Parathyroid tumors in the 5th edition of the WHO Classification of Tumors of the Endocrine Organs.

The diagnosis of pathological conditions of the parathyroid glands is the answer to clinically more frequently detected hypercalcemic conditions, including MEN syndromes. In routine biopsy practice, enlarged bodies are also a differential diagnosis for the diagnosis of thyroid nodules. In the chapter of parathyroid tumors, the 5th edition of the WHO classification brings changes influenced similarly to other endocrine organs by the increase in genetic information. At the terminological level, the concept of hyperplasia has been narrowed down to secondary hyperplasia, most of the previously primary hyperplasias are referred to as multiglandular parathyroid disease due to evidence of multiglandular clonal proliferations. The term atypical parathyroid tumor replacing atypical adenoma is newly introduced - the uncertain biological behaviour is emphasized. The basic examination includes parafibromin immunohis- tochemistry, the deficiency of parafibromin being an indicator of an inactivating CDC73 mutation and an increased risk of familial forms, or MEN. Methodologically, refinements are introduced in the quantification of mitotic activity per 10 mm2. Oncocytic subtypes have an arbitrarily declared threshold of more than 75% oncocytes. The definition of lipoadenoma (multiplication of both components, more than 50% of adipose tissue in the tumor) is similarly specified. The diagnosis of cancer remains histopathological with unequivocal evidence of invasion, or microscopically verified metastasis.

Evolution of Our Understanding of the Hyperparathyroid Syndromes: A Historical Perspective.

We review advancing and overlapping stages for our understanding of the expressions of six hyperparathyroid (HPT) syndromes: multiple endocrine neoplasia type 1 (MEN1) or type 4, multiple endocrine neoplasia type 2A (MEN2A), hyperparathyroidism-jaw tumor syndrome, familial hypocalciuric hypercalcemia, neonatal severe primary hyperparathyroidism, and familial isolated hyperparathyroidism. During stage 1 (1903 to 1967), the introduction of robust measurement of serum calcium was a milestone that uncovered hypercalcemia as the first sign of dysfunction in many HPT subjects, and inheritability was reported in each syndrome. The earliest reports of HPT syndromes were biased toward severe or striking manifestations. During stage 2 (1959 to 1985), the early formulations of a syndrome were improved. Radioimmunoassays (parathyroid hormone [PTH], gastrin, insulin, prolactin, calcitonin) were breakthroughs. They could identify a syndrome carrier, indicate an emerging tumor, characterize a tumor, or monitor a tumor. During stage 3 (1981 to 2006), the assembly of many cases enabled recognition of further details. For example, hormone non-secreting skin lesions were discovered in MEN1 and MEN2A. During stage 4 (1985 to the present), new genomic tools were a revolution for gene identification. Four principal genes ("principal" implies mutated or deleted in 50% or more probands for its syndrome) (MEN1, RET, CASR, CDC73) were identified for five syndromes. During stage 5 (1993 to the present), seven syndromal genes other than a principal gene were identified (CDKN1B, CDKN2B, CDKN2C, CDKN1A, GNA11, AP2S1, GCM2). Identification of AP2S1 and GCM2 became possible because of whole-exome sequencing. During stages 4 and 5, the newly identified genes enabled many studies, including robust assignment of the carriers and non-carriers of a mutation. Furthermore, molecular pathways of RET and the calcium-sensing receptor were elaborated, thereby facilitating developments in pharmacotherapy. Current findings hold the promise that more genes for HPT syndromes will be identified and studied in the near future. © 2018 American Society for Bone and Mineral Research.

[Clinical and morphological characteristics of parathyroid carcinoma]. / Kliniko-morfologicheskaia kharakteristika raka okoloshchitovidnoi zhelezy.

Parathyroid carcinoma (PTC) is a rare malignant tumor with the clinical manifestation of hyperparathyroidism, reliable morphological signs of invasive growth, and poor clinical prognosis. The differential diagnosis of PTC due to the rarity of this pathology, not always explicit morphological criteria, and the lack of a certain immunohistochemical panel is complex and needs further clarification. The paper summarizes an update on the clinical and morphological characteristics of PTC.

Raman Spectroscopy Applied to Parathyroid Tissues: A New Diagnostic Tool to Discriminate Normal Tissue from Adenoma.

Primary hyperparathyroidism is an endocrine disorder characterized by autonomous production of parathyroid hormone. Patients with the symptomatic disease should be referred for parathyroidectomy. However, the distinction between the pathological condition and the benign one is very challenging in the surgical setting; therefore, accurate recognition is important to ensure success during minimally invasive surgery. At present, all intraoperative techniques significantly increase surgical time and, consequently, cost. In this proof-of-concept study, Raman microscopy was used to differentiate between healthy parathyroid tissue and parathyroid adenoma from 18 patients. The data showed different spectroscopic features for the two main tissue types of healthy and adenoma. Moreover, the parathyroid adenoma subtypes (chief cells and oxyphil cells) were characterized by their own Raman spectra. The partial least-squares discriminant analysis (PLS-DA) model built to discriminate healthy from adenomatous parathyroid tissue was able to correctly classify all samples in the calibration and validation data sets, providing 100% prediction accuracy. The PLS-DA model built to discriminate chief cell adenoma from oxyphil cell adenoma allowed us to correctly classify >99% of the spectra during calibration and cross-validation and to correctly predict 100% of oxyphil and 99.8% of chief cells in the external validation data set. The results clearly demonstrate the great potential of Raman spectroscopy. The final goal would be development of a Raman portable fiber probe device for intraoperative optical biopsy, both to improve the surgical success rate and reduce surgical cost.

[Grading of neuroendocrine tumors]. / Grading neuroendokriner Tumoren.

The current WHO classification of neuroendocrine tumors (NET) differentiates between typical carcinoids (low grade NET), atypical carcinoids (intermediate grade NET) and small cell and large cell carcinomas (high grade NET) according to the prognosis. Neuroendocrine neoplasms (NEN) of the gastrointestinal tract and the pancreas are graded in an identical way. Together with the TNM system this enables a preoperative estimation of the prognosis in biopsies and fine needle aspirates. Well-differentiated tumors are graded into G1 tumors by the number of mitoses, <2 per 10 high-power fields (HPF) and the Ki-67 (index <3 %) and G2 tumors (2-20 mitoses/10 HPF, Ki-67 3-20 %). Discrepancies between the number of mitoses and the Ki-67 index are not uncommon and in these cases the higher value of the two should be applied. The more differentiated tumors of the G3 type have to be differentiated from undifferentiated carcinomas of the small cell type and large cell type with a much poorer prognosis. Prognosis relevant grading of thyroid cancers is achieved by special subtyping so that the G1-G3 system is not applicable. The rare cancers of the parathyroid gland and of the pituitary gland are not graded. Adrenal tumors also have no grading system. The prognosis is dependent on the Ki-67 index and with some reservations on the established scoring systems.

Genetics of parathyroid tumours.

Primary hyperparathyroidism (PHPT), due to parathyroid tumours, may occur as part of a complex syndrome or as an isolated (nonsyndromic) disorder, and both forms can occur as familial (i.e. hereditary) or nonfamilial (i.e. sporadic) disease. Syndromic PHPT includes multiple endocrine neoplasia (MEN) types 1 to 4 (MEN1 to MEN4) and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome. Syndromic and hereditary PHPT are often associated with multiple parathyroid tumours, in contrast to sporadic PHPT, in which single parathyroid adenomas are more common. In addition, parathyroid carcinomas may occur in ~15% of patients with the HPT-JT syndrome. MEN1 is caused by abnormalities of the MEN1 gene which encodes a tumour suppressor; MEN2 and MEN3 are due to mutations of the rearranged during transfection (RET) proto-oncogene, which encodes a tyrosine kinase receptor; MEN4 is due to mutations of a cyclin-dependent kinase inhibitor (CDNK1B); and HPT-JT is due to mutations of cell division cycle 73 (CDC73), which encodes parafibromin. Nonsyndromic PHPT, which may be hereditary and referred to as familial isolated hyperparathyroidism, may also be due to MEN1, CDC73 or calcium-sensing receptor (CASR) mutations. In addition, ~10% of patients presenting below the age of 45 years with nonsyndromic, sporadic PHPT may have MEN1, CDC73 or CASR mutations, and overall more than 10% of patients with PHPT will have a mutation in one of 11 genes. Genetic testing is available and of value in the clinical setting, as it helps in making the correct diagnosis and planning the management of these complex disorders associated with parathyroid tumours.

Parathyroid Carcinoma: Diagnosis and Clinical Implications.

Parathyroid carcinoma is a rare type of endocrine cancer, with significant morbidity and mortality associated with parathyroid hormone (PTH)-mediated hypercalcemia. Concerning clinical features for parathyroid cancer include severe hypercalcemia (albumin-corrected calcium > 3 mmol/L), a palpable neck mass ( > 3 cm), 3rd/2nd generation PTH assay ratio ( > 1), and intraoperative suspicion of local invasion or regional metastasis. A definite diagnosis of malignancy is rendered when a parathyroid tumor presents one of the following clinicopathological features: (1) vascular invasion, (2) perineural invasion, (3) gross invasion into adjacent anatomical structures, and/or (4) metastasis. In difficult cases, the use of ancillary biomarkers is critical to establish an accurate diagnosis. Recent advances in molecular pathology have uncovered the important role of CDC73/HRPT2, a tumor suppressor gene deregulated in parathyroid carcinomas. Loss of nuclear and/or nucleolar expression of parafibromin (the gene product of CDC73/HRPT2) is now regarded as a diagnostic, prognostic and predictive biomarker for parathyroid carcinoma. Furthermore, over 15-20% of seemingly sporadic parathyroid carcinomas have underlying germline CDC73/HRPT2 mutations. As a result, many centers have integrated the use of ancillary biomarkers, notably parafibromin staining, in their routine practise. Radical surgery with en bloc resection has emerged as a primary treatment modality in parathyroid cancer, achieving cure in some patients. However, in those with inoperable disease, there remains a dire need for new therapies, as current treatments are largely ineffective. This review provides an update on the current knowledge of parathyroid carcinoma and highlights its exciting changes in endocrine practice.

Application of Molecular Pathology in Endocrine Pathology.

Rapid growth in knowledge of cell and molecular biology led to the increased usage of molecular techniques in anatomical pathology. This is also due to the advances achieved in the techniques introduced in the last few years which are less laborious as compared to the techniques used at the beginning of the "molecular era". The initial assays were also very expensive and were not performed except for selected centers. Moreover, the clinicians were not sure how to make use of the accumulating molecular information. That situation has also changed and molecular techniques are being performed in a wide variety of medical settings which also has a reflection on the endocrine system pathology among other organ systems. This review will provide an update of genetic changes observed in different endocrine system pathologies and their diagnostic, therapeutic and prognostic values.

Classification of parathyroid cancer.

PURPOSE: Parathyroid cancer is rare and often has a poor outcome. There is no classification system that permits prediction of outcome in patients with parathyroid cancer. This study was designed to validate two prognostic classification systems developed by Talat and Schulte in 2010 ("Clinical Presentation, Staging and Long-term Evolution of Parathyroid Cancer," Ann Surg Oncol 2010;17:2156-74) derived from a retrospective literature review of 330 patients. METHODS: This study contains 82 formerly unreported patients with parathyroid cancer. Death due to disease was the primary end point, and recurrence and disease-free survival were the secondary end points. Data acquisition used a questionnaire of predefined criteria. Low risk was defined by capsular and soft tissue invasion alone; high risk was defined by vascular or organ invasion, and/or lymph node or distant metastasis. A differentiated classification system further classified high-risk cancer into vascular invasion alone (class II), lymph node metastasis or organ invasion (class III), and distant metastasis (class IV). Statistical analyses included risk analysis, Kaplan-Meier analysis, and receiver-operating characteristic (ROC) analysis. RESULTS: Follow-up ranged 2-347 months (mean 76 months). Mortality was exclusive to the high- risk group, which also predicted a significant risk of recurrence (risk ratio 9.6; 95% confidence interval 2.4-38.4; P < 0.0001), with significantly lower 5-year disease-free survival (χ(2) = 8.7; P < 0.005 for n = 45). The differentiated classification also provided a good prognostic model with an area under the ROC curve of 0.83 in ROC analysis, with significant impairment of survival between classes (98.6%, 79.2%, 71.4%, 40.0%, P < 0.05 between each class). CONCLUSIONS: This study confirms the validity of both classification systems for disease outcome in patients with parathyroid cancer.

A novel nomenclature to classify parathyroid adenomas.

BACKGROUND: A uniform and reliable description of the exact locations of adenomatous parathyroid glands is necessary for accurate communications between surgeons and other specialists. We developed a nomenclature that provides a precise means of communicating the most frequently encountered parathyroid adenoma locations. METHODS: This classification scheme is based on the anatomic detail provided by imaging and can be used in radiology reports, operative records, and pathology reports. It is based on quadrants and anterior-posterior depth relative to the course of the recurrent laryngeal nerve and the thyroid parenchyma. The system uses the letters A-G to describe exact gland locations. RESULTS: A type A parathyroid gland is a gland that originates from a superior pedicle, lateral to the recurrent laryngeal nerve compressed within the capsule of the thyroid parenchyma. A type B gland is a superior gland that has fallen posteriorly into the tracheoesophageal groove and is in the same cross-sectional plane as the superior portion of the thyroid parenchyma. A type C gland is a gland that has fallen posteriorly into the tracheoesophageal groove and on a cross-sectional view lies at the level of or below the inferior pole of the thyroid gland. A type D gland lies in the midregion of the posterior surface of the thyroid parenchyma, near the junction of the recurrent laryngeal nerve and the inferior thyroid artery or middle thyroidal vein; because of this location, dissection is difficult. A type E gland is an inferior gland close to the inferior pole of the thyroid parenchyma, lying in the lateral plane with the thyroid parenchyma and anterior half of the trachea. A type F gland is an inferior gland that has descended (fallen) into the thyrothymic ligament or superior thymus; it may appear to be "ectopic" or within the superior mediastinum. An anterior-posterior view shows the type F gland to be anterior to the trachea. A type G gland is a rare, truly intrathyroidal parathyroid gland. CONCLUSIONS: A reproducible nomenclature can provide a means of consistent communication about parathyroid adenoma location. If uniformly adopted, it has the potential to reliably communicate exact gland location without lengthy descriptions. This system may be beneficial for surgical planning as well as operative and pathology reporting.

Parafibromin immunoreactivity: its use as an additional diagnostic marker for parathyroid tumor classification.

Parafibromin is a protein product derived from the hyperparathyroidism 2(HRPT2) tumor suppressor geneand its inactivation has been coupled to familial and sporadic forms of parathyroid malignancy. In this study, we have conducted immunohistochemistry on 33 parathyroid carcinomas (22 unequivocal and 11 equivocal) using four parafibromin antibodies directed to different parts of the protein. Furthermore, for a fraction of cases, the immunohistochemical results were compared with known HRPT2 mutational status. Our findings show that 68% (15 out of 22) of the unequivocal carcinomas exhibited reduced expression of parafibromin while the 25 sporadic adenomas used as controls were entirely positive for parafibromin expression. Additionally, three out of the six carcinomas with known HRPT2 mutations showed reduced expression of parafibromin. Using all four antibodies, comparable results were obtained on the cellular level in individual tumors suggesting that there exists no epitope of choice in parafibromin immunohistochemistry. The results agree with the demonstration of a approximately 60 kDa product preferentially in the nuclear fraction by western blot analysis. We conclude that parafibromin immunohistochemistry could be used as an additional marker for parathyroid tumor classification, where positive samples have low risk of malignancy, whereas samples with reduced expression could be either carcinomas or rare cases of adenomas likely carrying an HRPT2 mutation.

Proposal for the histological classification of parathyroid carcinoma.

Although the criteria of Schantz and Castleman are widely used in the diagnosis of parathyroid carcinoma, many tumors diagnosed as carcinoma subsequently do not recur. In addition, although Bondeson's criteria are used to grade parathyroid carcinoma, instances of patient mortality have been documented even in cases where the histological features did not conform to the criteria for high grade. Considering our experience, we believe that the subclassification of parathyroid carcinomas defining tumors limited local infiltration as low-grade and those with widespread infiltration as high-grade may be useful.

Hematoma cervical espontáneo: complicación infrecuente de adenoma paratiroideo no funcionante / Spontaneous Cervical Hematoma: rare manifestation of unfunctioning parathyroid adenoma

Se presenta una paciente de 52 años que consultó por dolor cervical de aparición brusca durante la ingesta, odinofagia, fiebre y edema de la base del cuello con rápida extensión al mediastino, lo que motivó la exploración quirúrgica inmediata con sospecha de perforación del esófago cervical y mediastintis descendente. Se halló infiltración hemorrágica de los tejidos cervicales y una formación sólida, adherente al lóbulo tiroideo izquierdo, que fue extirpada. El esófago se hallaba indemne. El estudio anatomopatológico reveló que se trataba de un adenoma paratiroideo con profusa hemorragia. El cuadro, que la literatura denomina hematoma cervical espontáneo, es de presentación poco frecuente y su causa principal es la hemorragia extracapsular de adenomas paratiroideos

Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype.

Parathyroid tumors are heterogeneous, and diagnosis is often difficult using histologic and clinical features. We have undertaken expression profiling of 53 hereditary and sporadic parathyroid tumors to better define the molecular genetics of parathyroid tumors. A class discovery approach identified three distinct groups: (1) predominantly hyperplasia cluster, (2) HRPT2/carcinoma cluster consisting of sporadic carcinomas and benign and malignant tumors from Hyperparathyroidism-Jaw Tumor Syndrome patients, and (3) adenoma cluster consisting mainly of primary adenoma and MEN 1 tumors. Gene sets able to distinguish between the groups were identified and may serve as diagnostic biomarkers. We demonstrated, by both gene and protein expression, that Histone 1 Family 2, amyloid beta precursor protein, and E-cadherin are useful markers for parathyroid carcinoma and suggest that the presence of a HRPT2 mutation, whether germ-line or somatic, strongly influences the expression pattern of these 3 genes. Cluster 2, characterized by HRPT2 mutations, was the most striking, suggesting that parathyroid tumors with somatic HRPT2 mutation or tumors developing on a background of germ-line HRPT2 mutation follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumors. Furthermore, our findings likely preclude an adenoma to carcinoma progression model for parathyroid tumorigenesis outside of the presence of either a germ-line or somatic HRPT2 mutation. These findings provide insights into the molecular pathways involved in parathyroid tumorigenesis and will contribute to a better understanding, diagnosis, and treatment of parathyroid tumors.

Molecular classification of parathyroid neoplasia by gene expression profiling.

The current classification of sporadic parathyroid neoplasia, specifically the distinction of adenoma from multiple gland neoplasia (double adenoma and nonfamilial primary hyperplasia) is problematic and results in a relatively high rate of clinical error. Oligonucleotide microarrays (Affymetrix U133A) were used to evaluate parathyroid samples from 61 patients; 35 adenomas, 10 nonfamilial multiple gland neoplasia, 3 familial primary hyperplasia, 8 renal-induced hyperplasia, and 5 from patients without parathyroid disease (normals). A multiclass comparison using supervised clustering identified distinct gene signatures for each class of parathyroid samples. We developed a predictor model that correctly identified 34 of 35 cases of adenoma, 9 of 10 cases of nonfamilial multiple gland neoplasia, and identified a minimum set of 11 genes for the distinction of adenoma versus multiple gland neoplasia. All methods of unsupervised clustering showed two related but different types of parathyroid adenomas that we have arbitrarily designated as type 1 and type 2 adenomas. Multiple gland parathyroid neoplasia, which represents either synchronous or asynchronous autonomous growth in two, three, or all four parathyroid glands, is a distinct molecular entity and does not represent the molecular pathogenesis of adenoma occurring in multiple glands.

Carcinoma de paratiroides: evaluación de su diagnóstico preoperatorioe / Parathiroid carcinoma: useful parameters for preoperative diagnosis

Antecedentes: El carcinoma de paratiroides es una neoplasia maligna muy infrecuente, que representa cerca del 1 por ciento de los casos de hiperparatiroidismo primario. Objetivos: Describir una serie de carcinomas de paratiroides y comparar su presentación clínica con aquella de un grupo de pacientes con hiperparatiroidismo primario por patología benigna a fin de establecer parámetros útiles para su diagnóstico preoperatorio. Lugar de aplicación: Servicio de cirugía oncológica. Diseño: Estudio observacional comparativo retrospectivo. Población: 229 pacientes consecutivos operados por hiperparatiroidismo primario: 192 (83,8 por ciento) adenoma, 28 (12,2 por ciento) hiperplasia y 9 (3,93 por ciento) carcinoma. Método: Revisión de historias clínicas; los datos fueron registrados en el programa Epi Info 2000 para su tratamiento estadístico...(AU)

Hypothesis: the case for quaternary hyperparathyroidism.

We report the case of a young woman with hyperparathyroidism due to a large parathyroid adenoma associated with severe vitamin D deficiency. The case is noteworthy for the size of the parathyroid adenoma and for the young age at presentation, and is more typical of the presentation of hyperparathyroidism seen in developing countries where the prevalence of vitamin D deficiency is high. Vitamin D is known to have a suppressive effect on parathyroid cell proliferation and parathyroid hormone synthesis. Vitamin D deficiency may result in a compensatory increase in the secretion of parathyroid hormone (secondary hyperparathyroidism) which involves hyperplasia of all four parathyroid glands. Secondary hyperparathyroidism can become autonomous and this has been termed tertiary hyperparathyroidism, the underlying pathology of which has been variably described in the literature as adenoma formation or four gland hyperplasia. The pathogenesis of parathyroid adenoma formation in vitamin D deficiency remains unclear. It is possible that a proportion of cases represent the coincidence of primary hyperparathyroidism in patients with vitamin D deficiency. Alternatively, we hypothesise that autonomous four gland hyperplasia or tertiary hyperparathyroidism may progress to adenoma formation and that this should be termed 'quaternary hyperparathyroidism'.

[Hyperplasia and tumors of the parathyroid glands]. / Hyperplasien und Tumoren der Nebenschilddrüsen.

Hyperparathyroidism is mainly caused by hyperplasia or adenomas of the parathyroid glands. Formerly, the therapeutic strategy depended on the morphological diagnosis (preferentially already made intraoperatively by examination of frozen sections). Today, however, the extent of parathyroid surgery is in many cases guided both by substantial improvements in the preoperative clinical diagnosis as well as the intraoperatively determined decrease in the serum parathyroid hormone level. Nevertheless, the pathologist should be familiar with the differential diagnostic criteria of parathyroid hyperplasia, adenoma, and carcinoma.

[Pathology of important diseases of endocrine organs (excluding the thyroid)]. / Pathologie wichtiger Erkrankungen endokriner Organe (Schilddrüse ausgenommen).

Basic principles of classification of tumors of the pituitary, parathyroid glands, adrenals, paraganglionic system and endocrine pancreas and the differential diagnosis from non-endocrine tumors are presented. There are no uniform criteria of malignancy and common neuroendocrine immunohistological markers for unequivocal identification, as each organ has its own criteria. For pituitary tumors invasive growth is not a sign of malignancy, but only metastases. For tumors of the adrenal cortex a histopathological score has to be used for proving dignity. For pheochromocytomas, structural criteria (mitoses, angioinvasion) and immunostaining (S-100 protein, p53, Ki-67) are important. Endocrine tumors of the pancreas behave differently if they are angioinvasive or if they show more than two mitoses per 10 HPF, more than 2% Ki-67 positive nuclei or a size of more than 2 cm in diameter. They are malignant if gross local invasion or metastases are demonstrable. Clinical data have to be included in pathohistological reports. In many cases immunostaining in addition to structural analysis will be necessary.

Multiple endocrine neoplasia type 1 and 2: from morphology to molecular pathology 1997.

Multiple Endocrine Neoplasia (MEN) is an inherited syndrome which appears in two major forms referred to as type 1 (MEN-1) and type 2 (MEN-2). MEN-1 is characterized by the occurrence of neuroendocrine parathyroid, pancreas, duodenum and pituitary lesions. In addition to these tumors adrenocortical, lipomatous and neuroendocrine tumors in other locations may develop. The genetic defect of MEN-1 has recently been identified and involves a new form of tumor suppressor gene called mu on chromosome 11q13. It codes for a protein called menin which is expressed in a variety of human tissues and organs. In MEN-1 gene carriers inactivating germline frameshift, nonsense, missense and in-frame deletion mutations scattered throughout the 10 coding exons have been identified. The MEN-2 syndrome is divided into three clinical variants referred to as MEN-2A, MEN-2B and familial medullary thyroid carcinoma (FMTC) which share medullary thyroid carcinomas as part of the disease phenotype. In MEN-2A pheochromocytomas and parathyroid hyperplasia and in MEN-2B additional skeletal abnormalities and ganglioneuromatosis may also be encountered. All three MEN-phenotypes are associated with oncogenic point mutations of the RET protooncogene on chromosome 10q11.2 which encodes a receptor-type tyrosine kinase. Its ligand--the glial cell line derived neurotropic factor (GDNF)--forms a signaling complex with the alpha type of the GDNF receptor. All neuroendocrine tumors of the different MEN-phenotypes may also occur sporadically and there are only few clinical and pathomorphological features which are helpful to discriminate sporadic from MEN-associated neuroendocrine neoplasms. The recent achievements of molecular pathology now allow for the unambiguous identification of MEN gene carriers among patients with neuroendocrine neoplasms by DNA testing for mutations in the mu and RET gene. In this overview, distinct macroscopic and histopathological features of the two MEN phenotypes will be summarized and most recent findings on the molecular pathology of these syndromes will be outlined, together with molecular methods to identify disease-gene carriers.