoma component. On immunohistochemical study, all cases were positive for cytokeratin, synaptophysin and CD56. All metastatic cases and 4 primary cases were also positive for TTF-1. Of six patients with primary SmCC two died 4 and 9 months after operation, and two were alive with a follow-up of 25 and 138 months, respectively. Five of six cases with metastatic SmCC died 3 - 8 months after diagnosis. The other 3 cases were failed to follow-up.. Both primary and metastatic SmCC can be found in the kidney. Although rare, primary SmCC is located either in renal parenchyma or in pelvis. The diagnosis of SmCC relies on morphologic examination and immunohistochemical study. TTF-1 immunostaining cannot reliably distinguish primary from metastatic SmCC in kidney. Correlation with clinicoradiologic findings and demonstration of coexisting urothelial carcinoma component (if any) is helpful in delineation of the tumor origin.

Topics: Adult; Aged; Carcinoma, Neuroendocrine; Carcinoma, Renal Cell; Carcinoma, Small Cell; CD56 Antigen; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Keratins; Kidney Neoplasms; Lung Neoplasms; Lymphoma; Male; Middle Aged; Nephrectomy; Nuclear Proteins; Retrospective Studies; Sarcoma, Ewing; Synaptophysin; Thyroid Nuclear Factor 1; Transcription Factors; Treatment Outcome; Wilms Tumor

To study the clinical and pathologic characteristics of small cell neuroendocrine carcinoma of urinary tract.. All cases of urinary tract carcinoma encountered in the General Hospital of People Liberation Army during the period from 1999 to 2010 were retrospectively reviewed. The clinicopathologic data of small cell neuroendocrine carcinomas were further analyzed, with literature review.. A total of 16 cases of small cell neuroendocrine carcinoma were identified, including 10 from urinary bladder, 2 from ureter, 3 from renal pelvis, and 1 multifocal tumor involving renal pelvis and ureter. There were altogether 8 males and 8 females. The median age of the patients was 63 years (range = 24 to 79 years). Gross hematuria (11 cases) represented the main presenting symptom. Four patients had flank pain and 4 had urinary irritation symptoms. Seven patients underwent radical cystectomy. Six other patients underwent radical nephroureterectomy, 1 partial cystectomy, 1 TURBT and the remaining case biopsy only. The size of the tumor ranged from 0.8 to 8.0 cm (median = 4.5 cm). Histologically, 15 cases represented mixed small cell neuroendocrine carcinoma (with 13 mixed with transitional cell carcinoma and 2 with adenocarcinoma). Immunohistochemical study showed positive staining for neuroendocrine markers. On presentation, 1 patient was in stage pT1, 7 in stage pT2, 6 in stage pT3, 2 in stage pT4. Six patients died of the disease after operation. The overall survival was 25 months and the 5-year survival rate was 32.4%.. Small cell neuroendocrine carcinoma of urinary bladder is a highly malignant disease and associated with poor prognosis. The diagnosis relies on detailed histologic examination. Early diagnosis, when coupled with cystectomy or nephroureterectomy and adjuvant chemotherapy, represents the mainstay of management.

Topics: Adult; Aged; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; CD56 Antigen; Chemotherapy, Adjuvant; Cystectomy; Female; Follow-Up Studies; Humans; Keratins; Kidney Neoplasms; Male; Middle Aged; Neoplasm Staging; Nephrectomy; Phosphopyruvate Hydratase; Retrospective Studies; Survival Rate; Synaptophysin; Ureteral Neoplasms; Urinary Bladder Neoplasms; Urologic Neoplasms; Young Adult

We describe 10 cases of primary well-differentiated neuroendocrine carcinomas (carcinoid tumor) of the lung with extensive sclerotic changes. The patients were 6 women and 4 men from 20 to 69 years of age. Clinically, patients had symptoms of bronchial obstruction such as cough, dyspnea, and chest pain. Surgical resection of the tumors was accomplished in all the cases. Histologically, all tumors corresponded to the well-differentiated type; however, in 4 cases, lymph node metastases were present. Immunohistochemically, all tumors showed positive staining for neuroendocrine markers, including chromogranin, synaptophysin, CD56, and broad-spectrum keratin. Follow-up information showed that 8 patients were alive after a period ranging from 1 to 5 years. The cases presented highlight an important feature of neuroendocrine carcinomas of the lung not previously addressed, one that may pose a problem not only in the diagnosis but also in the grading of these neoplasms.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Neuroendocrine; CD56 Antigen; Chromogranin A; Female; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Lung; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Sclerosis; Synaptophysin; Treatment Outcome

The aim of the present study was to clarify protein profiling in small cell lung carcinoma (SCLC) and pulmonary large cell neuroendocrine carcinoma (LCNEC). The proteomic approach was used, and involved cell lysate from two cell lines (N231 derived from SCLC and LCN1 derived from LCNEC), with 2-D gel electrophoresis (2-DE). In the present study, 25 protein spots with greater than twofold quantitative differences between LCN1 and N231 cells on 2-DE gels were confirmed. Within the 25 identified proteins, cytokeratins (CK) 7, 8, 18 and 19 were upregulated in LCN1 cells compared with N231 cells. The expression of CK7, 8, 18, and 19 was further studied on immunohistochemistry with 81 formalin-fixed and paraffin-embedded pulmonary carcinomas, which included 27 SCLC, 30 LCNEC, 14 adenocarcinomas, and 10 squamous cell carcinomas. Although the expression of CK7, 8, 18, and 19 was observed in all histological types, the mean immunostaining scores of CK7, 8, 18, and 19 were significantly higher in LCNEC than in SCLC (P < 0.001, P < 0.001, P < 0.01 and P < 0.001, respectively). These data suggest that the biological characteristics of LCNEC and SCLC may be different and the expression of CK may serve as differential diagnostic markers.

Topics: Biomarkers, Tumor; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Electrophoresis, Gel, Two-Dimensional; Humans; Immunohistochemistry; Keratin-18; Keratin-19; Keratin-7; Keratin-8; Keratins; Lung Neoplasms; Small Cell Lung Carcinoma; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tissue Array Analysis

Small cell neuroendocrine carcinoma (SCNEC) of the urinary bladder is a rare but aggressive neoplasm that usually exhibits neuroendocrine differentiation. Here, the authors report a case of SCNEC in an 80-year-old man. The patient had gross hematuria and nodular mass involving the wall of the urinary bladder. Total cystectomy was done. The tumor consisted of small, uniform, round, and spindled-shaped cells with chromatin dark nuclei and numerous mitotic figures. The cells were reactive for chromogranin, neuron-specific enolase (diffuse), and keratin (focal). Ultrastructural studies revealed neurosecretory granules and intermediate filaments. The diagnosis of SCNEC with focal high-grade urothelial component was established. No metastasis was found at the time of diagnosis and the patient refused further chemotherapy or radiotherapy. The histogenesis, differential diagnosis, and prognosis of SCNEC of the urinary bladder were discussed.

Topics: Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Chromogranins; Cystectomy; Cytoplasmic Granules; Humans; Intermediate Filaments; Keratins; Male; Neurosecretory Systems; Phosphopyruvate Hydratase; Urinary Bladder Neoplasms

To study the clinicopathologic characteristics of thymic epithelial tumors and to evaluate the diagnostic reproducibility and clinical relevance of the 2004 WHO histologic classification system.. The morphology and immunophenotype of 52 cases of thymic epithelial tumor were reviewed. The tumors were classified according to the new WHO classification system and the clinical data were analyzed.. Of the 52 cases studied, 45 were thymomas and 7 were thymic carcinomas. Amongst the 45 cases of thymoma, 6 (13.4%) were type A, 15 (33.3%) were type AB, 4 (8.9%) were type B1, 9 (20.0%) were type B2, 9 (20.0%) were type B3 and 2 (4.4%) were metaplastic thymoma. Amongst the 7 cases of thymic carcinoma, 6 were squamous cell carcinomas and 1 was neuroendocrine carcinoma. The commonest presentations were cough and chest pain. Some cases were incidentally discovered by routine physical examination. Thirteen cases (25.0%) of thymoma were associated with myasthenia gravis. CT scan showed that 49 cases (94.2%) were located in the anterior mediastinum. All cases of type A, AB and B1 thymoma and most cases of B2 thymoma appeared as well-defined homogeneous mass, whereas a few cases of type B2 thymoma and most cases of type B3 thymoma and thymic carcinoma were poorly demarcated and heterogeneous. According to Masaoka staging system, 20 cases (41.7%) belonged to stage I, 15 cases (31.3%) stage II, 11 cases (22.9%) stage III and 2 cases (4.1%) stage IV. The histologic subtypes of thymic epithelial tumors significantly correlated with the clinical stages (chi(2) = 32.5, P < 0.01).. The 2004 revision of WHO histologic classification system for thymic epithelial tumors shows a high degree of reproducibility. Correlation with the radiologic, clinical and prognostic parameters is helpful in determining the management strategy for individual patients.

Topics: Adult; Aged; Antibodies, Monoclonal; Antigens, CD20; Carcinoma, Neuroendocrine; Carcinoma, Squamous Cell; CD5 Antigens; Female; Follow-Up Studies; Humans; Keratins; Male; Middle Aged; Myasthenia Gravis; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Radiotherapy, Adjuvant; Retrospective Studies; Thymoma; Thymus Neoplasms; Tomography, X-Ray Computed

Metastatic Merkel cell carcinoma uncommonly presents with an unidentified primary tumour. We report a patient who first presented with lichenoid dermatitis and was found to have Merkel cell carcinoma involving lymph nodes with an unknown primary site. With the rising incidence of Merkel cell carcinoma, it is important to recognize unusual manifestations of this disease as they may become more common in the future.

Topics: Aged, 80 and over; Carcinoma, Merkel Cell; Carcinoma, Neuroendocrine; Carcinoma, Squamous Cell; CD56 Antigen; Comorbidity; Dermatitis; Fatal Outcome; Humans; Keratins; Lichenoid Eruptions; Lymphatic Metastasis; Male; Neoplasms, Unknown Primary; Phosphopyruvate Hydratase; Skin Neoplasms; Synaptophysin

The purpose of this report is to present the clinical and histological features of a basaloid squamous cell carcinoma (BSCC) occurring in the retromolar trigone of a 59-year-old man and to relate its immunohistochemical characteristics.. BSCC is an aggressive distinct variant of squamous cell carcinoma (SCC) requiring recognition as a separate entity from SCC due to its peculiar behavior.. A clinical examination revealed a 12x07x07 mm nodular mass with a rubbery consistency, defined borders, covered by reddish mucosa and an absence of bleeding upon palpation. Histologically, nests and cords of closely packed, moderately pleomorphic basaloid cells with nuclear palisading along the periphery of the neoplastic nests surrounded by a fibrous stroma were found.. Since this tumor can mimic other neoplasms such as adenoid cystic carcinoma, neuroendocrine carcinoma, and basal cell adenocarcinoma, histological features are essential to differentiate between them. Furthermore, immunohistochemical testing can provide valuable diagnostic information that can have a profound impact on treatment options and the prognosis.. BSCC needs to be differentiated from other neoplasms as early as possible because of its adverse prognosis. Clinicians are advised to conduct a mucosal evaluation during oral examinations and take a thorough medical history which could ultimately save the life of a patient.

Topics: Adenocarcinoma; Carcinoma, Adenoid Cystic; Carcinoma, Neuroendocrine; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Cell Nucleus; Diagnosis, Differential; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Ki-67 Antigen; Laminin; Male; Middle Aged; Mitosis; Mouth Neoplasms; Necrosis; Tumor Suppressor Protein p53

High-grade neuroendocrine carcinomas of the head and neck overlap significantly in morphology with both basaloid squamous and solid-type adenoid cystic carcinomas. High-grade neuroendocrine carcinomas have sheets of small cells with scant cytoplasm, granular chromatin, and inconspicuous nucleoli. Basaloid squamous and adenoid cystic carcinomas are aggressive variants of their respective tumor types which both have nests of basaloid tumor cells with round nuclei, little cytoplasm, and inconspicuous nucleoli. As the management and prognosis of these tumors are very different, it is important to differentiate them. We performed high molecular weight cytokeratin (CK) and p63 immunohistochemistry on 19 neuroendocrine carcinomas, 18 basaloid squamous carcinomas, and 11 solid-type adenoid cystic carcinomas. All tumors were immunostained for p63, CK 34betaE12, CK 5/6, synaptophysin, chromogranin-A, S-100, and smooth muscle actin. All basaloid squamous and adenoid cystic carcinomas were positive for CK 5/6 and 34betaE12. Only 4 and 5 of the 19 neuroendocrine carcinomas, respectively, were positive for these markers. Staining was focal in the neuroendocrine cases when positive, whereas almost all basaloid squamous and adenoid cystic carcinomas showed strong staining. Almost all tumors of each type were positive for p63, including neuroendocrine carcinomas, but with different staining patterns. Basaloid squamous carcinomas were diffusely positive, neuroendocrine carcinomas were diffusely positive, but with weak staining, and adenoid cystic carcinomas showed a distinct pattern with staining at the periphery of the cell nests only. We conclude that high molecular weight cytokeratin immunostaining is helpful in distinguishing high-grade neuroendocrine carcinomas from similar tumor types.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; Carcinoma, Basosquamous; Carcinoma, Neuroendocrine; Diagnosis, Differential; Female; Head and Neck Neoplasms; Humans; Immunohistochemistry; Keratin-5; Keratin-6; Keratins; Male; Membrane Proteins; Middle Aged; Molecular Weight

To elucidate additional phenotypic differences between large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), we performed tissue microarray (TMA) analysis of surgically resected LCNEC and SCLC specimens. Immunostaining with 48 antibodies was scored based on staining intensity and the percentage of cells that stained positively. Four proteins were identified as significantly expressed in LCNEC as compared with SCLC: cytokeratin (CK)7, 113 vs 49 (P < .0301); CK18, 171 vs 60 (P < .0008); E-cadherin, 77 vs 9 (P < .0073); and beta-catenin, 191 vs 120 (P < .0286). Immunostaining of cross-sections containing LCNEC and SCLC components revealed significant expression of CK7, CK18 and beta-catenin in the LCNEC component compared with the SCLC component in 2 of 3 cases. Our results indicate that significant expression of CK7, CK18, E-cadherin, and beta-catenin is more characteristic of LCNEC than of SCLC, and these findings provide further support that these tumor types are separate entities morphologically and immunophenotypically, if not biologically.

Topics: beta Catenin; Biomarkers, Tumor; Cadherins; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Diagnosis, Differential; Humans; Immunohistochemistry; Keratin-7; Keratins; Lung Neoplasms; Neoplasm Proteins; Retrospective Studies; Tissue Array Analysis

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a malignant neuroendocrine tumor clinicopathologically similar to and falling in-between atypical carcinoid tumor and small cell lung carcinoma (SCLC). The diagnosis of LCNEC is based mainly on a characteristic neuroendocrine morphology and biological neuroendocrine differentiation. In order to know the discrepancy between morphological and biological neuroendocrine differentiation, LCNEC was immunohistochemically and molecular biologically compared with large cell carcinoma with neuroendocrine morphology (LCCNM), which lacked only biological neuroendocrine differentiation among the criteria of LCNEC. Immunohistochemically, disruption of the RB pathway, namely a lack of RB expression and simultaneous overexpression of p16 protein, was characteristic of LCNEC, but not LCCNM. In G2/M cell cycle regulation, 14-3-3 sigma expression was markedly reduced in LCNEC. Moreover, the antibody 34 beta E12 recognizing a set of large-sized keratin gave a different staining pattern between LCNEC and LCCNM. The immunohistochemical data suggested that LCNEC has a similar biological marker profile to SCLC and different from LCCNM. However, a loss of heterozygosity (LOH) analysis using microsatellite markers showed a high frequency of LOH at 3p in both LCNEC and LCCNM as well as in SCLC. Morphological neuroendocrine differentiation might not be identical to biological neuroendocrine differentiation in large cell carcinoma of the lung.

Topics: Aged; Antibodies, Neoplasm; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Differentiation; Female; Humans; Immunohistochemistry; Keratins; Male; Microsatellite Repeats; Middle Aged; Retinoblastoma Protein; Retrospective Studies

Neuroendocrine carcinoma of the posterior mediastinum is extremely rare. Described here is a patient with neuroendocrine carcinoma of the posterior mediastinum arising from a foregut cyst. A paravertebral mass detected in the posterior mediastinum of a 64-year-old man was spherical, solid and yellowish white. Some cystic or cleft-like spaces were present. Microscopically, the lesion was composed of proliferating round or polygonal tumor cells in a diffuse, solid or trabecular fashion with extensive necrosis and high mitotic activity. Components of glandular epithelia and smooth muscle layers were evident in the cystic wall. Immunohistochemically, the tumor cells were positive for both epithelial and neuroendocrine markers, including pan-cytokeratin, chromogranin A and synaptophysin. Neuroendocrine marker-positive cells were also present in the glandular epithelium of the cystic walls. It was considered that posterior mediastinal neuroendocrine carcinoma arose from a foregut cyst. Malignant change within a foregut cyst is very uncommon. This is the first report of a neuroendocrine carcinoma of the posterior mediastinum arising from a foregut cyst.

Topics: Carcinoma, Neuroendocrine; Chromogranin A; Chromogranins; Cysts; Fatal Outcome; Gastrointestinal Tract; Humans; Immunohistochemistry; Keratins; Male; Mediastinal Neoplasms; Middle Aged; Synaptophysin

This study was designed to consider the cytomorphological spectrum, differential diagnosis, and the role of ancillary studies in small-cell tumors of the liver. Three independent pathologists reviewed cytological slides from 91 cases of small-cell tumors of the liver. The results were compared with the findings of three recently published studies (Cytopathology 11 (2000) 262-267; Diagn Cytopathol 19 (1998) 29-32; and Acta Cytol 40 (1996) 937-947). The role of immunohistochemistry in reaching timely and specific diagnoses was also examined. The diagnostic categories included 44 cases of metastatic small-cell undifferentiated carcinoma, 15 cases of metastatic neuroendocrine carcinoma, 10 cases of metastatic adenocarcinoma, 7 cases of malignant lymphoma, 4 cases of hepatocellular carcinoma with small-cell features, 2 cases of cholangiocarcinoma, 1 case of poorly differentiated carcinoma, and 8 cases of rare tumors including granulosa cell tumor (2 cases), sarcoma (4 cases), malignant melanoma with small-cell features (1 case), and meningioma with small-cell features (1 case). Metastatic granulosa cell-tumor, metastatic melanoma, and metastatic meningioma should be included in the differential diagnoses of small-cell malignancies found in the liver.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Biopsy, Fine-Needle; Carcinoma, Hepatocellular; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Cholangiocarcinoma; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Liver; Liver Neoplasms; Lymphoma; Male; Middle Aged; Mucin-1; Review Literature as Topic; S100 Proteins; Vimentin

Topics: Adenoma; Carcinoma, Neuroendocrine; Cell Nucleus; Chromogranins; Cytoplasm; Ear Neoplasms; Ear, Middle; Humans; Immunohistochemistry; Keratin-7; Keratins; Pancreatic Polypeptide

A 50 year old woman presented with acute abdominal pain accompanied by nausea and vomiting and was found to have a mass in the head of the pancreas by imaging. The clinical impression was of a pancreatic carcinoma and a Whipple's procedure was performed. Microscopic examination of the tumour showed it to be a low grade neuroendocrine carcinoma arranged in a tubuloacinar or tubulopapillary pattern, and composed of cells harbouring very prominent intracytoplasmic inclusions. These inclusions varied in appearance from being pale pink and hyaline in quality to more eosinophilic and globular causing displacement of the nucleus. Ultrastructural examination showed typical paranuclear aggregates of intermediate filaments. Inclusions of this type have been described previously as "signet ring like" and "rhabdoid". It was felt that the inclusions more closely resemble the fibrous bodies that are seen in pituitary adenomas. In addition, it is suggested that both signet ring and rhabdoid are not appropriate because they do not reflect histogenesis and are not necessarily reflective of tumour biology. It is suggested that the term "cytokeratin aggresomes" should be used to describe this distinctive phenotype.

Topics: Carcinoma, Neuroendocrine; Cytoplasm; Female; Humans; Keratins; Middle Aged; Pancreatic Neoplasms; Rhabdoid Tumor; Terminology as Topic

Monoclonal antibody 34betaE12 (Ck34betaE12) recognizes a set of cytokeratins (1, 5, 10, 14) expressed in normal stratified squamous epithelium. We have recently reported its expression in squamous cell carcinoma and basaloid carcinoma, in contrast to large cell neuroendocrine carcinoma, an entity with overlapping morphological features with basaloid carcinoma. We have now examined the role of Ck34betaE12 in discriminating between neuroendocrine and non-neuroendocrine proliferations.. We performed an immunohistochemical study of 228 cases, comprising the whole spectrum of lung neuroendocrine proliferations and tumours. All cases of neuroendocrine cell hyperplasia (n = 15), tumorlet (n = 23), typical carcinoid (n = 27) and atypical carcinoid (n = 23) were completely negative for Ck34betaE12. Although the neuroendocrine cells of small cell lung carcinoma and large cell neuroendocrine carcinoma were consistently negative, a strong and diffuse positive staining was found in the non-neuroendocrine components of combined small cell carcinoma (three of eight cases) and combined large cell neuroendocrine carcinoma (11 of 12 cases). In addition, scattered Ck34betaE12+ cells were noted in 11 of 64 (17%) large cell neuroendocrine carcinoma and in seven of 56 (12.5%) small cell carcinoma, which were not obviously histologically combined. This heterogeneity of high-grade neuroendocrine tumours was not observed in carcinoids which lack Ck34betaE12 clusters of reactive cells. There was mutual exclusion between expression of neuroendocrine markers and that of Ck34betaE12.. We conclude that 34betaE12 expression excludes the neuroendocrine nature of tumour cells and uncovers the real frequency of combined forms in high-grade neuroendocrine tumours.

Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Fluorescent Antibody Technique, Indirect; Humans; Hyperplasia; Immunoenzyme Techniques; Keratins; Lung Neoplasms

We describe a distinctive neuroendocrine carcinoma (NEC) that proliferated intra-epithelially. The tumor was 35 mm in diameter and arose from the right superior turbinate of a 46-year-old woman. Histologically, the tumor exhibited papillary growth and the tumor cells were localized in the thickened mucosal epithelium. The tumor cells had round to oval and vesicular or hyperchromatic nuclei, and cohered without any specific structure such as a fibrillary background, rosette or glandular structure. No stromal invasion by the tumor was observed. Immunohistochemically, the tumor cells were positive for neuron-specific enolase focally. In addition, many tumor cells expressed cytokeratin (AE1/AE3 and CAM 5.2), mostly with characteristic perinuclear dot-like patterns. Electron microscopy revealed focal but well-eveloped cytoplasmic processes containing arrays of microtubules and a few dense core granules. The tumor was considered to be a poorly differentiated neuroendocrine carcinomas (NEC) that exhibited exceptional intra-epithelial proliferation. The tumor completely disappeared after the stereotactic radiosurgery and has not recurred for 40 months. It might be difficult to distinguish a poorly differentiated NEC in the sinonasal region from other neuroectodermal tumors, including olfactory neuroblastoma, but the differential diagnosis is important because each tumor has different clinicopathological characteristics.

Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Cytoplasmic Structures; Female; Humans; Immunohistochemistry; Keratins; Magnetic Resonance Imaging; Middle Aged; Nasal Cavity; Nose Neoplasms; Phosphopyruvate Hydratase; Radiosurgery; Treatment Outcome

A 58-year-old woman with a history of Cushing's syndrome for three years presented with a mediastinal mass and received the diagnosis of small cell neuroendocrine carcinoma of the thymus invading the pericardium. On immunohistochemical study, the neoplastic cells reacted with antibodies against cytokeratin, epithelial membrane antigen, neuron-specific enolase, chromogranin, synaptophysin, and ACTH. Clinicopathologic findings of this rare case of ectopic adrenocorticotropic hormone (ACTH) syndrome are discussed with a literature review.

Topics: Adrenocorticotropic Hormone; Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Chromogranins; Cushing Syndrome; Dexamethasone; Female; Humans; Immunoenzyme Techniques; Keratins; Middle Aged; Mucin-1; Phosphopyruvate Hydratase; Radiography, Thoracic; Synaptophysin; Thymus Neoplasms

Basaloid carcinoma (BC) and large-cell neuroendocrine carcinoma (LCNEC) are 2 recently recognized variants of large-cell lung carcinomas that may overlap in their morphology, and are discriminated by expression of neuroendocrine markers in LCNEC. Because thyroid transcription factor 1 (TTF-1) is expressed in lung adenocarcinomas but not in squamous cell carcinomas (SCC), and 34betaE12 recognizes a set of high-molecular-weight cytokeratins characteristic of basal stem cells, we hypothesized that these 2 markers could help in distinguishing BC from LCNEC. Immunostaining for TTF-1 was detected in 40.9% of pure LCNEC but in no BC or basaloid variant of SCC. In contrast, immunoreactivity for 34betaE12 was shown in all BC and basaloid variant of SCC but in only 1 LCNEC. Bouin fixation was less efficient than formalin in the immunodetection of both markers for its well-known deleterious effect on antigen preservation. Specificity of TTF-1 for LCNEC (100%) and that of 34betaE12 for BC (98.3%) exceeded that of NE markers for distinction of these 2 entities. These data show that TTF-1 and 34betaE12, in association with specific neuroendocrine markers, represent a useful panel of antibodies in differentiating carcinomas presenting with a solid pattern, palisading, or pseudorosettes, the expression of TTF-1 excluding the diagnosis of BC, and staining with 34betaE12 excluding pure LCNEC.

Topics: Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Nuclear Proteins; Retrospective Studies; Sensitivity and Specificity; Thyroid Nuclear Factor 1; Transcription Factors

An autopsy case of primary hepatic neuroendocrine carcinoma is described. A 72-year-old man had a large tumor mass measuring 22 cm in its greatest diameter and localized to the right, left and caudal lobes of the non-cirrhotic liver. Microscopically, the tumor was composed of middle-sized pleomorphic cells organized in ribbons or trabeculae, with scanty intersecting fibrous septae. Immunohistochemically, the tumor cells were positive for multikeratin C11, chromogranin A and synaptophysin. The patient also had metastases in the bone marrow. No alternative primary source of endocrine tumor was detected. The patient died 4 days after presentation.

Topics: Aged; Biomarkers, Tumor; Bone Marrow Neoplasms; Carcinoma, Neuroendocrine; Chromogranin A; Chromogranins; Fatal Outcome; Humans; Immunohistochemistry; Keratins; Liver Neoplasms; Male; Synaptophysin

Twenty-two cases of oncocytic thymic neuroendocrine carcinomas (carcinoid tumors) are presented. The patients were 17 men and 5 women between the ages of 26 and 84 years (median, 55 years). Nine were asymptomatic, and the tumor was found on routine examination; four patients presented with chest pain, two with weight loss, two with multiple endocrine neoplasia I syndrome, and one with Cushing's syndrome. Surgical resection of the mediastinal tumor was performed in all cases. The lesions were described as soft, light tan to brown, measuring from 3 to 20 cm in greatest diameter. On cut section, the tumors showed a homogeneous surface, soft consistency, and focal areas of hemorrhage. Microscopically, the lesions were characterized by nests or trabeculae of tumor cells that contained abundant granular to densely eosinophilic cytoplasm, with round to oval nuclei and in some areas prominent nucleoli. Mitotic figures ranged from 2 to 10 per 10 high-power fields; foci of comedonecrosis were seen in all cases. Immunohistochemical studies including broad spectrum keratin, CAM 5.2, chromogranin, synaptophysin, Leu-7, and p53 were performed in 12 cases. All of the tumors were strongly positive for CAM 5.2 low-molecular-weight cytokeratin, 11 showed strong positive reaction for Leu-7, 10 for broad-spectrum keratin, 8 for chromogranin, 7 for synaptophysin, and only 1 case showed focal positive staining of the tumor cells for p53. Clinical follow-up of 14 patients showed that 10 were alive between 2 and 11 years, and 4 patients had died of tumor from 4 to 11 years after diagnosis. Patients with good clinical outcome were those whose tumors showed low mitotic activity and minimal nuclear pleomorphism, whereas those who had died of their tumors were those whose tumors were characterized by marked nuclear atypia and higher mitotic rates. Oncocytic thymic carcinoids should be added to the differential diagnosis of anterior mediastinal neoplasms characterized by a monotonous population of tumor cells with prominent oncocytic features.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Carcinoma, Neuroendocrine; CD57 Antigens; Chromogranins; Female; Follow-Up Studies; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Synaptophysin; Thymus Neoplasms

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a newly proposed clinicopathologic entity; a few cases of LCNEC have been reported in other sites, such as the uterine cervix and the thymus. In the salivary glands, LCNEC is extremely rare and is not recognized as a specific entity in the World Health Organization classification. We retrospectively reviewed from our files 1675 cases of surgically resected primary parotid gland tumors and found 2 cases of LCNEC that fulfilled the criteria of pulmonary LCNEC. These cases occurred in 72- and 73-year-old men who had short histories of enlarging parotid gland tumors. The tumors were composed of large cells that exhibited organoid, solid, trabecular, and rosette-like growth patterns with a high mitotic rate and a conspicuous tendency for necrosis. The tumor cells were polygonal and characterized by a moderate nuclear:cytoplasmic ratio, coarse chromatin, and conspicuous nucleoli. Immunohistochemical examination revealed that the tumor cells were positive for six general neuroendocrine markers, cytokeratin, p53, bcl-2, epidermal growth factor receptor, and cyclin D1. Markedly reduced expressions of p21Waf1 and p27Kip1 were also noticed. The Ki-67 labeling index was more than 50% in both cases. One case showed loss of heterozygosity at TP53 accompanied by a p53 gene point mutation. Loss of heterozygosity at chromosome 9p21 was detected in both cases; one was accompanied by a p16 gene silent point mutation. Both patients died of the disease, with recurrence 5 months and 4 years after surgery, respectively. These findings indicate that LCNEC is a rare but distinct salivary gland tumor with highly aggressive biologic behavior. Multiple alterations of cell cycle regulators and tumor suppressor genes may play an important role in presenting the biologic characteristics of this rare parotid gland tumor.

Topics: Aged; Base Sequence; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Cyclin D1; Diagnosis, Differential; DNA Mutational Analysis; DNA, Neoplasm; ErbB Receptors; Humans; Keratins; Ki-67 Antigen; Loss of Heterozygosity; Lung Neoplasms; Male; Microscopy, Electron; Parotid Neoplasms; Point Mutation; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

We report the case of a 77-year-old woman in whom choroidal metastasis was the initial manifestation of a primary neoplasm presumed to be a pigmented pulmonary carcinoid tumor. The tumor initially was misdiagnosed cytologically and pathologically as a choroidal melanoma because it contained intrinsic melanin pigment. Positive immunoreactivity for cytokeratin, synaptophysin, chromogranin, and calcitonin and the presence of dense-core neurosecretory vesicles disclosed by electron microscopy established that the metastasis was a neuroendocrine tumor. Findings from systemic evaluation suggested that the primary tumor was located in the lung. The patient subsequently developed an intradural paraspinal metastasis, which also contained melanin pigment. The latter observation confirmed that the melanin in the uveal metastasis was intrinsic and did not represent secondary phagocytosis by tumor cells. Metastases from pigmented tumors of nonmelanocytic derivation are exceedingly rare but present a major diagnostic challenge to ocular pathologists and cytopathologists if the diagnosis is not suspected. Confirmatory immunohistochemical analysis should be obtained when a pigmented choroidal tumor thought to be a melanoma has atypical features. Arch Ophthalmol. 2000;118:841-845

Topics: Aged; Biomarkers, Tumor; Bronchial Neoplasms; Carcinoma, Neuroendocrine; Choroid Neoplasms; Chromogranins; Female; Humans; Keratins; Neoplasm Proteins; Synaptophysin

A small composite esophageal carcinoma measuring 1.5 x 1.4 x 1.0 cm is described. The tumor had a polypoid elevation with a superficial extension. Histologic examination revealed invasion of the submucosal layer and multidirectional differentiation, including neuroendocrine, squamous, ciliated glandular, and sarcomatous components. The neuroendocrine component was strongly positive for chromogranin and formed the bulk of the polypoid tumor. The squamous cell carcinoma exhibited a superficial extension. The adenocarcinoma was located in a small region of the tumor and contained ciliated glandular cells. The spindle cell sarcomatous component, which was positive for alpha-smooth muscle actin and negative for cytokeratin, exhibited no specific mesenchymal differentiation. Each component was found in 60%, 10%, 5%, and 25% of the tumor, respectively. Cases of small composite esophageal carcinoma containing various carcinomatous and sarcomatous components are extremely rare.

Topics: Actins; Adenocarcinoma; Carcinoma, Neuroendocrine; Carcinoma, Squamous Cell; Carcinosarcoma; Cell Differentiation; Chromogranins; Esophageal Neoplasms; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Muscle, Smooth

A primary neuroendocrine carcinoma with ganglion cell differentiation is described in a crural lymph node. The patient, a 48-year-old woman, presented a palpable lymph node of the crural region in March 1994. Histologically, the lesion was composed mostly of small cells immunoreactive for cytokeratins, neuron specific enolase and synaptophysin. The small cells merged gradually with areas containing ganglion cells immersed in a fibrillar matrix resembling neuropil. Ganglion cells expressed neuron-specific enolase, synaptophysin, neurofilament proteins and S-100 protein. Moreover, a minority of them featured cytokeratin expression. Electron microscopy was performed in the small cell component. These cells featured attenuated desmosomes and electron dense granules with an average size of 120 nm within bundles of intermediate filaments. Clinically, no tumour was found elsewhere despite extensive work-up over the 76-month follow-up period. Although similarities with previous cases of primary neuroendocrine carcinoma of lymph node, ganglion cell differentiation has never been described.

Topics: Carcinoma, Neuroendocrine; Cell Differentiation; Cell Nucleus; Cytoplasm; Female; Ganglia; Humans; Immunohistochemistry; Keratins; Leg; Lymph Nodes; Lymphatic Diseases; Microscopy, Electron; Middle Aged; Neurofilament Proteins; Phosphopyruvate Hydratase; S100 Proteins; Synaptophysin

A neuroendocrine carcinoma originating in the thymus was found in a 7-month-old, castrated male, Japanese Black calf. The neoplasm consisted largely of very primitive cells, characterized by the paucity of cytoplasmic organelles, but a few cells were immunoreactive for somatostatin or neurofilaments. The expression of both cytokeratin and neurofilament protein was a feature of neuroendocrine differentiation. This neoplasm considered to be a tumor of a thymic stem cell, with little but indubitable evidence of differentiation into somatostatin-producing cells.

Topics: Animals; Carcinoma, Neuroendocrine; Cattle; Cattle Diseases; Keratins; Male; Microvilli; Orchiectomy; Thymus Neoplasms

A Sertoli cell carcinoma of the ovary with lung metastases mimicking neuroendocrine carcinoma is presented. Lung metastases frequently occur. Primary and secondary tumors may exhibit similar growth patterns and differentiating primary from secondary tumors may be troublesome. This process may be more difficult when metastases occur from a tumor in which metastases are uncommon and morphologically resemble only a small portion of the primary tumor. We report the case of a 52-year-old woman who underwent resection of a 4,550-g Sertoli cell tumor of the ovary. Histologically, in addition to the characteristic tubular pattern of growth, 5% of the tumor consisted of poorly differentiated areas with tumor cells in sheets, a high mitotic rate, and areas of necrosis. Eleven months after this surgery she presented at a different institution with multiple pulmonary nodules. Microscopic examination of a subsequently resected lung nodule showed histologic findings similar to those of the poorly differentiated areas of the ovarian tumor and initial immunohistochemical studies showed positive staining for cytokeratin, neuron-specific enolase, and focal positivity for synaptophysin. Without knowledge of the ovarian tumor the lung lesion was interpreted as large-cell neuroendocrine carcinoma. On review of the clinical history and comparison with the previous surgical material, however, both tumors showed similar light microscopy and immunohistochemical reactivity, and a final diagnosis of metastatic Sertoli cell tumor was made. Immunohistochemical staining for inhibin revealed weak positivity in the poorly differentiated areas of the ovarian tumor but not in the lung metastasis. This is one of the rare reports of ovarian Sertoli cell tumor metastasizing to the lungs and it emphasizes the importance of complete clinical histories, ancillary studies, appropriate sampling, and review of archival material in such unusual cases.

Topics: Carcinoma, Neuroendocrine; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Inhibins; Keratins; Lung Neoplasms; Middle Aged; Ovarian Neoplasms; Phosphopyruvate Hydratase; Sertoli Cell Tumor; Synaptophysin

A primary hepatic carcinoma with a neuroendocrine pattern was detected in an adult female California sea lion (Zalophus californianus) found dead on Granito Island in the Gulf of California (Mexico) in January 1996. At necropsy, several light yellow nodules of different sizes were observed on the entire surface of the liver and spleen. Microscopic examination of these nodules using routine haematoxylin-eosin stain, revealed cubic, polyhedral and pleomorphic cells with three to four bizarre mitotic figures per field (40X). An immunohistochemistry test revealed a positive reaction of indirect immunoperoxide to cytokeratin (CK2). This is the first known case of a primary hepatic carcinoma in free-ranging California sea lions from Mexican waters.

Topics: Animals; Carcinoma, Neuroendocrine; Female; Immunohistochemistry; Keratins; Liver; Liver Neoplasms; Mexico; Sea Lions; Spleen; Splenic Neoplasms

Leukocyte common antigen (CD45/LCA) and keratin expression are generally mutually exclusive in diagnostic surgical pathology. CD45 reactivity is a reliable indicator of the hematolymphoid nature of a tumor, whereas keratin reactivity is typical of epithelial differentiation (carcinomas and some sarcomas). Some lymphomas, however, might lack detectable CD45 expression, whereas occasional ones might express keratins. CD45 immunoreactivity has been considered exquisitely specific for hematopoietic cells. We report three undifferentiated or neuroendocrine carcinomas that showed membrane-associated immunoreactivity for CD45 in addition to showing distinctive keratin cocktail (AE1/AE3) and epithelial membrane antigen reactivity (all cases); also, keratin 7 was demonstrated in one case and keratin 19 in another. Two cases were lymph node metastases of undifferentiated carcinomas, one of them from the lungs and the other of an unknown origin; the former case showed neuroendocrine features. The third case represented a pulmonary large-cell undifferentiated carcinoma. These cases were negative for lineage-specific leukocyte antigens and did not show clonal immunoglobulin heavy-chain gene rearrangements. Electron microscopic studies demonstrated desmosomes and keratin-like tonofilaments in all three cases, thus confirming the epithelial nature of these tumors. The exceptional membrane staining for CD45 seen in these undifferentiated carcinomas might be comparable to experimentally detected incorporation of leukocyte antigens into the cell membranes of nonleukocytic cells in a leukocyte-rich environment. This rare diagnostic pitfall should be considered in the diagnostic surgical pathology of undifferentiated tumors. It is best avoided by employing a panel of leukocyte and epithelial antigens and by use of electron microscopy, if possible.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Desmosomes; Diagnosis, Differential; Humans; Immunoenzyme Techniques; Intermediate Filaments; Keratins; Leukocyte Common Antigens; Lung Neoplasms; Lymphatic Metastasis; Lymphoma; Male; Middle Aged; Neoplasms, Unknown Primary

Primary small cell undifferentiated carcinomas (SCUCs) are unusual tumors of the colon and rectum. Histologically, these lesions represent a spectrum of neuroendocrine differentiation, with oat cell carcinoma being the most primitive subtype and carcinoid tumors being the most differentiated. This observation is supported by immunohistochemical and ultrastructural findings. We report a case of SCUC of the rectum in a patient with ulcerative colitis. To date, there have been only two reported cases of primary SCUC associated with ulcerative colitis. Recent theories of tumorigenesis attribute most colorectal cancers to a single, pluripotential mucosal stem cell, regardless of the tumor's histologic type.

Topics: Carcinoma, Neuroendocrine; Carcinoma, Small Cell; Colitis, Ulcerative; Fatal Outcome; Female; Humans; Immunohistochemistry; Intestinal Mucosa; Keratins; Middle Aged; Neoplastic Stem Cells; Phosphopyruvate Hydratase; Rectal Neoplasms; Rectum; Synaptophysin; Tumor Suppressor Protein p53

The female genital tract is an infrequent site of metastasis, particularly for extragenital primaries. The ovary and vagina are the sites within the female genital tract that are the most frequently affected. The uterine corpus, especially the endometrium, is a distinctly unusual site of involvement. Primary lung cancer is the source of metastatic tumor to the female genital tract in less than 5% of patients. In the reported instances of endometrial involvement by a primary lung cancer, adenocarcinoma has been the reported subtype. Here, we report a case of well-differentiated neuroendocrine carcinoma of the lung metastatic to the endometrium in a 68-year-old woman with postmenopausal bleeding. Immunohistochemical studies were performed to confirm the neuroendocrine nature of the neoplasm.

Topics: Aged; Biomarkers, Tumor; Carcinoma, Neuroendocrine; Endometrial Neoplasms; Female; Humans; Immunoenzyme Techniques; Keratins; Lung Neoplasms; Nerve Tissue Proteins

Primary neuroendocrine carcinoma of the skin (PNECS) is a rare cutaneous tumor occurring predominantly on sun-exposed skin of elderly people. This histomorphological appearance of this aggressive tumor can be highly variable depending on the predominating growth pattern. We present an unusual case of PNECS: the tumor masked by a dense lymphoid infiltrate with a well-formed follicular growth pattern. In these cases of PNECS, the differential diagnosis must be extended to lymphoid neoplasms as well as lymphoepithelial neoplasms.

Topics: Aged; B-Lymphocytes; Carcinoma, Neuroendocrine; Carcinoma, Squamous Cell; Cell Nucleus; Chromogranin A; Chromogranins; Cytoplasm; Diagnosis, Differential; Facial Neoplasms; Female; Humans; Immunohistochemistry; Keratins; Lymphocytes; Lymphoid Tissue; Neurofilament Proteins; Phosphopyruvate Hydratase; Skin; Skin Neoplasms

Immunohistochemical and flow cytometric analysis using formalin-fixed, paraffin-embedded sections was performed on 10 neuroendocrine carcinomas of the skin (NCS). Grimelius staining was positive in seven tumors. All tumors showed coexpression of CAM 5.2 and neuron-specific enolase with paranuclear dot-like or diffuse cytoplasmic reactivity. Neurofilament was positive in five cases, chromogranin in six, calcitonin and carcinoembryonic antigen in two each, and somatostatin and S-100 protein in one each. Eight primary lesions were diploid and the remaining two were aneuploid; however, two diploid NCS presented as aneuploid metastatic tumors. The follow-up periods ranged from 3 to 66 months (mean 13.6). Six patients died of metastatic diseases between 3 and 33 months (mean 9.2) after the diagnosis. There were no significant correlations among histologic features, DNA ploidy, S-phase fraction, and clinical outcome of the patients with NCS. These results indicate that a panel of antibodies may be required for immunohistochemical confirmation of neuroendocrine differentiation and that a flow cytometric analysis is not a good tool to predict the biologic behavior of NCS.

Topics: Aged; Aged, 80 and over; Aneuploidy; Calcitonin; Carcinoma, Neuroendocrine; Chromogranins; Female; Flow Cytometry; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Phosphopyruvate Hydratase; Ploidies; S100 Proteins; Skin Neoplasms; Somatostatin

A 21 cm retroperitoneal cystic mass was excised from a 71 year old woman. The cyst was filled with a hemorrhagic fluid and contained a 5 cm parietal hemorrhagic nodule. On histology, the nodule was composed of a uniform population of round cells arranged in trabeculae and nests. The neoplastic cells were immunoreactive to cytokeratin, EMA, NSE, chromogranin A, pancreatic polypeptide (PP) and Gastrin (G). Ultrastructural observation of neurosecretory granules confirmed the neuroendocrine nature of the tumor. No other lesions were detected and a diagnosis of primary epithelial neuroendocrine tumor was rendered. The histogenesis of the tumor including the possibility of a paraganglionic origin is discussed.

Topics: Aged; Biomarkers, Tumor; Calcitonin; Carcinoma, Neuroendocrine; Diagnosis, Differential; Epithelium; Female; Gastrins; Humans; Keratins; Neoplasm Proteins; Pancreatic Polypeptide; Paraganglioma; Retroperitoneal Neoplasms; S100 Proteins; Teratoma

We investigated the expression of keratin subtypes 7, 8, 10, 13, 14, 17, 18 and 19 in the normal cervix, in cervical intraepithelial neoplasia (CIN) lesions and in cervical carcinomas, using a selected panel of monoclonal keratin antibodies, reactive with routinely processed, formalin fixed paraffin embedded tissue fragments. The reaction patterns derived for each keratin antibody were compared with known expression patterns of the various epithelia, previously examined in frozen tissues. Although the reactivity of the antibodies was generally acceptable, considerable modifications to the manufacturers' staining instructions were often necessary. For some antibodies, which were previously thought to be reactive with fresh frozen tissue only, we developed staining protocols rendering them reactive with routinely processed material. As with previous findings in frozen sections we observed increasing expression of keratins 7, 8, 17, 18 and 19 with increasing grade of CIN. In cervical carcinomas the differences in keratin detectability between the main categories were more pronounced than in frozen sections, probably due to fixation and processing. For routine pathology, keratin phenotyping of cervical lesions may be of value in classification. The fact that keratin 7 was detected for the first time in reserve cells, and that this keratin was also found to be expressed in a considerable number of CIN lesions and cervical carcinomas supports the suggestion that reserve cells are a common progenitor cell for these lesions.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Carcinoma, Adenosquamous; Carcinoma, Neuroendocrine; Carcinoma, Squamous Cell; Epithelial Cells; Epithelium; Female; Histological Techniques; Humans; Immunoenzyme Techniques; Keratins; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Topics: Aged; Biopsy, Needle; Carcinoma, Neuroendocrine; Female; Humans; Keratins; Magnetic Resonance Imaging; Neoplasms, Unknown Primary; Phosphopyruvate Hydratase; Spinal Neoplasms; Thoracic Vertebrae