Paraganglia of the Gallbladder: An Underrecognized Incidental Finding and Potential Diagnostic Pitfall.

CONTEXT.­: The identification of paraganglia (PG) in the gallbladder (GB) is infrequent, and easily overlooked as it is not something routinely reported. Occasionally they may be misinterpreted as neoplastic cells, such as low-grade carcinomas, germ cell tumors, or because of their close resemblance to neuroendocrine cells, as low-grade neuroendocrine neoplasms. OBJECTIVE.­: To evaluate the incidence and histological features of PG of the GB in patients that underwent cholecystectomy, and discuss the potential misinterpretation of these benign structures as clusters of neoplastic cells. DESIGN.­: A retrospective study of cholecystectomy specimens performed during a 6-month period were reviewed for identification of PG. Immunohistochemical studies for chromogranin, synaptophysin, S100, and cytokeratin AE1/AE3 were performed in selected cases. RESULTS.­: A total of 365 GBs were reviewed and in 16 cases (4.4%) PG was identified within the subserosal connective tissue of the GB wall or cystic duct adjacent to small capillaries, nerves, and ganglia. They consisted of well-demarcated, lobular structures ranging in size from 0.2 to 0.5 cm, which were predominantly composed of chief cells, with strong expression for chromogranin and synaptophysin and negative CKAE1/AE3, and a minor component of S100-positive sustentacular cells. CONCLUSIONS.­: PG is an uncommon finding with a prevalence of 4.4% in our study. Awareness of their location, histologic features, and immunohistochemical profile may help practicing pathologists to confirm their benign nature, avoid a misdiagnosis of malignancy, and prevent unnecessary diagnostic work-up and treatment.

Approach to the Patient: Perioperative Management of the Patient with Pheochromocytoma or Sympathetic Paraganglioma.

Pheochromocytomas and sympathetic paraganglioma (PPGL) are rare chromaffin cell tumors originating in the adrenal medulla and sympathetic paraganglia, respectively, which share the capacity to synthesize and release catecholamines. The incidence of PPGL has increased in recent years. Surgical resection is the only curative treatment for PPGL. Management of patients with PPGL is complex and should be done by a specialized multidisciplinary team in centers with broad expertise. Surgical resection of a PPGL is a high-risk procedure for which optimal pretreatment with antihypertensive drugs is required in combination with state-of-the-art surgical procedures and anesthesiological techniques. In this article we discuss the underlying evidence and the pros and cons of presurgical medical preparation. Finally, the areas of uncertainty and controversies in this field are addressed.

Tumores suprarrenales en la infancia / Adrenal tumours in childhood

En este artículo se revisa y resume el estado actual del conocimiento de los 2 grandes grupos de tumores originados en la glándula suprarrenal: a) corticosuprarrenalomas, tumores derivados de la corteza de la glándula suprarrenal; y b) feocromocitomas y paragangliomas, tumores neuroendocrinos que tienen su origen en los paraganglios, formados por cúmulos ganglionares de células derivadas de la cresta neural, que se distribuyen simétricamente a lo largo del sistema nervioso autónomo, desde la pelvis a la base del cráneo, siguiendo el eje longitudinal del cuerpo (paragangliomas [PG]). Estos últimos (PG) pueden ser funcionantes y secretar catecolaminas que, al oxidarse con sales de cromo, adquieren un color marrón oscuro (tumores cromafines). Entre ellos, el término de feocromocitoma (FC) se reserva a los PG derivados de las células cromafines de la médula suprarrenal (PG intra-suprarrenales o de médula suprarrenal); mientras que, el término de PG hace referencia a los PG localizados fuera de la glándula suprarrenal, tanto simpáticos como parasimpáticos. Se analizará el estado actual de las bases conceptuales, patogénicas, fundamentos genéticos y elementos diagnósticos (manifestaciones clínicas, parámetros bioquímicos y hormonales, técnicas de imagen y estudios moleculares) y terapéuticos (cirugía, tratamiento médico pre y postoperatorio, quimioterapia y radioterapia) de aplicación en la actualidad o en desarrollo (AU)

This special article aims to summarise the current knowledge regarding the two groups of tumours with their origin in the adrenal gland: 1) adrenocortical tumours, derived from the cortex of the adrenal gland and 2) phaeochromocytomas and paragangliomas, neuroendocrine tumours derived from nodes of neural crest derived cells symmetrically distributed at both sides of the entire spine (paragangliomas [PG]). These PGs can be functioning tumors that secrete catecholamines, which confers their typical dark colour after staining with chromium salts (chromaffin tumors). Among these, the term phaeochromocytoma (PC) is restricted to those PGs derived from the chromaffin cells in the adrenal medulla (intra-adrenal PGs), whereas the term PG is used for those sympathetic or parasympathetic ones in an extra-adrenal location. We analyse the state of the art of their pathogenic and genetic bases, as well as their clinical signs and symptoms, the tests currently available for performing their diagnosis (biochemical, hormonal, imaging and molecular studies) and management (surgery, pre- and post-surgical medical treatment), considering the current and developing strategies in chemo- and radiotherapy (AU)

Malignant paraganglioma of the mesentery: a case report and review of literature.

Paragangliomas represent only 10% of chromaffin tissue tumors and those arising from the mesentery seem to be a rare occurrence. We report a case of a 55 year old man in whom an abdominal mass was discovered fortuitously by ultrasonography during a routine health exam. He presented occasional heart palpitations and diaphoresis as well as a well-demarcated mass upon abdominal physical examination. CT scan revealed a solid polylobulated mass in the right lower quadrant. Exploration laparotomy revealed a voluminous multi-nodular tumoral mass, which contained hemorrhagic spots. Histopathological studies confirmed the presence of a paraganglioma. The excision of the mass as well as the surrounding intestine and mesentery also revealed two lymphatic metastases, the first among 14 documented cases to be described concerning mesenteric paragangliomas. One year follow up and CT scan revealed neither recurrence nor the presence of distant metastases.

Manifestaciones adrenérgicas de los tumores del tejido cromafín extraadrenal / High percentage of adrenergic symtoms in extraadrenal chromaffin toumors

ResumenEstudio descriptivo retrospectivo de 14 pacientes con un diagnóstico histológico de paraganglioma (PGL) recogidos en el Hospital Universitario de Vigo, Pontevedra, durante los últimos 25 años. Hemos analizado las características clínicas y la evolución de esta serie de enfermos.ResultadosLa forma de presentación de los 14 pacientes fue por efecto masa en 10, clínica adrenérgica en 3 e incidental en uno. Algunos enfermos con PGL simpáticos (PGLS) (6/9) y PGL parasimpáticos (PGLPS) (2/5) presentaron clínica de hiperproducción adrenérgica antes del diagnóstico. La determinación de catecolaminas urinarias fue positiva en los 4 enfermos con PGLPS en quienes se determinó. El tamaño tumoral medio fue de 37,8±18,9mm, sin diferencias entre los PGLS y los PGLPS. Dos PGLS fueron malignos. La evolución resultó favorable en 11 pacientes, 2 pacientes con PGLS fallecieron y el tumor de un paciente con PGLPS intracraneal no se pudo extirpar en su totalidad.ConclusionesLos PGL se presentan con frecuencia clínica adrenérgica secundaria a la producción de catecolaminas. Las características de estos tumores aconsejan un estudio detallado en un ámbito especializado antes de la cirugía(AU)

AbstractDescriptive retrospective study of 14 patients with paragangliomas (PGL) attended in the University Hospital of Vigo (Pontevedra) during the last 25 years to evaluating their characteristics and neuroendocrine potential.Results71.4% were diagnosed due to mass tumoral effect, 21.4% due to adrenergic symptoms and 7.1% incidentally. Regarding to symptoms and signs 66.7% of PGL Simpatic (PGLS) and 40% of PGL Parasimpatic (PGLPS) presented adrenergic symptoms. Urine catecholamine analysis was carried out to 4 PGLS and high levels were found in all patients. The tumoral size reached a mean value of 37.8±18.9mm, there were not differences found between both types of tumors. Inmunohistoquimia showed positive Chromogranine A stain in all patients. Two PGLS were maligns. Eleven patients had positive outcome, 2 PGLS died, and 1 PGLPS remains not cured.ConclusionsHigh percentage of patients had clinical manifestations related to catecholamine hyperproduction. We believe that due to the risk related to surgical treatment, malignance, multiple location and family associations, it would be advisable to carry out a complete examination prior to surgery(AU)

Multiple minute nests of incidentally detected paraganglionic cells associated with urothelial carcinoma of the urinary bladder in a 73-year-old woman.

A 73-year-old woman who had undergone resection of urothelial carcinoma (UC) (G3 > G2) of the ureter was also found to have UC (G3) in the urinary bladder, spread throughout the urinary bladder with multiple foci of carcinoma in situ and small papillary cancers. Total cystectomy was therefore performed. On detailed microscopic examination of the extirpated urinary bladder, multiple minute cell nests, 14 in number and less than 2 mm in diameter each, consisting of cells harboring small nuclei and clear cytoplasm, were incidentally detected within the sub-mucosal layer and the proper muscle layer, mainly in the posterior wall of the urinary bladder. Some cell nests were clearly associated with ganglion cells. The cells in minute nests were positive on Grimelius staining and also strongly positive on staining with antibodies to chromogranin A, neuron-specific enolase (NSE), synaptophysin, and vimentin on immunohistochemical staining. In addition, sustentacular cells in the minute cell nests were positive for S100 protein. Staining with antibodies to pancytokeratin AE1/AE3, glial fibrillary acidic protein, and p53 was negative in the cell nests. Based on these findings, the multiple minute foci were diagnosed as paraganglionic cells (PGCs) incidentally detected in the urinary bladder of an elderly woman, in association with UC. Although PGCs are rarely detected in adult human urinary bladder on routine histopathological examination, the possibility of their existence should be kept in mind by pathologists, especially in coexistence with UC. This is the first case of PGCs associated with UC in the human urinary bladder in the English literature.

Peripheral chemoreceptors: postnatal development and cytochemical findings in Sudden Infant Death Syndrome.

The aim of the present study is to give a review of the postnatal development of peripheral chemoreceptors - carotid body, paraganglia, and pulmonary neuroendocrine cells (PNEC) - with implications in Sudden Infant Death Syndrome (SIDS). In the postnatal period, the hypoxic chemosensitivity of the carotid body gradually develops. Changes include proliferation of type I and II cells, increased numbers of dense core vesicles and K+ channels, and modifications of neurotransmitter/neuromodulator and receptor expression. Chromaffin paraganglia show increased expression of nitric oxide synthase and neuropeptides, and increased innervation. Innervation of PNEC develops fully only in the first postnatal period, after which their density falls. The neuropeptides produced by PNEC also changes, with increased expression of calcitonin gene-related peptide and neuropeptide YY and reduced expression of calcitonin and gastrin-releasing peptide. Most of the findings in the carotid body of SIDS victims, i.e., decrease in type I cells and dense cytoplasmic granules, and increase in progenitor cells, indicates immaturity of the carotid body, which may play a role in SIDS in the form of underlying biologic vulnerability. Aorticopulmonary paraganglia hyperplasia and increase of PNEC are also found in SIDS, and may be epiphenomena of alterations of the respiratory function with a pathogenetical role in SIDS. A comprehensive view of the pathogenesis of SIDS should also arise from the integration of peripheral chemoreceptors findings with neuro- and cardiopathologic ones.

Paraganglioma do órgão de Zuckerkandl: relato de caso / Paraganglioma Zuckerkandl's organ: case report

Os autores relatam o caso de uma mulher de 50 anos de idade que procurou auxílio médico referindo aumento do volume abdominal há 8 meses. Negava quaisquer outros sintomas. Tomografia computadorizada do abdome mostrou lesão sólida retroperitoneal medindo aproximadamente 6 por 5,2 cm na região inter-aórtico-caval. A biópsia percutânea da lesão revelou tratar-se de neoplasia indiferenciada compatível com feocromocitoma extra-adrenal. A paciente submeteu-se a laparotomia com resseção completa da lesão. O exame histopatológico do espécime cirúrgico foi compatível com paraganglioma. A paciente está bem e sem evidências de recidiva da doença 9 meses após a operação.

Paraganglia of the gallbladder: a report of two cases with an immunohistochemical study.

Paraganglionic tissues incidentally observed in the gallbladder are presented. The patients, a 51- and a 55-year-old woman, underwent gallbladder resection for chronic cholecystitis with gallstones. Two and one paraganglionic tissues were observed in the subserosal connective tissue of the two gallbladders, respectively. Immunohistochemically, the chief cells were positive for chromogranin A, and the sustentacular cells were positive for S100 protein. Tyrosine hydroxylase (in two of three), dopamine beta-hydroxylase (in one of three), methionine-enkephalin (in two of three), and leucine-enkephalin (in two of three) were also positive in a small amount of the chief cells. These structures, which slightly resembled adrenal medulla or retroperitoneal paraganglia, might be misunderstood as an infiltration of primary or metastatic carcinoma into the subserosal connective tissue.

IGF2 expression is a marker for paraganglionic/SIF cell differentiation in neuroblastoma.

Neuroblastoma is a childhood tumor of the sympathetic nervous system. Observations in the Beckwith-Wiedemann syndrome suggest that sympathetic embryonal cells with an abundant expression of the insulin-like growth factor 2 gene (IGF2) may be involved in the genesis of low-malignant infant neuroblastomas. We have therefore compared the cell type-specific IGF2 expression of the human sympathetic nervous system during early development with that of neuroblastoma. An abundant expression in normal sympathetic tissue was specific to extra-adrenal chromaffin cells, ie, paraganglia and small intensely fluorescent (SIF) cells, whereas sympathetic neuronal cells were IGF2-negative. A subpopulation of neuroblastomas expressed IGF2, which correlated with an early age at diagnosis, an extra-adrenal tumor origin, and severe hemodynamic signs of catecholamine secretion. Histologically IGF2-expressing tumors displayed a lobular growth pattern, and expression was restricted to the most mature and least proliferative cells. Typically, these cells were morphologically and histochemically similar to paraganglia/SIF cells and formed distinct ring-like zones in the center of the lobules around a core of apoptosis-like tumor cells. The similarities found between IGF2-expressing neuroblastoma cells and paraganglia/SIF cells in terms of histological features, anatomical origin, and age-dependent growth suggest a paraganglionic/SIF cell lineage of most infant tumors and also of extra-adrenal tumors diagnosed after infancy. Furthermore, since paraganglia/SIF cells undergo postnatal involution, the same cellular mechanism may be responsible for spontaneous regression in infant neuroblastoma.

Paraganglia of the prostate. Location, frequency, and differentiation from prostatic adenocarcinoma.

In contrast to paraganglia of the urinary bladder, prostatic paraganglia have been largely unreported. Following the discovery of paraganglia in two separate radical prostatectomy specimens, we reviewed 100 randomly selected radical prostatectomy specimens to document the location and frequency of prostatic paraganglia. Twelve additional paraganglia were identified in eight resections, for a total of 14 paraganglia in 10 cases. Most paraganglia were located in or adjacent to lateral neurovascular bundles and, rarely, in lateral prostatic stroma. The size of paraganglia ranged from 0.1 to 1.7 mm (median 0.9 mm). Paraganglia consisted of clusters of cells in patterns that ranged from lobular to diffuse, usually with a prominent stromal vascular component. The cells contained bland oval nuclei and clear cytoplasm, which was often abundant. Occasionally, larger cells with larger nuclei were present. Immunohistochemical stains for chromogranin, neuron-specific enolase, and synaptophysin were positive; those for prostatic-specific antigen were uniformly negative. In one of our cases, histologic similarity was noted between a paraganglion and an adjacent prostatic adenocarcinoma with a "hypernephroid" pattern. Recognition of prostatic paraganglia, with appropriate immunohistochemical stains when necessary, will obviate the possibility of confusing these structures with prostatic adenocarcinoma.

Paraganglia of the urinary bladder. An autopsy study.

This is the first full-scale analysis on the paraganglia of the urinary bladder (PUB) by means of histological examination of a large number of autopsy cases. PUB were demonstrated by routine histology in 51.8% of the cases examined. PUB were present in any portion of the urinary bladder as well as in any layer of its mural structure. Immunohistochemistry revealed strong to moderate positivity for chromogranin A and neuron-specific enolase, respectively. A moderate immunoreactivity for S 100 protein was demonstrated in the sustentacular cells of PUB. There has been a statistically significant male preponderance in the incidence of PUB. Contrary to the general consensus, PUB degenerate very slowly throughout the entire lifetime. Middle-aged and elderly subjects suffering from chronic lung diseases exhibit a statistically significant increase in the incidence of PUB, suggesting chronic hypoxemia as a stimulant for the persistence of PUB.

[Changes in the cardiovascular chemo-baroreceptors as a possible basis for sudden infant death (SIDS)]. / Alterazioni dei chemobarorecettori cardiovascolari quale possible substrato di morte improvvisa del lattante (SIDS).

A male sixty days old infant, dying suddenly, has been diagnosed as sudden infant death syndrome (SIDS). Autopsy visualized plurifocal haematic suffusions, typical for an asphyxial status. Abnormalities were not found in the conduction system, but aorticopulmonary paraganglia hyperplasia with mild inflammatory characters has been noted. The role of aorticopulmonary paraganglia, as baro-chemoreceptors, in the cardiovascular regulation, has been anatomical substrate for explaining a sudden infant death, according to a multifactorial theory of SIDS.

Híbridos de gânglio e paragânglio em coraçäo de chagásico crônico hipertenso: relato de caso / Hybrid ganglion and paraganglion in the heart of a hypertensive patient with chronic Chagas' disease: a case report

No septo interatrial de um paciente chagásico crônico e hipertenso, com ninho de formas amastigotas de T. cruzi na musculatura lisa da veia central da supra-renal, foram encontradas duas estruturas híbridas de gânglio nervoso e paragânglio, nas quais os tecidos nervoso e paraganglionar se fundiram. Além destes, havia mais um paragânglio isolado na gordura interatrial. Exsudato inflamatório constituído por mononucleares foi observado nos gânglios nervosos intracardíacos, nos híbridos de gânglio e paragânglio, no paragânglio e na medular das supra-renais. Embora o exsudato mononuclear pareça relacionado com a tripanossomíase, a abundância de tecido paraganglionar cardíaco pode ter relaçäo com a hipertensäo arterial sistêmica

Cardioneuropathy and extracardiac neural disease.

The pathology of cardiac innervation, both intrinsic and external to the heart (aortopulmonary glomera included), is scarcely known, yet it can be critical to life-threatening disorders in cardiac performance, or to reflexes discharging outside the heart, or both. Evidence has been supplied in cardiac neuroanatomy relevant to cardioneuropathy. The arrhythmogenic potential of imbalanced autonomic input in the heart has been corroborated by histopathologic findings in intrinsic plexuses. In turn, significant neurogenic substrates for cardiomyopathy have not been confirmed. Changes in the extrinsic sympathetic chain (left stellate ganglion) and in the prevailing vagal cardiac plexus were found in subjects with arrhythmias (with long QT interval and ventricular tachycardia/fibrillation, respectively). In myocardial infarction with sudden cardiac death, a complicating mediastinitis often presented and was seen to produce focal inflammation of mediastinal nerve plexus and paraganglia. This can worsen the imbalance in autonomic control of the performance of the heart and interfere with barochemoreflex regulation of the systemic or coronary circulation, or both. Such ill-understood sequelae of infarction as the shoulder-hand, chest pain and Dressler syndromes might also correlate with the newly described neuromediastinitis.

The ultrastructure of hypertrophied paraganglia in aged rats.

The catecholamine-storing cells in the paraganglia of old rats showed structural characteristics common to adrenomedullary and paraganglionic cells of young animals. No sign of degeneration was found. Lipofuscin pigment was observed in most cells. The paraganglia were innervated and well supplied by fenestrated sinusoidal capillaries. Their fine structure suggests active endocrine function. An increase in the total bulk of the paraganglia in old rats suggests that they have a physiological role in senescence.