Management of Neuroendocrine Breast Carcinoma (NEBC): Review of Literature.

Extra pulmonary high-grade poorly differentiated neuroendocrine carcinomas (EP-NECs) are rare tumors that usually arise in the gastrointestinal and genitourinary tracts. Primary neuroendocrine carcinoma of the breast (NEBC) is extremely rare, representing less than 0.1% of all breast cancers and less than 1% of neuroendocrine neoplasms. Consequently, they can be misdiagnosed as other types of breast cancer, however, proper immunohistochemical (IHC) studies can assist with making the correct diagnosis. Management of NEBC can be challenging given the paucity of evidence-based literature and should not routinely follow the therapeutic guidelines of other breast cancers. In this article, we review the current literature regarding the management of NEBC.

Management of advanced high grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): comprehensive review of the current literature.

The classification and management of neuroendocrine neoplasms (NENs) arising in the tubular gastrointestinal (GI) tract and pancreas have significantly evolved over the last decades. In the latest WHO classification published in 2022, NENs are separated regardless of their primary origin into two main groups: well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). The substantial changes in the grading system changed the definition of grade 3 to include high-grade well-differentiated NETs (G3-NETs), and poorly differentiated NECs (-NECs). Although these two subgroups are considered high grades with Ki-67 >20%, they have different genomic profiles, prognosis, and clinical behavior, which critically influence their treatment strategies. The available clinical trial data to guide therapy of these high-grade subgroups are extremely limited, which impacts their management. In this review, we will summarize the current advances in the multidisciplinary approach for the management of high-grade gastroenteropancreatic NENs (GEP-NENs) including G3-NETs and NECs.

Diagnosis and pathologic characteristics of medullary thyroid carcinoma-review of current guidelines.

Background: Medullary thyroid carcinoma (mtc) is a rare malignancy of the thyroid gland, and raising awareness of the recommended diagnostic workup and pathologic characteristics of this malignancy is therefore important. Methods: We reviewed the current clinical practice guidelines and recent literature on mtc, and here, we summarize the recommendations for its diagnosis and workup. We also provide an overview of the pathology of mtc. Results: A neuroendocrine tumour, mtc arises from parafollicular cells ("C cells"), which secrete calcitonin. As part of the multiple endocrine neoplasia (men) type 2 syndromes, mtc can occur sporadically or in a hereditary form. This usually poorly delineated and infiltrative tumour is composed of solid nests of discohesive cells within a fibrous stroma that might also contain amyloid. Suspicious nodules on thyroid ultrasonography should be assessed with fine-needle aspiration (fna). If a diagnosis of mtc is made on fna, patients require baseline measurements of serum calcitonin and carcinoembryonic antigen. Calcitonin levels greater than 500 pg/mL or clinical suspicion for metastatic disease dictate the need for further imaging studies. All patients should undergo dna analysis for RET mutations to diagnose men type 2 syndromes, and if positive, they should be assessed for possible pheochromocytoma and hyperparathyroidism. Summary: Although the initial diagnosis of a suspicious thyroid nodule is the same for differentiated thyroid carcinoma and mtc, the remainder of the workup and diagnosis for mtc is distinct.

CEACAM1 impedes thyroid cancer growth but promotes invasiveness: a putative mechanism for early metastases.

CEACAM1, also known as biliary glycoprotein (BGP), CD66a, pp120 and C-CAM1, is a member of the CEA immunoglobulin superfamily. CEACAM1 is a putative tumor suppressor based on diminished expression in some solid neoplasms such as colorectal carcinoma. However, CEACAM1 is overexpressed in some tumors such as non-small cell lung cancer. To clarify the mechanism of action of this cell adhesion molecule, we studied thyroid carcinoma that has a spectrum of morphologies and variable behavior allowing separation of proliferation from invasion and metastasis. CEACAM1 is expressed in thyroid carcinoma cell lines derived from tumors that exhibit aggressive behavior. Introduction of CEACAM1 into endogenously deficient WRO cells resulted in reduced cell cycle progression associated with p21 upregulation and diminished Rb phosphorylation. Forced CEACAM1 expression enhanced cell-matrix adhesion and migration and promoted tumor invasiveness. Conversely, small interfering RNA (siRNA)-mediated downregulation of CEACAM1 expression in MRO cells accelerated cell cycle progression and significantly enhanced tumor size in xenografted mice. CEACAM1 is not appreciably expressed in normal thyroid tissue or benign thyroid tumors. In a human thyroid tissue array, CEACAM1 reactivity was associated with metastatic spread but not with increased tumor size. These findings identify CEACAM1 as a unique mediator that restricts tumor growth whereas increasing metastatic potential. Our data highlight a complex repertoire of actions providing a putative mechanism underlying the spectrum of biologic behaviors associated with thyroid cancer.

Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice.

Dopamine secreted from hypophysial hypothalamic neurons is a principal inhibitory regulator of pituitary hormone secretion. Mice with a disrupted D2 dopamine receptor gene had chronic hyperprolactinemia and developed anterior lobe lactotroph hyperplasia without evidence of adenomatous transformation. Unexpectedly, the mutant mice had no hyperplasia of the intermediate lobe melanotrophs. Aged female D2 receptor -/- mice developed uterine adenomyosis in response to prolonged prolactin exposure. These data reveal a critical role of hypothalamic dopamine in controlling pituitary growth and support a multistep mechanism for the induction and perpetuation of lactotroph hyperplasia, involving the lack of dopamine signaling, a low androgen/estrogen ratio, and a final autocrine or paracrine "feed-forward" stimulation of mitogenesis, probably by prolactin itself.

Growth hormone-releasing hormone-producing tumors: clinical, biochemical, and morphological manifestations.

This paper has reviewed current knowledge of clinical, biochemical, and morphological manifestations of extracranial GRH-producing tumors. Excessive GRH release stimulates pituitary somatotrophs causing elevation of blood GH levels and acromegaly. In some patients with GRH-containing tumor, blood GH concentrations are normal and no acromegaly develops. GRH-producing tumors associated with acromegaly are rare. Based on a critical analysis of the literature, 30 tumors are accepted as definitive. They possess unique features: occurrence in young age, female preponderance, foregut derivation, benign biological behavior, small secretory granules, and frequent association with MEN type I syndrome. The pancreas and lung are common primary sites. GRH-containing tumors unassociated with acromegaly include those of gut and thymus, small cell carcinoma of lung, and medullary carcinoma of thyroid. Several tumors are plurihormonal. In contrast to somatotroph adenoma seen in patients with classical acromegaly, the hypophysial lesion represents somatotroph hyperplasia in acromegalic patients with GRH-producing tumor. This finding indicates that GRH not only increases somatotroph secretory activity but causes somatotroph proliferation. Studies of GRH-producing tumors are of fundamental importance in obtaining a deeper insight into endocrine activity of pituitary somatotrophs and the pathogenesis of GH-secreting pituitary adenomas associated with acromegaly; the importance of GRH in the etiology of acromegaly is still unresolved. The relationship between GRH-secreting tumors and MEN type I syndrome is controversial; further studies are required to elucidate whether they represent two distinct entities or whether GRH-producing tumors accompanied by acromegaly are only forme fruste manifestations of MEN type I syndrome.

From pituitary adenoma to pituitary neuroendocrine tumor (PitNET): an International Pituitary Pathology Club proposal.

The classification of neoplasms of adenohypophysial cells is misleading because of the simplistic distinction between adenoma and carcinoma, based solely on metastatic spread and the poor reproducibility and predictive value of the definition of atypical adenomas based on the detection of mitoses or expression of Ki-67 or p53. In addition, the current classification of neoplasms of the anterior pituitary does not accurately reflect the clinical spectrum of behavior. Invasion and regrowth of proliferative lesions and persistence of hormone hypersecretion cause significant morbidity and mortality. We propose a new terminology, pituitary neuroendocrine tumor (PitNET), which is consistent with that used for other neuroendocrine neoplasms and which recognizes the highly variable impact of these tumors on patients.

My approach to pathology of the pituitary gland.

The sellar region is the site of a large number of pathological entities arising from the pituitary and adjacent anatomical structures, including brain, blood vessels, nerves and meninges. The surgical pathology of this area requires the accurate identification of neoplastic lesions, including pituitary adenoma and carcinoma, craniopharyngioma, neurological neoplasms, germ cell tumours, haematological malignancies and metastases, as well as non-neoplastic lesions such as cysts, hyperplasias and inflammatory disorders. This review provides a practical approach to the diagnosis of pituitary specimens that are sent to the pathologist at the time of surgery. The initial examination requires routine haematoxylin and eosin staining to establish whether the lesion is a primary adenohypophysial proliferation or one of the many other pathologies that occurs in this area. The most common lesions resected surgically are pituitary adenomas. These are evaluated with several special stains and immunohistochemical markers that are now available to accurately classify these pathologies. The complex subclassification of pituitary adenomas is now recognised to reflect specific clinical features and genetic changes that predict targeted treatments for patients with pituitary disorders.

Worrisome histologic alterations following fine-needle aspiration of the parathyroid.

Fine-needle aspiration (FNA) is a procedure that is increasingly being performed. Artefacts occurring after FNA are reported to complicate the histological analysis of the tissue, mainly in the thyroid; WHAFFT (worrisome histologic alterations following FNA of thyroid) is well documented in the literature. The case of a male patient with hypercalcaemia who was subsequently found to have a nodule in the thyroid gland is reported here. He underwent FNA, followed by a total thyroidectomy and parathyroidectomy. The abnormality in the parathyroid gland showed worrisome histological changes that were suspicious of a malignant lesion, resembling the changes seen in the thyroid gland after FNA. Parathyroid cells were identified by a review of the previous FNA. The concept of WHAFFT, which can mimic the features of malignancy in the parathyroid gland, is therefore introduced.

Cushing's syndrome due to ectopic CRH secretion by adrenal pheochromocytoma accompanied by renal infarction.

Ectopic production of corticotropin-releasing hormone (CRH) by a pheochromocytoma is an infrequent cause of Cushing's syndrome. We report the case of a 43-year-old man with Cushing's syndrome due to a CRH-producing adrenal pheochromocytoma. The patient had clinical and biochemical evidence of hypercortisolism in conjunction with high ACTH levels and non-suppressible serum cortisol levels on low-dose and high-dose dexamethasone suppression testing. In addition to these clinical features of one month's duration, the patient developed symptoms of pheochromocytoma including headache, hypertension that was resistant to conventional therapy and excessive sweating. Biochemical testing confirmed elevated 24-hour urinary catecholamines and metabolites. Abdominal CT revealed a 4.5 x 4 x 3.5 cm mass in the left adrenal gland. He underwent elective left adrenalectomy. Light microscopic and immunochemical studies revealed a pheochromocytoma that contained immunoreactive CRH and was negative for ACTH. Plasma ACTH and dexamethasone supression tests normalized after surgery. This is an unusual case of a CRH-secreting pheochromocytoma. This was complicated by renal infarction, illustrating further the complexity of Cushing's syndrome in a patient with pheochromocytoma caused by CRH hypersecretion.

Immunocytochemical localization of parathyroid hormone-like peptide in the rat fetus.

Studies of parathyroid hormone-like peptide (PLP) have demonstrated that PLP gene expression is inducible by serum, growth factors, and cycloheximide. Rapid induction of PLP gene expression has also been observed following the induction of cell differentiation. These features of PLP gene expression are consistent with a role for PLP in the regulation of cell growth and differentiation. To understand the biology of PLP in developing cells and tissues, we have studied the distribution of PLP gene expression in the fetal and neonatal rat. PLP was localized by immunocytochemistry to skin, vascular smooth muscle, skeletal muscle, heart, liver, kidney, lung, and gastrointestinal tract in Day 14 fetal rat. By Day 18 PLP immunopositivity was also detected in both fetal pituitary and adrenal medulla, as well as in endocrine pancreas. Whereas few PLP-immunopositive cells were detected in Day 14 brain, scattered areas of PLP immunopositivity were evident in Day 18 brain, in regions such as the choroid plexus. Immunostaining for PLP was also detected in Day 18 tissues that were positive on Day 14. The pattern of staining in fetal testis, where PLP was strongly localized to seminiferous tubules, differed from adult testis, where PLP was localized predominantly in Leydig cells. PLP was localized to the hepatocytes but not to the hematopoietic elements in fetal liver. Neonatal hepatocytes were weakly PLP immunopositive, and PLP was not detected in adult rat liver. Northern blot analysis demonstrated the presence of a single 1.4-kilobase PLP mRNA transcript in fetal brain, liver, heart, lung, and intestine. The results of these studies demonstrate that the PLP gene is widely expressed in a diverse number of fetal rat tissues. The cellular and tissue localization of PLP immunopositivity remains fairly constant in the transition from fetal to neonatal and adult tissues except in the testis, where a cellular switch in PLP-producing cells occurs, and the liver, where PLP gene expression is progressively extinguished postnatally.

Expression of the prostate-specific antigen gene by a primary ovarian carcinoma.

We describe a patient with primary ovarian carcinoma that developed after liver transplantation whose tumor was highly positive for prostate-specific antigen (PSA). PSA in tumor tissue was characterized by two immunoassays, HPLC, immunohistochemistry, reverse transcription-PCR, Southern blotting, and DNA sequencing. PSA in the ovarian tumor was present as free, M(r) 33,000 protein (> 90%) and as PSA bound to alpha 1-antichymotrypsin (M(r) 100,000; < 10%). Immunohistochemistry localized PSA in the cytoplasm of epithelial cells of the tumor. Two separate reverse transcription-PCRs for PSA amplified the expected products which hybridized specifically to a PSA cDNA probe on Southern blots. Sequencing of the PCR products, representing the whole coding sequence of the PSA gene, revealed identity with the sequence of PSA cDNA from prostate tissue. These data suggest that the PSA produced by the ovarian tumor was identical in molecular weight and sequence to prostatic PSA. Based on data of tissue culture experiments with breast carcinoma cell lines, we speculate that the PSA gene in the tumor of this patient was up-regulated by the therapeutically administered glucocorticoids after liver transplantation.

Mutations of the MEN1 tumor suppressor gene in pituitary tumors.

Although pituitary adenomas are monoclonal proliferations, somatic mutations involving genes that govern cell proliferation or hormone production have been difficult to identify. The genetic etiology of most pituitary tumors, therefore, remains unknown. Pituitary adenomas can develop sporadically or as a part of multiple endocrine neoplasia type 1 (MEN1). Recently, the gene responsible for MEN1 was cloned. To elucidate the potential etiological role of the MEN1 gene in pituitary tumorigenesis, 39 sporadic pituitary adenomas from 38 patients and 1 pituitary adenoma from a familial MEN1 patient were examined for MEN1 gene mutations and allelic deletions. Four of 39 sporadic pituitary adenomas showed a deletion of one copy of the MEN1 gene, and a specific MEN1 gene mutation in the remaining gene copy was detected in 2 of these tumors. The corresponding germ-line sequence was normal in all sporadic cases. A specific MEN1 mutation was detected in a pituitary adenoma and corresponding germ-line DNA in a patient with familial MEN1. An allelic deletion of the remaining copy of the MEN1 gene was also found in the patient's tumor. Genetic alterations of the MEN1 gene represent a candidate pathogenetic mechanism of pituitary tumorigenesis. The data suggest that somatic MEN1 gene mutations and deletions play a causative role in the development of a subgroup of sporadic pituitary adenomas.

Gonadotrope Tumors.

Gonadotrope tumors arise from the gonadotropes of the adenohypophysis. These cells rarely give rise to hyperplasia, usually only in the setting of long-standing premature gonadal failure. In contrast, gonadotrope tumors represent one of the most frequent types of pituitary tumors. Despite their relatively common occurrence, the pathogenesis of gonadotrope tumors remains unknown. Effective nonsurgical therapies remain out of reach. We review the pituitary gonadotrope from the morphologic and functional perspectives to better understand its involvement as the cell of origin of a frequent type of pituitary tumor.

The molecular pathogenetic role of cell adhesion in endocrine neoplasia.

It is becoming increasingly evident that cell adhesion is an important determinant of organised growth and the maintenance of architectural integrity. Indeed, reduced adhesiveness between cells and with the extracellular matrix is a hallmark of neoplastic growth. In neuroendocrine tissues, neural cell adhesion molecule is implicated in modulating cell growth, migration, and differentiation. This review will focus on the molecular pathways involving key growth factor receptors that govern normal adhesive forces. The extent to which disruption of these adhesive forces contributes to the tumorigenic process in neuroendocrine tissues will be highlighted. Validation of the functional relevance of these adhesive pathways will be discussed in light of targeted pharmacotherapeutic studies that are unmasking novel approaches to the treatment of neuroendocrine tumours.

Pituitary cells producing more than one hormone human pituitary adenomas.

The existence of cells capable of producing more than one hormone in nontumorous human adenohypophyses and pituitary adenomas has been conclusively proved. In light of the evidence, current concepts on pituitary structure, function, and regulation as well as adenoma cytogenesis and classification have to be reconsidered.

Expression of the prostate specific antigen gene by lung tissue.

We describe a female patient with lung adenocarcinoma whose tumor extract was highly positive for prostate specific antigen (PSA) immunoreactivity. PSA was present in its Mr 33,000 free form. Using reverse transcription-PCR, we were able to amplify a 754-bp fragment that specifically hybridized to a PSA RNA probe on Southern blots. The PCR fragment was sequenced and found to represent PSA cDNA and not human glandular kallikrein cDNA. PSA immunoreactivity in the lung tissue was localized by immunohistochemistry to normal epithelial cells adjacent to the tumor which was completely negative for PSA. Tissue culture experiments suggested that beclomethasone, a glucocorticoid used to treat the patient, was able to up-regulate PSA gene expression. This is the first report that unequivocally demonstrates PSA expression in lung tissue. We speculate that PSA expression was mediated by the exogenously administered steroid beclomethasone.

Islet cell and extrapancreatic expression of the LIM domain homeobox gene isl-1.

The phenotypically distinct cell types of the islets of Langerhans express a number of different hormone genes in a regulated and cell-specific manner. Analysis of the molecular factors important for the control of insulin gene transcription has led to the identification of a number of insulin gene-binding proteins. The cDNAs for several of these proteins have been isolated, including isl-1, a LIM domain homeobox protein reported to be preferentially expressed in islet cells. We now report that isl-1 mRNA transcripts are present not only in islet cells, but also in pheochromocytoma (PC-12) cell lines. Isl-1 mRNA transcripts were also detected in several different regions of rat brain as well as in rat kidney. Analysis of the patterns of gene expression in rat islet cell lines and human pancreatic endocrine tumors demonstrated a variable relationship between the hormonal phenotype of the tumor and expression of the isl-1 and insulin genes. Immunocytochemical studies demonstrated both cytoplasmic and nuclear staining for isl-1 in human pancreatic endocrine tumors, in normal pancreatic A, B, D, and PP cells, and in distal tubular cells of the kidney. Isl-1 immunoreactivity was also widely distributed in neurons in both the central and peripheral nervous system, pituitary, and several human pituitary tumors and pheochromocytomas. The results of these studies implicate a potential role for isl-1 outside the endocrine pancreas in the nervous system and kidney.

The parathyroid hormone-like peptide gene is expressed in the normal and neoplastic human endocrine pancreas.

PTH-like peptide (PLP) is produced by a number of tumors commonly associated with the development of hypercalcemia. Analysis of the expression of the PLP gene has demonstrated that a variety of non-neoplastic endocrine and nonendocrine tissues contain PLP mRNA transcripts. Using a combination of Northern blot analysis, immunohistochemistry, and RIAs, we have demonstrated that the PLP gene is expressed in normal human and rat fetal and adult islets of Langerhans. PLP gene expression was not confined to cells containing a single pancreatic islet hormone, but was found in cells of all four major endocrine subtypes. PLP mRNA transcripts were also detected in RNA prepared from isolated rat islets, and small amounts of PLP immunoreactivity were secreted by cultured rat islets. Fifteen human pancreatic endocrine tumors not associated with hypercalcemia were analyzed and PLP-immunopositive tumor cells were found in 13. These observations demonstrate that the PLP gene is expressed in the normal and neoplastic islets of Langerhans, and suggests a possible role for this peptide in the growth or function of the endocrine pancreas.