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.

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.

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.

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 breast cancer susceptibility FGFR2 provides an alternate mode of HER2 activation.

Fibroblast growth factor receptor 2 (FGFR2) has been shown reproducibly in genome-wide association studies to be associated with increased breast cancer risk. Here we show that mouse mammary tumor virus-neu mice develop breast carcinomas with FGFR2 immunoreactivity that parallels HER2 expression. FGFR2 signaling promotes HER2 shedding through the metalloprotease ADAM10 leading to intracellular accumulation of the truncated p95HER2 protein. This is accompanied by enhanced HER2 signaling and diminished sensitivity to trastuzumab. Functionally, FGFR2 facilitates HER2-mediated cell proliferation, acinar growth in three-dimensional morphogenesis assays and promotes tumor progression in mouse xenografts. These data implicate FGFR2 in a novel mechanism of ErbB activation and demonstrate an important interaction between FGFR2 and HER2 in promoting breast cancer progression.Oncogene advance online publication, 2 February 2015; doi:10.1038/onc.2014.440.

Radionuclide therapy in neuroendocrine tumours: a systematic review.

The purpose of this systematic review was to investigate the effects of therapeutic radiopharmaceuticals in patients with different types of advanced neuroendocrine tumour (NETs). A literature search was carried out in MEDLINE and EMBASE from January 1998 to November 2010. The Cochrane Library (to Issue 10, 2010) and the Standards and Guidelines Evidence Inventory of Cancer Guidelines, including over 1100 English-language cancer guidelines from January 2003 to June 2010, were also checked. No existing systematic reviews or clinical practice guidelines based on a systematic review or randomised controlled trials focusing on this topic were found. Twenty-four fully published articles were abstracted and summarised: 16 articles focused on five peptide receptor radionuclide therapy ((111)In-DTPAOC, (90)Y-DOTALAN, (90)Y-DOTATOC, (90)Y-DOTATATE, and (177)Lu-DOTATATE) and eight focused on (131)I-MIBG treatment. Limited evidence from a historical comparison of studies in one centre supported that (177)Lu-DOTATATE might be associated with greater clinical outcomes compared with (90)Y-DOTATOC or (111)In-DTPAOC. The severe toxicities for (177)Lu-DOTATATE included hepatic insufficiency in 0.6%, myelodysplastic syndrome in 0.8% and renal insufficiency in 0.4% of patients in this study. Insufficient evidence suggested efficacy of (131)I-MIBG in adult NET patients, but the overall tumour response rate from (131)I-MIBG was 27-75% for malignant neuroblastoma, paraganglioma or pheochromocytoma. Haematological toxicities were the main severe side-effects after (131)I-MIBG and 4% of patients developed secondary malignancies in one study. To date, peptide receptor radionuclide therapy seems to be an acceptable option and is relatively safe in adult advanced NET patients with receptor uptake positive on scintigraphy, but patients' renal function must be monitored. (131)I-MIBG may be effective for malignant neuroblastoma, paraganglioma or pheochromocytoma, but its side-effects need to be considered. No strong evidence exists to support that one therapeutic radiopharmaceutical is more effective than others. Well-designed and good-quality randomised controlled trials are required on this research topic.

The insulin resistance Grb14 adaptor protein promotes thyroid cancer ret signaling and progression.

The growth factor receptor-bound protein (Grb) 14 is an adaptor molecule of the Grb7/10/14 family with characteristic Between Plekstrin and SH2 (BPS) domains serving to avidly bind tyrosine kinases. Grb14 inhibits insulin receptor (IR) catalytic activity through interaction with the BPS domain and impedes peptide substrate binding. Members of this Grb family have also been shown to interact with other kinases through their SH2 domain. Here we examined the functional role of Grb14 in thyroid cancer using loss- and gain-of-function approaches. Stable knockdown of Grb14 in thyroid cancer cells facilitated IR signaling. In contrast, RET phosphorylation was diminished in concert with reduced activation of Akt and signal transducer and activator of transcription 3 (STAT3). Loss of Grb14 also resulted in diminished cell proliferation and invasion both in vitro and in mouse flank xenografts. In complementary studies, forced expression of Grb14 interrupted IR signaling but facilitated RET activation, STAT3 and Akt phosphorylation. Consistent with these findings Grb14 overexpression enhanced cell invasion and resulted in striking metastases in an orthotopic thyroid cancer mouse xenograft model. Primary human thyroid cancer microarrays revealed a positive correlation between Grb14 expression and invasive behavior. Our findings uncover a new role for Grb14 in finely tuning receptor signaling and modulating thyroid cancer progression.

Brain metastasis from medullary thyroid carcinoma.

The brain is an exceedingly rare site of metastasis in medullary thyroid carcinoma (MTC). A 50-year-old female who had a history of micro-MTC 11 years prior developed a cerebellar metastasis which was incidentally discovered. Imaging revealed a right cerebellar hemispheric mass with contrast enhancement on CT scans. Histopathologic exam demonstrated a metastatic tumour composed of nodules and sheets of large tumour cells with abundant cytoplasm. Immunohistochemistry confirmed the origin from a MTC. This case report highlights the unique features of an unusual metastatic brain tumour, which followed an indolent course for a long time despite multiple distant metastases.

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.

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.

Double adenomas of the pituitary: transcription factors Pit-1, T-pit, and SF-1 identify cytogenesis and differentiation.

The diagnosis of double adenomas of the pituitary can be very complex and is usually suspected on histological assessment of a specimen and confirmed by immunohistochemical and ultrastructural studies. The most commonly applied technique is currently immunohistochemical staining to localize the six pituitary hormones. Application of this technique may fail to identify double adenomas when hormone immunoreactivity is weak or absent in one or both cell populations. We examined specimens from eight patients diagnosed with double adenomas over a 15-yr period. We tested the ability to detect the difference in the two adenomas in each case using three immunostains for the pituitary transcription factors Pit-1, T-pit, and SF-1. We conclude that immunohistochemical localization of the transcription factors Pit-1, T-pit, and SF-1 accurately detects and classifies the distinct cytodifferentiation of double adenomas of the pituitary.

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.

FGF receptor signaling at the crossroads of endocrine homeostasis and tumorigenesis.

Multiple endocrine neoplasia (MEN) syndromes represent familial disorders characterized by endocrine cell growth and hormone production dysregulation. For several decades, the fibroblast growth factor (FGF) system has been suspected of playing a unique function in MEN-type I (MEN I). However, specific elucidation of these actions has been hampered by the overwhelming redundancy of this complex system. The human FGF family is composed of 22 members organized into 6 groups based on phylogenetic relationships. Signaling is mediated through membrane-spanning tyrosine kinase receptors encoded by four independent genes, some of which generate multiple products via alternative splicing or transcription initiation. High-affinity interaction between an FGF and its cognate receptor induces receptor dimerization and activation. Many FGFs display high-affinity interactions with multiple FGFRs, while some activate unique receptors or receptor isoforms. Most FGFs have demonstrated mitogenic activity in a variety of systems; however, a growing number display predominantly metabolic actions. This review will examine the evidence that FGF/FGFRs play a role in sporadic endocrine neoplasia and the pathways in which these molecules may be selectively targeted for therapeutic purposes.

Pancreatic endocrine tumour with cytoplasmic keratin whorls. Is the term "rhabdoid" appropriate?

A 50 year old woman presented with acute abdominal pain accompanied by nausea and vomiting and was found to have a mass in the head of the pancreas by imaging. The clinical impression was of a pancreatic carcinoma and a Whipple's procedure was performed. Microscopic examination of the tumour showed it to be a low grade neuroendocrine carcinoma arranged in a tubuloacinar or tubulopapillary pattern, and composed of cells harbouring very prominent intracytoplasmic inclusions. These inclusions varied in appearance from being pale pink and hyaline in quality to more eosinophilic and globular causing displacement of the nucleus. Ultrastructural examination showed typical paranuclear aggregates of intermediate filaments. Inclusions of this type have been described previously as "signet ring like" and "rhabdoid". It was felt that the inclusions more closely resemble the fibrous bodies that are seen in pituitary adenomas. In addition, it is suggested that both signet ring and rhabdoid are not appropriate because they do not reflect histogenesis and are not necessarily reflective of tumour biology. It is suggested that the term "cytokeratin aggresomes" should be used to describe this distinctive phenotype.

Cutaneous manifestations of thyroid cancer: a report of four cases and review of the literature.

Cutaneous metastases from thyroid carcinoma are rare. This report describes four cases of thyroid carcinoma metastatic to the skin. Two cases were medullary carcinoma and two were papillary thyroid carcinoma. In two cases, skin metastases were the presenting feature of the underlying thyroid carcinoma. Examination of the skin lesions by conventional light microscopy suggested the possibility of metastatic carcinoma and immunohistochemical tests confirmed the diagnosis. Subsequent investigations identified primary thyroid lesions. In two cases, the skin metastasis was the first evidence of the recurrence of known thyroid carcinoma. These cases identify a novel presentation of thyroid carcinoma.

My approach to oncocytic tumours of the thyroid.

The traditional approach to oncocytic thyroid lesions classified these as a separate entity, and applied criteria that are somewhat similar to those used for follicular lesions of the thyroid. In general, the guidelines to distinguish hyperplasia from neoplasia, and benign from malignant were crude and unsubstantiated by scientific evidence. In fact, there is no basis to separate oncocytic lesions from other classifications of thyroid pathology. The factors that result in mitochondrial accumulation are largely unrelated to the genetic events that result in proliferation and neoplastic transformation of thyroid follicular epithelial cells. The concept of classifying oncocytic lesions, including follicular variant papillary carcinomas, based on nuclear morphology, immunohistochemical profiles, and molecular markers may pave the way for a better understanding of the biology of oncocytic lesions of the thyroid.