Immunohistochemical and Ultrastructural Analysis of Bronchopulmonary Neuroendocrine Neoplasms. I. Carcinoids

Twenty-five strictly defined bronchopulmonary carcinoids were studied by light microscopic immunohistochemistry by the peroxidase technique for NSE (neuronspecific enolase), serotonin, and a broad spectrum of neuropeptides. Eighteen cases were also studied by electron microscopy.

Twenty-three of the twenty-five cases showed immunostaining for NSE; 24 cases displayed immuno-staining for at least two of the hormones tested for; the single case that failed to show hormonal immuno-reactivity was however positive for NSE and had granules by electron microscopy. Serotonin was the most frequently demonstrated hormone followed by bombesin, vasoactive intestinal peptide, gastrin, leuenkephalin, alphamelanocyte stimulating hormone, somatostatin, substance P, and calcitonin. In several cases, adjacent-step sections stained for different hormones strongly indicated immunoreactivity for more than one hormone in single neoplastic cells.

By electron microscopy, all 18 cases studied showed generally abundant neurosecretory granules, which, however, displayed considerable heterogeneity in their size, shape, and density. Twelve of these eighteen cases displayed evidence of squamous differentiation and 10 showed characteristic exocrine lumina.

The capability of single neuroendocrine tumors and single neuroendocrine tumor cells to produce more than one immunoreactive hormone is hereby amply confirmed; these broad capabilities are certainly reflected in the heterogeneous granule populations seen by electron microscopy. The synchronous presence of squamous and exocrine features in bronchopulmonary carcinoids indicates that they too are capable of multidirectional differentiation, which should not detract from their being regarded basically as well-differentiated neuroendocrine neoplasms. The clinical significance of strictly defining bronchial carcinoids is underscored by the fact that of 25 cases followed for 2-13 years, only one developed metastases 9 years postoperatively.     

Breast carcinomas with neuroendocrine differentiation

Twenty-two breast carcinomas with membrane bound granules by electron microscopy were tested for the presence of neuron specific enolase (NSE), neuropeptides and serotonin by immunohistochemistry. By light microscopy the cases studied included infiltrating ductal carcinomas, intraductal carcinomas, apocrine carcinomas, infiltrating lobular carcinomas of both classical and alveolar types, mixed lobular/colloid carcinomas, carcinoid growth pattern and one unclassified carcinoma. Ten cases showed immunoreactivity for 1 or 2 neuropeptides in scattered cells whereas all cases were positively and rather diffusely stained with anti-NSE. Immunohistochemical staining at the ultrastructural level was carried out; the presence of neuropeptides could not be confirmed. Scattered granules were marked with gold particles when antiserum against casein was used. We conclude that neither argyrophilia, nor NSE immunoreactivity nor membrane bound granules seen by electron microscopy constitute at present sufficient evidence to designate a breast carcinoma as neuroendocrine. However, our study indicates that certain breast carcinomas of several types do include cells with neuroendocrine features demonstrable convincingly by light microscopic immunohistochemistry. We have no evidence that these breast carcinomas with neuroendocrine features behave differently from their counterparts lacking such features. The intriguing speculation is that neuropeptides produced by certain breast carcinomas may act as local modulators of tumor growth and differentiation.     

Breast Carcinomas with Neuroendocrine Differentiation

Twenty-two breast carcinomas with membrane bound granules by electron microscopy were tested for the presence of neuron specific enolase (NSE), neuropeptides and serotonin by immunohistochemistry. By light microscopy the cases studied included infiltrating ductal carcinomas, intraductal carcinomas, apocrine carcinomas, infiltrating lobular carcinomas of both classical and alveolar types, mixed lobular/colloid carcinomas, carcinoid growth pattern and one unclassified carcinoma. Ten cases showed immunoreactivity for 1 or 2 neuropeptides in scattered cells whereas all cases were positively and rather diffusely stained with anti-NSE. Immunohistochemical staining at the ultrastructural level was carried out; the presence of neuropeptides could not be confirmed. Scattered granules were marked with gold particles when antiserum against casein was used.

We conclude that neither argyrophilia, nor NSE immunoreactivity nor membrane bound granules seen by electron microscopy constitute at present sufficient evidence to designate a breast carcinoma as neuroendocrine. However, our study indicates that certain breast carcinomas of several types do include cells with neuroendocrine features demonstrable convincingly by light microscopic immunohistochemistry. We have no evidence that these breast carcinomas with neuroendocrine features behave differently from their counterparts lacking such features. The intriguing speculation is that neuropeptides produced by certain breast carcinomas may act as local modulators of tumor growth and differentiation.     

Neuroendocrine differentiation in prostatic carcinoma

Specimens from 53 cases of prostatic carcinoma obtained during total prostatectomy or transurethral resection of prostate were analyzed for neuroendocrine differentiation with immunocytochemical tests for serotonin, neuron-specific enolase, and chromogranin as well as with the Churukian-Schenk argyrophil reaction. Forty-seven per cent (25 of 53) of the prostatic carcinomas were positive for neuroendocrine differentiation, usually with an overlapping combination of these techniques. Nine per cent (five cases) contained areas with numerous neuroendocrine cells, 11 per cent (six cases) had focal scattered neuroendocrine cells, and 26 per cent (14 cases) had rare neuroendocrine cells. The positive cases spanned the histologic spectrum of prostatic adenocarcinoma; histologically none resembled a carcinoid tumor or a small cell carcinoma. Positive cases were further studied with a battery of antisera to 12 polypeptide hormones. Immunoreactivity to only bombesin (one case) and calcitonin (two cases) was detected. In five cases, neuroendocrine differentiation was studied by electron microscopy and verified at the ultrastructural level.     

Neurone specific enolase immunostaining in the diagnosis of breast carcinomas with neuroendocrine differentiation. Its usefulness and limitations

Thirty-eight infiltrating ductal carcinomas, nine infiltrating lobular carcinomas, two tubular carcinomas and one papillary carcinoma were studied by light microscopy, immunocytochemistry and electron microscopy. Seventeen cases showed immunoreactivity for NSE. Immunostaining for different peptide-hormones was observed in 12 of these 17 cases and in none of the 10 NSE-negative cases used for controls. Scattered cells were positive for gastrin in five cases, pancreatic polypeptide in five, leu-enkephalin in three, sub-P in two, ACTH in one, bombesin in one and beta-endorphin in one case. Four cases revealed immunoreactivity for more than one peptide-hormone. Typical neuroendocrine granules were seen in five cases (all positively stained for NSE). Small, electron dense granules of possible neuroendocrine nature were not found in any of the 33 NSE-negative tumours. Our results confirm that immunoreactivity for NSE is present in a high proportion of breast carcinomas, but that neuroendocrine differentiation cannot be proved to be present in all these cases.     

Neuroendocrine differentiation in cervical carcinoma.

AIMS: To examine neuroendocrine differentiation, as shown by chromogranin A (CGA) expression, in cervical carcinomas. METHODS: Sixty seven cervical carcinomas were studied and were classified as adenocarcinomas, adenosquamous carcinomas or squamous cell carcinomas based on the assessment of haematoxylin and eosin staining and stains for mucin. Where features of glandular differentiation were identified, sections were also stained for evidence of intestinal type mucin. CGA immunostaining was done and the results were graded on a three point scale: 0, + (1-5% of cells positive) and ++ (> 5% of cells positive). These findings were then analysed with respect to lymph node status, tumour differentiation and clinical outcome. RESULTS: There were 32 adenocarcinomas, 18 adenosquamous carcinomas and 17 squamous cell carcinomas. Positive staining was seen in 14 (20.9%) cases, of which four were strongly positive. All but one case were either adenocarcinomas or adenosquamous carcinomas. There was a trend for CGA positivity to be related to intestinal differentiation but this failed to reach statistical significance. No correlation could be demonstrated between CGA staining and lymph node status, tumour differentiation and clinical outcome. CONCLUSIONS: Neuroendocrine differentiation is common in cervical carcinomas where there is evidence of glandular differentiation. Whilst the numbers in this study are relatively small, the presence of neuroendocrine cells in otherwise typical carcinomas does not seem to have any association with clinical behaviour.     

A study of different markers for neuroendocrine differentiation in breast carcinomas

Forty-two breast carcinomas were studied with different markers for detecting neuroendocrine differentiation. The Bodian and Grimelius silver stains were applied, as well as immunostaining for neurone specific enolase (NSE), chromogranin, prealbumin and a battery of hormones. All cases were studied by electron microscopy as well. The material included 29 infiltrating ductal carcinomas, 10 infiltrating lobular carcinomas and 3 tubular carcinomas. Immunostaining for hormones was obtained in 11 cases (gastrin and PP (4 cases each), leu-enkephalin (3 cases), substance P (2 cases), beta-endorphin (2 cases), ACTH (1 case) and bombesin (1 case). Three cases revealed immunostaining for more than one hormone. Sixteen cases were positively stained with rabbit anti-NSE (Dako Corporation) and included all the 11 cases with proven immunoreactivity for hormones. 20 cases were positively stained with sheep anti-NSE and only 8 of the 11 cases with immunoreactivity for hormones were included. Immunostaining for prealbumin was observed in only 1 case and chromogranin in only 5 cases. All cases were unstained with the Bodian stain, whereas 3 cases showed a positive argyrophilic reaction with the Grimelius technique. Ultrastructural studies revealed typical small membrane-bound electron dense granules in cytoplasm in 4 cases, all among the 11 cases with immunoreactivity for hormones. We conclude that immunostaining with rabbit anti-NSE is the best screening method for detecting breast carcinomas with neuroendocrine differentiation.     

Investigation of somatostatin receptor profile of neuroendocrine carcinomas of the breast

Carcinomas of the breast with neuroendocrine features are rare primary neoplasms positive for neuroendocrine markers. According to the WHO classification of tumours of the breast they are divided into three morphologically distinct categories. They comprise neuroendocrine tumour (NET), neuroendocrine carcinoma (NEC) and carcinoma with neuroendocrine differentiation (NED). The purpose of this study was to investigate for the first time the full spectrum of sstr expression status in breast carcinomas with neuroendocrine features.Fifteen primary breast carcinomas with histological and immunohistochemical neuroendocrine features were studied. Four of them were classified as NETs and two as NECs, and the remaining 9 as carcinomas with NED. All six types of somatostatin receptor (sstr) types (sstr1, sstr 2A, sstr2B, sstr3, sstr4 and sstr5) were investigated by immunohistochemistry. To assess the distribution and intensity of membranous receptor immunoreactivity, a four-scale scoring system was used. Overall predominant receptors were sstr2A, sstr2B, sstr3 and sstr5 showing the highest membranous staining scores 3+ and 2 + . The sstr1 was not detected.Given that carcinomas with neuroendocrine features represent distinct entities, patients with such tumours may benefit from sstr targeting therapies. Immunohistochemistry for sstrs can predict the effectiveness of administration of SST analogues to those patients, thus contributing to achieve the maximum therapeutic outcome, particularly in NETs and NECs with scores 2+ and 3 + .     

胃癌中内分泌细胞与癌分化程度的关系

利用11例胃类癌和13例胃低、未分化癌的切除标本,探讨内分泌细胞出现的数量与胃癌类型和分化程度的关系。切片均作了嗜银、亲银组化染色,并用4种神经内分泌抗血清(胃泌素、生长抑素、胰多肽、血清素)PAP法免疫组化染色,4例作了电镜检查。结果胃类癌每例至少一项阳性,其中4例电镜证实有神经分泌颗粒;低、未分化癌组多数病例各项检查阴性,但4例不同阳性结果,其中2例阳性细胞数超过50%,可称内分泌细胞癌。表明肿瘤愈原始,愈多向分化。最后对胃癌中内分泌细胞与癌分化程度的关系,以及胃类癌和胃内分泌细胞癌的特征、名称和组织发生进行了讨论。     

Neuroendocrine and mucinous differentiation in signet ring cell carcinoma of the stomach: evidence for a common cell of origin in composite tumors

Composite tumors are rare neoplasms containing a mixture of 2 different cellular components present in roughly equal proportions. It is hypothesized that composite tumors arise from a multipotential stem cell with subsequent bidirectional differentiation. We present an unusual composite tumor of the stomach composed equally of signet ring cell carcinoma and low-grade neuroendocrine carcinoma. Twenty-one additional patients with signet ring cell carcinomas of the stomach were studied to determine the prevalence of neuroendocrine differentiation by morphology and immunohistochemistry for synaptophysin and chromogranin A. Immunohistochemistry for mucins 5AC and 2 was performed to assess for divergent differentiation toward foveolar and intestinal mucin phenotypes, respectively, and to evaluate for any potential relationship with neuroendocrine differentiation. We found morphologic evidence of neuroendocrine carcinoma in 4 (19%) of 21 consecutive signet ring carcinomas. E-cadherin immunostaining was subsequently performed on these 4 tumors plus the index case. All 5 tumors demonstrated concordance between the signet ring and neuroendocrine components. There was no distinct relationship to mucin 5AC/mucin 2 profiles, with the exception that all 11 intramucosal signet ring cell carcinomas from 4 patients with germ line cadherin 1 gene mutations were composed exclusively of mucin 5AC+ signet ring cells that lacked intestinal mucin and neuroendocrine differentiation. The concordant E-cadherin status in the neuroendocrine and signet ring cell tumor components and the frequent admixture of mucin 5AC+ cells with foveolar differentiation and mucin 2+ cells with intestinal differentiation may support the hypothesis that composite tumors arise from a common stem cell with bilineage or multilineage differentiation.     

Immunohistochemical and ultrastructural analysis of bronchopulmonary neuroendocrine neoplasms. II. Well-differentiated neuroendocrine carcinomas

We have attempted to characterize a group of bronchopulmonary neoplasms that share certain structural features with true carcinoids but appear distinctly more pleomorphic and behave far more aggressively. In reviewing our files from 1973 to 1982, 11 such neoplasms were identified; the original diagnoses were "atypical bronchial carcinoid" (3 cases), "malignant carcinoid" (1 case), "bronchial carcinoid" (3 cases), "peripheral carcinoid" (2 cases), and "peripheral oat cell carcinoma" (2 cases). Of the 11 neoplasms, 5 were central and 6 were peripherally located. At presentation, 7 patients had lymph node metastases and 1 had a distant metastasis. No patient had a conventionally defined hormonal syndrome; however, 2 patients had a history of episodic flushing, one of which was associated with diarrhea. All cases were studied by light microscopy and light microscopic immunohistochemistry for NSE (neuron-specific enolase), serotonin, and broad-spectrum neuropeptides. Five cases were studied by electron microscopy. By light microscopy, the tumors were composed of solid clusters of polygonal to fusiform cells in an evident organoid arrangement. Foci of glandular and/or squamous differentiation were seen in 7 cases. Pleomorphism was moderate and mitoses were readily found. Focal necrosis was seen. By immunohistochemistry, 10 cases expressed NSE immunoreactivity. All cases demonstrated hormonal immunoreactivity; in 9 cases, immunoreactivity for more than one hormone was observed. The hormones most frequently expressed were serotonin, bombesin, gastrin, leu-enkephalin, and ACTH. By electron microscopy, all cases studied contained heterogeneous populations of neurosecretory granules; the latter, however, were not abundant and tended to aggregate either in the basal pole of the cells or, more frequently, interlacing "dendritelike" cytoplasmic processes. Aggregates of intermediate filaments were frequently seen. Basal lamina deposition was seen but gaps and larger areas of discontinuity were frequent. We believe that these neoplasms constitute a distinct pathologic entity for which the term "well-differentiated neuroendocrine carcinoma" has been proposed. Clinically, these tumors merit special attention since they are demonstrably more aggressive than true carcinoids but are distinctly less malignant than the intermediate or small cell variants of neuroendocrine carcinoma.     

Neuroendocrine carcinomas of the skin: light microscopic, ultrastructural, and immunohistochemical analysis

Three primary skin carcinomas were analyzed by light microscopy, immunohistochemistry, and electron microscopy. In all cases, local recurrences, regional lymph node metastases, distant metastases, or all three developed. One patient had elevated serum calcitonin levels that did not decrease after thyroidectomy but did return to normal after removal of the skin tumor recurrences, its metastases, or both. The tumor cells were arranged in solid clusters; a trabecular arrangement was occasionally seen. In 2 cases the cells were of intermediate size and showed vesicular central nuclei and pale, moderately abundant cytoplasm. In the remaining case the cells were distinctly smaller and either round or fusiform. Mitoses were more abundant in the latter case than in the former two. By immunohistochemistry, calcitonin- and somatostatin-containing cells were demonstrated in all cases and ACTH in one. By electron microscopy, the cases consisting of intermediate-size cells displayed moderately abundant neurosecretory-type granules irregularly dispersed throughout the cytoplasm. The case consisting of smaller cells displayed fewer and smaller granules that tended to concentrate in slender cytoplasmic processes. We conclude that these tumors constitute parts of the broadening spectrum of neuroendocrine skin carcinomas that may derive from Merkel cells.     

Primary breast carcinomas with neuroendocrine features: Clinicopathological features and analysis of tumor growth patterns in 36 cases

Primary breast carcinoma with neuroendocrine features (NEBC) is an uncommon tumor. In the classification of WHO 2012, these tumors were categorized as: 1- neuroendocrine tumor, well-differentiated; 2- neuroendocrine carcinoma, poorly differentiated/small cell carcinoma; and 3- invasive breast carcinoma with neuroendocrine differentiation. In this study, we reviewed NEBC except poorly differentiated/small cell carcinoma variant in order to define the morphological growth patterns and cytonuclear details of these tumors. All breast surgical excision materials between 2007 and 2016 were re-evaluated in terms of neuroendocrine differentiation. Thirty-six cases showing positive staining for synaptophysin and/or chromogranin A in ≥50% of tumor cells were included in the study. All cases were female with a mean age of 67.4. Mean tumor diameter was 26 mm. Multifocality was noted in 5 cases. Grossly, they were mostly infiltrative mass lesions. T stages, identified in 34 cases, were as follows: 13 cases with pT1; 19 pT2 and 2 pT3. We described schematically 4 types of patterns depending on predominant growth pattern, except one case: 1) Large-sized solid cohesive groups (6 cases), 2) Small- to medium-sized solid cohesive groups with trabeculae/ribbons and glandular structures (6 cases), 3) Mixed growth patterns (20 cases), 4) Invasive tumor with prominent extracellular and/or intracellular mucin (3 cases). The tumor cells were mostly polygonal-oval with eosinophilic/eosinophilic-granular cytoplasm. The nuclei of tumor cells were mostly round to oval with evenly distributed chromatin. Only 5 cases showed high grade nuclear and histological features. Molecular subtypes of the cases were as follows: 33 luminal A, 2 luminal B, and 1 triple negative. NEBC should come to mind when a tumor display one of the morphological patterns described above, composed of monotonous cells with mild to moderate nuclear pleomorphism and abundant eosinophilic/eosinophilic granular or clear cytoplasm, especially in elderly patients.     

Non-small cell lung carcinomas with neuroendocrine features. A light microscopic, immunohistochemical and ultrastructural study of 11 cases

Eleven resected primary lung carcinomas classified as large cell carcinomas or squamous cell carcinomas, but showing some microscopic resemblances to bronchial carcinoid and small cell carcinoma, were studied. All cases were neurone-specific enolase and protein gene product 9.5 positive, indicating neuroendocrine differentiation. Staining for bombesin, C-terminal peptide of human pro-bombesin and chromogranin was positive in some cases. Electron microscopy showed dense-core granules in six of seven cases investigated, the remaining case showing small granules of uncertain nature. All but one patient died within 15 months after operation. These data indicate that neuroendocrine differentiation in non-small cell carcinomas of the lung may in some cases be suspected on routine histology. The follow-up data suggest that the identification of these cases might have implications for prognosis and therapy, and consequently for diagnostic lung tumour classification.     

Frequent presence of neuroendocrine small cells in thymic carcinoma: a light microscopic and immunohistochemical study

AIMS: Neuroendocrine differentiation has been described in conventional carcinomas of various organs. Small cells postulated to be neuroendocrine cells were observed previously in some thymic carcinomas. This study was conducted to confirm and characterize the presence of neuroendocrine small cells in thymic carcinomas by light microscopy and immunohistochemistry. METHODS AND RESULTS: Twenty-two thymic carcinomas were studied by light microscopy to detect the presence of small neuroendocrine-like cells. They were found in four of 10 squamous cell carcinomas (SCC) and seven of eight adenosquamous carcinomas (ASC). No small cells were observed in three lymphoepithelioma-like carcinomas (LELC) and one adenocarcinoma. The small cells were located within the tumour nests and constituted less than 1% of the entire tumour. In one case, small cells also extended outside the tumour nests. Rosette formation was seen in three cases. They were proved to be neuroendocrine cells by their immunoreactivity to neuron-specific enolase, chromogranin A, and/or synaptophysin. A few scattered neuroendocrine small cells were found only by immunohistochemistry in one case each of SCC, ASC, and LELC. The small cells were also strongly positive for cytokeratin (CK) 8 and CK18 but negative for CK19 and CK20. The predominant carcinoma cells other than the neuroendocrine small cells also displayed neuroendocrine markers in 68% of the cases studied. CONCLUSIONS: Neuroendocrine small cells can be recognized by light microscopic examination in approximately 61% of thymic SCC and ASC. Neuroendocrine markers, CK8 and CK18 can aid in confirming their presence. The neuroendocrine small cells present in thymic carcinomas are different from the main carcinoma cells displaying immunohistochemical neuroendocrine markers. The presence of neuroendocrine small cells could be an useful marker for the differentiation of thymic carcinomas from thymomas and carcinomas of other sites.     

Neuroendocrine differentiation in breast lesions

A review of neuroendocrine features in breast carcinomas is presented and markers for neuroendocrine cells are discussed. Immunostaining for neuron specific enolase is the best screening marker for neuroendocrine cells in breast carcinomas, but immunoreactivity for hormones is not present in all neuron specific enolase (NSE) positive cases. Normal myoepithelial cells are also NSE positive. Thirty per cent of breast carcinomas are NSE positive. Biochemical demonstration of ACTH, PTH and calcitonin, and immunohistochemical demonstration of ACTH, bombesin, serotonin, prolactin, gastrin, VIP, leu-enkephalin, pancreatic polypeptide, beta-endorphin and sub P has been reported in breast carcinomas. Neuroendocrine cells have not been convincingly demonstrated in the normal breast or in benign breast lesions.     

Neuroendocrine Carcinomas of the Skin: Light Microscopic,Ultrastructural, and Immunohistochemical Analysis

Three primary skin carcinomas were analyzed by light microscopy, immunohistochemistry, and electron microscopy. In all cases, local recurrences, regional lymph node metastases, distant metastases, or all three developed. One patient had elevated serum calcitonin levels that did not decrease after thyroidectomy but did return to normal after removal of the skin tumor recurrences, its metastases, or both.

The tumor cells were arranged in solid clusters; a trabecular arrangement was occasionally seen. In 2 cases the cells were of intermediate size and showed vesicular central nuclei and pale, moderately abundant cytoplasm. In the remaining case the cells were distinctly smaller and either round or fusiform. Mitoses were more abundant in the latter case than in the former two.

By immunohistochemistry, calcitonin- and somatostatin-containing cells were demonstrated in all cases and ACTH in one. By electron microscopy, the cases consisting of intermediate-size cells displayed moderately abundant neurosecretory-type granules irregularly dispersed throughout the cytoplasm. The case consisting of smaller cells displayed fewer and smaller granules that tended to concentrate in slender cytoplasmic processes.

We conclude that these tumors constitute parts of the broadening spectrum of neuroendocrine skin carcinomas that may derive from Merkel cells.     

Hepatoblastomas: an ultrastructural and immunohistochemical study.

Seven hepatoblastomas were studied by electron microscopy, and four of these were studied by immunohistochemistry. Five tumors were purely epithelial, and two were mixed epithelial-mesenchymal. They showed a spectrum of cellular differentiation ranging from primitive epithelial cells to differentiated cells resembling adult hepatocytes. Glycogen, lipid, basal lamina, and canaliculi were present in all cases. Mitochondria with large, membrane-bound, amorphous inclusions were present in one tumor, and large, complex, basal cell processes were present in two tumors. Ultrastructural features most characteristic of hepatocytes were most common in fetal type hepatoblastomas. Immunoreactive chromogranin cells were present in two tumors, one of which also contained immunoreactive somatostatin cells. The somatostatin-positive tumor had cells with granules resembling those seen in somatostatin-containing cells of normal pancreas and somatostatin-containing neuroendocrine carcinomas. Other immunoreactive substances were present, including alpha 1-antitrypsin (four cases), vimentin (embryonal cells in four cases; fetal cells in three cases), low-molecular weight cytokeratin (embryonal cells in three cases; fetal cells in four cases), and high-molecular weight cytokeratin (embryonal cells in one case; fetal cells in two cases). Osteoidlike material was positive for epithelial membrane antigen, vimentin, and S-100 protein.     

The 'grey area' between small cell and non-small cell lung carcinomas. Light and electron microscopy versus clinical data in 14 cases

We studied 14 lung tumours which on light microscopy had posed difficulties on classification as either small cell or non-small cell carcinomas. The light and electron microscopical features were compared with patient follow-up data. Electron microscopy showed neuroendocrine granules in 12 cases, and adeno- and squamous cell differentiation but no neuroendocrine granules in the remaining two cases. The latter two cases showed prolonged patient survival (both patients alive after 2 1/2 and 2 years, respectively). Ten of the cases with neuroendocrine granules showed a rapid course of disease (death between 2 1/2 weeks and 15 months after diagnosis) and marked initial response to multiagent chemotherapy. Thus, the clinical impression of these cases was that of small cell carcinoma. The remaining two cases with neuroendocrine granules showed a more protracted course, with death after 1 1/2 and 2 1/2 years. These two tumours did not show the light microscopical features of atypical carcinoid. The results illustrate the value of electron microscopy in predicting clinical behaviour of carcinomas difficult to place into small cell or non-small cell carcinoma groups. They also point to the existence of neuroendocrine carcinomas other than carcinoids with a more protracted course than small cell carcinomas.     

The nature of breast dense core granules: chromogranin reactivity

Ultrastructural immunoreactivity for chromogranin with the LK2H10 antibody was examined in nine cases of breast carcinoma and one example of normal resting breast. These tissues were selected for study on the basis of argyrophilia or LK2H10 immunostaining by light microscopy. In two cases, positive reactivity with the chromogranin antibody was seen in breast neuroendocrine-like dense core granules. In a further six cases chromogranin reactivity was not seen in similar granules that showed the neuroendocrine properties of ultrastructural argyrophilia and uranaffinity. Inability to exhibit the full complement of neuroendocrine characteristics in breast carcinomas contrasts with the facility to demonstrate them in tissues of usual neuroendocrine differentiation. Furthermore, in two mucoid carcinomas and one example of normal resting breast ultrastructural cytoplasmic LK2H10 reactivity was evident, which was not localized to dense core granules, although these were present in two of the cases. Our findings demonstrate the heterogeneity of breast dense core granules and discourage acceptance of such characteristics as evidence of histogenesis of these carcinomas from a neuroendocrine cell type in breast tissue.