Exocrine and endocrine modulation in common gastric carcinoma

Diagnostic and prognostic implications of endocrine differentiation were evaluated in 103 common gastric adenocarcinomas and undifferentiated carcinomas. Maturely differentiated exocrine and endocrine phenotypes were evaluated by using gastric exocrine and endocrine markers along with intestinal exocrine and endocrine markers. Immunohistochemical analysis revealed that 66 tumors (64%) were positive for generic endocrine markers such as chromogranin A and/or synaptophysin. The 14 patients with more than 20% tumor cells positive for at least 1 endocrine marker experienced a poorer prognosis than patients with no (n = 37) or 1% to 20% (n = 52) positivity. The 16 carcinomas expressing the maturely differentiated exocrine gastric phenotype significantly correlated with poorer outcome compared with carcinomas with mature exocrine intestinal (n = 22) or mixed/gastrointestinal (n = 64) phenotypes. Among tumors expressing chromogranin A and/or synaptophysin, the maturely differentiated endocrine gastric phenotype (n = 26) was a negative prognostic factor compared with mature endocrine intestinal (n = 21) and mixed/gastrointestinal (n = 5) phenotypes. Endocrine differentiation and maturely exocrine/endocrine gastric phenotypes are associated with an unfavorable prognosis and may identify subsets of patients for tailored therapy.     

Divergent differentiation in neuroendocrine lung tumors

The classification of neuroendocrine (NE) lung tumors has been revised in the 1999 World Health Organization (WHO) classification of lung tumors, allowing sharp morphological definition of typical versus atypical carcinoids, and atypical carcinoids versus large cell neuroendocrine carcinoma (LCNEC), a newly described class of high-grade NE lung tumors which differs from small-cell lung cancer by a large-cell phenotype. Divergent differentiation accounts for the high frequency of glandular differentiation with mucin production, and ultrastructural features in carcinoids and LCNEC, and low frequency of squamous differentiation in both LCNEC and SCLC. Specific NE markers (chromogranin, synaptophysin, neural cell adhesion molecule) and epithelial markers consistently negative in neuroendocrine components (cytokeratins 1, 5, 10, 14; epidermal growth factor (EGF)-receptor, human leukocyte antigen beta 2 (HLA-beta2) microglobuline) help to recognize divergent differentiation in NE tumors. At morphological level, divergent differentiation in NE tumors is recognized in WHO classification as variants: combined SCLC and combined LCNEC. The derivation of all lung tumors from a common endodermal stem cell and adoption of amine precursor uptake and decarboxylation properties by this endodermal stem cell explains divergent differentiation in NE lung tumors and the occurrence of NE subsets in NSCLC.     

Immunohistochemical analysis of colon carcinomas applying exocrine and neuroendocrine markers

Eighty colon carcinomas reflecting the histologic spectrum were studied immunohistochemically; their epithelial characteristics had been established by demonstrating cytokeratin polypeptides. Paraffin sections were immunostained with monoclonal antibody (Mab) A-80 that recognizes a mucin-like glycoprotein related to exocrine differentiation. Sequential sections were immunostained with neuroendocrine (NE) differentiation antibodies: NSE, human chromogranin A, serotonin, somatostatin, substance P and VIP. Twenty-one/80 carcinomas immunoreacted exclusively with Mab A-80; these included adenocarcinomas with variably defined glands, colloid, "solid", and linitits plastica carcinomas. Eleven/80 carcinomas immunoreacted only with antibodies to NE markers. Twenty-nine/80 carcinomas of histologically variable patterns expressed both exocrine and NE antigens. A notable group of 19 adenocarcinomas immunostaining with Mab A-870 included a minority NE cell subpopulation. We tentatively conclude that given a limited battery of immunoprobes, colon carcinomas comprise 4 groups: 1) pure exocrine carcinomas, 2) pure NE carcinomas, 3) mixed exocrine and NE carcinomas, and 4) exocrine carcinomas with occasional NE cells. Thus, phenotypically mixed exocrine and NE carcinomas comprise the largest group while the second largest group exhibited exclusively features of exocrine phenotype. Preliminary clinical correlative data indicate that pure NE colon carcinomas behave more aggressively than their exocrine counterparts; moreover, colon carcinomas containing a NE subpopulation, even if small, also seem to behave worse than their counterparts without an NE subpopulation.     

Immunoreactivity for epithelial and neuroendocrine antibodies are useful in the differential diagnosis of lung carcinomas

The histologic classification of pulmonary neoplasms can have important implications regarding appropriate management of patients. Although the histologic classification of lung tumors is predominantly based on morphology, ancillary studies such as immunohistochemistry can be used in difficult cases, and the diagnosis of large cell neuroendocrine carcinoma requires confirmation of neuroendocrine differentiation by immunohistochemistry or electron microscopy. We immunostained 142 lung tumors for B72.3, keratin 34betaE12, keratin 7, keratin 14, keratin 17, synaptophysin, and chromogranin to determine the utility of neuroendocrine markers and epithelial markers in the differential diagnosis. Among neuroendocrine carcinomas (small cell carcinoma and large cell neuroendocrine carcinoma), 84% (37 of 44) were chromogranin positive, 64% (21 of 36 small cell, 6 of 6 large cell neuroendocrine) were synaptophysin positive, 5% (2 of 43) were keratin 34betaE12 positive, 9% (4 of 44) were keratin 7 positive, and 5% (2 of 37) of small cell carcinomas and 50% (3 of 6) of large cell neuroendocrine carcinomas were B72.3 positive. Among non-neuroendocrine carcinomas, 5% (5 of 98) were chromogranin positive, 3% (3 of 96) were synaptophysin positive, and 97% (95 of 98) were positive for either keratin 34betaE12 or keratin 7 and 99% (97 of 98) were positive for either keratin 34betaE12, keratin 7 or B72.3. An antibody panel consisting of keratin 7, keratin 34betaE12, chromogranin, and synaptophysin separated 132 of 141 tumors (94%) into distinct groups. We conclude that immunostaining with both neuroendocrine markers and epithelial markers can be useful in the differential diagnosis of lung neoplasms.     

Application of monoclonal antibody 44-3A6 in the cytodiagnosis and classification of pulmonary carcinomas

Thirty-five pulmonary carcinomas were studied retrospectively with monoclonal antibody (MCA) 44-3A6 raised against a human adenocarcinoma cell line. The antibody was applied to cytologic smears of bronchial brushings originally stained with the Papanicolau method, and to conventional tissue sections. Ten of 12 adenocarcinomas (ADC) immunostained strongly in sections and smears, as did five of seven large-cell "undifferentiated" carcinomas (LCUC). Eight neuroendocrine carcinomas (NEC) and eight squamous-cell carcinomas (SCC) were negative, except for rare weakly positive foci. We conclude that MCA 44-3A6 can be effectively applied on cytologic smears, and that it could be valuable in the precise classification of pulmonary carcinomas. The immunoreactivity of the ADC and SCC was predictable. Positive immunostaining in some LCUC confirms that these constitute a heterogeneus tumor class that includes cases that are phenotypically ADC despite the absence of obvious glands. Occasional immunostaining in NEC suggests focal exocrine differentiation as previously noted by electron microscopy.     

Tissue microarray analysis of neuroendocrine differentiation and its prognostic significance in breast cancer

The aim of this study was to detect neuroendocrine differentiation (NE), to determine its association with major clinicopathological parameters of breast cancer, and to study the prognostic significance of NE differentiation in a group of breast carcinomas by using tissue microarray (TMA) methodology. NE differentiation was studied by using 3 markers, synaptophysin (Syn), chromogranin A (ChA), and neuron-specific enolase (NSE) in a group of 334 patients with breast carcinoma. TMA blocks were made by using duplicate 0.6-mm-diameter tissue cores from each paraffin block. Results of immunostaining were scored on a 4-point scale, that is, as negative, weak, intermediate, and strong immunoreactivity. Positive staining of breast cancers for any of the 3 NE markers was detected in 19.5% of cases. Expression of a single marker was present in 16.2% of cases, and expression of 2 or 3 markers in combination was detected in 3.3% of cases. There was no statistically significant correlation of NE phenotype with tumor morphology, except mucinous carcinoma (3 of 6 cases positive), estrogen receptor, progesterone receptor, or nodal status. A weak correlation was noted between synaptophysin staining and higher tumor grade (P = 0.029). Analysis of disease-specific and overall survival based on up to 20 years of follow-up data showed a correlation between NSE expression and improved disease-specific (P = 0.043) and overall survival (P = 0.03) in univariate but not in multivariate analysis. The expression of Syn and ChA, as well as coexpression of multiple NE markers, had no prognostic significance.     

Neuroendocrine expression in metastatic prostate cancer: evaluation of high throughput tissue microarrays to detect heterogeneous protein expression

The theory that poorly differentiated prostate carcinoma develops a neuroendocrine (NE) phenotype is controversial. Supportive data is variable with NE expression being observed in anywhere from 5% to 83% of prostate cancers. These percentages are derived from standard immunohistochemistry studies, which make no attempt to quantify the results. High-density tissue microarrays (TMAs), represent a novel method for evaluating up to 1000 tissue samples with a 0.6 mm diameter on a single glass slide. This high throughput technology for screening antibodies, however, requires validation to determine if TMAs are useful in evaluating heterogeneously expressed proteins such as the NE markers chromogranin A (CGA) and synaptophysin (SYN). This study compares results from standard slides to TMAs in 50 primary and metastatic prostate tumors taken from 12 rapid autopsies from men with hormone refractory prostate cancer. One hundred standard and 2 TMA slides were immunostained for CGA and SYN. Using standard slides, focal NE expression was seen in 1/12 primary prostate tumors. Overall, 13/100 (13%) standard slides showed focal NE expression for both primary and metastatic prostate tumors; NE expression was observed in 4/12 autopsy cases (33%) when all tumor sites per case were considered. 458 tissue elements (tumor and normal) were arrayed into one paraffin block. Seventy-three percent (332/458) of the elements placed into the TMA were confirmed histologically to represent tumor. Seventy-five percent (250/332) and 66% (218/332) could be evaluated for CGA and SYN expression, respectively. Six of the metastatic tumors expressed CGA and SYN or 2.4% (6/250; 95% CI = 0.9% to 5.2%) and 2.3% (6/218; 95% CI = 0.8% to 5.3%), respectively. In conclusion, only focal NE expression was observed by both methods (eg, standard and TMA slides). The focal expression in these advanced prostate tumors was unexpected given data from prostate tumor cell lines and animal models suggesting that progression to the NE phenotype parallels tumor progression. This study also supports the use of high density TMAs to screen for protein expression, even when expression is focal.     

Neuroendocrine differentiation in poorly differentiated lung carcinomas: a light microscopic and immunohistologic study

Frozen, unfixed tissue sections from 56 poorly differentiated, non-small cell primary lung tumors were examined by the immunoperoxidase technique with a panel of monoclonal antibodies to neuroendocrine (chromogranin A (CGA), synaptophysin (SYN), S-100) and intermediate filament (cytokeratin, vimentin, neurofilament) antigens. Although light microscopic features of neuroendocrine (NE) differentiation were not present, staining for CGA and/or SYN was identified in 5/17 (29%) large cell carcinomas (LCC) and 4/19 (21%) poorly differentiated adenocarcinomas (PDA). Diffuse, strong SYN staining was present in two LCC and one PDA. Heterogeneous intermediate filament expression (vimentin and/or neurofilament) was frequent (LCC, 10/17 (59%); PDA, 10/19 (53%)) and accompanied NE markers in 8/9 (89%) cases. Poorly differentiated squamous carcinomas were more homogeneous, with focal SYN in only 1/20 (5%) and focal presence of intermediate filaments other than cytokeratin in only 2/20 (10%). We conclude: (a) immunohistologic evidence of NE differentiation is present in a significant proportion of pulmonary large cell and poorly differentiated adenocarcinomas and rare in poorly differentiated squamous carcinomas; (b) NE differentiation is generally accompanied by heterogeneous intermediate filament expression; (c) divergent NE differentiation is not necessarily reflected by light microscopic features.     

Histidine decarboxylase expression as a new sensitive and specific marker for small cell lung carcinoma.

Histidine decarboxylase is one of the enzymes of the amine precursor uptake and decarboxylation system and is known to be distributed in mast cells and enterochromaffin-like cells. With the hypothesis that histidine decarboxylase expression is a marker for neuroendocrine differentiation, we studied the immunoreactivity of histidine decarboxylase in neuroendocrine cells and tumors of the thyroid gland, adrenal medulla, lung, and gastrointestinal tract. Formalin-fixed paraffin sections were subjected to immunohistochemistry using anti-histidine decarboxylase antibody, and the sensitivity and specificity were compared with those of conventional neuroendocrine markers (CD56, chromogranin A, synaptophysin, and neuron-specific enolase). Enterochromaffin or enterochromaffin-like cells, adrenal chromaffin cells, and thyroid C-cells were positive for histidine decarboxylase, and related tumors (carcinoid tumor, pheochromocytoma, medullary carcinoma) showed a high percentage of positive staining. Furthermore, we used the antibody to distinguish small cell lung carcinoma from non-neuroendocrine lung carcinoma and also to detect neuroendocrine differentiation in large-cell neuroendocrine carcinoma and gastrointestinal small-cell carcinoma. The anti-histidine decarboxylase antibody stained most small cell lung carcinoma (18 of 23, sensitivity 0.78), and was rarely reactive with non-neuroendocrine lung tumors (2 of 44; specificity, 0.95). These values were close to those obtained from CD56 staining (sensitivity/specificity, 0.87/0.98). Histidine decarboxylase was also positive for 6 of 12 large cell neuroendocrine carcinomas and 4 of 7 gastrointestinal small cell carcinomas. In conclusion, we demonstrated that histidine decarboxylase is useful to distinguish between small cell lung carcinoma and non-neuroendocrine carcinoma and to demonstrate neuroendocrine differentiation.     

肺腺癌神经内分泌分化的生物学特性

目的探讨肺腺癌伴神经内分泌(neuroendocrine NE)分化的生物学特性。方法采用免疫组化S-P法检测47例肺腺癌神经内分泌标记物的表达。结果肺腺癌组织中NE标记物神经元特异性烯醇化酶(NSE)和突触素(Syn)的阳性表达率分别为63.83%、44.68%,均显著高于正常组织(P<0.01)。肺腺癌伴NE分化与肺癌的淋巴结转移、分化程度无关。NSE的表达在死亡组显著高于生存组(P<0.05)。结论肺腺癌伴有NE分化与生存时间呈负相关,与淋巴结转移和分化程度无相关性。     

NCAM (neural cell adhesion molecules) expression in malignant mesotheliomas

Neural cell adhesion molecules (NCAM) are adhesion molecules expressed by neural and neuroendocrine tumors and a few biphasic tumors such as synovialosarcomas and breast phyllode tumors. To investigate NCAM expression in mesotheliomas, we studied 26 cases of epithelioid (n = 12), biphasic (n = 11), and sarcomatoid (n = 3) malignant mesotheliomas (MM), in comparison with normal mesothelium, and 50 primary non-small cell lung carcinomas (NSCLC) (25 adenocarcinomas [ADC] and 25 squamous cell carcinomas [SCC]), using electron microscopy as a gold standard for recognition of MM. NCAM reactivity using 123C3 antibody was compared with that of NE markers such as chromogranin A and synaptophysin. Although normal mesothelium remains negative, NCAM was expressed in 19 of 26 MM (73%) with a membranous staining on frozen or paraffin sections. In 6 of 12 epithelioid MM, the tumor cells expressed NCAM, whereas in 5 cases stromal fibroblasts showed a strong but focal staining. In 11 biphasic MM, 4 presented an NCAM reactivity of both epithelioid and spindle cell components, whereas in 7, only fusiform component was NCAM positive. Two of 3 sarcomatoid MM showed an NCAM expression. Chromogranin expression was never seen, whereas synaptophysin was noticed in 2 cases. No case of NSCLC showed membranous 123C3 staining, whereas 2 ADC weakly expressed synaptophysin. We conclude that NCAM expression in MM is reminiscent of its expression in mesoderm during fetal life and consistent with that reported in other biphasic tumors. These data show that NCAM expression occurs in 73% of MM, highly exceeding that observed in lung cancer.     

Neuroendocrine differentiation in adrenocortical carcinoma. New immunohistochemical findings supported by electron microscopy.

Ten adrenocortical carcinomas including two tumors with clinically detectable corticosteroid production, were immunohistochemically analyzed for their intermediate filament proteins, and for neuroendocrine markers. Keratins were present in 6 of 10, vimentin in all 10, and the 68 kilodalton kD neurofilament subunit protein in 6/10 tumors. Keratins numbers 8 and 18 were most prevalent, whereas only traces of keratins 19 and 7 were found. Eight tumors were positive for synaptophysin at least focally, and 3 showed extensive positivity in more than 30% of tumor cells. The tumors showed approximately similar levels of neuron-specific enolase (NSE) expression as judged by immunohistochemistry. Chromogranin was not detected, and there was no immunoreactivity for 3 neuropeptides (calcitonin, gastrin, somatostatin). In normal adrenal cortex, neuron-specific enolase, synaptophysin and neurofilaments were restricted to the nerves seen between the cortical cells. Electron microscopy revealed clusters of dense-core granules in 4 of 5 tumors, consistent with neuroendocrine granules. These results indicate that adrenocortical carcinomas may show signs of neuroendocrine differentiation and share some features with the adrenal medullary tumors.     

The PAS positive material in gastric cancer cells of signet ring type is not mucin

Purpose

The purpose of this study is to assess the exocrine and neuroendocrine properties of tumour cells in diffuse gastric cancer with signet ring cell differentiation.

Material and methods

Mucin mRNA and protein expressions (MUC1, 2, 3, 4, 5AC, 6 and MUC13) were assessed by immunohistochemistry and in situ hybridization. The neuroendocrine properties were evaluated by protein and mRNA expression of the general neuroendocrine markers chromogranin A and synaptophysin.

Results

No MUC expression was observed in signet ring tumour cells including the amorphous substance in any of the nine cases. All cases showed immunoreactivity to synaptophysin, and seven out of nine cases immunoreactivity to chromogranin A in signet ring and non-signet ring tumour cells. Chromogranin A mRNA expression was observed in tumour cells in all samples with retained mRNA.

Conclusions

The lack of MUC protein and mRNA in signet ring tumour cells suggests the amorphous substance is not mucin. The lack of MUC mRNA expression in non-signet ring tumour cells questions exocrine differentiation in this tumour group. The abundant protein expression of the general neuroendocrine markers CgA and synaptophysin, and mRNA expression in tumour cells strengthens the hypothesis that this tumour group may be of neuroendocrine origin.     

Neuroendocrine differentiation in thymic epithelial tumors with special reference to thymic carcinoma and atypical thymoma

To determine the neuroendocrine (NE) features of thymic epithelial tumor, immunohistochemistry and electron microscopy studies were performed on eight NE tumors (thymic carcinoids) and 26 non-NE tumors (nine thymic carcinomas, five atypical thymomas, and 12 thymomas other than lymphocytic thymoma). Immunohistochemical studies were performed with antibodies against general markers for NE cells (synaptophysin, a subunit of a guanine nucleotidebinding protein, Go, and small-cell lung carcinoma cluster 1 antigen), and a broad panel of antibodies for hormonal substances. Thymic carcinoid showed synchronous diffuse immunoreactivity for the three NE markers and contained cells that were positive for a variety of hormonal products: human chorionic gonadotropin (hCG) a-subunit (eight of eight), hCG β-subunit (three of eight), adrenocorticotropic hormone (ACTH) (three of eight), calcitonin (two of eight), calcitonin gene-related peptide (two of eight), and serotonin (one of eight). Conversely, although positivity for NE markers was neither synchronous nor diffuse in non-NE tumors, seven of nine thymic carcinomas, three of five atypical thymomas (focal or dispersed distribution), and none of the five thymomas were positive for at least two of these NE markers. A small number of neoplastic cells were positive for hCGa-subunit or ACTH in three thymic carcinomas and one atypical thymoma. Ultrastructurally, dense core granules (DCG) were much more frequent in thymic carcinoid, but several DCG-like granules were identified in 12 of 13 non-NE tumors with or without immunoexpression of NE markers. The presence of focal or dispersed NE cells in thymic carcinoma and atypical thymoma may reflect multidirectional differentiation within the tumor, which, like cytological atypia, epithelial CD5 expression, and lack of immature T cell infiltration, may be another feature of this group at thymic tumors.     

Immunohistochemical evaluation of neuroendocrine cells and neoplasms of the lung

The dispersed neuroendocrine (NE) system is represented in the bronchopulmonary tract by submucosal nerves and ganglion cells and, in the mucosal lining by solitary NE cells and neuroepithalial bodies (NEB's). The latter two components variably express pan-NE markers including NSE, chromogranin (s) and, notably, synaptophysin. The expression of serotonin, bombesin, calcitonin and leu-enkephalin has been well established; additional eutopic materials include somatostatin and calcitonin gene-related peptide. Solitary NE cells and NEB's are epithelial structures as defined by their consistent cytokeratin expression. Hyperplasia and dysplasia of NE cells may be found in association with various forms of chronic injury; they have been noted in chronic bronchiectasis and in the vicinity of neoplasms of various types. Hyperplastic and dysplastic pulmonary NE cells frequently express ectopic materials particularly ACTH. NE neoplasms of the bronchopulmonary tract comprice a spectrum that includes a) carcinoids, b) well differentiated NE carcinomas, c) intermediate cell NE carcinomas and d) small cell NE carcinomas. The precise pathologic criteria defining these entities are discussed in detail as are their clinical implications. The entire spectrum of lung NE neoplasms express NE markers demonstrable by immunocytochemistry; these include pan-NE markers, serotonin and numerous neuropeptides. The expression of multiple hormonal materials is frequent. Within any given tumor, some variation in expression may be noted in different sites and in different periods of the "normal" or therapeutically modified lifespan of the tumor. The entire spectrum of lung NE neoplasms is epithelial for they express cytokeratin polypeptides and desmoplakin; subsets of the tumors coexpress cytokeratins and neurofilament proteins. Also, subsets of these NE neoplasms may be immunostained with monoclonal antibodies to antigens related to exocrine phenotype suggesting focal amphicrine features.     

Double neuroendocrine ductal carcinomas in situ coexisting with a background of diffuse idiopathic neuroendocrine cell hyperplasia of breast: a case report and hypothesis of neuroendocrine tumor development

This article reports the case of a 72-year-old woman with two nodules of neuroendocrine (NE) ductal carcinoma in situ coexistent with a background of NE cell hyperplasia. Both tumors, 15 and 3 mm in size, were incidentally revealed on computed tomography without any apparent clinical symptoms. The tumors showed similar histological features, and more than 50% of the tumor cells patchily expressed NE markers, such as chromogranin A, synaptophysin, CD56, and somatostatin receptor type 2. The surrounding nontumor ductal cells also showed spotty or linear positivity for NE markers in contrast to the cells of normal atrophic breasts, which rarely present with NE cells. Moreover, focal mucin production was also observed in the peripheral ducts. It is hypothesized that idiopathic breast NE cell hyperplasia with multiple small nests of NE cells may extend to form a true mass of NE neoplasms.     

Expression of novel neuroendocrine marker insulinoma-associated protein 1 (INSM1) in genitourinary high-grade neuroendocrine carcinomas: An immunohistochemical study with specificity analysis and comparison to chromogranin,synaptophysin, and CD56

Confirmation of genitourinary high-grade neuroendocrine carcinomas (GU-HGNECs) often requires immunohistochemical staining. Here we evaluated a novel neuroendocrine marker, insulinoma-associated protein 1 (INSM1), in GU-HGNECs with comparison to chromogranin, synaptophysin and CD56. Immunohistochemical expression of INSM1, chromogranin, synaptophysin, and CD56 was evaluated in 39 GU-HGNECs using full tissue sections [4 in kidney, 28 in urinary bladder, and 7 in prostate; 31 small cell carcinomas (SmCCs), 6 large cell neuroendocrine carcinomas (LCNECs), 2 mixed SmCC-LCNECs]. In 33 SmCCs/components, INSM1 showed similar sensitivity (93.9 %) to chromogranin (87.8 %), synaptophysin (93.9 %) and CD56 (87.8 %), and stained a similar percentage of tumor cells (52 %) to chromogranin (49 %) and CD56 (52 %), but lower than synaptophysin (87 %) (p < 0.0001). In 8 LCNECs/components, INSM1 is similar to chromogranin, synaptophysin or CD56 in sensitivity (62.5 %, 62.5 %, 75 %, 62.5 %, respectively) and the mean percentage of positively stained tumor cells (21 %, 44 %, 48 %, 37 %, respectively). INSM1 is more sensitive for SmCCs than LCNECs (93.9 % vs. 62.5 %, p = 0.015). INSM1 showed 97.4 % specificity upon analyzing 273 genitourinary non-neuroendocrine tumors on tissue microarrays. Our study indicates that INSM1 is a sensitive marker for genitourinary HGNECs with high specificity. For genitourinary SmCCs, INSM1 shows similar sensitivity to chromogranin, synaptophysin and CD56 but stains a lower percentage of tumor cells than synaptophysin. For genitourinary LCNECs, INSM1 showed similar sensitivity to chromogranin, synaptophysin and CD56. INSM1 is more sensitive for genitourinary SmCCs than LCNECs. Our result and literature review indicate that whether INSM1 is more sensitive than conventional neuroendocrine markers for HGNECs depends on the tumor primary sites.     

Synaptophysin and neurofilament proteins as markers for neuroendocrine tumors

Synaptophysin, a membrane glycoprotein of presynaptic vesicles, and neurofilament (NF) proteins were tested as immunohistochemical markers for neuroendocrine tumors. Synaptophysin was consistently present in the tumor cells of pheochromocytomas (10/10), thyroid medullary carcinomas (8/8), and pancreatic islet cell tumors (6/6). Most gastrointestinal and thoracic carcinoid tumors (12/13) were positive, as were neuroendocrine carcinomas (7/9), of which two Merkel cell carcinomas were negative. The NF proteins were present in all pheochromocytomas, in three thoracic and one gastric carcinoid tumors, in four of eight thyroid medullary carcinomas, and in five of six pancreatic islet cell tumors. All intestinal carcinoids were negative for NF proteins, as were neuroendocrine carcinomas, except for two Merkel cell carcinomas that were positive. The 68-kilodalton (kd) NF subunit protein was the most prevalent in all NF-positive neuroendocrine tumors, and the 160-kd subunit was relatively often present, although in a smaller number of cells. The 200-kd NF subunit protein was regularly found in pheochromocytomas and only occasionally found in other neuroendocrine tumors. A series of nonneuroendocrine tumors, such as adenocarcinomas, sarcomas, lymphomas, and melanomas, were negative for both synaptophysin and NF proteins. Thus, synaptophysin is a specific and fairly sensitive marker for neuroendocrine tumors of both low and high grades of malignancy. The NF proteins are good markers for pheochromocytoma, and their presence is of basic tumor biologic interest and of potential diagnostic value in other neuroendocrine neoplasms.     

Synaptophysin expression in neuroendocrine neoplasms as determined by immunocytochemistry.

Synaptophysin is an integral membrane glycoprotein originally isolated from presynaptic vesicles of bovine neurons. The authors have studied a wide spectrum of neuroendocrine (NE) neoplasms by immunofluorescence microscopy on cryostat sections of freshly frozen tissues using a monoclonal antibody to this protein (SY 38). Without exception, they found the identical--or a very similar--protein expressed in all neuroblastomas, ganglioneuroblastomas, ganglioneuromas, pheochromocytomas, and paragangliomas studied. In these "neural" type NE neoplasms, synaptophysin was coexpressed with neurofilament proteins. Synaptophysin was also demonstrated in NE neoplasms of "epithelial" type in which it was predominantly coexpressed with cytokeratins and desmoplakin. It was invariably found in all variants of islet cell neoplasms and in all medullary thyroid carcinomas. Synaptophysin was also demonstrated in several adenomas of the hypophysis and parathyroids, in the majority of carcinoids of the bronchopulmonary and gastrointestinal tracts, and in many, though not all, NE carcinomas of the same sites, and of the skin. Conversely, SY 38 did not immunostain any of a large number of benign and malignant non-NE epithelial neoplasms; nor was any immunostaining obtained in a group of mesenchymal tumors. It is remarkable that SY 38 did not immunostain a number of malignant melanomas, including several that were immunostained for neuron-specific enolase (NSE) and several neuropeptides. Parallel studies conducted on conventionally fixed, paraffin-embedded tissue sections immunostained by the use of the avidin-biotin complex technique yielded very similar results. The findings indicate that synaptophysin is expressed in the whole range of NE neoplasms without detectable relation to the expression of other NE markers such as NSE, serotonin, and neuropeptides. Nor could the expression of synaptophysin by these tumors be correlated with their epithelial and/or neural cytoskeletal characteristics, their clinical aggressiveness, or the presence or absence of endocrinologic abnormalities. While the consistent expression of synaptophysin by the "neural" type of NE neoplasms would seem predictable its presence in diverse benign and malignant NE tumors of "epithelial" type is remarkable. It is concluded that synaptophysin is a significant as well as novel NE marker, and the use of antibody SY 38 as a broad range marker for the study and diagnosis of NE neoplasms is proposed.