Ultrastructural features of tumor-associated mast cells in parasympathetic paragangliomas (chemodectomas) of the neck.

The mechanisms of the pathogenesis of neck paraganglioma (PGL) and the possible role of mast cells (MCs) in its development and metastasis are still poorly understood. We analyzed MCs' morphologic characterization, activation, and the properties of their cytoplasmic/released granules in PGLs, using light and transmission electron microscopy. Paragangliomas showed a large tumor-associated MC population both in the connective tissue layers of the tumor and between the tumor cells. Notably, MCs were presented by a high expression of specific proteases, size variation, polymorphism, and variable ultrastructural phenotype of granules. A massive number of granules were released surrounding the degranulated MCs while the integrity of MC membrane was maintained. Granules were electron-dense with or without a membrane, ranging from 0.2 to 0.8 µm in diameter. MC plasmalemma was not found at the site of MC-collagen fibrils contact, whereas the secretome and fibrils were directly contacted. We observed direct and mediator-based interactions between MCs and paraganglioma cells. The latter preserved their membrane integrity when MC granules were not in proximity. The effects of the MC secretome on the paraganglioma microenvironment demonstrated its pathogenetic role in tumor progression and allow its application to new diagnostic criteria and the development of protocols for personalized therapy. RESEARCH HIGHLIGHTS: Ultrastructural analysis reveals novel regulatory effects of mast cells via diverse secretory pathways on the pathogenesis of parasympathetic paraganglioma, including fibrous extracellular matrix remodeling and mediator-based interactions between MCs and cells of the tumor microenvironment.

[Glomuvenous malformation: a clinicopathological analysis of 31 cases].

Objective: To investigate the clinicopathological features of glomuvenous malformation (GVM). Methods: Thirty-one cases of GVM diagnosed at the Henan Provincial People's Hospital from January 2011 to December 2021 were collected. Their clinical and pathological features were analyzed. The expression of relevant markers was examined using immunohistochemistry. The patients were also followed up. Results: There were 16 males and 15 females in this study, with an average age of 11 years (range, 1-52 years). The locations of the disease included 13 cases in the limbs (8 cases in the upper limbs, 5 cases in the lower limbs), 9 cases in the trunks, and 9 cases in the foot (toes or subungual area). Twenty-seven of the cases were solitary and 4 were multifocal. The lesions were characterized by blue-purple papules or plaques on the skin surface, which grew slowly. The lumps became larger and appeared to be conspicuous. Microscopically, GVM mainly involved the dermis and subcutaneous tissue, with an overall ill-defined border. There were scattered or clustered irregular dilated vein-like lumens, with thin walls and various sizes. A single or multiple layers of relatively uniform cubic/glomus cells were present at the abnormal wall, with scattered small nests of the glomus cells. The endothelial cells in the wall of abnormal lumen were flat or absent. Immunohistochemistry showed that glomus cells strongly expressed SMA, h-caldesmon, and collagen IV. Malformed vascular endothelial cells expressed CD31, CD34 and ERG. No postoperative recurrence was found in the 12 cases. Conclusions: GVM is an uncommon type of simple venous malformation in the superficial soft tissue and different from the classical glomus tumor. Morphologically, one or more layers of glomus cells grow around the dilated venous malformation-like lumen, which can be combined with common venous malformations.

Immunohistochemical Expression of Choline Acetyltransferase and Catecholamine-Synthesizing Enzymes in Head-and-Neck and Thoracoabdominal Paragangliomas and Pheochromocytomas.

Paragangliomas (PGLs) are neural-crest-derived, non-epithelial neuroendocrine tumors distributed along the parasympathetic and sympathetic nerves. Head-and-neck PGLs (HNPGLs) have been recognized as nonchromaffin, nonfunctional, parasympathetic tumors. By contrast, thoracoabdominal paragangliomas and pheochromocytomas (PPGLs) are chromaffin, functional, sympathetic tumors. Although HNPGLs and PPGLs have the same histological structure, the zellballen pattern, composed of chief and sustentacular cells surrounded by abundant capillaries, the pathobiological differences between these types of PGLs remain unclarified. To determine the phenotypic features of these PGLs, we performed an immunohistochemical study using specific antibodies against choline acetyltransferase (ChAT), an enzyme involved in acetylcholine synthesis, and enzymes for the catecholamine-synthesis, tyrosine hydroxylase (TH), and dopamine beta-hydroxylase (DBH), in 34 HNPGLs from 31 patients, 12 thoracoabdominal PGLs from 12 patients, and 26 pheochromocytomas from 22 patients. The expression of ChAT, TH, and DBH was 100%, 23%, and 10% in the HNPGLs; 12%, 100%, and 100% in the pheochromocytomas; and 25%, 67%, and 100% in the thoracoabdominal PGLs, respectively. These results designate HNPGLs as acetylcholine-producing parasympathetic tumors, in contrast to PPGLs being catecholamine-producing tumors. The other most frequently used neuroendocrine markers are synaptophysin and chromogranin A expressed 100% and 80%, respectively, and synaptophysin was superior to chromogranin A in HNPGLs. This is the first report of HNPGLs being acetylcholine-producing tumors. Immunohistochemistry of ChAT could be greatly useful for pathologic diagnosis of HNPGL. Whether measurement of acetylcholine levels in the blood or urine could be a tumor marker of HNPGLs should be investigated soon.

SDHC Methylation Pattern in Patients With Carney Triad.

Carney triad is a multitumor syndrome affecting almost exclusively young women in a nonfamilial setting, which manifests by multifocal gastric gastrointestinal stromal tumors, paragangliomas, and pulmonary chondroma. The Carney triad-associated tumors are characterized by a deficiency of the mitochondrial succinate dehydrogenase enzymatic complex. Recently, it has been observed that the deficiency results from epigenetic silencing of the SDHC gene by its promoter hypermethylation. To elucidate anatomic distribution of SDHC promoter methylation in Carney triad patients and thus to shed some light on the possible natural development of this epigenetic change, both neoplastic and available non-neoplastic tissues of 3 patients with Carney triad were tested for hypermethylation at the SDHC promoter site. SDHC promoter hypermethylation was proven in all tumors studied. Lack of SDHC epigenetic silencing in the non-neoplastic lymphoid and duodenal tissue (ie, tissues not involved in the development of Carney triad-associated tumors) together with the finding of SDHC promoter hypermethylation in the non-neoplastic gastric wall favors the hypothesis of postzygotic somatic mosaicism as the biological background of Carney triad; it also offers an explanation of the multifocality of gastrointestinal stromal tumors of the stomach occurring in this scenario as well. However, the precise mechanism responsible for the peculiar organ-specific distribution of Carney triad-associated tumors is still unknown.

Update on Pheochromocytoma and Paraganglioma from the SSO Endocrine/Head and Neck Disease-Site Work Group. Part 1 of 2: Advances in Pathogenesis and Diagnosis of Pheochromocytoma and Paraganglioma.

This first part of a two-part review of pheochromocytoma and paragangliomas (PPGLs) addresses clinical presentation, diagnosis, management, treatment, and outcomes. In this first part, the epidemiology, prevalence, genetic etiology, clinical presentation, and biochemical and radiologic workup are discussed. In particular, recent advances in the genetics underlying PPGLs and the recommendation for genetic testing of all patients with PPGL are emphasized. Finally, the newer imaging methods for evaluating of PPGLs are discussed and highlighted.

A 46-Year-Old Woman With a Mediastinal Mass.

CASE PRESENTATION: A 46-year-old otherwise healthy woman visited the ED twice over a period of 4 days for chest discomfort, midback pain, and dyspnea. The pain was localized, constant, nonpleuritic in nature, moderate in severity, and was not relieved by over-the-counter medications.

Loss of BAP1 in Pheochromocytomas and Paragangliomas Seems Unrelated to Genetic Mutations.

Breast cancer-associated protein 1 (BAP1) gene is a broad-spectrum tumor suppressor. Indeed, its loss of expression, due to biallelic inactivating mutations or deletions, has been described in several types of tumors including melanoma, malignant mesothelioma, renal cell carcinoma, and others. There are so far only two reports of BAP1-mutated paraganglioma, suggesting the possible involvement of this gene in paraganglioma (PGL) and pheochromocytoma (PCC) pathogenesis. We assessed BAP1 expression by immunohistochemistry (IHC) in a cohort of 56 PCC/PGL patients (and corresponding metastases, when available). Confirmatory Sanger sequencing (exons 1-17) of BAP1 has been performed in those samples which resulted negative by IHC. BAP1 nuclear expression was lost in 2/22 (9.1%) PGLs and in 12/34 (35.3%) PCCs, five of which harboring a germline mutation predisposing the development of such tumors (MENIN, MAX, SDHB, SDHD, and RET gene). Confirmatory Sanger sequencing revealed the wild-type BAP1 status of all the analyzed samples. No heterogeneity between primary and metastatic tissue was observed. This study documents that the loss of BAP1 nuclear expression is quite a frequent finding in PCC/PGL, suggesting a possible role of BAP1 in the pathogenesis of these tumors. Gene mutations do not seem to be involved in this loss of expression, at least in most cases. Other genetic and epigenetic mechanisms need to be further investigated.

Frequency and extent of cytokeratin expression in paraganglioma: an immunohistochemical study of 60 cases from 5 anatomic sites and review of the literature.

The absence of cytokeratin expression in paraganglioma helps to differentiate it from other neuroendocrine neoplasms such as carcinoid tumor. Although rare cytokeratin positive paragangliomas have been reported, there are no large systematic studies of this phenomenon. The aim of this study was to determine the frequency and extent of cytokeratin expression in paragangliomas using a large cohort of cases from multiple anatomic sites. Immunohistochemical staining for keratin AE1/AE3 (mouse monoclonal, MAB3412; Millipore) and CAM 5.2 (mouse monoclonal, 349 205; Becton-Dickinson) was performed on whole-tissue sections from 60 resected paragangliomas from the head and neck (36), thorax (10), abdomen (8), intradural/epidural spine (5) and bone, left iliac (1). Cytokeratin expression was identified in only 2/60 (3.3%) cases. One was a mediastinal paraganglioma with moderate to strong expression of keratin AE1/AE3 and CAM 5.2 in <5% tumor cells. The other was a lumbar intradural paraganglioma positive for CAM 5.2 (moderate to strong, 80% of tumor cells) but negative for keratin AE1/AE3. All other paragangliomas (58/60, 96.7%) were negative for keratin AE1/AE3 and CAM 5.2. This study - the largest series of cytokeratin-stained whole-tissue sections of paragangliomas to date - supports the dictum that most paragangliomas are cytokeratin negative. Rare exceptions may be site-related.

Paragangliomas in Carney-Stratakis Syndrome.

Carney-Stratakis Syndrome (CSS) comprises of paragangliomas (PGLs) and gastrointestinal stromal tumors (GISTs). Several of its features overlap with Carney Triad (CT) - PGLs, GISTs, and pulmonary chondromas. CSS has autosomal dominant inheritance, incomplete penetrance, and greater relative frequency of PGL over GISTs. The PGLs in CSS are multicentric and GISTs are multifocal in all the patients, suggesting an inherited susceptibility and associating the two manifestations. In this review, we highlight the clinical, pathological, and molecular characteristics of CSS, along with its diagnostic and therapeutic implications.

Clinical significance and peculiarities of succinate dehydrogenase B and hypoxia inducible factor 1α expression in parasympathetic versus sympathetic paragangliomas.

BACKGROUND: Succinate dehydrogenase subunit B (SDHB) immunohistochemistry was considered a valuable tool to identify patients with inherited paraganglioma/pheochromocytoma (PGL/PCC). However, previous studies jointly analyzed 2 related but clinically distinct entities, parasympathetic head and neck paragangliomas (HNPGLs) and sympathetic PCCs/PGLs. Additionally, a role for hypoxia inducible factor-1α (HIF-1α) as a biomarker for succinate dehydrogenase (SDHx)-mutated tumors has not been studied. Here, we evaluated the utility of SDHB/HIF-1α proteins in HNPGLs and PCCs/PGLs as clinically useful biomarkers. METHODS: The SDHB/succinate dehydrogenase subunit A (SDHA)/HIF-1α immunohistochemistry analysis was performed in 158 genetically defined patients. RESULTS: Similarly to PCCs/PGLs, SDHB immune-negativity correlated with SDHx-mutations in HNPGLs (P < .0001). The HIF-1α stabilization was associated with SDHx-mutations in HNPGLs (P = .020), not in PCCs/PGLs (P = .319). However, 25% of SDHx-HNPGLs lacked HIF-1α positive cells. CONCLUSION: As in PCCs/PGLs, SDHB immunohistochemistry in HNPGLs is a valuable method for identification of candidates for SDHx-genetic testing. On the contrary, although SDHx mutations may favor HIF-1α stabilization in HNPGLs, this is not a clinically useful biomarker.

PHEOCHROMOCYTOMA: A GENETIC AND DIAGNOSTIC UPDATE.

OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathologic studies are performed to prove, localize, treat, and monitor disease progression. Improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (<1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment. METHODS: This review outlines the most updated approach to PPGL patients and presents a new diagnostic protocol for physicians to increase earlier tumor identification and accurately assess metastatic behavior. CONCLUSION: We present the most recent advances in genetics, epigenetics, metabolomics, biochemical, and imaging diagnoses of this rare tumor to properly assess disease, decide treatment options, and manage follow-up. We also elaborate on new therapeutic perspectives in these very rare neoplastic entities. ABBREVIATIONS: ATRX = ATRX chromatin remodeler; ccRCC = clear cell renal cell carcinoma; c-MYC = MYC proto oncognene; CT = computed tomography; DOTATATE = DOTA-octreotate; EGLN1/2 = egl-9 family hypoxia inducible factor 1/2; EGLN2/PHD1 = egl-9 family hypoxia inducible factor 2; EPAS1/HIF2A = endothelial PAS domain protein 2/hypoxia-inducible factor 2α; ERK = extracellular signal-regulated kinase; HIFs = hypoxia-inducible factors; HIF-α = hypoxia-inducible factor alpha; HNPGLs = head and neck paragangliomas; 177Lu-DOTATATE = lutetium octreotate; MAX = myc-associated factor X; MDH2 = malate dehydrogenase; MIBG = metaiodobenzylguanidine; MN = metanephrine; MRI = magnetic resonance imaging; mTOR = mammalian target of rapamycin; NETs = neuroendocrine tumors; NF1 = neurofibromin 1; NMN = normetanephrine; PHD = prolyl hydroxylase domain protein; PI3K = phosphoinositide 3-kinase; PPGLs = pheochromocytoma and paragangliomas; PRRT = peptide receptor radionuclide therapy; Pvhl = von Hippel-Lindau protein; RAS = rat sarcoma oncogene; RET = rearranged during transfection proto-oncogene; SDH = succinate dehydrogenase; SDHA, -B, -C, -D = succinate dehydrogenase subunits A, B, C, D; SDHAF2 = succinate dehydrogenase complex assembly factor 2; SDHB, C, D = succinate dehydrogenase subunits B, C, D; SDHx = succinate dehydrogenase subunits; SSTRs = somatostatin receptors; VHL = von Hippel-Lindau.

68Ga-DOTA-TATE PET/CT for Molecular Imaging of Somatostatin Receptor Expression in Extra-adrenal Paraganglioma in a Case of Complete Carney Triad.

Carney triad is a very rare syndrome characterized by the synchronous or metachronous occurrence of gastrointestinal stromal tumors, pulmonary chondroma, and extra-adrenal paraganglioma. We present the case of a 36-year-old woman with complete Carney triad who underwent a Ga-DOTA-TATE PET/CT scan for restaging of metastasizing extra-adrenal paraganglioma and for evaluation of targeted radionuclide therapy potential. On the Ga-DOTA-TATE PET scan, increased tracer accumulation was observed in paraganglioma metastases. This case highlights the usefulness of Ga-DOTA-TATE PET/CT for restaging of metastasizing paraganglioma in Carney triad and the option of targeted radionuclide therapy in this entity.

Dopamine-Secreting Paraganglioma in the Retroperitoneum.

Pheochromocytomas and paragangliomas, which exclusively produce dopamine, are very rare. Herein, we report for the first time a Japanese case of an exclusively dopamine-producing paraganglioma accompanied by detailed immunohistochemical analyses. A 70-year-old Japanese woman was referred to our hospital for functional examination of her left retroperitoneal mass. Her adrenal functions were normal, except for excessive dopamine secretion. After the tumorectomy, her dopamine level normalized. The histopathological diagnosis of the tumor was paraganglioma; this was confirmed by positive immunostaining of chromogranin A (CgA), tyrosine hydroxylase (TH), dopamine ß-hydroxylase (DBH), and succinate dehydrogenase gene subunit B (SDHB). However, the immunostaining of CgA in the tumor cells showed peculiar dot-like staining located corresponding to Golgi complex in the perinuclear area, rather than the diffuse cytoplasmic staining usually observed in epinephrine- or norepinephrine-producing functional pheochromocytomas and paragangliomas. The immunohistochemical results suggested that the tumor cells had sparse neuroendocrine granules in the cytoplasm, resulting in inhibition of catecholamine synthesis from dopamine to norepinephrine in neurosecretory granules. This may be the mechanism responsible for exclusive dopamine secretion in the present case.

Smoothelin and WT-1 expression in glomus tumors and glomuvenous malformations.

BACKGROUND: Smoothelin is a specific marker for smooth muscle cells with contractile capacity which has not been widely studied in glomus lesions. In the same way, the expression for Wilms tumor 1 (WT1) has only been studied occasionally in the endothelial cells of glomovenous malformations and in the glomus cells of glomus tumours. OBJECTIVE: We studied the significance of immunohistochemical expression of smoothelin and WT1 in 25 glomus lesions. METHODS: We assessed 9 cases of solid glomus tumors (SGT), 8 cases of glomus tumors with vascular ectasia (VEGT), 2 cases of glomangiomyomas (GMM) and 6 cases of glomuvenous malformation (GM). Immunohistochemistry was performed, evaluating the expression of WT1, smoothelin, smooth muscle actin (SMA), smooth muscle myosin (SMM), h-caldesmon and desmin. RESULTS: Glomic cells showed cytoplasmic positivity for smoothelin, and WT1 expression was present in all studied cases. SGT showed WT1 positivity in all endothelia. However, in regarding VEGT and GMM, WT1 endothelial expression was positive in some areas, but not in others. GM did not show endothelial cell positivity for WT1. CONCLUSIONS: Smoothelin expression in glomic cells indicates that they are contractile smooth muscle cells, and thus its role in routine diagnosis should be considered. The absence of WT1 expression in the endothelium of the vascular structures of the GM is a differential characteristic between SGT, VEGT and GMM.

Carney triad, SDH-deficient tumors, and Sdhb+/- mice share abnormal mitochondria.

Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other lesions, including pheochromocytomas and adrenocortical tumors. The gene(s) that cause CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues that carry SDH defects, but they have not been studied in CTr. For the present study, we examined mitochondrial structure in human tumors and GI tissue (GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), those with isolated GIST (n=1), and those with CSS caused by SDHC (n=1) and SDHD (n=2) mutations were studied by electron microscopy (EM). Samples of GIT from mice with a heterozygous deletion in Sdhb (Sdhb(+) (/-), n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located, round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GISTs of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained an increased number of mitochondria with a 'hypoxic' phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities, and were of variable size. Occasionally, mitochondria were small and round; rarely, they were thin and elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. A similar mitochondrial hypoxic phenotype was seen in Sdhb(+) (/-) mice. We concluded that tissues from SDH-deficient tumors, those from mouse GIT, and those from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still-elusive CTr defect(s) is(are) likely to affect mitochondrial function, just like germline SDH-deficiency does.

Increased SSTR2A and SSTR3 expression in succinate dehydrogenase-deficient pheochromocytomas and paragangliomas.

Many neuroendocrine tumors, including pheochromocytomas (PCs) and paragangliomas (PGLs), express one or more somatostatin receptors (SSTR1-5). A number of studies have reported SSTR expression in PCs and PGLs. However, receptor expression patterns have been conflicting, and until recently, specific monoclonal antibodies were not available against SSTR1-5. The aim of this study was to compare SSTR1-5 expression in succinate dehydrogenase (SDH)-deficient PCs and PGLs (defined as having absent SDHB immunostaining) to those tumors with normal SDHB staining. Immunohistochemistry for SDHB and SSTR1-5 was performed using specific monoclonal antibodies on archived formalin-fixed, paraffin-embedded tissue from patients who had undergone surgery for PC or PGLs. A total of 182 PC/PGLs were included (129 adrenal, 44 extra-adrenal, 9 metastases); 32 tumors were SDH deficient, whereas 150 tumors had positive SDHB staining. SDH-deficient tumors were more likely to demonstrate moderate or strong staining for SSTR2A and SSTR3 when compared with SDH-sufficient tumors (91% versus 49% [P < .0001] and 50% versus 21% [P = .0008], respectively). Immunostaining for the other SSTRs was not different between SDH-deficient and tumors with preserved SDHB staining. SSTR2A and SSTR3 are more likely to be expressed in SDH-deficient PC/PGLs as compared with tumors demonstrating normal SDHB staining pattern. These findings suggest that the role of somatostatin analogue therapy (unlabeled or radiolabeled) should be reexamined in the context of the underlying SDHB immunohistochemistry pattern.

Paraganglioma of the thyroid gland: a case report.

INTRODUCTION: Thyroid paraganglioma is a very rare malignant neuroendocrine tumor. Immunohistochemical features of thyroid paraganglioma are helpful for the diagnosis. CASE REPORT: A 69-year-old female came to hospital with the presence of a growing thyroid nodule of the left lobe. Ultrasonic neck examination showed 5 cm hypoechoic nodule in the left thyroid lobe. Thyroid scintigraphy showed a big cold nodule in the left lobe. Computed tomography (CT) scan showed left lobe thyroid tumor with tracheal deviation on the right site. Extended total thyroidectomy was done. Intraoperative consultation with the pathologist confirmed thyroid cancer. The pathologist diagnosed thyroid paraganglioma on the base of immuohistochemical investigation. This thyroid paraganglioma was positive for neuron-specific enolase, chomogranin A, synaptophysin, and S-100 protein highlighted the sustentacular cells. Tumor cells were negative for thyroglobulin, epithelial membrane antigen, cytokeratin, calcitonin, and carcinoembryonic. After the surgery the patient was treated with chemotherapy, peptide receptor radionuclide therapy, and permanent TSH suppressive therapy. The patient was followed with measurements of thyroid hormone and serum neuron-specific enolase, chromogranin A level, every 6 months. Gastroscopy, colonoscopy, chest and abdomen CT scan as well as further tests (chest xray, ultrasound of the neck, and whole body octreotide scintigraphy) were done. No primary neuroendocrine tumor in digestive sistem or in the chest was found. After more than 3 years the patient has no evidence of the recurrent disease. CONCLUSION: Radical resection of thyroid paraganglioma, followed by chemotherapy and peptide receptor radionuclide therapy, should be considered the treatment of choice in patients with thyroid gland paraganglioma.

Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad.

Carney triad (CT) is a rare condition with synchronous or metachronous occurrence of gastrointestinal stromal tumors (GISTs), paragangliomas (PGLs), and pulmonary chondromas in a patient. In contrast to Carney-Stratakis syndrome (CSS) and familial PGL syndromes, no germline or somatic mutations in the succinate dehydrogenase (SDH) complex subunits A, B, C, or D have been found in most tumors and/or patients with CT. Nonetheless, the tumors arising among patients with CT, CSS, or familial PGL share a similar morphology with loss of the SDHB subunit on the protein level. For the current study, we employed massive parallel bisulfite sequencing to evaluate DNA methylation patterns in CpG islands in proximity to the gene loci of all four SDH subunits. For the first time, we report on a recurrent aberrant dense DNA methylation at the gene locus of SDHC in tumors of patients with CT, which was not present in tumors of patients with CSS or PGL, or in sporadic GISTs with KIT mutations. This DNA methylation pattern was correlated to a reduced mRNA expression of SDHC, and concurrent loss of the SDHC subunit on the protein level. Collectively, these data suggest epigenetic inactivation of the SDHC gene locus with functional impairment of the SDH complex as a plausible alternate mechanism of tumorigenesis in CT.

Duodenal gangliocytic paraganglioma, a rare entity among GEP-NET: a case report with immunohistochemical and molecular study.

Gastroenteropancreatic neuroendocrine tumors are the most incident neuroendocrine tumors. In the new WHO classification (2010) the embryological derivation of each neoplastic entity is one of the most important parameters. Gangliocytic Paraganglioma is a tumor originating in the hindgut, a rare neoplasm, generally affecting the second portion of the duodenum, the majority of which are benign.Cases of gangliocytic paraganglioma with local metastasis or local recurrence have also been reported.We describe a GP in a 48-year-old caucasian male with an unusual site (4th portion of duodenum) and an interesting immunohistochemical and molecular pattern. In particular, we examined the expression of some neuroendocrine markers and a marker of neuronal differentiation, NeuroD1, whose expression can help to better understand the nature of this neoplasia. VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3720959161096807.