Neuroendocrine Morphology Research Articles

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Mixed hepatocellular carcinoma-neuroendocrine carcinomas (HCC-NECs)1 are rare, and they usually carry a poor prognosis. We report a fascinating case of mixed HCC-NEC — the neuroendocrine component of the tumor was diagnosed retrospectively after discovery of the metastatic neuroendocrine carcinoma (NEC).2 A 50-year-old man with cirrhosis underwent resection of a 2.7 cm hepatocellular carcinoma (HCC)3 at the segment II of the liver. Thirteen months after the surgery he had local recurrence in the liver that was treated with radio-embolization. Eighteen months after the initial diagnosis, he was found to have metastatic NEC in the left shoulder. Later, re-evaluation of the previously resected liver tumor revealed a small focus of tumor cells with neuroendocrine morphology within the tumor, which were negative for HepPar1 and positive for synaptophysin, whereas the majority of the tumor cells were positive for HepPar1 and negative for synaptophysin that reclassified the liver tumor as a combined type of mixed HCC-NEC tumor. Upon discovery of the metastatic NEC, the patient was treated with eight cycles of cisplatin and etoposide with a partial response. Nonetheless, his disease progressed two months after finishing chemotherapy, and he was treated with nivolumab for two cycles. In addition, he received palliative radiation to different skeletal metastases. The patient died of sepsis thirty-three months after the initial diagnosis of liver tumor. In conclusion, mixed HCC-NECs are rare and aggressive— an accurate diagnosis may require a high degree of clinical suspicion and re-evaluation of the pathological specimen, especially when one of the components is scarce. Strategic use of multiple modalities of treatment may prolong the life of patients with this type of aggressive tumor.

Neuroendocrine carcinomas of the pancreas with 'Rhabdoid' features.

Neuroendocrine carcinomas of the pancreas are rare neoplasms whose morphologic features generally mirror those seen in neuroendocrine tumors in other organs. Rarely, however, they may display unusual morphologic appearances that can introduce difficulties for diagnosis. We report four cases of primary neuroendocrine carcinomas of the pancreas (islet cell tumors) that were characterized by prominent "rhabdoid" features of the tumor cells. The lesions occurred in two men and two women 37-79 years of age who presented with symptoms of biliary obstruction and epigastric pain; one patient had recurrent gastric ulcers and an elevated gastrin level. The tumors were located in the head and tail of the pancreas and measured 2.5-4.5 cm in greatest diameter. Histologic examination revealed sheets of monotonous tumor cells with uniform round nuclei showing dispersed chromatin and containing abundant densely eosinophilic cytoplasmic inclusions that displaced the nuclei toward the periphery. In all cases, the rhabdoid elements appeared to merge with areas showing a more conventional neuroendocrine morphology. Immunohistochemical studies in all cases showed strong cytoplasmic positivity of the rhabdoid tumor cells for chromogranin, synaptophysin, and cytokeratin. Recognition of this unusual morphologic appearance is of importance to avoid mistaking these lesions for other types of malignant neoplasm.

Large cell neuroendocrine carcinoma and large cell carcinomas with neuroendocrine morphology of the lung: prognosis after complete resection and systematic nodal dissection

Background Large cell neuroendocrine carcinoma (LCNEC) and large cell carcinoma with neuroendocrine morphology of the lung are both currently classified as subtypes of large cell carcinomas according to the World Health Organization IASLC classification system for lung and pleural tumors. Prognosis is reported as similar to that of small cell carcinomas. There is no consensus on management of this subset and adjuvant chemotherapy is recommended by some for early stage LCNEC to impact long-term prognosis. We retrospectively reviewed a cohort of patients at our institution who had this type of tumor to determine factors that might influence survival. Methods Twenty-one cases of LCNEC and large cell carcinoma with neuroendocrine morphology were identified in the files of the Royal Brompton Hospital between 1986 and 1999. All patient data were reviewed, and complete follow-up was achieved with 20 of these patients. Results Of the 21 patients identified, 20 underwent resection with systematic nodal dissection in 18. There was no in-hospital mortality. Of those patients fully staged by systematic nodal dissection, 9 were stage I, 5 were stage II and 4 were stage III. Median follow-up was 25 months (range, 2 to 120 months). At the time of review, 11 patients were alive and free of disease. One patient was alive and free of disease when lost to follow-up. Nine patients had died, 7 related and 2 unrelated to disease. The 5-year actuarial survival for the entire group was 47%. The actuarial survival of accurately staged, stage I patients at 5 years was 88%. The actuarial survival of patients in stage II and III was 28% at 5 years. Conclusions LCNEC and large cell carcinoma with neuroendocrine morphology are aggressive tumors, but patients with completely resected disease after systematic nodal dissection have a better prognosis than previously described. Patients with more advanced disease have a poor prognosis.

Immunohistochemical neuroendocrine differentiation is an independent prognostic factor in surgically resected large cell carcinoma of the lung

The clinical significance of neuroendocrine (NE) differentiation is unclear in large cell carcinoma (LCC) of the lung. Fifty-five surgically resected carcinomas of the lung with an original pathologic diagnosis of LCC were reviewed histologically with special attention to NE morphology. Antibodies against neural cell adhesion molecule (NCAM), chromogranin A (CGA) and synaptophysin (SY) were used to confirm the NE differentiation. Thirteen (24%) cases were classified as large cell neuroendocrine carcinoma, 9 (16%) as LCC with NE differentiation, and 33 (60%) as pure LCC. There was no significant difference in overall survival between the three groups. When the 55 carcinomas were divided into three groups depending on the number of NE marker expression, there was significantly better overall survival in the NE⪰2 ( P=0.02). Multivariate analysis proved NE⪰2 was an independent predictor of survival. The number of NE markers was more important in terms of survival than histological sub-classification.

Neuroendocrine differentiation of human prostatic primary epithelial cells in vitro.

Dispersed prostatic neuroendocrine cells are involved in growth regulation of the prostate and are considered to play a role in the pathogenesis of prostate carcinoma and benign prostatic hyperplasia (BPH). They are meant either to be derived from the neural crest during embryogenesis or by direct differentiation of the cells from locally present precursor cells. An in vitro model was developed for human prostatic epithelial and neuroendocrine cell differentiation. Minced explants from radical prostatectomies were seeded on collagen I-coated plates. The majority of outgrowing cells were basal cells, positive for cytokeratin markers K 5/14 and CD 44, as determined by confocal laser scanning microscopy. A small fraction of interdispersed single cells expressing c-kit, which is found on pluripotent precursors, was identified by immunofluorescence. From these basal cells, in vitro differentiation of cells with neuroendocrine morphology could be achieved within 3 days. These were at rest, i.e., non-bromodeoxyuridine incorporating cells and characteristically coexpressed K 5/14, K 18, and the neuroendocrine marker chromogranin A. Luminal cells staining for K 8 or 18 were not observed. Neuroendocrine differentiation of adult prostatic cells was achieved in vitro, favoring the hypothesis that neuroendocrine cells are derived from peripheral precursor cells. The acceleration of this differentiation pathway may be the reason for the increased presence of neuroendocrine cells in areas of epithelial hyperplasia in BPH.

Prostatic adenocarcinoma metastases mimicking small cell carcinoma on fine-needle aspiration.

Prostate adenocarcinoma (PA) is known to metastasize widely to bone, lung, lymph nodes, and other sites. We have observed a rare, although distinctive, neuroendocrine (NE) cytomorphology of metastatic PA on fine-needle aspiration (FNA) that mimics small cell carcinoma (SCC). From a total of 117 cases, eight cases of metastatic PA diagnosed on FNA showed cytomorphologic features indistinguishable from SCC. All specimens were reviewed, along with immunoperoxidase (IPOX) studies using prostate specific (PSA, PSAP) and NE markers (synaptophysin, chromogranin, etc.). The patients ranged in age from 51-68 (mean age = 63). The PSA levels at the time of FNA ranged from <0.1 to 2,892 ng/ml (normal postprostatectomy <0.2 ng/ml). Sites of FNA included liver (two), soft tissue (five), and lymph node (one). FNA was performed from 11 mo to 6 yr after the initial diagnosis of the primary tumor. All primary PA were of high Gleason grade ranging from 7-9. None of the primary PA showed neuroendocrine morphology. Cytomorphologic characteristics observed on FNA included predominantly single cells with occasional sheets or loose cell aggregates. A predominant NE nuclear morphology was evident (i.e., hyperchromasia, fine dusty chromatin, inconspicuous nucleoli, nuclear molding, chromatinic crush artifact, karyorrhexis, mitoses, etc.), with none of the tumors displaying glandular formation. Taken together, these features gave these metastases a cytomorphology indistinguishable from SCC. IPOX studies revealed PSA-positivity (5/7), PSAP-positivity (4/7), and only focal NE markers positivity (3/6). Metastatic prostate carcinoma may rarely mimic a SCC (6.8% in this study). This often necessitates further patient workup to identify the primary source for the patient's metastasis, particularly if the patient has multiple lesions. An accurate diagnosis of these lesions as PA metastases is essential for effective, timely treatment and therapeutic design.

Focal neuroendocrine differentiation in non-small cell carcinoma is not predicted by pre-operative routine investigation

Aims: Between 10 and 35% of resected non-small cell carcinomas of the lung show focal neuroendocrine differentiation. The significance of this is uncertain but recent studies have suggested that these tumours may be more responsive to chemotherapeutic agents than other non-small cell carcinomas. This study was undertaken to determine if focal neuroendocrine differentiation in surgically resected non-small cell carcinomas could be predicted in patients who had undergone traditional routine pre-operative diagnostic investigations. Methods: Sixty-six consecutive resections for non-small cell carcinoma were reviewed for the presence of focal neuroendocrine morphology or positive immunohistochemical staining with neuroendocrine markers. Pre-operative biopsy and cytology samples from these patients were then sought for similar assessment. Results: Ten of the 66 cases showed either morphological or immunohistochemical evidence of neuroendocrine differentiation. All 10 patients had undergone pre-operative investigation including bronchoscopy but in only four were pre-operative diagnostic samples obtained (two cytology and two biopsies). None of these specimens showed features to suggest the presence of neuroendocrine differentiation within the resected tumours. Conclusion: The presence of focal neurendocrine features in an unselected series of resected non-small cell carcinomas was not predicted by traditional pre-operative diagnostic investigations This indicates that focal neuroendocrine differentiation in patients with unresectable non-small carcinoma cannot be reliably identified for inclusion in clinical trials using traditional investigate approaches.

Clinical characterization of pulmonary large cell neuroendocrine carcinoma and large cell carcinoma with neuroendocrine morphology.

Large cell carcinoma has been classified as four potential types based on its neuroendocrine morphology and evidence of neuroendocrine differentiation discernible by immunohistochemistry or electron microscopy. However, the clinical relation among these four categories has not been clearly defined. In 1999, the World Health Organization (WHO) categorized large cell neuroendocrine carcinoma as a variant of large cell carcinoma. MATERIAL AND METHODS The authors analyzed 119 cases of large cell carcinoma from a total of 2070 primary lung carcinoma cases resected surgically between 1969-1999. Using light microscopy, electron microscopy, and immunohistochemical staining, the authors reclassified these cases into large cell neuroendocrine carcinoma (LCNEC), large cell carcinoma with neuroendocrine differentiation (LCCND), large cell carcinoma with neuroendocrine morphology (LCCNM), and classic large cell carcinoma (CLCC). In multivariate analyses, the authors found that large cell carcinoma with neuroendocrine features, which combined LCNEC, LCCND, and LCCNM, impacted both the overall survival and disease-free survival of patients. The clinical behavior of LCCNM was similar to that of LCNEC. Large cell carcinomas with neuroendocrine features appear to be more clinically aggressive than CLCCs. The authors' findings suggest that the histologic identification of neuroendocrine features in tumor tissue from patients diagnosed with large cell carcinoma of the lung may have clinical relevance.

Adjuvant chemotherapy for large cell carcinoma with neuroendocrine features.

In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma, large cell carcinoma with neuroendocrine differentiation, and large cell carcinoma with neuroendocrine morphology as a variant of large cell carcinoma. Patients with large cell carcinoma with neuroendocrine features have poor prognoses, comparable to those for small cell lung carcinoma. Small cell lung carcinoma is sensitive to chemotherapy; however, it is still unclear whether large cell carcinoma with neuroendocrine features is responsive to adjuvant chemotherapy. The authors analyzed 73 patients with large cell carcinoma with neuroendocrine features who underwent resection of the tumor and studied the effect of adjuvant chemotherapy for large cell carcinoma with neuroendocrine features. In patients with Stage I disease, the overall survival for patients with adjuvant chemotherapy based on cisplatin, carboplatin, or cyclophosphamide, which were used as standard chemotherapy for small cell lung carcinoma, were significantly higher than the overall survival for patients without adjuvant chemotherapy. In patients with Stage II, III, and IV disease, there was no significant difference between patients with adjuvant chemotherapy and without adjuvant chemotherapy. Adjuvant chemotherapy based on cisplatin, carboplatin, or cyclophosphamide prolongs survival of patients with large cell carcinoma with neuroendocrine features in early stage.

Neuroendocrine tumours of the lung

Neuroendocrine differentiation is common in pulmonary tumours and these neoplasms now have a separate category in the latest World Health Organization classification. Tumours with a neuroendocrine morphology comprise a spectrum of lesions in which four reasonably well-defined entities are recognised, the typical and atypical carcinoids and the large cell and small cell neuroendocrine carcinomas. Their differential diagnosis can be difficult, but the criteria for their distinction are now reasonably well-defined, the mitotic count and the presence and pattern of necrosis being crucial for separating the first three tumours in the spectrum, and cytological characteristics being most important in distinguishing large cell from small cell carcinomas. Immunochemical identification of neuroendocrine markers is ineffective in separating them, but may be very useful in distinguishing them from non-neuroendocrine tumours arising within or metastasising into the lungs. Also now included in the classification are three further groups of lesions. One comprises morphologically non-neuroendocrine tumours which display immunochemical or ultrastructural features of neuroendocrine differentiation, one comprises proliferative lesions of pulmonary neuroendocrine cells that may have preneoplastic potential and one includes a miscellany of tumours displaying neuroendocrine differentiation but that do not fall readily into the above categories.

Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid.

Neuroendocrine tumors of the lung embrace a spectrum from low-grade typical carcinoid (TC), intermediate-grade atypical carcinoid (AC), and high-grade categories of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). We studied 200 neuroendocrine lung tumors to critically evaluate the Arrigoni histologic criteria for AC using statistical analysis to delimit more rigorously an intermediate survival for AC between TC and the high-grade tumors of LCNEC and SCLC. Histologic features that might predict prognosis were used for Kaplan-Meier and Cox proportional hazards survival analysis, and an optimal mitotic range for AC was calculated. The optimal mitotic range for AC was 2 to 10 mitoses per 2 mm2 of viable tumor (10 high-power fields). Based on this finding, we collapsed mitoses into three categories (< 2; 2-10; > or = 11) and performed Cox multivariate analysis for all 200 neuroendocrine tumors. Mitotic counts were the only independent predictor of prognosis. Based on this analysis, we propose that AC be defined as a tumor with neuroendocrine morphology, mitotic counts between 2-10 per 2 mm2 of viable tumor (10 high-power fields), or coagulative necrosis. Using these criteria, the 200 neuroendocrine tumors were classified as 51 TC, 62 AC, 37 LCNEC, and 50 SCLC. The 5- and 10-year survival was 87% and 87% for TC, 56% and 35% for AC, 27% and 9% for LCNEC, and 9% and 5% for SCLC, respectively. After stratification for stage, survival for AC was significantly worse than for TC (p < 0.001); for LCNEC and SCLC it was significantly worse than for AC; but the survival for LCNEC was no different than that for SCLC.

Neuronal differentiation is accompanied by NSP-C expression.

Neuroendocrine-specific protein (NSP) reticulons are expressed in neural and neuroendocrine tissues and cell cultures derived therefrom, while most other cell types lack NSP-reticulons. Three major subtypes have been identified so far, designated NSP-A, NSP-B, and NSP-C. We have investigated the correlation between the degree of neuronal differentiation, determined by morphological and biochemical criteria, and NSP-reticulon subtype expression. For this purpose, several human neuroblastoma cell lines, exhibiting different degrees of neuronal differentiation, were examined immuno(cyto)chemically. It became obvious that the expression of NSP-C, as detected by immunofluorescence microscopy and Western blotting, is most prominent in cell lines with a high degree of neuronal differentiation, such as LA-N-5. Such highly differentiated cells also express other neural and neuroendocrine markers, such as neural cell adhesion molecule (NCAM), neurofilament proteins, synaptophysin, and chromogranin. NSP-A was observed in all cell lines to a different extent. However, no clear correlation was observed with the degree of neuronal differentiation as defined by other neuronal and neuroendocrine markers or morphology. NSP-B could not be detected. The induction of neuronal differentiation with nerve growth factor, dbcAMP, and retinoic acid in the rat pheochromocytoma cell line PC12 and the human teratocarcinoma cell line hNT2, respectively, induced the expression of NSP-A and NSP-C in these cell lines parallel to the induction of neurofilament protein expression. It is concluded that NSP-C expression, in particular, is strongly correlated with neuronal differentiation.

Intrinsic controls of intracellular calcium and intercellular communication in the regulation of neuroendocrine cell activity.

1. The magnocellular hypothalamoneurohypophysial system, consisting chiefly of the supraoptic and paraventricular nuclei and their axonal projections to the pituitary neural lobe, has become a model for the study of neuroendocrine cell morphology, function, and plasticity. 2. Decades of research have produced a wealth of knowledge about the physiological conditions that activate this system, the peripheral target tissues affected by its outputs, and its capacity to undergo use-dependent, reversible reorganization. 3. Earlier research on the neural control of this system concentrated largely on the synaptic inputs that influence the activity of these magnocellular neurons and, while that task is still far from completed, methods have now been developed that permit insights to be gained into the control exercised by intrinsic cellular and molecular mechanisms. 4. This article reviews the current state of knowledge of roles played by these intrinsic mechanisms, including influences of intracellular calcium buffering, calcium release from internal stores and intercellular communication through gap junctions, in the control of neuroendocrine cell activity.

Neuroepithelial endocrine and nervous system in the respiratory tract of Cynops pyrrhogaster with special reference to the distribution of nitric oxide synthase and serotonin.

The respiratory tract of urodeles harbours an intramural nerve network comprising an innervated system of neuroepithelial endocrine (NEE) cells. However, striking differences have been noted between phylogenetically closely related species. Zamboni- or formaldehyde-fixed whole-mount preparations and sections of the saclike lungs of a Japanese salamander, Cynops salamander, Cynops pyrrhogaster, have been investigated for the immunocytochemical detection of nitric oxide synthase (NOS), serotonin (5-HT), VIP, somatostatin, calcitonin, and bombesin; for the enzyme-cytochemical demonstration of NADPH diaphorase (NADPHd); and for formaldehyde-induced fluorescence. In addition, the ultrastructural morphology has been examined by using glutaraldehyde/osmium tetroxide fixed lung tissues. Ovoid 5-HT-immunoreactive (IR) NEE cells occur singly or grouped in the ciliomucous epithelium of the trachea and lungs of Cynops, and a few somatostatin-, calcitonin-, and bombesin-like IR NEE cells are also observed. These cells exhibit a characteristic neuroendocrine morphology as seen with the electron microscope. In addition, large numbers of 5-HT-IR interstitial cells, with round to oval cell bodies and two or three long, slender, sometimes branching processes, are located preferentially along large blood vessels in the connective tissue capsule of the lung and trachea. Immunoelectronmicroscopy shows that 5-HT is localized over large dense granules in the cell bodies and processes of these interstitial cells. NOS-like immunoreactivity occurs in a nerve plexus composed of thick nerve bundles and nerve cells, and in a fine varicose nerve network that originates at least partly from intrapulmonary NOS-containing nerve cells. VIP-like immunoreactivity appears to be colocalized with NOS in the latter network. All NOS-positive nerve fibres in the lungs of Cynops pyrrhogaster and Ambystoma mexicanum stain for NADPHd. It is concluded that the pulmonary NEE cells observed in Cynops pyrrhogaster are similar to those described in other vertebrate species and that the 5-HT-IR interstitial cells resemble mast cells. In addition, nitric oxide is likely to be a bioactive substance involved in nonadrenergic, noncholinergic inhibitory neurotransmission in the pulmonary nervous system of urodeles, where it may be colocalized with VIP.

Univariate and Multivariate Models for Evaluating Long-Term Changes in Neurobiological Development, Maturity and Aging

Publisher Summary This chapter focuses on the univariate and multivariate models for evaluating long-term changes in neurobiological development, maturity and aging. Studies of development are restricted from conception to sexual maturity and of aging to the progressive decline after reproductive maturity. Multicellular organisms have life cycles which can be subdivided after conception into development, maturity and senescence. Although these three stages represent only different aspects of a life cycle, there has been a separation of these stages, particularly for species with long life spans. Development has been defined in terms of cellular differentiation, growth and increasing functional capacity because of maturation. Maturity has generally been associated with reproductive capacity. Decreases in modifiability of behavior and the brain from development to maturity and senescence have been attributed to greater chemical and morphological “plasticity” of the brain prior to its adult organization. Results from a multidisciplinary study are presented in which stress effects on behavior, brain and neuroendocrine chemistry and morphology are examined during maturity and senescence in C57BL/I 0 mice.