Fine needle aspiration biopsy of neuroendocrine breast carcinoma metastatic to the thyroid. A case report

BACKGROUND: Tumors showing neuroendocrine differentiation arise in a wide range of organs, and metastatic neuroendocrine tumors may be difficult to differentiate from primary tumors. This report describes an unusual case of metastatic breast carcinoma with neuroendocrine differentiation that presented as a solitary thyroid nodule. The diagnosis was made by fine needle aspiration biopsy (FNAB). CASE: A 52-year-old woman presented with a thyroid nodule and bilateral enlarged supraclavicular fossa lymph nodes. FNAB revealed a neuroendocrine carcinoma. Further questioning revealed that the patient had had a breast carcinoma resected eight years previously. The diagnosis of metastatic neuroendocrine breast carcinoma was established by immunocytochemistry. The patient received antiestrogen therapy but subsequently developed skeletal metastases. CONCLUSION: Neuroendocrine carcinomas from various sites show similar cytologic features. In this case, a diagnosis of breast carcinoma metastatic to the thyroid was suggested by the clinical history and confirmed by FNAB with immunocytochemistry.     

Incidence and relative survival of pancreatic adenocarcinoma and pancreatic neuroendocrine neoplasms in Germany, 2009–2018. An in-depth analysis of two population-based cancer registries

BackgroundPancreatic neuroendocrine neoplasms are categorized as neuroendocrine tumors and neuroendocrine carcinomas. Until now, cancer registry reporting of pancreatic cancers does not include a stratification by these two subgroups. We studied the incidence and survival of pancreatic cancer with a special focus on pancreatic neuroendocrine neoplasms.MethodsWe analyzed data from the population-based cancer registries of North Rhine-Westphalia (NRW) and Saarland (SL), Germany, of the years 2009–2018. We included primary malignant pancreatic tumors and report morphology-specific age-standardized (World Standard population) incidence rates for ages 0–79 years and age-standardized relative survival (period approach, ICSS standard). All analyses were restricted to non-death certificate only cases.ResultsWe analyzed 23,037 patients with a newly diagnosed primary pancreatic cancer. Among morphologically specified cancers, adenocarcinoma (92 %) and neuroendocrine neoplasms (7 %) were the most common morphologies. The age-standardized incidence rates of adenocarcinoma, neuroendocrine tumors and neuroendocrine carcinomas were 4.0–5.5 (in NRW and SL), 0.1–0.3, and 0.1–0.3 per 100,000 person-years, respectively. Neuroendocrine tumors had the highest age-standardized 5-year relative survival with 75.5 % (standard error, SE 2.3) in NRW and 90.6 % (SE 10.2) in SL followed by neuroendocrine carcinomas (NRW: 30.0 %, SE 3.1; SL: 32.3 %, SE 8.7) and adenocarcinomas (NRW: 11.3 %, SE 0.4; SL: 10.2 %, SE 1.5).DiscussionThe distinction between neuroendocrine tumors and neuroendocrine carcinomas by the WHO divides neuroendocrine neoplasms into two prognostically clearly distinct subgroups that should be separately analyzed in terms of survival. The first year after diagnosis of pancreatic cancer is the most critical year in terms of survival.     

Adrenomedullin is a novel marker of tumor progression in neuroendocrine carcinomas.

Adrenomedullin is a multi-functional polypeptide hormone. Its involvement in angiogenesis and vasodilator action support the hypothesis that adrenomedullin may be a secretory product of neuroendocrine tumors and contribute to tumor progression. Plasma levels of adrenomedullin were measured by radioimmunoassay in 46 patients with neuroendocrine carcinomas of the gastroenteropancreatic and bronchial system. Tissue expression of adrenomedullin was studied using monoclonal antibodies on pretreated paraffin embedded tissues in a group of 31 patients. Adrenomedullin plasma levels were significantly elevated in patients compared to healthy age-matched controls (p < 0.001). The highest plasma levels were found in patients with neuroendocrine carcinomas of bronchial, midgut and unknown origin. Patients with progressive disease had higher plasma levels than patients with stable disease (p < 0.001). Of the examined tumor samples, 55 % showed cytoplasmic staining for adrenomedullin > 5 % of the total tumor area. Plasma levels and tissue expression of adrenomedullin did not correlate with functional activity of the tumors or presence of the carcinoid syndrome, but did with tumor progression (p < 0.001 and p < 0.014). In conclusion, plasma and tissue expression of the angiogenic peptide adrenomedullin are predictive of tumor progression in patients with neuroendocrine carcinomas. Adrenomedullin might represent a useful prognostic marker in patients with neuroendocrine carcinomas.     

Cytopathologic features of pituitary carcinoma with cervical vertebral bone metastasis: a case report

BACKGROUND: Pituitary carcinomas are extremely rare tumors of the adenohypophysis. The presence of craniospinal and/or systemic extracranial metastases is the only reliable criterion for the diagnosis of pituitary carcinoma. To date, only 2 cases have been reported correctly by fine needle aspiration biopsy (FNAB). We present an additional case of pituitary carcinoma with FNAB features. CASE: A 60-year-old woman presented with clinical features of Cushing's disease and a pituitary tumor. She underwent transsphenoidal resection of the tumor. The initial diagnosis was an adrenocorticotrophic hormone (ACTH)-producing invasive pituitary adenoma. The patient presented again with neck pain 6 years after the operation. Magnetic resonance imaging revealed metastatic tumor masses at the level of C5-C6 of the cervical vertebrae. Intraoperative fine needle aspiration and incomplete excision of metastatic tumors were performed. Cytologically, tumor cells were composed of a combination of loose groups and single cells. Neoplastic cells had a relatively monotonous appearance and displayed characteristic neuroendocrine tumor features. Immunocytochemistry from cell block sections revealed AE1/ AE3, synaptophysin chromogranin A and ACTH positivity in the tumor cells. CONCLUSION: Pituitary carcinoma with extracranial systemic metastases demonstrates typical neuroendocrine features on fine needle aspiration. In the differential diagnosis, metastatic neuroendocrine carcinomas should be kept in mind. In the absence of sufficient clinical data, these 2 entities cannot be distinguished correctly through the cytologic features.     

Signet ring cells in gastric carcinomas are derived from neuroendocrine cells.

Adenocarcinomas are malignant tumors with glandular growth and/or supposed intracellular mucin as identified by periodic acid-Schiff (PAS) positivity. Gastric signet ring cell carcinomas are classified as diffuse type. A proportion of diffuse-type adenocarcinomas have previously been suggested to be of neuroendocrine origin. In the present study we examined gastric signet ring cell carcinomas for neuroendocrine differentiation. Of 11 gastric signet ring cell carcinomas, 8 contained areas with PAS-positive signet ring cells that also were immunoreactive for one or several neuroendocrine markers: synaptophysin, chromogranin A, and histidine decarboxylase, the latter an enterochromaffin-like (ECL) cell marker. Whereas PAS positivity was located in the central cytoplasm, neuroendocrine immunoreactivity was often located as a rim surrounding an otherwise non-immunoreactive cytoplasm, presumed to represent the area with PAS-positive material. These findings indicate that signet ring cell carcinomas could be of neuroendocrine origin. We propose that signet ring cell carcinomas develop by gradual dedifferentiation from ECL cells via signet ring cells with neuroendocrine immunoreactivity toward signet ring cells where the cytoplasm mainly consists of PAS-positive material. This finding could have implications for the classification and understanding of gastric carcinogenesis.     

The levels of three enolase subunits in human tumors; a low α-/γ-subunit ratio as indicator of tumors of neuronal and neuroendocrine nature

The contents of three subunits (α, β and γ) of enolase isoenzymes of various human tumors, especially of neuronal and neuroendocrine tumors, were determined by a highly sensitive enzyme immunoassay system. A high level of γ-subunit was detected in neuronal and neuroendocrine tumors, including small cell carcinomas of the lung. The level of α-subunit was generally higher in all tumors and varied according to the tumor. The β-subunit level was elevated in rhabdomyosarcomas. Furthermore, analyzing the relationship between the contents of each enolase subunit among the tumors, the α-/γ-subunit ratios were the lowest in neuronal tumors and increased in order of neuroendocrine and non-neuroendocrine tumors. This result suggested that the α-/γ-subunit ratio is an important indicator to evaluate neuronal and neuroendocrine differentiation of the tumor rather than the amount of γ-subunit of enolase itself.     

TDP-43 toxicity in yeast

Metaiodobenzylguanidine (MIBG) is a tracer that selectively targets neuroendocrine cells. On this basis, radiolabeled iodinated-MIBG (I-131-MIBG) has been introduced as a molecular nuclear therapy in the management of neuroendocrine tumors, including neuroblastoma, pheochromocytoma, paraganglioma, neuroendocrine carcinomas, and other rare neuroendocrine tumors. Extensive work has been addressed to develop I-131-MIBG therapy: doses, therapeutic schemes, and efficiency. In this paper, we present an overview on I-131-MIBG therapy, with main focus on different aspects how to perform this treatment.     

Comparative proteomics of pulmonary tumors with neuroendocrine differentiation

We aimed to evaluate neuroendocrine pulmonary tumors (NEPT) by a novel method involving map tree construction by comparing all of the protein spots. We performed a proteomics analysis to assess the similarities in protein expression between neuroendocrine pulmonary tumors (NEPT), including typical carcinoids (TC), atypical carcinoids (AC), large cell neuroendocrine carcinomas (LCNEC) and small cell carcinomas (SCLC). Total protein lysates were obtained from seven histologically confirmed frozen NEPT tissues, including 1TC, 2 SCLC, and 4 cases ranging from AC to LCNEC. 2-DE demonstrated that TC was similar to normal lung. AC, LCNEC, and SCLC were similar to each other, forming a group separate from TC, however, SCLC at an early stage showed a similarity to TC. MALDI analysis detected 9 surrogate endpoint biomarkers, including eIF5A1, GST M3, cytokeratin 18 (CK 18), FK506-binding protein p59, p63, MAGE-D2, mitochondrial short-chain enoyl-coenzyme A hydratase 1, tranferrin and poly (rC) binding protein 1. Immunohistochemical staining revealed a gradual decrease in expression rate of p63 and CK 18 with poor differentiation of NEPT. Our results demonstrate that (1) the comparative proteomics of NEPT match the WHO classification except for AC and LCNEC; (2) SCLC show differences in their proteomics according to tumor stage; and (3) CK 18 and p63 may be useful as diagnostically and prognostically available markers.     

The Contrasting Role of p16Ink4A Patterns of Expression in Neuroendocrine and Non-Neuroendocrine Lung Tumors: A Comprehensive Analysis with Clinicopathologic and Molecular Correlations

Lung cancer encompasses a constellation of malignancies with no validated prognostic markers. p16^Ink4A expression has been reported in different subtypes of lung cancers; however, its prognostic value is controversial. Here, we sought to investigate the clinical significance of p16^Ink4A immunoexpression according to specific staining patterns and its operational implications. A total of 502 tumors, including 277 adenocarcinomas, 84 squamous cell carcinomas, 22 large cell carcinomas, 47 typical carcinoids, 12 atypical carcinoids, 28 large cell neuroendocrine carcinomas, and 32 small cell carcinomas were reviewed and subjected to immunohistochemical analysis for p16^Ink4A and Ki67. The spectrum of p16^Ink4A expression was annotated for each case as negative, sporadic, focal, or diffuse. Expression at immunohistochemical level showed intra-tumor homogeneity, regardless tumor histotype. Enrichments in cells expressing p16^Ink4A were observed from lower- to higher-grade neuroendocrine malignancies, whereas a decrease was seen in poorly and undifferentiated non-neuroendocrine carcinomas. Tumor proliferation indices were higher in neuroendocrine tumors expressing p16^Ink4A while non-neuroendocrine malignancies immunoreactive for p16^Ink4A showed a decrease in Ki67-positive cells. Quantitative statistical analyses including each histotype and the p16^Ink4A status confirmed the independent prognostic role of p16^Ink4A expression, being a high-risk indicator in neuroendocrine tumors and a marker of good prognosis in non-neuroendocrine lung malignancies. In this study, we provide circumstantial evidence to suggest that the routinary assessment of p16^Ink4A expression using a three-tiered scoring algorithm, even in a small biopsy, may constitute a reliable, reproducible, and cost-effective substrate for a more accurate risk stratification of each individual patient.     

Molecular and cellular biology of neuroendocrine lung tumors: Evidence for separate biological entities

Pulmonary neuroendocrine tumors (NETs) are traditionally described as comprising a spectrum of neoplasms, ranging from low grade typical carcinoids (TCs) via the intermediate grade atypical carcinoids (ACs) to the highly malignant small cell lung cancers (SCLCs) and large cell neuroendocrine carcinomas (LCNECs). Recent data, however, suggests that two categories can be distinguished on basis of molecular and clinical data, i.e. the high grade neuroendocrine (NE) carcinomas and the carcinoid tumors. Bronchial carcinoids and SCLCs may originate from the same pulmonary NE precursor cells, but a precursor lesion has only been observed in association with carcinoids, termed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. The occurrence of mixed tumors exclusively comprising high grade NE carcinomas also supports a different carcinogenesis for these two groups. Histopathologically, high grade NE lung tumors are characterized by high mitotic and proliferative indices, while carcinoids are defined by maximally 10 mitoses per 2mm(2) (10 high-power fields) and rarely have Ki67-proliferative indices over 10%. High grade NE carcinomas are chemosensitive tumors, although they usually relapse. Surgery is often not an option due to extensive disease at presentation and early metastasis, especially in SCLC. Conversely, carcinoids are often insensitive to chemo- and radiation therapy, but cure can usually be achieved by surgery. A meta-analysis of comparative genomic hybridization studies performed for this review, as well as gene expression profiling data indicates separate clustering of carcinoids and carcinomas. Chromosomal aberrations are much more frequent in carcinomas, except for deletion of 11q, which is involved in the whole spectrum of NE lung tumors. Deletions of chromosome 3p are rare in carcinoids but are a hallmark of the high grade pulmonary NE carcinomas. On the contrary, mutations of the multiple endocrine neoplasia type 1 (MEN1) gene are restricted to carcinoid tumors. Many of the differences between carcinoids and high grade lung NETs can be ascribed to tobacco consumption, which is strongly linked to the occurrence of high grade NE carcinomas. Smoking causes p53 mutations, very frequently present in SCLCs and LCNECs, but rarely in carcinoids. It further results in other early genetic events in SCLCs and LCNECs, such as 3p and 17p deletions. Smoking induces downregulation of E-cadherin and associated epithelial to mesenchymal transition. Also, high grade lung NETs display higher frequencies of aberrations of the Rb pathway, and of the intrinsic and extrinsic apoptotic routes. Carcinoid biology on the other hand is not depending on cigarette smoke intake but rather characterized by aberrations of other specific genetic events, probably including Menin or its targets and interaction partners. This results in a gradual evolution, most likely from proliferating pulmonary NE cells via hyperplasia and tumorlets towards classical carcinoid tumors. We conclude that carcinoids and high grade NE lung carcinomas are separate biological entities and do not comprise one spectrum of pulmonary NETs. This implies the need to reconsider both diagnostic as well as therapeutic approaches for these different groups of malignancies.     

BCA-225 immunostain: is it of value in liver fine needle aspiration?

OBJECTIVE: To determine the utility of BCA-225 immunostain in differentiating hepatocellular carcinoma (HCC) from other malignant tumors in liverfine needle aspiration specimens. STUDY DESIGN: Cell block materialfrom 87fine needle aspirates of liver lesions, including 25 HCCs, 9 neuroendocrine carcinomas, 12 adenocarcinomas metastatic from the colon, 19 other metastatic adenocarcinomas, 13 other metastatic tumors and 2 cholangiocarcinomas, were immunostained with BCA-225 antibody using both the EnVision avidin-biotin method (Dako U.S.A., Carpinteria, California, U.S.A.), and the traditional avidin-biotin method, without antigen retrieval. Three independent observers evaluated the cases, and a consensus was reached. RESULTS: Strong immunostaining for BCA-225 in at least 10% of malignant cells was considered positive. Two of 25 HCCs, 9 of 19 adenocarcinoma metastases, 1 of 9 neuroendocrine carcinomas, 4 of 13 other metastases and 1 of 2 cholangiocarcinomas were positive. No colon metastases were considered positive. CONCLUSION: BCA-225 may help exclude the diagnoses of metastatic colon adenocarcinoma, neuroendocrine carcinoma and well- to moderately differentiated HCC in this cytologic setting.     

Immunohistochemical evaluation of ras oncogene expression in pulmonary and pleural neoplasms

We undertook an immunohistochemical analysis of human bronchopulmonary epithelial neoplasms and pleural mesotheliomas using a monoclonal antibody which recognizes ras oncogene products (p21ras). The monoclonal antibody, RAP-5, recognizes both unaltered and certain mutated p21ras. Formalin fixed and paraffin embedded tissue samples of 187 lung epithelial tumors and 27 pleural mesotheliomas were investigated; normal and bronchiectatic lungs were similarly studied. Normal lung and pleural tissue did not immunostain except for occasional type II pneumocytes. Reactive type II pneumocytes adjacent to carcinomas and bronchiectasis immunostained consistently. Twenty four/34 (71%) squamous carcinomas immunostained. Only 8/50 (16%) adenocarcinomas immunostained focally and weakly whereas 19/24 (79%) bronchioloalveolar carcinomas immunostained. Eleven/18 (61%) large cell carcinomas immunostained with variable intensity. Eleven/13 (85%) carcinoids, 6/7 (85%) well differentiated neuroendocrine carcinomas, and 18/21 (86%) intermediate cell neuroendocrine carcinomas immunostained while none of 20 small cell neuroendocrine carcinomas immunostained. Only a few mesotheliomas were immunostained focally. Two/14 (14%) epithelial type and 1/9 (11%) biphasic type mesotheliomas immunostained weakly; none of 4 spindle cell mesotheliomas immunostained. We conclude that while at least occasional cases of most types of pulmonary epithelial neoplasms express p21ras, the frequency and intensity of the expression are distinctly greater in certain tumor types such as squamous, bronchioloalveolar, and neuroendocrine neoplasm except for the small cell type. Contrary to these lung epithelial neoplasms, most mesotheliomas did not immunostain for p21ras. Whether the enhanced p21ras expression may point to a different mechanism of transformation or may merely reflect differentiation features remains undetermined.     

Somatostatin receptor imaging in the diagnosis and treatment of neuroendocrine tumors.

Somatostatin analogs are used in the control of hormonal hypersecretion and tumor growth of patients with acromegaly, islet cell carcinomas and carcinoids. Recently we showed that somatostatin receptor positive tumors can be visualized in vivo after the administration of radioactive isotope-labelled somatostatin analogs. Receptor imaging was positive in 18/21 islet cell tumors, 30/31 carcinoids, 26/28 paragangliomas, 9/14 medullary thyroid carcinomas, 5/7 small cell lung cancers, 6/7 neuroblastomas, 38/49 primary breast cancers, and 0/18 pancreatic adenocarcinomas. Also 11/11 meningiomas, 4/4 astrocytomas and 0/3 glioblastomas could be visualized. Somatostatin receptor imaging is an easy, harmless and painless diagnostic method. It is an in vivo method for the recognition of neuroendocrine cancers. It localizes multiple and/or metastatic tumors, predicts the successful control of hormonal hypersecretion by octreotide and seems of prognostic value in certain types of cancer. This scintigraphic method might help in patient selection for clinical trials with somatostatin analogs in the treatment of neuroendocrine cancers.     

The presence of somatostatin receptors in malignant neuroendocrine tumor tissue predicts responsiveness to octreotide.

In 77 percent of patients suffering from a malignant carcinoid syndrome, administration of the somatostatin analog, octreotide (SMS 201-995, Sandostatin) induced clinical improvement coupled with a decrease in 24-hour urinary 5-hydroxyindole acetic acid (5-HIAA). This finding prompted an evaluation to determine the correlation between the presence of somatostatin receptors in tumor tissue and the response to octreotide in patients with advanced, metastatic, neuroendocrine tumors. In tissues of 31 tumors (20 carcinoid, eight islet-cell carcinoma, three medullary thyroid carcinomas), the presence of somatostatin receptors was analyzed by binding of the somatostatin analog 125I-Tyr3-SMS 201-995 and autoradiography. Receptors were detected in 16 of 20 samples of carcinoid tissues; all but one patient with receptor-positive tumors improved clinically after treatment with octreotide, and the urine 5-HIAA level was reduced a median of 63 percent (range, 39-94 percent) compared to values before treatment. Of the receptor-negative carcinoid patients, only one showed clinical improvement, which was minimal, and there was a negligible reduction in 5-HIAA after octreotide therapy. All eight patients with metastatic islet-cell carcinomas were positive for somatostatin receptors. Symptomatic improvement and a > 50 percent decrease in the level of at least one of the pathologically elevated marker hormones was seen in all eight. None of the three patients with medullary carcinoma of the thyroid had a decrease in calcitonin, and all three were initially somatostatin receptor-negative. We conclude that the presence of somatostatin receptors in malignant neuroendocrine tumor tissue appears to correlate with the response to octreotide therapy. Analysis of somatostatin receptors in malignant neuroendocrine carcinoma tissue should be included in future prospective clinical trials of this synthetic peptide.     

Fine needle aspiration cytopathology of bronchial carcinoid tumors: an analytical study of the cells

While frequently considered to originate in a common stem-cell of neuroendocrine origin, bronchial carcinoid tumors and small-cell anaplastic carcinomas differ significantly in their biologic potential and treatment. Patient management is often dependent on the diagnostic specificity of a pulmonary fine needle aspiration specimen. This study evaluated the cellular features in fine needle aspiration samples from seven bronchial carcinoid tumors and four small-cell anaplastic carcinomas of the "intermediate" type. Planimetric measurements were performed on tracings of 1,100 cells. An analysis of specific cytoplasmic and nuclear features was also obtained on 2,200 cells. Significant quantitative and qualitative differences in the cytomorphology of the cells derived from bronchial carcinoid and small-cell anaplastic neoplasms were obtained, clearly demonstrating that differentiation of these neoplasms is possible on a cytopathologic basis in fine needle aspiration samples.     

Electron microscopic localization of chromogranin A in osmium-fixed neuroendocrine cells with a protein A-gold technique

An antibody (LK2H10) to chromogranin A has been recommended for use in ultrastructural identification of neuroendocrine secretory granules. Previous studies have demonstrated immunoreactive chromogranin A in specimens prepared for electron microscopy by glutaraldehyde fixation only. In this study, the effect of specimen post-fixation by osmium tetroxide on post-embedding localization of chromogranin A was evaluated. Human tissues from benign endocrine glands, neuroendocrine tumors, and non-neuroendocrine tumors were post-fixed in osmium, embedded in epoxy resin, and the sample thin sections immunolabeled using a protein A-gold technique. Chromogranin A-positive neurosecretory granules were detected in pancreatic islets, adrenal medulla, stomach, ileum, anterior pituitary, and parathyroid. Mid-gut carcinoids, bronchial carcinoids, pheochromocytomas, paragangliomas, carotid body tumors, and thyroid medullary carcinomas contained immunoreactive granules. Cytoplasmic granules in non-neuroendocrine tumors did not react for chromogranin A. Tissues post-fixed in osmium tetroxide had optimally preserved ultrastructural features, and use of this fixative is compatible with postembedding localization of chromogranin A in neurosecretory granules.     

Ultrastructure of mammary carcinomas in male rats induced by 7,12-dimethylbenz(a)anthracene

The morphology of mammary tumors induced by 7,12-dimethylbenz(a)anthracene in male rats was investigated by light and electron microscopy. All tumors induced in male rats were carcinomas with prominent epithelial growth which shows a medullary or cribriform appearance. Neither mammary dysplasias nor fibroadenomas were induced in male rats. Foci of adenoid cystic carcinoma were encountered in some parts of tumors. Papillary and/or tubular patterns, which have been observed frequently in mammary carcinomas in female rats, were not prominent histologic features in male rats. Secretory activity was not remarkable. The morphology of mammary carcinomas in male rats was unchanged in primary and transplanted tumors under various hormonal conditions. This finding supports our previously published results that the mammary carcinomas in male rats are hormone-independent, although our previous biochemical study revealed that the tumors contain both estrogen and estrogen-dependent progesterone receptors.