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BACKGROUND: Primary pulmonary paragangliomasare rare tumors. To our knowledge, there is no prior re-port on fine needle aspirationcytology (FNAC) in pul-monary paraganglioma.CASE: A 34-year-old manpresented with an incidental-ly found solitary pulmonarymass. FNAC showed papil-larylike clusters of epithelioidcells with round to oval nu-clei, evenly dispersed chro-matin, micronucleoli and occasional anisonucleosis.These cytologic features were suggestive of a sclerosinghemangioma or bronchioloalveolar carcinoma. A rightlower lobectomy revealed a primary pulmonary paragan-glioma.CONCLUSION: The possibility of pulmonary paragan-

glioma should be considered in the differential diagnosisof FNAC showing pseudopapillary clusters of epithelioid

cells. (Acta Cytol 2001;45:459–464)

Keywords: paragan-glioma, lung neoplasms,aspiration biopsy.

Pulmonary paraganglio-mas are rare tumors. Pul-monary manifestations

of extraadrenal paragangliomas and pheochromo-cytomas are found more frequently than a primarylesion.15,18,19 Only 19 cases of primary pulmo-nary paragangliomas, including the present one,have been reported in the English-language litera-ture.6-8,17,20

From the Department of Pathology, Korea University College of Medicine, Seoul, Korea.

Dr. M. K. Kim is Chief Resident.

Dr. Park is Resident.

Drs. H. D. Cho and S. J. Cho are Fellows.

Dr. A. Kim is Assistant Professor.

Drs. H. K. Kim, Yeom and Choi are Professors.

Dr. C. H. Kim is Associate Professor.

Address reprint requests to: Chul Hwan Kim, M.D., Department of Pathology, Guro Hospital, Korea University College of Medicine, 80Gurodong Gurogu, Seoul, 152-705, Korea (chkap@kumc.or.kr).

Financial Disclosure: The authors have no connection to any companies or products mentioned in this article.

Received for publication June 12, 2000.

Accepted for publication October 19, 2000.

Fine Needle Aspiration Cytology of PrimaryPulmonary ParagangliomaA Case Report

Min Kyung Kim, M.D., Seong Hwan Park, M.D., Hyun Deuk Cho, M.D.,Seong Jin Cho, M.D., Aeree Kim, M.D., Han Kyeom Kim, M.D.,Bom Woo Yeom, M.D., Jong Sang Choi, M.D., and Chul Hwan Kim, M.D.

Acta Cytologica

0001-5547/01/4503-0459/$19.00/0 © The International Academy of CytologyActa Cytologica

Primary pulmonary paragangliomashould be considered in the

differential diagnosis when FNACfindings include papillarylike or loose

clusters of epithelioid cells....

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Fine needle aspiration cytology (FNAC) is ofvalue in the diagnosis of paragangliomas; however,the majority of reported cases have been carotidbody or retroperitoneal extraadrenal paragan-gliomas.2,4,5,9,10 FNAC of a jugulotympanic bodyparaganglioma and a metastatic paraganglioma inthe chest wall were also reported.5 As far as weknow, there has been no report on FNAC of pri-mary pulmonary paragangliomas.

The FNAC findings of a primary pulmonaryparaganglioma are described, with histologic andultrastructural findings, and immunohistochemicalresults.

Case Report

A 34-year-old man was admitted to the Departmentof Psychiatry because of a manic episode. On phys-ical examination, his blood pressure was 110/80mm Hg and heart rate 72 beats per minute. A 3-cm,round mass was incidentally detected in the rightlower lung field on a routine chest roentgenogram(Figure 1). Chest computed tomography (CT)showed a round, intrapulmonary mass; there was

no lymphadenopathy. CT-guided percutaneousFNAC was performed.

The cytologic smears were cellular. Many three-dimensional, papillarylike clusters of epithelioidcells with intervening vascular cores were present(Figure 2). A few clusters forming acini and manyscattered naked nuclei were also noted. The majori-ty of cells had round to oval nuclei. The chromatinwas finely granular and evenly dispersed. The nu-cleoli were small but occasionally conspicuous.Most of the cells had abundant, granular, am-phophilic cytoplasm with indistinct cytoplasmicborders. Some tumor cells showed anisonucleosis(Figure 3). The cell block section showed a fewfragments of round to oval epithelioid cells withcentral vascular cores. A few intranuclear inclu-sions were present (Figure 3, inset).

460 Acta CytologicaKim et al

Figure 1 Chest roentgenogram showing a round, well-circumscribed density in the right lower lung field.

Figure 2 Aspirate showing large, three-dimensional clusters ofepithelioid cells traversed by thin vascularized stroma (Papanicolaou stain, × 200).

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Based on these cytologic findings the lesion wasconsidered to be a papillary lesion, such as a scle-rosing hemangioma or bronchioloalveolar carcino-ma. Lobectomy of the right lower lobe was per-formed. During the operation, the blood pressureand heart rate remained stable. The resected tumorwas a well-demarcated, round, gray-yellow, solidperibronchial mass measuring 3 × 2.8 × 1.7 cm (Fig-ure 4). On probing the bronchial tree, no endo-bronchial lesion was identified.

Microscopic examination demonstrated thetumor to be composed of oval to round cells withabundant eosinophilic or clear cytoplasm arrangedin nests separated by thin, vascular stroma (Figure5). Mitoses were extremely infrequent. The centralportion of the tumor showed hemorrhage, which

could have been the result of fine needle aspiration.The tumor compressed the pulmonary parenchymaand was surrounded by a thin, incomplete, fibrouscapsule. The tumor cell nests penetrated throughthe fibrous capsule and invaded the adjacent lungparenchyma. The tumor had no connection with thebronchial mucosa.

Reticulin stain demonstrated a delicate reticulinnetwork surrounding the tumor cell nests. Im-munohistochemical staining showed diffuse reac-tivity with antisera to neuron-specific enolase, chro-mogranin and synaptophysin. Scattered spindlecells in perivascular areas were reactive with anti-sera to S-100 protein. Only a few scattered spindlecells were reactive with antisera to cytokeratinAE1/AE3. The tumor cells were nonreactive withantisera to epithelial membrane antigen, smooth

Volume 45, Number 3/May–June 2001 461FNAC of Pulmonary Paraganglioma

Figure 4 Right lower lobe of lung with a 3-cm-diameter, well-demarcated, gray-yellow, solid mass.

Figure 3 Aspirate showing tumor cells with anisonucleosis, finely granular and evenly dispersed chromatin, and micronucleoli (Papanicolaou stain, × 400). Inset: a few intranuclear inclusions (hematoxylin and eosin, × 600).

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muscle actin, vimentin, surfactant apoprotein andcarcinoembryonic antigen.

Ultrastructurally, many pleomorphic, mem-brane-bound granules with electron-dense coreswere packed in some dark cells, whereas a few neu-rosecretory granules were scattered betweenswollen mitochondria and smooth endoplasmicreticulum in light cells. The neurosecretory gran-ules were round, oval and comma shaped andshowed a wide diameter range, 125–600 nm.

The microscopic features, immunohistochemicalresults and ultrastructural findings favored the di-agnosis of pulmonary paraganglioma. Becausethere was no evidence of extrapulmonary tumor onabdominal CT and neck sonography, the presentcase was considered a primary pulmonary para-ganglioma. No recurrence occurred during the sub-sequent seven months.

Discussion

Paragangliomas are rare tumors arising from neu-ral crest–derived paraganglionic tissue, which iswidely distributed in the body. Pulmonary para-ganglia are identified in close proximity to bloodvessels and nerves and often are located near thebranching pulmonary artery.12 Based on the pres-ence of genuine pulmonary paraganglia, it is ac-cepted that primary pulmonary paraganglioma ex-ists.

Among the reported 19 cases of primary pul-monary paraganglioma, 15 patients were femaleand 4 male.7,8,13,17 The age range was 18–69 years,and the mean age was 48. Eight patients, includingthe present one, were asymptomatic. Eight patientsshowed pulmonary symptoms, such as cough, dys-pnea, chest pain and pneumonia; two patients hadassociated hypertension, and the remaining casedeveloped Cushing’s syndrome. The tumors werelocated in the right lung in 15 cases and left lung in4. The tumors were solitary masses with a size rang-ing from 1 to 13 cm. Three cases (10.5%) of the re-ported 19 primary pulmonary paragangliomaswere diagnosed as malignant because of lymphnode metastases. There has been no reported localrecurrence in any case after surgical excision orlobectomy.

The cytologic characteristics of paragangliomasinclude loosely cohesive clusters and syncytial tis-sue fragments of medium-sized epithelioid cellswith variable sizes and shapes; a tendency to formacini or follicular structures; round to oval nucleiwith a smooth nuclear membrane; finely granularand evenly dispersed to coarsely granular chro-matin; a moderate amount of granular, am-phophilic cytoplasm with indistinct cell borders;and occasional anisonucleosis and small nucle-oli.4,9,10,14,22

Most of the cytologic features in this case weresimilar to those in previously reported cases ofparagangliomas and adrenal pheochromocytomas.The prominent three-dimensional, papillarylikeclusters of tumor cells were misleading features,suggesting papillary lesions, such as sclerosing he-mangioma or bronchioloalveolar carcinoma. Theepithelioid tumor cells, arranged in nests separatedby thin, vascular stroma, are considered to result inpapillalike clusters from aspiration.

With the above cytologic findings, it is quite diffi-cult to consider the possibility of rare paragan-gliomas in the case of a pulmonary mass. The dif-ferential diagnosis should include carcinoid

462 Acta CytologicaKim et al

Figure 5 Pulmonary paraganglioma. Histologic section showinga tumor cell with a “Zellballen” pattern (hematoxylin and eosin,× 200).

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tumors, sclerosing hemangiomas, bronchioloalveo-lar carcinomas, and metastatic or primary adeno-carcinomas.

Pulmonary carcinoids can present similar cyto-logic and histologic features.1,12 The described cy-tologic features of carcinoid tumor include round tocuboidal cells, isolated or in loose aggregates andoccasionally arranged in cords, trabeculae androsettes. Nuclei are uniform and round, with stip-pled nuclear chromatin, small but prominent nucle-oli, and a small amount of cytoplasm with distinctcell borders. Lack of nuclear molding is a diagnos-tic feature. Minimal cytoplasm, distinct cell bordersand stippled nuclear chromatin were not features ofthis case. Histologically the presence of sustentacu-lar cells, identified by S-100 protein immunostain-ing, and dense-core neurosecretory granules of thechief cell type support the diagnosis of paragan-glioma.

FNAC of sclerosing hemangiomas shows severalpatterns, including abundant papillary or frondlikeexcrescences lined with round to columnar cellswith clear to granular cytoplasm, a flat or pave-mentlike collection of bland cells merging withatypical reactive pneumocytes, blood spaces sur-rounded by aggregates of tumor cells, and tumorcells aligned together, giving a septal configura-tion.3,23 The tumor cells have relatively uniform nu-clei, frequent distinct nucleoli and intranuclear in-clusions. The presence of two cell populations,benign “stromal” cells and atypical reactive alveo-lar or bronchial epithelial cells, and numerous redblood cells and hemosiderin-laden macrophages,which were not found in this case, are also featuresthought to favor a sclerosing hemangioma.3,23

In bronchioloalveolar carcinoma the tumor cellsare frequently in loosely cohesive groups, syncytialtissue fragments, monolayered sheets, or three-dimensional clusters containing closely packed nu-clei in multiple planes of focus.11 Some cases showacini and/or a papillary pattern. Tumor cells aregenerally small, uniform and round to oval, withvariable amounts of secretory vacuoles. They ex-hibit various degrees of nuclear pleomorphism,central to eccentric nuclei, finely granular and even-ly dispersed chromatin, and micronucleoli orprominent macronucleoli. Intranuclear inclusionsare also seen. In this case the papillarylike struc-tures and three-dimensional, cohesive clusters oftumor cells with occasional anisonucleosis resem-bled a bronchioloalveolar carcinoma, whereas theabsence of nuclear atypia or secretory vacuoles sug-

gested a benign neoplasm. However, it was impos-sible for us to rule out the possibility of malignancywhen making a cytologic diagnosis.

Intranuclear cytoplasmic inclusions have beenfound in a variety of tumors, including papillarythyroid carcinoma, malignant melanoma, endome-trial adenocarcinoma, hepatocellular carcinoma,meningioma, carcinoid tumor, sclerosing heman-gioma, bronchioloalveolar carcinoma and some sar-comas.21,23 Intranuclear inclusions have also beenobserved in carotid body paragangliomas,4retroperitoneal paragangliomas,16,21 and adrenalpheochromocytomas.5 Although intranuclear in-clusions are not a diagnostic feature of paragan-gliomas, it may be helpful to know that intranuclearinclusions may be found in pulmonary paragan-gliomas.

In conclusion, primary pulmonary paragan-glioma should be considered in the differential di-agnosis when FNAC findings include papillarylikeor loose clusters of epithelioid cells with highly vas-cularized stroma, occasional anisonucleosis with-out obvious cellular atypia and absence of two cellpopulations, benign stromal and atypical epithelialcells.

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2. Capella C, Riva C, Cornaggia M, Chiaravalli AM, Frigerio B,Solcia E: Histopathology, cytology, and cytochemistry ofpheochromocytomas and paragangliomas includingchemodectomas. Pathol Res Pract 1988;183:176–187

3. Chow LTC, Chan SK, Chow WH, Tsui MS: Pulmonary scle-rosing hemangioma: Report of a case with diagnosis by fineneedle aspiration. Acta Cytol 1991;36:287–292

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