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Background

Paragangliomas are tumors that arise within the sympathetic nervous system, originating anywhere from the neck to the pelvis in locations paralleling the sympathetic ganglion chain. Tumors of both adrenal and extra-adrenal origin are often active secretors of catecholamines and can cause symptoms such as labile hypertension, palpitations, headache, and sweating. Most tumors are benign but about 10% of paragangliomas may metastasize. The pheochromocytoma of the adrenal gland is a paraganglioma.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/Other Diagnostic Testing  
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

EPIDEMIOLOGY CHARACTERIZATION
AGE RANGE-MEDIAN 5-6th decades
SEX (M:F)
10% occur in children

 

DISEASE ASSOCIATIONS CHARACTERIZATION
Multiple endocrine neoplasia type 2 syndrome
(MEN II)
 
STROMAL TUMORS OF THE GASTROINTESTINAL TRACT  
Functioning Paraganglioma and Gastrointestinal Stromal Tumor of the Jejunum in Three Women: Syndrome or Coincidence.

Perry CG, Young WF Jr, McWhinney SR, Bei T, Stergiopoulos S, Knudson RA, Ketterling RP, Eng C, Stratakis CA, Carney JA.

From the Departments of *Medicine (Endocrinology) and daggerLaboratory Medicine and Pathology, Mayo Clinic, Rochester, MN; the double daggerHuman Cancer Genetics Program, Department of Medicine, Ohio State University, Columbus, OH; and the section signSection on Endocrinology and Genetics, Developmental Endocrine Branch, National Institute of Child Health, Bethesda, MD. The current address of Dr. Perry is Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, Scotland, UK.

Am J Surg Pathol. 2006 Jan;30(1):42-49. Abstract quote  

Functioning paraganglioma and gastrointestinal stromal tumor (GIST) are uncommon tumors that occur mostly in a sporadic and isolated form, occasionally as components of multiple neoplasia syndromes, either separately or together. Separately, they occur in several inherited syndromes including multiple endocrine neoplasia 2, and the GIST, lentigines, and mast cell tumor syndrome.

Together, they are variably prominent components of three syndromes: the familial paraganglioma and gastric GIST syndrome, neurofibromatosis type 1, and the Carney triad. The two former conditions are inherited as autosomal dominant traits; the latter does not appear to be inherited and affects young women predominantly. This article reports the nonfamilial occurrence of functioning paraganglioma and GIST of the jejunum in 3 women, 1 young (22 years) at initial presentation. The occurrences were unexpected because of the infrequency of the tumors. The neoplasms, respectively, did not show germline SDHA, SDHB, SDHC, and SDHD, and KIT mutations associated with familial paraganglioma and familial GIST.

The paraganglioma-jejunal GIST combination may be the harbinger of a rare genetic syndrome, a variant of the Carney triad or the paraganglioma-gastric stromal sarcoma syndrome, or be coincidental.

PATHOGENESIS CHARACTERIZATION
APOPTOSIS  


G2M arrest, blocked apoptosis, and low growth fraction may explain indolent behavior of head and neck paragangliomas.

Dekker PB, Kuipers-Dijkshoorn N, Hogendoorn PC, Van Der Mey AG, Cornelisse CJ.

 

Hum Pathol. 2003 Jul;34(7):690-8. Abstract quote

Head and neck paragangliomas are characterized by unusually slow growth and a strong hereditary component, which is associated with inactivating mutations in subunits of complex II of the mitochondrial respiratory chain. It is unclear how mutations induce tumorigenesis and lead to the indolent clinical behavior that often plays a prominent role in treatment strategies.

To better understand the natural course of the tumors, we studied a number of growth-related parameters in 42 hereditary and sporadic paragangliomas. Computerized image analysis showed that the fraction of Ki-67-positive cells was generally below 1%, in accordance with the slow growth. Weak or negative immunohistochemical staining indicated wild-type TP53 status, whereas p-21(waf) expression was heterogeneous. Most tumors showed strong expression of Bcl-x(L), and no apoptotic cells could be detected with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay. Flow cytometry showed abnormal DNA content profiles in 52% of the tumors, including overt aneuploidy as well as G(2)/M arrest or tetraploidization.

These results fit into a model in which a stress-activated cell cycle checkpoint at the G(2) to M transition and inhibition of apoptosis permit the expansion of only a minor fraction of cycling cells with high likelihood of polyploidization.

SPHD GENE  
Mutation analysis of the SDHD gene in four kindreds with familial paraganglioma: description of one novel germline mutation.

Velasco A, Palomar-Asenjo V, Ganan L, Catasus L, Llecha N, Panizo A, Palomar-Garcia V, Quer M, Matias-Guiu X.

Department of Otorhinolaryngology, Hospital Universitari Arnau de Vilanova, University of Lleida, Lleida, Spain.

Diagn Mol Pathol. 2005 Jun;14(2):109-14. Abstract quote

 

 


The familial paraganglioma syndrome is an autosomal dominant disorder characterized by the presence of carotid body paragangliomas and, less frequently, paragangliomas of the glomus jugulare, glomus vagale, and adrenal pheochromocytomas. Germline mutations of the genes for succinate dehydrogenase subunits D, B, or C (SDHD, SDHB, SDHC) have been identified in some kindreds with familial paraganglioma.

In this study, we report the clinicopathologic features of four different kindreds with familial paraganglioma, which were screened for germline mutations in the SDHD gene. DNA was obtained from tumor and normal tissue, as well as from peripheral blood. Mutation analysis was performed by single-strand conformation polymorphism analysis and DNA sequencing. SDHD germline mutations were detected in the affected family members of the four families, as well as in several asymptomatic carriers. An identical mutation in exon 4 of SDHD (334-337delACTG) was identified in two apparently unrelated kindreds. The third family showed a germline mutation in exon 2 (W43X). The mutations present in these three families had been previously described in Spanish families, suggesting a founder effect. The fourth family exhibited a mutation in exon 2 of SDHD (170-171delTT), which had not been previously identified. The affected family members of the four kindreds showed paragangliomas, located in the head and neck region, and all of them were benign.

These results confirm that genetic testing of SDHD may be a powerful tool for the identification of the syndrome in patients with multiple or bilateral paragangliomas.
Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.

Neumann HP, Pawlu C, Peczkowska M, Bausch B, McWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C; European-American Paraganglioma Study Group.

Department of Nephrology and Hypertension, Albert-Ludwigs-University, Freiburg, Germany.
JAMA. 2004 Aug 25;292(8):943-51. Abstract quote

CONTEXT: Germline mutations of the genes encoding succinate dehydrogenase subunits B (SDHB) and D (SDHD) predispose to paraganglioma syndromes type 4 (PGL-4) and type 1 (PGL-1), respectively. In both syndromes, pheochromocytomas as well as head and neck paragangliomas occur; however, details for individual risks and other clinical characteristics are unknown.

OBJECTIVE: To determine the differences in clinical features in carriers of SDHB mutations and SDHD mutations.

DESIGN, SETTING, AND PATIENTS: Population-based genetic screening for SDHB and SDHD germline mutations in 417 unrelated patients with adrenal or extra-adrenal abdominal or thoracic pheochromocytomas (n = 334) or head and neck paragangliomas (n = 83), but without syndromic features, from 2 registries based in Germany and central Poland, conducted from April 1, 2000, until May 15, 2004.

MAIN OUTCOME MEASURES: Demographic and clinical findings with respect to gene mutation in SDHB vs SDHD compared with nonmutation carriers.

RESULTS: A total of 49 (12%) of 417 registrants carried SDHB or SDHD mutations. In addition, 28 SDHB and 23 SDHD mutation carriers were newly detected among relatives of these carriers. Comparison of 53 SDHB and 47 SDHD total mutation carriers showed similar ages at diagnosis but differences in penetrance and of tumor manifestations. Head and neck paragangliomas (10/32 vs 27/34, respectively, P<.001) and multifocal (9/32 vs 25/34, respectively, P<.001) tumors were more frequent in carriers of SDHD mutations. In contrast, SDHB mutation carriers have an increased frequency of malignant disease (11/32 vs 0/34, P<.001). Renal cell cancer was observed in 2 SDHB mutation carriers and papillary thyroid cancer in 1 SDHB mutation carrier and 1 SDHD mutation carrier.

CONCLUSIONS: In contrast with SDHD mutation carriers (PGL-1) who have more frequent multifocal paragangliomas, SDHB mutation carriers (PGL-4) are more likely to develop malignant disease and possibly extraparaganglial neoplasias, including renal cell and thyroid carcinomas. Appropriate and timely clinical screening is recommended in all patients with PGL-1 and PGL-4.

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
General  
VARIANTS  
BRONCHUS  

Gangliocytic Paraganglioma of the Bronchus: A Case Report With Follow-up and Ultrastructural Assessment.

Kee AR, Forrest CH, Brennan BA, Papadimitriou JM, Glancy RJ.
Am J Surg Pathol. 2003 Oct;27(10):1380-5. Abstract quote  

SUMMARY: We report a case of gangliocytic paraganglioma of bronchus. A 54-year-old woman underwent bronchoscopy following two episodes of right lower lobe pneumonia over the previous 5 months with unresolved chest radiographic changes. A computerized tomographic scan showed a right lower lobe endobronchial lesion, and at bronchoscopy there was a mass partly occluding the lumen of the bronchus. The biopsy and subsequent bronchoscopic resection showed a tumor with morphologic, immunohistochemical, and ultrastructural features of paragangliomatous, gangliocytic, and Schwann cell differentiation consistent with a gangliocytic paraganglioma. The lesion was treated conservatively with bronchoscopic resection and laser therapy.

Histopathologic examination of recurrent tumor at 6 months showed features consistent with paraganglioma. Ten months after initial diagnosis, there was no bronchoscopic evidence of residual tumor.

The occurrence of gangliocytic paraganglioma in diverse sites gives cause for the reappraisal of the histogenesis of this fascinating lesion. The variable morphology of this lesion may be an expression of the potential for divergent differentiation of a pluripotent stem cell.
CEREBELLUM  

Cerebellar paraganglioma.

Prayson RA, Chahlavi A, Luciano M.
Ann Diagn Pathol. 2004 Aug;8(4):219-23. Abstract quote  

Paragangliomas arising as primary neoplasms in the intracranial portion of the central nervous system are relatively uncommon and only have been rarely reported.

We report a case of apparent primary paraganglioma arising in the left cerebellar hemisphere in an 11-year-old girl who presented with a 6-month history of headaches. The tumor was marked by a nested architectural pattern (zellballen), delimited by S-100-positive sustentacular cells.

Morphologic and immunohistochemical features of the neoplasm are discussed and literature is reviewed regarding involvement of the central nervous system by paraganglioma.
GALLBLADDER  
Gallbladder paraganglioma: a case report with review of the literature.

Mehra S, Chung-Park M.

Department of Pathology, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio, USA.
Arch Pathol Lab Med. 2005 Apr;129(4):523-6. Abstract quote  

We report a case of gallbladder paraganglioma that was discovered during nonrelated surgery. Retrospective study disclosed a family history of pheochromocytoma.

The occurrence of gallbladder paraganglioma in the presence of family history of endocrine neoplasia supports that gallbladder paraganglioma may indeed occur as a part of the multiple endocrine neoplasm syndrome. Gallbladder paraganglioma is a rare tumor, and so far to our knowledge only 6 cases have been reported in the literature.

Three cases were discovered incidentally during cholecystectomy for cholelithiasis, 2 presented with right upper quadrant pain, and 1 manifested with gastrointestinal bleeding. We herein review all reported cases of paraganglioma of gallbladder and biliary system.
LARYNGEAL TUMORS Arch Pathol Lab Med 1988;112:809-815
ORL 1991;53:220-234
Ann Otol Rhinol Laryngol 1994;103:525-536
Arch Otolaryngol Head Neck Surg 2001;127:565-569
LIVER  


Primary paraganglioma strictly confined to the liver and mimicking hepatocellular carcinoma: an immunohistochemical and in situ hybridization study.

Corti B, D'Errico A, Pierangeli F, Fiorentino M, Altimari A, Grigioni WF.

Pathology Division of the "Felice Addarii" Institute, Department of Oncology and Haematology, Bologna University School of Medicine, Bologna, Italy.

Am J Surg Pathol 2002 Jul;26(7):945-9 Abstract quote

We describe a case of primary nonfunctioning paraganglioma that, unlike any other previously reported case, was strictly confined to the liver and must therefore have arisen on liver parenchyma.

An asymptomatic 46-year-old man was referred to us for laparotomy and a right hemihepatectomy after a preoperative diagnosis of fibrolamellar hepatocellular carcinoma, based on a fine-needle biopsy. An 8-cm resiliently firm, pale gray nodule with a large central area of fibrosis and a thin fibrous capsule was resected. The polygonal eosinophilic tumor cells containing round nuclei lacking nucleoli were arranged in small nests set in a vascularly rich stroma. At immunohistochemistry neoplastic cells were strongly positive for chromogranin A, neuron-specific enolase, synaptophysin, and IGF-II protein; they were negative for keratin, S-100 protein, CD10, vimentin, and smooth muscle actin. In situ hybridization confirmed that, as in other sites, liver paraganglioma can express IGF-II gene. Conversely (and unlike hepatocellular carcinomas), the neoplastic cells did not express albumin mRNA, which was detected only in surrounding hepatocytes.

The clinical course was benign and the patient is well and free of neoplastic disease 9 years after surgery. Knowledge of the entity should avoid possible confusion with hepatocellular carcinoma, especially of the fibrolamellar variety.

LUNG  
Primary paraganglioma of the lung.

Aubertine CL, Flieder DB.

Ann Diagn Pathol. 2004 Aug;8(4):237-41. Abstract quote  

There are few reported cases of primary pulmonary paraganglioma in the pathology literature. Given the historical confusion surrounding bronchial tumors, widespread use of the term "chemodectoma" and classification of these lesions as paraganglioma in an outdated World Health Organization classification of lung tumors, the recognition of tumors arising from paraganglia within the lung has not been accepted by leading authorities.

We present a well-documented case of a primary pulmonary paraganglioma with typical morphologic features and a supporting immunohistochemical profile. The 0.9 cm endobronchial tumor was submucosal and composed of nests of ovoid cells with abundant eosinophilic cytoplasm, cytoplasmic vacuoles, round to oval nuclei with speckled chromatin, and occasional conspicuous nucleoli. The nests of cells were surrounded by thin-walled vascular channels and stellate spindle cells. The ovoid cells showed strong diffuse staining for chromogranin A, synaptophysin, and faint staining for S-100; they were negative for cytokeratin AE1/AE3, Cam 5.2, and epithelial membrane antigen. The stellate spindle cells stained intensely positive for S-100 protein. A critical review of reported cases of pulmonary chemodectomas and paragangliomas in the English literature features few, if any, well-documented examples.

While this exceedingly rare tumor should be discerned from carcinoid tumor, it remains unknown if primary pulmonary paragangliomas behave aggressively like intra-abdominal extra-adrenal paragangliomas, or in a more indolent manner observed with extra-adrenal paragangliomas in other locations.
Primary pulmonary paraganglioma: report of a functioning case with immunohistochemical and ultrastructural study.

Shibahara J, Goto A, Niki T, Tanaka M, Nakajima J, Fukayama M.

Department of Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
Am J Surg Pathol. 2004 Jun;28(6):825-9. Abstract quote  

We describe a case of primary pulmonary paraganglioma, a tumor that has not been reported in sufficient detail in previous literature.

The patient was a 55-year-old woman with hypertension accompanied by an elevated serum norepinephrine level (2651 pg/mL; normal 100-450 pg/mL). Computed tomography revealed a well-circumscribed solid mass, 3.5 cm in diameter, located in the lower lobe of the left lung. In the lobectomy specimen, the tumor had invaded the B8 bronchus and hilar lymph nodes with microscopic metastasis to the mediastinal nodes.

The tumor showed histologic, immunohistochemical, and ultrastructural features of paraganglioma: argyrophilic cells arranged in a nesting (Zellballen) or anastomosing trabecular pattern within an arcuate vascular network. Neoplastic chief cells positive for neuroendocrine markers (CD56, synaptophysin, chromogranin A) were surrounded by sustentacular cells positive for S-100 protein. Neurofilament protein was positively stained, but cytokeratins were totally negative. On electron microscopy, chief cells possessed abundant dense core granules with an eccentric halo ("norepinephrine-type" granules).

The patient's blood pressure began to decline soon after the resection, and her serum norepinephrine promptly returned to almost normal.

On the basis of our experience, our case is a bona fide primary pulmonary paraganglioma, a tumor heretofore subject to considerable skepticism.

Pulmonary Gangliocytic Paraganglioma Case Report and Comparative Immunohistochemical Study of Related Neuroendocrine Neoplasms

Mitsugu Hironaka, etal.

Am J Surg Pathol 2001;25:688-693 Abstract quote

The authors report a case of gangliocytic paraganglioma of the lung, which has not yet been described in a pulmonary neoplasm.

A 75-year-old man underwent right middle and lower lobe lobectomy. A slightly yellowish mass was located at the bifurcation between the lower and middle lobe bronchus, protruding into the truncus intermedius. The neoplastic cells were composed of three cellular elements: uniform endocrine cells in a Zellballen arrangement, large ganglion-like cells within the nests of endocrine cells, and spindle-shaped cells arranged in streams to surround the nests. Each component exhibited the characteristic immunohistochemical properties, which were similar to those of the corresponding neuroendocrine neoplasms: Endocrine cells were positive for CAM 5.2, chromogranin A, and synaptophysin, like carcinoid tumor; ganglion-like cells were positive only for neurofilament, like ganglioneuroma; and spindle-shaped cells were positive for neurofilament and S-100 protein, like paraganglioma. These results agreed with those in gangliocytic paraganglioma of the duodenum.

Pulmonary gangliocytic paraganglioma is similar to that in the duodenum, and is a hamartomatous proliferation of epithelial endocrine and neuronal cells of the bronchus.

NASOPHARYNGEAL  

Nasopharyngeal Gangliocytic Paraganglioma

Prasanna Sinkre, MD, Guy Lindberg, MD, and Jorge Albores-Saavedra, MD

From the Division of Anatomic Pathology, University of Texas Southwestern Medical Center, Dallas.

Arch Pathol Lab Med 2001;125:10981100. Abstract quote

Gangliocytic paraganglioma (GP) is a rare neoplasm described almost exclusively in the gastrointestinal tract, especially the periampullary region. However, several examples have been reported at various sites, including the stomach, jejunum, and appendix.

Herein we report a case of GP involving the nasopharynx. To our knowledge, this is the first report of GP at this site. A 44-year-old woman presented with headaches and symptoms of fullness and pressure related to mass effect. An initial endoscopic biopsy was followed by surgical excision of the nasopharyngeal mass. The triphasic tumor fulfilled the morphologic and immunohistochemical criteria for GP. The histogenesis of GP is uncertain, and the current belief is that it arises from the embryonic ventral pancreas. This concept is based largely on the location of most cases, which is along the embryologic migration route of the ventral pancreas, as well as the expression of pancreatic polypeptide by the tumor. The nasopharyngeal location of our case clearly refutes the pancreatic origin of GP.

We propose that the tumor probably arises from totipotential adult stem cells, which in the right microenvironment differentiate along nonnative cell lineages.

PHEO-CHROMOCYTOMA  
RETROPERITONEAL  
Nonfunctioning retroperitoneal paragangliomas
Am J Surg 1980;139:257-61.
SKIN  
Metastatic paraganglionoma presenting as a scalp nodule J Am Acad Dermatol 2001;44:321-3
SPINAL CORD  

Gangliocytic paraganglioma in cauda equina region with biochemical and neuropathological studies

Llena JF, Wisoff HS, Hirano A.

J Neurosurg 1982;56:2802.
URINARY BLADDER  

Paraganglioma of the urinary bladder: a lesion that may be misdiagnosed as urothelial carcinoma in transurethral resection specimens.

Zhou M, Epstein JI, Young RH.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, and dagger James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Am J Surg Pathol. 2004 Jan; 28(1): 94-100. Abstract quote  


SUMMARY: Paraganglioma of the urinary bladder is a rare tumor with characteristic histologic and immunohistochemical features. However, in our experience, it may be misdiagnosed as urothelial cancer because of 1) its frequent involvement of the muscularis propria; 2) morphology that may suggest urothelial cancer in transurethral resection specimens, particularly if there are artifactual changes induced by that procedure; 3) failure of pathologists to include it in their differential diagnosis when evaluating a bladder tumor; and 4) only a minority of the cases are associated with symptoms that might prompt consideration of the diagnosis.

Distinction between paraganglioma and urothelial cancer is important because of likely different therapeutic options. In this report, we describe our experience with the histopathology of paragangliomas of the urinary bladder with emphasis on the histologic features that have led to their being misdiagnosed as conventional urothelial cancer and, most importantly, those that will help pathologists recognize this rare tumor of the bladder. Fifteen cases of paraganglioma of the urinary bladder were studied, 11 of them consult cases. They affected patients (8 male, 7 female) with a mean age of 49.5 years; only two had symptoms suggestive of the diagnosis, including hypertension during cystoscopy and episodic headache. Three consult cases were submitted with a diagnosis of "transitional cell carcinoma" and 4 with a diagnosis only of "bladder tumor." Histologically, "zellballen" and diffuse patterns were present in 12 (80%) and 3 (20%) of the cases. A delicate fibrovascular stroma was obvious in 14 (93%) cases. Other patterns included irregular nests and pseudorosette formation. Tumor necrosis, significant cautery artifact, and muscularis propria invasion were present in 1 (7%), 3 (20%) cases, and 10 (67%) cases, respectively. All 15 tumors were composed of large polygonal cells with abundant granular cytoplasm. Focal clear cells were present in 3 (20%). The nuclei were mostly uniform, although occasional pleomorphic nuclei were seen in 6 (40%) cases, and 2 (13%) had frequent pleomorphic nuclei. Mitoses were rare overall, and no abnormal mitotic figures were found. The major histologic features that led to misdiagnosis included a diffuse growth pattern, focal clear cells, necrosis, and muscularis propria invasion, with significant cautery artifact compounding the diagnostic problems.

Immunohistochemically, 2 of 2 tumors were positive for neuron-specific enolase, 9 of 10 tumors for chromogranin, and 2 of 3 tumors for synaptophysin; 3 of 3 tumors were negative for cytokeratin and 1of 1 tumor negative for HMB-45.

Paraganglioma of the urinary bladder may be misdiagnosed as urothelial cancer, but a careful search for the characteristic histologic features and, if necessary, supportive immunohistochemical studies, should lead to a correct diagnosis.

 

HISTOLOGICAL TYPES CHARACTERIZATION
General

Solid and often encapsulated
Large cells with eosinophilic cytoplasm in a trabecular or honeycomb pattern, dense fibrous septa, and prominent vascularization
Intratumoral hemorrhage common
Intracellular eosinophilic granules are present and may become as large as the nucleus

Mitotic activity is rare in benign and malignant tumors and both may have large, bizarre-shaped cells

VARIANTS  
GANGLIOCYTIC

Am J Clin Pathol 1989;92:19.
Hum Pathol 1986;17:11517.
Cancer 1971;27:6170.
Am J Surg Pathol 1977;1:20716.
Am J Surg Pathol 1985;9:3141.

Consists of three kinds of neoplastic cells: neuroendocrine cells, ganglion-like cells, and neuroid spindle cells

Occurs almost exclusively in the second portion of the duodenum

Contains many endocrine cells that are positive for pancreatic polypeptide, it is considered to represent a hyperplastic or neoplastic proliferation originating from the ventral primordium of the pancreas

Duodenal gangliocytic paraganglioma has also been reported in the jejunum and stomach

Duodenal gangliocytic paraganglioma: a radiological-pathological correlation.

Plaza JA, Vitellas K, Marsh WL Jr.

Department of Pathology, The Ohio State University Medical Center, Columbus, OH 43210, USA.
Ann Diagn Pathol. 2005 Jun;9(3):143-7. Abstract quote  

Duodenal gangliocytic paraganglioma is a rare tumor that characteristically occurs in the second portion of the duodenum and typically presents with gastrointestinal bleeding.

Gangliocytic paragangliomas have a characteristic triphasic microscopic appearance with epithelioid cells, spindle cells, and ganglion cells, resulting in a complex histology with features of paraganglioma, carcinoid, and ganglioneuroma. Duodenal gangliocytic paragangliomas have an excellent prognosis after surgical resection but metastatic spread to regional lymph nodes and recurrence may rarely occur.

We report a case of duodenal gangliocytic paraganglioma and discuss the radiological and pathological differential diagnosis of this rare entity.
SCLEROSING  
Sclerosing Paraganglioma: Report of 19 Cases of an Unusual Variant of Neuroendocrine Tumor That May Be Mistaken for an Aggressive Malignant Neoplasm.

Plaza JA, Wakely PE Jr, Moran C, Fletcher CD, Suster S.

From the *Department of Pathology, Ohio State University Medical Center, Columbus, OH; daggerDepartment of Pathology, the University of Texas M.D. Anderson Cancer Center, Houston, TX; and the double daggerDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.



Am J Surg Pathol. 2006 Jan;30(1):7-12. Abstract quote  

Nineteen cases of a distinctive variant of paraganglioma characterized by extensive collagen deposition resulting in a pattern of growth that resembled an invasive malignant neoplasm are described. The patients were 3 men and 16 women, 32 to 69 years of age (mean, 50.5 years). The tumors were located in the carotid body region, parapharyngeal region, and mediastinum.

Tumor size ranged from 2 to 6 cm in greatest diameter. Grossly, the tumors were described as rubbery to firm, tan-red, and with extensive areas of sclerosis.

Histologic examination showed nests and cords of tumor cells separated by broad bands of fibrous tissue. The tumor cells ranged from round to polygonal with abundant cytoplasm to elongated spindle cells with scant cytoplasm. Nuclear cytomegaly was present focally enhancing the atypical appearance of the tumor cell population in 17 cases. Mitoses were sparse (<1 x 10 HPF), and there was no evidence of necrosis in any of the cases. Foci of vascular and perineural invasion were present in 2 and 4 cases, respectively. The most striking morphologic feature was the presence of irregular cords and bands of hyalinized fibrous tissue that compartmentalized the lesion into irregular nests, islands, or cords of tumor cells, imparting them with an infiltrative appearance. All the tumors showed positive immunostaining for chromogranin, synaptophysin, and monoclonal neuron specific enolase. S-100 protein stains identified a sustentacular cell network, whereas cytokeratin AE1/AE3 was negative in all cases. Clinical follow-up in 14 cases, ranging from 2 months to 20 years (mean follow-up, 6.6 years) showed evidence of local recurrence in 2 cases and the development of a separate tumor in the contralateral neck in 1 case. The remainder of patients were free of recurrence or metastasis following simple local excision. Because of the prominent sclerosis, a diagnosis of an invasive malignant neoplasm was initially considered in the majority of cases.

Sclerosing paraganglioma should be included in the differential diagnosis of sclerosing lesions of the head and neck region and mediastinum. Appropriate immunohistochemical stains may be of aid for establishing the correct diagnosis.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE
CHARACTERIZATION
Immunoperoxidase Positive for S-100 in sustentacular cells
Chief cells positive for chromogranin, synaptophysin, and neuron-specific enolase proteins.
  Chief cells negative for cytokeratin, CEA, calcitonin, and S-100


The role of calretinin, inhibin, melan-A, BCL-2, and C-kit in differentiating adrenal cortical and medullary tumors: an immunohistochemical study.

Zhang PJ, Genega EM, Tomaszewski JE, Pasha TL, LiVolsi VA.

Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19147, USA.

Mod Pathol. 2003 Jun;16(6):591-7. Abstract quote

Morphologic distinction between adrenal cortical and medullary tumors can be difficult. Previous studies have shown inhibin, melan-A, and BCL-2 to be useful markers for adrenal cortical tumors.

We have recently observed a high level of calretinin expression in normal adrenal cortex but not the medulla and therefore evaluated its diagnostic application for adrenal tumors in comparison with inhibin, melan-A, and BCL-2. C-kit is a transmembrane tyrosine kinase receptor. Immunodetection of c-kit expression has been recently used for tumor diagnosis, and c-kit-positive tumors can potentially benefit from kit kinase inhibitor treatment. Although c-kit expression was reported in adrenal medulla and pheochromocytoma, it has not been evaluated in adrenal cortical tumors.

In this study, 28 adrenal cortical tumors (12 carcinomas, 16 adenomas), 20 pheochromocytomas, and 20 extraadrenal paragangliomas were evaluated for calretinin, inhibin, melan-A, BCL-2, and c-kit expression by standard immunohistochemical assays on paraffin sections. The percentage of immunoreactivity in adrenal cortical tumors was as follows: calretinin, 96%; melan-A, 89%; inhibin, 92%; BCL-2, 20%; and c-kit, 5%. Normal adrenal medulla did not stain for c-kit but was positive for BCL-2. Eighty-six percent of pheochromocytomas stained for BCL-2 and none for calretinin, with the exception of the ganglioneuromatous areas in composite pheochromocytomas (n = 5). Extraadrenal paragangliomas showed reactivity with calretinin in 25%, melan-A in 5%, inhibin in 16%, BCL-2 in 38%, and c-kit in 8% of the cases.

Our results indicate that calretinin is the most sensitive among all the adrenal markers tested. Like melan-A and inhibin, calretinin is also a very specific marker in differentiating cortical from medullary adrenal tumors. In addition, calretinin can be used to confirm a composite pheochromocytoma. BCL-2 does not appear to be useful in differentiating adrenal cortical from medullary tumors. C-kit is not useful in the diagnosis of adrenal tumors, and kit kinase inhibitor might have a limited role in the treatment of adrenal tumors and paraganglioma because of the low frequency of c-kit expression in these tumors.

NESP-55  
Neuroendocrine Secretory Protein-55 (NESP-55) Expression Discriminates Pancreatic Endocrine Tumors and Pheochromocytomas From Gastrointestinal and Pulmonary Carcinoids.

Srivastava A, Padilla O, Fischer-Colbrie R, Tischler AS, Dayal Y.

*Tufts-New England Medical Center, Boston, MA; and daggerDepartment of Pharmacology, University of Innsbruck, Innsbruck, Austria.

Am J Surg Pathol. 2004 Oct;28(10):1371-1378. Abstract quote  

Neuroendocrine secretory protein-55 (NESP-55), the latest addition to the chromogranin family, is a product of a genomically imprinted gene transcribed exclusively from the maternal allele. Initial studies have shown it to have a less widespread distribution than that of chromogranin A in normal tissues. It has also been suggested that NESP-55 may be a marker of neuroendocrine tumors differentiating toward the adrenal chromaffin and pancreatic islet cells. Metastatic gastrointestinal and pulmonary carcinoids may occasionally be difficult to distinguish from pancreatic endocrine tumors (PETs) and pheochromocytomas on morphologic grounds alone.

We studied neuroendocrine tumors from these sites to see if NESP-55 expression could reliably discriminate pulmonary and gastrointestinal carcinoids from neuroendocrine tumors arising in the pancreas or the adrenal medulla. Sixty-three neuroendocrine tumors positive for one or more immunohistochemical marker of neuroendocrine differentiation (chromogranin A, chromogranin B, synaptophysin, secretogranin II, neuron-specific enolase) were selected for the study and consisted of 34 typical carcinoids (15 pulmonary, 11 ileal, 4 gastric, and 4 rectal), 19 PETs, and 10 pheochromocytomas (4 sporadic, 3 MEN-2, 2 neurofibromatosis type 1, and 1 VHL). All cases were stained for NESP-55 after microwave antigen retrieval using a rabbit polyclonal antibody at a dilution of 1:1000. Sections of normal adrenal medulla were used as positive controls for NESP-55 staining. Negative controls consisted of omission of primary antibody and replacement with normal rabbit serum at an equivalent concentration. NESP-55 immunoreactivity was seen as brown finely granular cytoplasmic staining with prominent perinuclear accentuation. All gastric and ileal carcinoids studied were completely negative for NESP-55. One of four rectal and 1 of 15 pulmonary carcinoids showed focal positivity for it in less than 5% of tumor cells.

In contrast, all 10 pheochromocytomas and 14 of 19 PETs showed strong immunohistochemical staining in a variable proportion of tumor cells. Diffuse positivity (>75% of tumor cells) was seen in 6 of 14 PETs and 8 of 10 pheochromocytomas.

Our results indicate that, in contrast to the other granins, NESP-55 reactivity is restricted to endocrine tumors of the pancreas and the adrenal medulla. Immunohistochemical expression of NESP-55 may thus be useful in assigning a pancreatic or adrenal origin to metastatic endocrine tumors of unknown orgin.
PROLIFERATION MARKERS  


KI-67 AND hTERT Expression Can Aid in the Distinction between Malignant and Benign Pheochromocytoma and Paraganglioma.

Elder EE, Xu D, Hoog A, Enberg U, Hou M, Pisa P, Gruber A, Larsson C, Backdahl M.

Departments of Surgery (EEE, UE, MB), Molecular Medicine (EEE, CL), Oncology and Pathology (EEE, AH, PP), and Medicine, Division of Haematology (DX, MH, AG), Karolinska Hospital, Stockholm, Sweden.

 

Mod Pathol 2003 Mar;16(3):246-55 Abstract quote

The clinical and histopathological distinction between benign and malignant pheochromocytomas and paragangliomas is difficult, and reliable diagnostic markers are lacking.

Here we have evaluated the prognostic value of human telomerase reverse transcriptase (hTERT) gene expression detected by reverse transcription PCR (RT-PCR); telomerase activity (TA) measured by TRAP (telomeric repeat amplification protocol) assay; immunohistochemical staining for Ki-67/MIB-1; and the mRNA expression of matrix metalloproteinase (MMP)-2 and EMMPRIN (extracellular matrix metalloproteinase inducer) analyzed by in situ hybridization in 32 primary pheochromocytomas or abdominal paragangliomas. hTERT was expressed in 7/11 malignant tumors (defined as presence of metastasis and/or extensive local invasion) as compared with in 2/21 benign tumors.

All of the benign tumors showed <1% proliferative activity, as measured by Ki-67/MIB-1 staining. In all three patients with malignant tumors who developed metastases and/or invasive local recurrence during follow-up, the tumors were positive for either hTERT expression or Ki-67/MIB-1 immunoreactivity. TA was not a significant discriminator between benign and malignant tumors, and the value of EMMPRIN and MMP-2 as predictive markers was limited.

In conclusion, the findings imply that the combined use of Ki-67/MIB-1 and hTERT, in addition to histopathology, provides a highly specific tool to identify benign pheochromocytoma and abdominal paraganglioma cases that are not at risk of developing recurrent or metastatic disease.

 

PROGNOSIS AND TREATMENT CHARACTERIZATION
PROGNOSIS

Malignant potential is defined after a metastatic lesion or direct invasion is found in a site with no residual embryonic paraganglionic tissue

No reliable histologic criteria to predict malignant tumors

Metastasis Bones, liver, lung, and central nervous system
  10% of paraganglionomas arising within the adrenal gland
  Greater than 24% for extra-adrenal origin
TREATMENT Conservative surgical excision

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