Philipp U. Heitz

Immunocytochemical markers of uncommon pancreatic tumors. Acinar cell carcinoma, pancreatoblastoma, and solid cystic (papillary‐cystic) tumor

Nine acinar cell carcinomas of the pancreas, 2 pancreatoblastomas, 16 solid‐cystic (papillary‐cystic) tumors, and 20 ductal adenocarcinomas were immunocytochemically investigated using antisera against four pancreatic enzymes (alpha‐amylase, lipase, trypsinogen, chymotrypsinogen), four pancreatic hormones, neuron specific enolase (NSE), alpha‐1‐antitrypsin (AAT), carcinoembryonic antigen (CEA), and CA 19–9. Lipase, trypsinogen, and chymotrypsinogen, but no alpha‐amylase were detected in all acinar cell carcinomas and pancreatoblastomas. In contrast, solid‐cystic tumors (SCT) were negative for pancreatic enzymes but 2 of 16 stained with NSE. No neuroendocrine granules or pancreatic hormones could be demonstrated. AAT was found in all tumors except ductal adenocarcinomas, which stained with CEA and CA 19–9. The study established pancreatic enzymes (except alpha‐amylase) as immunocytochemical markers for acinar cell carcinomas and pancreatoblastomas. There is as yet no marker specific for SCT, which would elucidate the obscure histogenetic origin and phenotypic differentiation of these tumors. Cancer 59:729‐747, 1987.

Prognostic factors in medullary thyroid carcinomas. Survival in relation to age, sex, stage, histology, immunocytochemistry, and DNA content

Patients with medullary thyroid carcinomas (MTC) were analyzed according to age, sex, and tumor stage. In addition, the MTC were screened for the predominant histologic pattern, immunocytochemical spectrum (60 tumors), and DNA content (DNA cytophotometry and DNA flow cytometry, 25 tumors). These findings were correlated with follow‐up data available for 45 of these patients. Forty‐eight percent of the tumors revealed a polygonal cell pattern, whereas 22% showed spindle‐cell predominance. All tumors contained cytokeratin, chromogranin A, and calcitonin (CT). Calcitonin gene‐related peptide (CGRP) was present in 92%, carcinoembryonic antigen (CEA) in 77%, neuron‐specific enolase (NSE) in 75%, and vimentin in 53% of cases. Positivity for neurotensin, somatostatin, neurofilaments, bombesin, and alpha human chorionic gonadotropin (a‐hCG) and serotonin ranged between 3% and 27%. All MTC were negative for substance P, adrenocorticotropic hormone (ACTH), thyroglobulin (TG), or S‐100 protein. Local recurrences and regional lymph node metastases revealed identical staining patterns as the primaries. Prognosis of MTC was found not to be related to histologic features (dominant architectural pattern, cellular shape, presence of amyloid deposits) or immunocytochemical pattern. Instead, survival was significantly correlated to age, sex, and stage of disease. The best prognosis was seen in women younger than 40 years and revealing an early stage of disease. DNA measurements added valuable information in assessing the prognosis of MTC.

Glycoprotein-hormone alpha-chain production by pancreatic endocrine tumors: A specific marker for malignancy. Immunocytochemical analysis of tumors of 155 patients

Human chorionic gonadotropin (hCG) or its α‐ and β‐subunits have been proposed as specific quantitative markers for malignant pancreatic endocrine tumors.1 Since proof of malignancy of pancreatic endocrine tumors is difficult early in the course of the illness, we tested retrospectively a series of 157 pancreatic endocrine tumors of 155 patients for α‐ or β‐subunits of hCG by immunocytochemistry. Human CG‐α‐immunoreactive cells were present in 42 of 56 (75%) functioning malignant pancreatic endocrine tumors but in only one, possibly benign, glucagonoma of 67 functioning benign tumors, in only one of 17 nonfunctioning malignant and in none of 17 nonfunctioning benign tumors. No β‐hCG‐immunoreactivity was localized in the tumors. Human CG‐α‐appears to be a reliable quantitative and qualitative marker for malignancy in functioning pancreatic endocrine tumors.

Ectopic hormone production by endocrine tumors: Localization of hormones at the cellular level by immunocytochemistry

Clinical and laboratory data, histologic, electron microscopic and immunocytochemical findings of the tumors of eight patients suffering from Cushings syndrome and of one patient with hypercalcemia are described. The unlabeled antibody enzyme method was used for the detection of insulin, glucagon, somatostatin, pancreatic polypeptide, corticotropin, β‐lipotropin, calcitonin, parathyroid hormone, and gastrin. Ectopic Cushings syndrome was caused by pancreatic endocrine tumors, medullary thyroid carcinoma, a bronchial, a gastric and a thymic carcinoid, and a carcinoid of the mediastinum. Hypercalcemia in one patient was related to a pancreatic endocrine tumor. After surgery the clinical symptoms disappeared in two patients, but persisted or relapsed in five patients. ACTH‐immunoreactivity could be demonstrated in six of eight tumors; calcitonin‐immunoreactivity was found in the tumor of the patient suffering from hypercalcemia. ACTH‐immunoreactivity could be localized to secretory granules by immunoelectron microscopy, and the presence of ACTH and β‐LPH in the same tumor cells could be shown in one pancreatic tumor. A combination of production of orthotopic and ectopic hormones was found in one, and secretion of two ectopic hormones was detected in another pancreatic endocrine tumor.

Gains of 12q13-14 and overexpression of mdm2 are frequent findings in intimal sarcomas of the pulmonary artery.

Abstract. The characterization of clinical, histopathological, immunohistochemical, and genetic features of intimal sarcomas arising in the pulmonary artery is presented in this study. Four resected lungs, one endarterectomy specimen and three biopsies from eight patients (four males and four females; median age 41xa0years) suffering from intimal sarcomas of the pulmonary artery using conventional stains, immunohistochemistry, and comparative genomic hybridization (CGH) were analyzed. The predominant clinical presentation was dyspnea (all eight patients) and febrile pulmonary disease (six of eight). Signs of embolic lung disease were present in all patients. One patient died postoperatively, six patients died of disease 8–35xa0months after presentation, and one patient was alive 6xa0months after surgery. Histopathological examination of the submitted material showed spindle cell, partially myxoid and pleomorphic sarcomas. Metastases were histologically confirmed in three patients (lung, pleura, and skull). Immunohistochemically, vimentin was strongly expressed in all tumors. Focal positivity was observed for alpha smooth muscle actin, CD117, CD68, p53, and bcl2. No reaction could be obtained for endothelial markers. The proliferation index Ki-67 was between 5% and 80%. Six examined tumors were positive for mdm2. In the CGH analysis, gains and amplifications in the 12q13–14 region were found in six of eight tumors (75%). Other, less consistent alterations, were losses on 3p, 3q, 4q, 9p, 11q, 13q, Xp, and Xq, gains on 7p, 17p, and 17q, and amplifications on 4q, 5p, 6p, and 11q. Intimal sarcomas of the pulmonary artery are tumors with an unfavorable prognosis and poorly differentiated morphology. A majority of tumors show a consistent genetic alteration (gains and amplifications in the 12q13–14 region) and overexpression of mdm2, implicating the mdm2/p53 pathway as a possible mechanism in the tumor pathogenesis.

Identification of neoplastic Paneth cells in an adenocarcinoma of the stomach using lysozyme as a marker, and electron microscopy.

A large number of cells containing large eosinophilic granules in their supranuclear cytoplasm was observed in a well differentiated adenocarcinoma of the stomach and its metastases. These cells were identified as Paneth cells by electron microscopy and by their content of lysozyme. Lysozyme-immunoreactivity was well preserved after fixation of tumor tissue in liquid formaldehyde followed by postfixation in osmium tetroxide. Immunoreactivity at immunoelectron microscopy was confined to the large osmiophilic secretory granules. We conclude that morphologically and biochemically differentiated Paneth cells occasionally occur in neoplasms of the gastrointestinal tract.

Dopamine, norepinephrine and serotonin production by an intestinal carcinoid tumor.

Substantial amounts of both dopamine and norepinephrine in addition to serotonin were found in a mesenteric metastasis of an ileal carcinoid tumor. Correspondingly, the norepinephrine‐synthesizing enzymes were present in the tumor tissue and tyrosine hydroxylase was found in amounts substantially higher than the levels normally present in adrenal medullary cells. These findings confirm that the carcinoid tumors belong to the APUDomas and indicate that catecholamines might play an important role in the pathogenesis of the carcinoid syndrome.

Thyroglobulin production by malignant thyroid tumors: an immunocytochemical and radioimmunoassay study

Four hundred thirty surgical and biopsy specimens of malignant thyroid tumors of 323 patients were analyzed by histologic and immunocytochemical examination for their thyroglobulin (TG) content. Almost 95% of the differentiated thyroid carcinomas of follicular origin contained immunoreactive TG. The authors could not demonstrate TG in anaplastic carcinomas. Postoperative follow‐up and serum TG determinations were available for 111 athyroid patients. Serum TG was elevated in five patients with metastatic or recurrent moderately differentiated follicular carcinoma, in two patients with metastasizing papillary, and in one patient with anaplastic carcinoma. Four patients had detectable serum TG levels without clinical and radiologic evidence of recurrence or metastases. In addition to conventional histologic examination, immunocytochemical demonstration of TG is a reliable and valuable aid in the diagnosis, classification, and determination of the grade of differentiation of malignant thyroid tumors. From this the pathologist can provide a pathologic basis for postoperative patient management.

Evaluation of polysialic acid in the diagnosis of Wilms' tumor. A comparative study on urinary tract tumors and non-neuroendocrine tumors.

SummaryThe polysialic acid moiety of the neural cell adhesion molecule has been shown to represent an onco-developmental antigen which can be detected in both embryonic human kidney and Wilms’ tumor but not in normal adult human kidney. In the present comparative study, Wilms’ tumors, clear cell (bone-metastasizing) sarcomas of kidney, cystic nephromas, renal cell carcinomas, transitional cell carcinomas and papillomas of the renal pelvis, ureter and urinary bladder (as well normal transitional epithelium from these regions), Ewing sarcomas, hepatoblastomas, rhabdomyosarcomas, and carcinomas of the stomach, colon, exocrine pancreas, lung, and esophagus, were investigated immunohistochemically for the presence of polysialic acid. In addition, immunoblot analysis was performed in selected tumors. With the exception of Wilms’ tumor, none of the tumors investigated was positive for polysialic acid. In Wilms’ tumor, blastemal cells and all epithelial components were positive but no immunostaining was observed in the stroma. These observations emphasize the potential value of a monoclonal anti-polysialic acid antibody in identifying blastemal metanephric cells and their epithelial differentiatives in Wilms’ tumor.

Differentiation of two types of amyloid occuring in pituitary adenomas

Two types of amyloid can be differentiated by light microscopy, immunocytochemistry, and electron microscopy. The more frequent type (stellate/perivascular amyloid) is a secretory product of the adenoma cells whereas the second, rare type (spheroid amyloid) is formed by remnants of the cytoskeleton of necrotic adenoma cells.