A fluorescence in situ hybridization (FISH) procedure to assist in differentiating benign from malignant melanocytic lesions.

OBJECTIVE: Misdiagnosis of melanocytic lesions can result in unnecessary psychological distress to patients, under- or overtreatment, inaccurate prognosis and improper follow-up and family member surveillance. It is well recognized that, despite many attempts to 1) put forth a set of histologic criteria that can accurately and reproducibly be used to diagnose melanocytic lesions, and 2) identify reliable markers of malignancy as an adjunct to routine histopathology, misdiagnoses still occur in a significant number of cases. METHOD: A multi-color FISH probe mixture has been devised to assist pathologists in differential diagnosis of difficult melanocytic lesions. The mixture includes a centromeric probe for chromosome 6 and unique sequence probes for three other chromosomal regions that have most frequently shown amplifications or deletions in melanoma. We have carried out a preliminary evaluation of this new probe set in 25 cases of benign and malignant pigmented lesions. RESULTS: The tool reliably identified all nevi and ordinary melanomas, and only failed to identify a pigmented epithelioid melanocytoma and two malignant lesions that, by morphology and behavior, have distinct features from common invasive melanomas, i.e., a desmoplastic melanoma and a nevoid melanoma. Considering this, 100% specificity and 75% sensitivity was achieved. CONCLUSION: The FISH tool used in this study was able to separate accurately benign nevi from ordinary melanoma. Failure to identify uncommon melanocytic lesions adds to its advantage and calls for further studies to unveil the molecular profile of these rare entities.

A new observation of the Carney's triad with long follow-Up period and additional tumors.

The etiology of the Carney's triad (gastrointestinal stromal tumors, pulmonary chondromas, and paragangliomas) is unknown, and only 57 cases have been reported since its identification in 1977. We report the clinical course of a female with the complete triad and some additional tumors. Bilateral vagal paragangliomas were treated surgically and with radiotherapy between the ages of 24 and 26 years. Subsequently she underwent surgery for a gastric leiomyosarcoma (27 years), a pleomorphic adenoma of the parotid gland (49 years) and a multifocal breast cancer with axillary spread (50 years). A calcified lesion was also noticed in the left lung, the radiologic diagnosis of which was consistent with chondroma. A mediastinal paraganglioma, detected at 56 years on a control X-ray of the chest, was partially excised at 63 years. At the last control, performed at 66 years, the patient was alive with residual cervical and mediastinal paraganglioma. Her younger brother was affected by Hirschsprung's disease and died at 54 years of rectal cancer. Her daughter is 33 and has been suffering since birth with severe constipation. In conclusion, this is one of the longest followed-up patients with Carney's triad. Her case illustrates the need for early recognition of the setting in order to detect the component tumors at a stage when surgery may be curative, and careful and life-long follow-up, both because the multicentricity of the classic components tends to manifest metachronously and because of the tendency to develop other tumors, some of which may be malignant. Furthermore, the presence of Hirschsprung's disease in the patient's family, coupled with the alleged common origin of two component lesions from derivatives of the neural crest, open new avenues for the understanding of this disorder.

Prognostic value of clinicopathologic characteristics including neuroectodermal differentiation in osseous Ewing's sarcoma family of tumors in children.

AIMS AND BACKGROUND: The aim of the present study was to determine the relationship between clinico-pathologic parameters, including neuroectodermal differentiation, and their impact on survival in a series of pediatric patients with osseous tumors of the Ewing's sarcoma family admitted to the Pediatric Department of the Istituto Nazionale Tumori of Milan. METHODS: Seventy-three patients were enrolled. The variables analyzed were sex, age, site of primary tumor, serum lactate dehydrogenase (LDH) level at diagnosis, involvement of periosseous soft tissues by primary tumor, presence of metastatic disease, status of disease after the treatment plan, as well as the presence of mitoses, morphologic and immunocytochemical neural markers, and neuroendocrine markers in the primary tumor. RESULTS: Neural and neuroendocrine markers were not significantly associated with any of the other parameters. In the univariate analysis, significant risk factors related to unfavorable outcome were elevated LDH, metastatic disease, lack of complete remission after treatment, presence of mitoses and of morphological neural markers; immunocytochemical neural and neuroendocrine markers lacked prognostic value. In the multivariate analysis, only LDH levels and the status of disease following the treatment were retained. CONCLUSIONS: LDH level at diagnosis might be a useful marker to identify different risk levels; neuroectodermal differentiation might have no clear-cut impact on the clinical management of osseous Ewing's sarcoma family of tumors.

Functioning human insulinomas. An immunohistochemical analysis of intracellular insulin processing.

Sixty-seven insulinomas were investigated by immunohistochemistry using site-directed antibodies against insulin, proinsulin, chromogranin A, HISL-19, and four proteins directly or indirectly involved in the proteolytic processing of proinsulin: the prohormone convertases PC2 and PC3, carboxypeptidase H (CPH) and 7B2. Results were expressed in a six-grade score according to the frequency of immunoreactive tumour cells. Insulin was expressed by all tumours, appearing in either a diffuse or a polarized pattern and being detected in more than 30% of tumour cells in all cases but three. Proinsulin was also expressed in all tumours, with more than 50% of tumour cells immunoreactive in all cases but 5. It was consistently localized in the Golgi apparatus. In about half the cases, moreover, it also showed diffuse cytoplasmic staining, usually with a very sparse distribution. Trabecular and solid insulinomas did not present specific, homogeneous patterns of insulin immunostaining. However, insulin immunoreactivity was much more abundant in trabecular than in solid neoplasms, being present in virtually all tumour cells (score 6) in 50% and 8% of cases, respectively. Virtually all insulinomas expressed PC2, PC3, CPH and 7B2, usually in 30-100% of tumour cells, with a frequency significantly related to that of insulin. However, detection of PC2 and 7B2 was slightly less frequent than that of PC3 and CPH. In consecutive sections these proteins were found to be mostly co-localized with insulin and chromogranin A but not with proinsulin. They were heavily expressed in all 10 tumours with more than 10% of cells showing cytoplasmic proinsulin immunoreactivity, indicating that the leakage of proinsulin from the Golgi compartment is not associated with faulty expression of converting enzymes and possibly reflects a saturated processing capacity. HISL-19 immunoreactivity was found in both Golgi apparatus and insulin stores, indicating that the relevant antigen is different from all other proteins investigated. These results do not support a defect in expression or localization of proinsulin-processing enzymes in most insulinomas.

Argyrophilia and chromogranin A and B immunostaining in patients with sporadic medullary thyroid carcinoma. A critical appraisal of their prognostic utility.

The purpose of the present study was to evaluate the prognostic utility of tumour argyrophilia and chromogranin A (CgA) and B (CgB) immunocytochemical expression in patients with sporadic medullary thyroid carcinoma. To this end, the histo-immunocytochemical data on a consecutive series of 99 such tumours were submitted to statistical analysis. In univariate analysis, a significantly increased risk of disease progression and death was present in patients with CgA-poor and CgB-poor tumours, respectively. Multivariate analyses were performed by adding the histo-immunocytochemical variables to the final (reference) models obtained in earlier work on the same case series, in which 18 clinicopathological variables had been taken into account. This addition did not change the prognostic impact of the variables considered in the two reference models; it did, however, increase the prognostic information for overall survival, since the adjunctive contribution of CgB immunocytochemical expression (as assessed by the likelihood ratio test) was statistically significant. It is concluded that the chromogranin B immunostaining pattern of the primary tumour allows the distinction of patients with an increased risk of death. Argyrophilia and expression of chromogranin A seem instead to be of no prognostic value in patients with sporadic medullary thyroid carcinoma.

Differentiation in paediatric peripheral primitive neuroectodermal tumours of bone. A critical contribution to its assessment.

Differentiation was studied in 73 paediatric peripheral primitive neurorectodermal tumours (pPNETs) of bone observed during 1974 through 1992. The presence of rosettes, pseudorosettes, and/or a rosette-like arrangement of tumour cells (the morphological neural marker, MNM) occurred in 29% of these cases. NSE and N-CAM were expressed by nearly all tumours; synaptophysin was present in 30% of cases, not significantly associated with the MNM status. Neuroendocrine (NE) markers were present in 25% (chromogranin B, secretogranin II) to 40% (chromogranin A, 7B2 protein) of cases. Focal expression of cytokeratins, S100 protein and/or desmin was also noted in a minority of cases. In univariate statistical analysis, only the presence of MNM conferred a significantly higher (about twofold) risk of death than its absence. This study demonstrates the occurrence of at least one immunocytochemical N and/or NE differentiation marker in all pPNETs of bone and a focal expression of cytokeratins, S100 protein and/or desmin in a minority of cases. Synaptophysin and MNM were present each in less than 1/3 of the cases, and no association was noted between them. Statistical analyses highlighted the prognostic role of MNM per se and discourage the sole use of immunocytochemistry in the assessment of neuroectodermal differentiation for prognostic purposes in paediatric pPNETs of bone.

Somatic in frame deletions not involving juxtamembranous cysteine residues strongly activate the RET proto-oncogene.

Somatic RET mutations have been identified in a variable proportion (about 30-70%) of sporadic Medullary Thyroid Carcinoma (MTC) cases. They are represented by the Met918Thr substitution (exon 16) typical of Multiple Endocrine Neoplasia type 2B (MEN2B) and, to a lesser extent, by nucleotide changes occurring at one of five critical cysteine residues (exons 10 and 11) typical of MEN type 2A (MEN2A). An in vitro transforming activity has already been demonstrated for these mutations. A few different MTC somatic mutations have been reported so far whose biological activity has still to be tested. In this paper we report the identification, in two MTC tumor samples, of two interstitial deletions of 48 bp and 6 bp occurred in exons 10 and 11 respectively. Both were somatic heterozygous in frame mutations, not involving any cysteine residue. Moreover, the expression of a full length RET cDNA carrying one of the two deletions demonstrated a strong transforming capacity in NIH3T3 cells.

Islet transplantation in IDDM patients.

This single-centre study investigated parameters that positively correlated with the success rate after islet allotransplantation in insulin-dependent diabetic (IDDM) patients. Twenty-one intrahepatic, fresh islet transplantations were performed in 20 IDDM patients (one patient had two transplants), after or simultaneous with kidney transplantation. The correlation between number and purity of transplanted islets and final outcome was investigated. One patient died of a cardiac arrest several hours after islet transplantation; this patient was not included in the follow-up analysis. Three patients (15%) experienced acute, irreversible, early failure of islet function, which was considered as a 'presumed rejection'. Nine patients (45%) achieved either complete insulin-independence (seven cases) or a reduction (> 50%) of exogenous insulin requirement (two cases), with sustained serum C-peptide secretion (0.89 +/- 0.04 nmol/l; duration: 21 +/- 7 months, range 2-58 months). Liver biopsy, performed 3 years after transplantation in one successful case, showed normal islets within the hepatic parenchyma. Eight cases (40%) did not show any metabolic effect of islet transplantation, with low serum C-peptide levels ('presumed function exhaustion'). Metabolic investigations performed in successful cases showed an early phase of insulin release after arginine, mild and reversible postprandial hyperglycaemia and normal HbA1c levels. Success of islet transplantation positively correlates with the number (p < 0.05) of the transplanted islets. Islet transplantation is a safe procedure, with 45% success rate, in terms of insulin-independence or relevant reductions of exogenous insulin requirement, although success can be transient.

Prognostic impact of thyroid lymphocytic infiltration in patients with medullary thyroid carcinoma.

A retrospective search for lymphocytic infiltration of the thyroid was performed on archival paraffin specimens from 95 cases of thyroid medullary carcinoma observed at a single institution during a 30-year period. A mild lymphocytic infiltration of the nonneoplastic thyroid tissue, mainly concentrated at the edge of the tumor mass, was observed in 33 cases, while in a further 24 cases a moderate to marked lymphocytic infiltration, resembling that seen in chronic lymphocytic thyroiditis, was homogeneously distributed all over the gland, with no apparent relationship to the site of the primary tumor. Virtually no lymphocytic infiltration was detected inside of any of the tumors. The presence of chronic lymphocytic thyroiditis seemed to be a characteristic of the host rather than a tumor-induced event. Statistical univariate analysis of relapse-free survival and overall survival showed that lack of chronic lymphocytic thyroiditis marked those patients with an increased risk of disease recurrence and death. However, the observed risk for survival was statistically nonsignificant, whereas that for disease recurrence was significant and remained in a multivariate model of statistical analysis.

Multivariate analysis of prognostic factors in sporadic medullary carcinoma of the thyroid. A retrospective study of 109 consecutive patients.

BACKGROUND: Because of the rarity of medullary thyroid carcinoma, adequate information for determination of the prognostic characteristics and clinical course of this disease can be obtained only from a database that serves a large population. METHODS: A retrospective review of 109 patients with sporadic medullary thyroid carcinoma was conducted; all were diagnosed and treated at a single institution over a 30-year period. The series included 57 males and 52 females with a median follow-up of 5.3 years. Statistical univariate analysis of relapse free survival and overall survival was done for 18 clinicopathologic variables, including sex, age, TNM staging, completeness of surgical resection, postoperative calcitoninemia, histologic subtype, tumor size, thyroid capsule invasion, amyloid, katacalcin, calcitonin, and calcitonin gene-related peptide immunostaining patterns of the primary tumor. RESULTS: Risk factors for unfavorable outcome were male sex, age > 60 years, incomplete tumor resection, mixed cell subtype, tumor size > 4 cm, extrathyroid tumor invasion, lack of amyloid, N1 and M1 categories, and heterogeneous calcitonin and katacalcin immunostaining pattern. In the multivariate analysis, only capsule status, M category, and age at diagnosis remained in the final model for overall survival. In the final model for relapse free survival, capsule status remained, together with sex and amyloid status. CONCLUSIONS: Extrathyroid tumor invasion, the presence of distant metastases, and age > 60 years are characteristic of patients at high risk of death from disease sooner, whereas extrathyroid invasion, male sex, and the absence of amyloid characterize patients who are at high risk for recurrence. Extrathyroid tumor invasion appears to be the worst prognostic factor and may allow for the breakdown of patients into two categories, amenable to different therapeutic regimens.

Malignant pheochromocytoma in multiple endocrine neoplasia type 2B syndrome. Case report and review of the literature.

A malignant behavior (i.e., distant metastatic spread) has been recorded in 3-4% pheochromocytomas occurring in the context of multiple endocrine neoplasia type 2A syndrome, but has never been documented in patients with the type 2B form. In this report we describe a case of malignant pheochromocytoma arising in the latter syndrome setting. The patient, a white young male, had the full-blown syndrome, including multicentric, bilateral medullary thyroid carcinoma metastatic to regional lymph nodes, mucosal neuromas, digestive ganglioneuromatosis, marfanoid habitus, and bumpy lips. Three and a half years after surgical resection of an apparently benign adrenal pheochromocytoma he developed widespread osseous metastases. The presence of hypertensive crises and high urinary catecholamine excretion rates, coupled to moderate hypercalcitoninemia, normal circulating carcinoembryonic antigen levels, negative whole-body 99mTc-(V) dimercaptosuccinic acid scan, and absence of neck or mediastinal disease by magnetic resonance imaging, proved that the metastases were from his previous adrenal and not thyroid tumor. Furthermore, since the bone metastases strongly accumulated 131I-metaiodobenzylguanidine, several courses of the radiocompound were given, which resulted in an objective, though partial, tumor regression.

Development of the sympathoadrenal system in the chick embryo: an immunocytochemical study with antibodies to pan-neuroendocrine markers, catecholamine-synthesizing enzymes, proprotein-processing enzymes, and neuropeptides.

BACKGROUND: The adrenal chromaffin cells synthesize, store and secrete a complex mixture containing amines, structural proteins, enzymes, and neurohormonal polypeptides. Most of the studies dealing with the development of the avian sympathoadrenal system have been based on antibodies recognizing signal molecules like HNK-1, NC-1, and N-CAM. METHODS: The development of the chick sympathoadrenal system was studied from 3 1/2 to 21 days of incubation, both morphologically and immunocytochemically, using antibodies to 17 separate antigens, including antibodies to pan-neuroendocrine markers, catecholamine synthesizing enzymes, proprotein-processing enzymes, and neuropeptides. RESULTS: Some of the antigens studied were heavily expressed from the first days of development, e.g., chromogranin-A, chromogranin-B, Go protein-alpha subunit, tyrosine hydroxylase, and galanin, while for others a strong heterogeneity both in number of immunoreactive cells and intensity of immunostaining was recorded at the different stages, e.g., dopamine-beta-hydroxylase,, 7B2 protein, proprotein convertase 2, somatostatin, met-enkephalin, secretogranin II, proprotein convertase 3, neuropeptide Y, phenyl-N-methyl transferase, and neuron-specific enolase. The first immunoreactivities to appear at day 3 1/2 were those for HNK-1, tyrosine hydroxylase, chromogranin-A, and chromogranin-B. Except for HNK-1, immunoreactivity for all the remaining antigens showed a steady increase up to the hatching. CONCLUSIONS: Three expression patterns were found, in the developmental adrenal-gland: defining early permanent markers (chromogranin-A, chromogranin-B, Go protein-alpha subunit, tyrosine hydroxylase, and galanin), others that show a progressively increased expression until the day 10 of development (dopamine-beta-hydroxylase, 7B2 protein, proprotein convertase 2, somatostatin, met-enkephalin), and late-appearing antigens (secretogranin II, proprotein convertase 3, neuropeptide Y, phenyl-N-methyl transferase, and neuron-specific enolase).

Proprotein convertases (PC1/PC3 and PC2) in normal and neoplastic human tissues: their use as markers of neuroendocrine differentiation.

By immunocytochemistry and immunoblotting, we examined normal and neoplastic human tissues with polyclonal antibodies raised against selected peptide regions of proprotein convertase-2 and -3 (PC2 and PC3), two proteases that have been shown to selectively cleave neuroendocrine precursor molecules at pairs of basic residues. Immunoreactivity for both enzymes was detected in neuroendocrine cells of pituitary, gut, pancreas, thyroid, and adrenals and in tumors thereof, but was absent in thyroid follicular cells, parathyroids, adrenal cortex, testes, and a number of nonneuroendocrine tissues, both normal and tumorous. Although both PCs were virtually universal concomitants of the neuroendocrine system, cells with a neural phenotype (e.g. pheochromocytes and Merkel cells) predominantly contained PC2, whereas classic endocrine cells contained mostly PC3. PC3 immunoreactive cells were abundant all along the gastrointestinal tract, whereas PC2 was highly expressed only in the pyloric antrum and proximal third of duodenum. Double immunostaining experiments revealed colocalization of PC3 with virtually all gastrointestinal peptides, whereas PC2 immunoreactivity was mostly expressed in gastrin, cholecystokinin, and somatostatin cells. Noticeably, the proportion of glucagon-producing cells immunoreactive for PC3 was high in the gut and low in pancreatic islets and glucagonomas, whereas the reverse occurred for PC2. At the ultrastructural level, immunostaining was confined to the mature dense core granules, the site of storage of granins and peptide hormones. With the exception of parathyroid cells, PC2 and/or PC3 expression correlated with the occurrence of granins, canonical markers of the secretory granules. Immunoblotting experiments confirmed the identity of the immunocytochemical reactivities. It is concluded that PC2 and PC3 are highly sensitive markers of neuroendocrine differentiation and have distinct distribution patterns, and that antibodies to these enzymes may play an important role in the analysis of tumors.

Immunocytochemical detection and characterization of intrahepatic human pancreatic islets after combined liver-islet allotransplantation.

The unique availability of an explanted liver-islet allograft, removed for primary nonfunction of the liver, led us to evaluate distribution and phenotype of exocrine and endocrine components of the pancreatic graft. Immunocytochemistry was used to map patterns of gene products for islet hormones, proprotein processing enzymes, panneuroendocrine markers, and pancreatic exocrine markers. When compared with age-matched control pancreases, insulin-, glucagon-, somatostatin-, and pancreatic polypeptide-producing cells were similarly represented and distributed within the grafted islet. We also demonstrate that the intrahepatic transplanted islets retained the enzyme machinery able to process the hormone precursors into bioactive fragments. In the clinical setting, this resulted in an immediate functioning of the graft and insulin-independence of the patient one month after transplantation. The purity in islets, as assessed by immunocytochemistry with antibodies to tissue constituents of endocrine and exocrine lineages, was around 40%. Despite the massive intraportal presence of pancreatic acinar tissue, no signs or symptoms attributable to ectopic hypersecretion of exocrine enzymes occurred. In fact, when tested with antibodies to such enzymes, low levels of immunoreactivity were observed in the grafted acinar cells.

Mucinous carcinoma of the breast. A clinicopathologic, histochemical, and immunocytochemical study with special reference to neuroendocrine differentiation.

We studied the clinical, histologic, histochemical, and immunocytochemical characteristics of 61 mucinous tumors (38 pure, 23 mixed) retrieved from a consecutive series of 1,689 infiltrating carcinomas of the female breast. The only statistically significant predictors of favorable survival were histologic (pure) type coupled with the absence of axillary lymph node metastases. Other factors, including classification into A and B types according to Capella et al., and neuroendocrine status, as assessed by the presence of argyrophilia, granins, neuron-specific enolase (NSE), and synaptophysin (SYN),-all had no influence on survival. Argyrophilic cells were found in 16 pure mucinous tumors (42%) and in the mucinous component of four mixed tumors (17%). Granin (chromogranin A or B), NSE, and SYN immunoreactivities were demonstrated in all the argyrophilic tumors. We also found NSE- and SYN-immunoreactive cells in 31 of 41 and 16 of 41 nonargyrophilic (granin-unreactive) mucinous tumors, which supports the view that mucinous carcinomas of the breast as a whole are neuroendocrine-programmed tumors.

Argyrophilia and granin (chromogranin/secretogranin) expression in female breast carcinomas. Their relationship to survival and other disease parameters.

Ninety-one tumors (5.6%) containing argyrophilic cells were identified in a series of 1,628 consecutive primary breast carcinomas diagnosed between 1968 and 1972 at the Istituto Nazionale Tumori, Milan, Italy. Histological evaluation of these argyrophilic tumors showed the presence, either throughout the whole tumor mass (pure form) or in some areas (mixed form), of distinctive though not pathognomonic cellular features. Immunocytochemistry revealed the presence of chromogranin A or chromogranin B (secretogranin I) immunoreactivity in 86% of these argyrophilic carcinomas and of neuron-specific enolase (NSE) immunoreactivity in all of them. The three neuroendocrine markers were also immunolocalized at the ultrastructural level in the dense-core granules (granins) and the cytoplasmic matrix (NSE). Immunoblotting studies confirmed the chromogranin A and B and NSE immunoreactivities and documented the presence of secretogranin II. We also studied the relation of the histologic, histochemical, and immunocytochemical features to prognosis. There was no significant correlation between argyrophilia and such clinical parameters as age, menopausal status, tumor size, and overall survival; however, the pure form of argyrophilic tumors had a significant association with less frequent lymph node involvement and a low histologic grade.

Well-differentiated neuroendocrine carcinoma of the lung: a clinicopathologic and ultrastructural study of 10 cases.

The clinico-pathologic characteristics of 10 resected pulmonary tumors, which proved to be well-differentiated neuroendocrine carcinomas (WDNC) on the basis of light microscopic, immunocytochemical, ultrastructural and immunoelectron microscopic investigations, were evaluated. The tumors showed a wide spectrum of histologic features that could be referred to three basic patterns: 1) a carcinoid-like pattern; 2) an organoid pattern characterized by palisading cells at the edge of cellular areas, and 3) a prevalent adenocarcinoma-like pattern. The second pattern was the most distinct even though it often mimicked the small cell/large cell subtype of small cell carcinoma (SCC) owing to its association with marked atypia and poor differentiation. All but one of the patients were males and smokers. The mean age was 58 years. Half of the tumors were centrally located including those showing the adenocarcinoma-like pattern. Disease-free and overall survival and type of tumor dissemination in four patients were similar to those of SCC. Five evaluable patients were alive and disease-free after a mean follow-up of 74 months. Two of these were initially diagnosed as SCC. We conclude that, because of its impact on prognosis, the diagnosis of WDNC appears to be relevant although other factors able to adversely affect the clinical course remain undefined.

Argyrophilic carcinoma of the male breast. A neuroendocrine tumor containing predominantly chromogranin B (secretogranin I).

Argyrophilic tumors were diagnosed in 28 of 134 (20.8%) consecutive male patients who had a carcinoma of the breast removed between 1961 and 1990. Histologically, most argyrophilic tumors showed uniform cellularity and prevalent expansive growth. Ultrastructural observation disclosed the presence of electron-dense cored granules in the cytoplasm of the tumor cells. By immunocytochemistry, 17 of 28 argyrophilic tumors (60.7%) contained chromogranin B (secretogranin I)-immunoreactive cells, whereas chromogranin A was present in four of these 17 tumors only (14.2%). Immunoblotting studies showed chromogranin B immunoreactivity similar to that found in normal neuroendocrine cells. Despite these findings, which would argue for a distinct morphologic and immunochemical entity, no statistically significant differences between argyrophilic and common male breast carcinomas were found when a number of clinicopathologic features and relapse-free survival were considered.

C-cell hyperplasia accompanying thyroid diseases other than medullary carcinoma: an immunocytochemical study by means of antibodies to calcitonin and somatostatin.

Eighteen normal thyroid glands and unaffected thyroid tissue adjacent to 37 follicular cell-derived benign and malignant tumors and to ten thyroid metastases were studied immunocytochemically with calcitonin (CT) and prosomatostatin/somatostatin (SMS) antibodies. CT- and SMS-immunoreactive cells were found in 100% of cases, though with ample variations in number. Most but not all SMS-immunoreactive cells also contained CT. Diffuse and/or nodular C-cell hyperplasia was seen in 30% of pathological thyroid glands; in concomitance with follicular adenomas, the mean C-cell number more than doubled that found in normal glands. Furthermore the proportion of SMS-immunoreactive C-cells increased from about 1% of CT-immunoreactive cells in normal adult thyroid glands to 2.5% in follicular adenomas, 3% in follicular carcinomas, 4.6% in papillary carcinomas, and 5.7% in metastases. The findings suggest that C-cell hyperplasia may be causally related to pathologic disorders affecting follicular cells. Furthermore, the demonstration that the intrathyroidal SMS cell mass is readily affected by alterations of the follicular structure of the gland suggests a possible regulatory role of SMS in the thyroidal microenvironment.