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A Vascular Lesion with Smooth Muscle Differentiation Presenting as a Coin Lesion in the Lung: Glomus Tumor versus Hemangiopericytoma BROOKE ALT, M.D., WILLIAM E. HUFFER, M.D., AND DEBORAH A. BELCHIS, M.D. A 34-year-old black man presented with an asymptomatic coin lesion in the lung. The diagnosis was narrowed to a differential between glomus tumor and hemangiopericytoma. The authors found that the terminology applied to such tumors in the literature is confusing largely because of lack of consistency in criteria used to establish the diagnosis. The authors propose that the term glomus tumor be reserved for tumors composed of endothelial-lined vascular spaces surrounded by smooth muscle cells. Hemangiopericytoma should be used for similar tumors composed of pericytes with or without other types of perivascular mesenchymal cells. According to these criteria, this case is the third glomus tumor reported in the lung. (Key words: Glomus tumor; Hemangiopericytoma; Smooth muscle cells) Am J Clin Pathol 1983; 80: 765-771 Department of Pathology, University of Wisconsin Clinical Sciences Center and William S. Middleton Veterans Administration Hospital, Madison, Wisconsin, and Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado hemangiopericytoma was favored by some pathologists, we have reviewed the literature concerning this differential diagnosis and present our conclusions herein. Report of a Case A 34-year-old black man was admitted to the William S. Middleton Veterans Administration Hospital in August 1982 for surgical evaluation of a 2-cm solitary nodule in the right upper lobe,firstnoted in December 1980. At that time, the lesion seen on chest x-ray was a round nodular density at the level of the right second costochondral junction. Tomograms did not reveal calcification. The nodule had not changed in size since 1980. Skin testing for tuberculosis, histoplasmosis, and coccidioidomycosis had negative results in 1980 and 1982. In addition, complement fixation was negative for blastomycosis, histoplasmosis, and coccidioidomycosis. A CBC and sedimentation rate were normal, as were pulmonary function tests. The patient had vague complaints of "tightness" in the right upper thorax for six months before admission. There was no history of cough, and the patient denied cigarette smoking, travel, or tuberculosis exposure. The medical history was significant for mental illness (schizo-affective psychosis) over the previous 15 years. The patient was treated with psychotropic medications. Four months before admission the patient underwent bronchoscopy with biopsy, but the specimens obtained were nondiagnostic. Upon the present admission, a thoracotomy was performed. GLOMUS TUMORS AND HEMANGIOPERICYTOMAS were regarded by Stout and Murray as closely related tumors, both derived from pericytes.21,29,30,31 The principle distinguishing feature was an organoid (glomus tumor) or a nonorganoid (hemangiopericytoma) pattern of growth.29 Hemangiopericytomas also were described originally as showing a spectrum of differentiation towards smooth muscle cells,29 which was lacking in glomus tumors.21 Masson earlier had described glomus cells as showing myofibrils by light microscopy.17 Since that time, ultrastructural studies have shown that normal glomera9,10 and glomus tumors1'8""'3,16,20'33,35"37 are composed of perivascular cells with light and electron microscopic features of smooth muscle cells. Some ultrastructural studies of tumors classified by light microscopy as hemangiopericytomas have described perivascular cells similar to normal pericytes,5,7,19,22,28,34 but other studies of similar tumors have described cells showing varying degrees of smooth muscle,15,23,25,26 fibroblastic,3,23 or myofibroblast^23 differentiation as pericytes. In this report we describe a lesion with light microscopic features of a glomus tumor and ultrastructural features of smooth muscle differentiation. Since a diagnosis of Pathologic Findings Gross Received February 25, 1983: received revised manuscript and accepted for publication April 25, 1983. Supported in part by a generous gift of the R. J. Reynolds Industries. Inc., to the Department of Pathology, University of Colorado Health Sciences Center. Address reprint requests to Dr. Huffer: Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado 80262. At surgery, a peripheral nodule in the posterior segment of the right upper lobe was shelled out. The tissue received in surgical pathology consisted of a 2 cm in diameter, round, soft, fleshy, yellow-tan, faintly lobulated mass with a smooth external surface and a smooth, glistening cut surface. Light Microscopy The tumor was fixed in 10% neutral buffered formalin, embedded in paraffin, sectioned at 5 n, and stained with 0002-9173/83/1100/0765 $01.15 © American Society of Clinical Pathologists 765 ALT, HUFFER, AND BELCHIS 766 wis*-- a < i ^ v^rft; <§*>«£ ;*' ,4.*i: i>*i'}m*-^ zAWto" $• (, c • * A.J.C.P. • November 1983 vol. 80. No. 5 CASE REPORTS 767 FIG. 1 (upper, left). Light microscopic photomicrograph showing area of tumor with round to elongate cells surrounding vascular spaces. Hematoxylin and eosin (X70). FIG. 2 (upper, right). PAS-positive material surrounding individual cells with distinct borders. Periodic acid-Schiff(X300). FIG. 3 (lower). Electron micrograph of cells arranged around vascular space (X5.600). < hematoxylin and eosin, periodic acid-Schiff (PAS), Masson trichrome, toluidine blue, the Fontana-Masson stain, and Wilder's reticulum stain by standard technics (AFIP manual). Histologically, the tumor was demarcated sharply, but not encapsulated. A few alveolar septae focally surrounded the mass, but there was not sufficient normal lung parenchyma to determine its relationship to the whole periphery of the tumor. The tumor was composed of cells that were round to slightly oval and were around numerous dilated vascular spaces, some of which had an angular appearance. In some areas, the cells were arrayed closely and dispersed fairly evenly. In other areas there was a loose arrangement with abundant hyalinized stroma (Fig. 1). A reticulum stain showed a definite reticulum membrane between the endothelial cells of the blood vessels and the surrounding cells. In addition, there was abundant reticulum surrounding individual cells as well as small clusters of cells. The nuclei were predominantly round with finely granular chromatin, though in some areas they had a slight spindled configuration. There was a moderate amount of palely staining to slightly eosinophilic cytoplasm, and cell borders were usually very distinct. PAS-positive material surrounded individual cells (Fig. 2). In some areas the cells were separated by abundant hyalinized material, which appeared collagenous by trichrome stain. The latter stain also showed some of the cells to have slightly granular, reddish cytoplasm. Another striking feature of this tumor was the presence of abundant mast cells scattered throughout. Toluidine blue stain showed prominent metachromatic granules in these cells. Fontana-Masson stain for neurosecretory argentaffin granules was negative. No nerve fibers were identified either within or surrounding the tumor mass. Electron Microscopy Formalin-fixed tissue was minced in 2% glutaraldehyde in buffer pH 7.5, postfixed in Os0 4 , and embedded in Epon® 8-12. Thin sections were examined on a Philips electron microscope. Ultrastructurally, the tumor cells were arranged concentrically around round or slightly irregularly shaped vascular spaces continously lined by endothelial cells having the usual characteristics including numerous cytoplasmic filaments, Weibel-Palade bodies, pinocytotic vesicles, and a well-developed endoplasmic reticulum (Fig. 3). Cell junctions between endothelial cells were identified. A basement membrane separated the endothelial cells from the surrounding tumor cells. The tumor cells had round-to-oval nuclei, some of which had an irregular nuclear outline. The chromatin was clumped peripherally, and there was an occasional nucleolus. The cytoplasm contained numerous electrondense attachment bodies around its peripheral membrane. Myofibrils were identified entering these attachments as well as entering randomly placed electron dense bodies within the cytoplasm. A moderate number of pinocytotic vesicles also were identified around the periphery of the cytoplasmic membranes (Fig. 4). Other cytoplasmic organelles included scattered mitochondria, sparse profiles of rough endoplasmic reticulum, only occasional Golgi apparatus and centrioles, and in one cell a structure resembling a cilia. Each cell was surrounded completely by a basal lamina. In addition, there was abundant smudgy, granular material between cells corresponding to the light microscopic areas of hyalinization. In some areas this resembled basement-membrane-like substance. In other areas the stroma was fibrillar or had a periodicity suggesting both closely spaced as well as long-spaced collagen. Numerous mast cells with abundant dense-core granules were scattered throughout the tumor (Fig. 5). Discussion Typical glomus tumors are thought to arise from the glomus apparatus or Suquet-Hoyer canal, an arteriovenous anastomosis associated with both blood flow and temperature control. 410 The tumor has been described as an enlarged "caricature" of the glomus apparatus and regarded by some as a hyperplastic or hamartomatous process rather than a neoplasm.21 Glomus tumors are usually benign, although malignant ones have been reported,16'32 thus supporting the concept that the lesion is a true neoplasm. Although glomus tumors most often occur subcutaneously in the hands and fingers," similar tumors occur elsewhere in superficial and deep soft tissues and visc e r a 1.2,11,14.21 ivt urTa y a n ( j stout suggested that the tumor has its origin in the pericyte of Zimmerman, which might be found anywhere in the body.21 Ultrastructural studies have shown that normal glomus cells 910 and cells of glomus tumors 11112,20-35,36 closely resemble normal smooth muscle cells. They have numerous 768 ALT, HUFFER, AND BELCHIS A.J.C.P. • November 1983 Vol. 80 • No. 5 769 CASE REPORTS FlG. 4. Electron micrograph of cell with pinocytotic vesicles {arrow), dense attachment plaques and cytoplasmic fibrils {bracketed area, left lower area) (X29.700). Insert {upper right) shows prominent dense body in cytoplasm with attached fibrils and basal lamina {between arrows) (X28.500). Insert {lower left) shows higher power of pinocytotic vesicles (X61,200). cytoplasmic myofibrils approximately 40-80A in diameter; condensation plaques on the cytoplasmic membrane and electron-dense bodies within the cytoplasm, both associated with myofibrils; numerous pinocytotic vesicles along the cytoplasmic membranes; and basement membrane and/or abundant osmiophilic basement-membranelike material surrounding individual cells.19 These findings do not rule out a pericytic origin for glomus cells, but they indicate that Stout's original concept that glomus cells were equivalent to Zimmerman's pericytes21 was incorrect. Hemangiopericytomas are vascular neoplasms originally described by Stout and Murray29 as nonorganoid pericytic tumors closely related to glomus tumors. Tumors classified by light microscopy as hemangiopericytomas have shown a wide spectrum of ultrastructural differentiation5'719'22'28,34 leading to confusion in diag- nosing this neoplasm and the statement that pericytes are poorly defined cells.719 Ultrastructural studies by Rhodin 27 have described pericytes as cells with multiple processes surrounding the endothelial cells and enclosed in the endothelial cell basement membranes of capillaries and veins up to 50 n in diameter. They have prominent Golgi and rough endoplasmic reticulum, lysosomal granules, and scattered cytoplasmic filaments not organized into bundles. They have no fusiform dense bodies and only rudimentary plasma membrane attachment zones. They are distinct from "veil cells," which resemble fibroblasts and primitive and mature smooth muscle cells. Cells described as venous pericytes by Kuhn and Rosai had small bundles of fibrils and dense material along the plasma membrane interpreted as the analogue of smooth muscle attachment sites." These cells were distinguished from mature smooth mus- tr^i s- • **£; *><••> S s J t a 5>s •* A ; * FIG. 5. Electron micrograph of mast cell located amidst tumor cells. The latter show numerous attachment plaques and are surrounded completely by basal lamina (X7,500). 770 A.J.C.P. • November 1983 ALT, HUFFER, AND BELCHIS cle cells because of the smaller size of the attachment bodies and fibrils. They seem to correspond to cells defined by Rhodin as primitive smooth muscle cells27 rather than pericytes. From the descriptions above, it is clear that pericytes have their own distinctive ultrastructural features, which do not include extensive smooth muscle differentiation. It seems logical to agree with Kuhn and Rosai15 and others3'5,719-20'22-28 that hemangiopericytomas should be composed at least in part of perivascular cells with characteristics of normal pericytes. What is not clear from the literature is whether hemangiopericytomas are composed solely of pericytes. This is implied by the definition of hemangiopericytomas as a uniform population of cells without myofibrils by light microscopy.6 On the other hand, as mentioned above, several authors have described tumors called hemangiopericytomas, composed of cells with smooth muscle and other types of differentiation. Some of these have been referred to as transitional types between glomus tumors and hemangiopericytomas.15,24 From the discussion above, it is apparent that there is confusion in the literature regarding the diagnosis of glomus tumors and hemangiopericytomas. Because hemangiopericytomas are usually thought to have a worse prognosis than glomus tumors, it is important to attempt to distinguish these as separate entities. We suggest that classification would be simplified if the definition of hemangiopericytoma was broadened to include tumors composed of pericytes, with or without other types of perivascular cells such as immature and mature15-23,25,26 smooth muscle cells, fibroblasts,3 endothelial cells,3 and myofibroblasts.23 This terminology is consistent with and extends Stout's original description of hemangiopericytomas as a class of tumors showing a spectrum of differentiation from pericytes to smooth muscle cells.29 The term glomus tumor would be restricted to neoplasms with endothelial channels surrounded only by smooth muscle cells and lacking pericytes. Transitional tumors such as those described by Stout30 and Kuhn and Rosai15,24 would be classified as hemangiopericytomas. According to the definitions above, our tumor should be diagnosed as a glomus tumor. Three other tracheal tumors 8,13,37 and two other peripheral lung tumors 16,33 also fit this definition of glomus tumor. Though there are at least 24 cases of hemangiopericytoma in the lung,18 we have been unable to find ultrastructural findings to compare with glomus tumors in the tracheopulmonary tree. Acknowledgments. The authors thank G. Reza Hafez, M.D., for his suggestions in preparing this article. Kenneth Powers and Don Walker for their technical assistance, John LeBosquet for his photographic contribution, and Debra Mann and Diane Venden for assistance in preparation of the manuscript. References 1. Almagro UA, Schulte WJ, Norback DH, Turcotte JK: Glomus tumor of the stomach. Histologic and ultrastructural features. Am J Clin Pathol 1981; 75:415-419 2. Appelman HD, Helwig EB: Glomus tumor of the stomach. Cancer 1969;23:203-213 3. Battifora H: Hemangiopericytoma: Ultrastructural study offivecases. Cancer 1973;31:1418-1432 4. Carroll RE, Berman AT: Glomus tumors of the hand. Review of the literature and report of twenty-eight cases. J Bone Joint Surg 1972; 54:691-703 5. Eimoto T: Ultrastructure of an infantile hemangiopericytoma. Cancer 1977;40:2161-2170 6. Enzinger FM, Smith BH: Hemangiopericytoma. Analysis of 106 cases. Hum Pathol 1976; 7:61-82 7. Enzinger FM, Weiss SW: Soft tissue tumors. CV Mosby Co, St. Louis, 1983 8. Fabich DR, Hafez GR: Glomangioma of the trachea. Cancer 1980; 45:2337-2341 9. Fine G, Morales AR: The ultrastructure of the "normal" human glomus apparatus of the nailbed. Abstract. Am J Clin Pathol 1973;60:131-132 10. Goodman TF: Fine structure of the cells of the Suquet-Hoyer canal. J Invest Dermatol 1972; 59:363-369 11. Hamilton CW, Shelburne JD, Bossen EH, Lowe JE: A glomus tumor of the jejunum masquerading as a carcinoid tumor. Hum Pathol 1982; 13:859-861 12. Harris M: Ultrastructure of a glomus tumor. J Clin Pathol 1971; 24:520-523 13. Heard BE, Dewar A, Firmin RK, Lennox SC: One very rare and one new tracheal tumor found by electron microscopy: Glomus tumor and acinic cell tumor resembling carcinoid tumors by light microscopy. Thorax 1982; 37:97-103 14. Kay S, Callahan, WP Jr, Murray MR, Randall HT, Stout AP: Glomus tumors of the stomach. Cancer 1951; 4:726-736 15. Kuhn C, Rosai J: Tumors arising from pericytes. Ultrastructure and organ culture of a case. Arch Pathol 1969; 88:653-663 16. Mackay B, Legha SS: Coin lesion of the lung in a 19-year-old male. Ultrastruc Pathol 1981; 2:289-294 17. Masson P: Le glomus neuromyo-arteriel des regions tactiles et ses tumeurs. Lyon Chir 1924; 21:257-280 18. Meade JB, Whitwell F, Bickford BJ, Waddington JKB: Primary hemangiopericytoma of lung. Thorax 1974; 29:1-15 19. Morales AR, Fine G, Pardo V, Horn RC, Jr: The ultrastructure of smooth muscle tumors with a consideration of the possible relationship of glomangiomas, hemangiopericytomas, and cardiac myxomas. Pathol Annu 1975; 10:65-92 20. Murad TM, vonHaam E, Murthy MSN: Ultrastructure of a hemangiopericytoma and a glomus tumor. Cancer 1968; 22:1239-1249 21. Murray MR, Stout AP: The glomus tumor. Investigation of its distribution and behavior, and the identity of its "epithelioid" cell. Am J Pathol 1942; 18:183-203 22. Newland RC, Maxwell LE, Constance TV, Fox RM: Malignant hemangiopericytoma: Case report and ultrastructural study. Pathology 1978; 10:277-283 23. Nunnery, EW, Kahn LB, Reddick RL, Lipper S: Hemangiopericytoma: a light microscopic and ultrastructural study. Cancer 1981; 47:906-914 24. Osamura RU, Watanabe K, Yoneyama K, Hayashi T: Glomus tumor of the stomach. Light and electron microscopic study with literature review ofrelatedtumors. Arch Pathol Jpn 1977; 27:533539 25. Pena CE: Intracranial hemangiopericytoma. Ultrastructural evidence of its leiomyoblastic differentiation. Acta Neuropathol 1975; 33:279-284 26. PopoffNA, Malinin TI, RosomoffHL: Fine structure of intracranial hemangiopericytoma and angiomatous meningioma. Cancer 1974; 34:1187-1197 27. Rhodin JAG: Ultrastructure of mammalian venous capillaries, venules, and small collecting veins. J Ultrastruct Res 1968; 25:452500 CASE REPORTS Vol. 80 • No. 5 28. Silverberg SG, Wilson MA, Board JA: Hemangiopericytoma of the uterus. An ultrastructural study. Am J Obstet Gynecol 1971; 110:397-404 29. Stout AP, Murray MR: Hemangiopericytoma: A vascular tumor featuring Zimmerman's pericytes. Ann Surg 1942; 116:26-33 30. Stout AP: Tumor Seminar (Case 5). Texas State Med J 1951; 47:559585 31. Stout AP: Tumors featuring pericytes. Glomus tumor and hemangiopericytoma. Lab Invest 1956; 5:217-223 32. Symmers WSC: Glomus tumors. Br Med J 1973; 2:50-51 771 33. Tang CK., Toker C, Foris NP, Trump BF: Glomangioma of the lung. Am J Surg Pathol 1978; 2:103-109 34. Tavassoli FA, Weiss SW: Hemangiopericytoma of the breast. Am J Surg Pathol 1981; 5:745-752 35. Tsuneyoshi M, Enjoji M: Glomus tumor: A clinicopathologic and electron microscopic study. Cancer 1982; 50:1601-1607 36. Venkatachalam MA, Greally JG: Fine structure of glomus tumor: Similarity of glomus cells to smooth muscle. Cancer 1969; 23:1176-1184 37. Waiter A, Vetter JM, Morand G, Philippe E: Tumeur glomique de la trachee. Arch Anat Cytol Pathol 1980; 28:184-190 Fatality Due to Paraquat Intoxication: Confirmation by Postmortem Tissue Analysis SANDRA E. CONRADI, M.D., LAWRENCE S. OLANOFF, PH.D., M.D., AND WILLIAM T. DAWSON, JR., M.D. A brief case report is presented describing a patient who unknowingly ingested a fatal amount of paraquat, presumably mixed in some illicit moonshine alcohol. Despite an initial clinical presentation typical of paraquat intoxication, the herbicide was absent upon analysis of multiple urine and blood specimens, and the diagnosis was comfirmed only postmortem after determination of high paraquat tissue concentrations in all the major organs. Autopsy results are presented along with a discussion of the histopathologic changes observed in the lungs, liver, and kidneys. Because the combination of toxicologic sequelae attributable to acute paraquat poisoning is fairly unique to this agent, the diagnosis must be suspected highly early in the clinical course of such cases and appropriate therapy initiated, despite the inability to isolate paraquat on preliminary laboratory screening. (Key words: Paraquat; Signs and symptoms; Autopsy findings) Am J Clin Pathol 1983; 80: 771-776 PARAQUAT, a bipyridilium herbicide, produces multiple organ system injury in humans. After exposure, by ingestion or by significant skin contact, toxic changes have been demonstrated in the lungs,6,7 kidneys,28 liver,20 heart,4 adrenals,25 central nervous system," skin,30 oral mucosa,26 and esophagus.' Mortality rates following paraquat ingestion have been estimated at 33-50%,2 and fatal cases have been reported resulting from ingestion or by direct exposure of the skin to concentrated solutions of the herbicide.3,21 A report of a fatality secondary to paraquat ingestion is presented. Report of a Case A 39-year-old black man, with a history of 1 pint to 1 quart of alcohol ingestion per day for the last 1 to 2 months, was otherwise in good medical health until six days prior to admission, when he reported Received March 8, 1983; received revised manuscript and accepted for publication May 2, 1983. Address reprint requests to Dr. Conradi: Department of Pathology, Medical University of South Carolina, Charleston, South Carolina 29425. Departments of Pathology, Pharmacology and Pulmonary Medicine, Medical University of South Carolina, Charleston, South Carolina developing acute left lower quadrant abdominal pain, nausea, and vomiting after drinking an unknown quantity of illicit "moonshine" alcohol. On the following day, he developed a severe pharyngitis and began to expectorate small quantities of blood and tissue from the roof of his oral cavity and abruptly ceased urinating. The patient entered a local hospital four days after ingestion of the substance, where his initial examination was remarkable only for glossitis and pharyngitis. Laboratory results at that time are presented in Table 1 (preadmission). Urinalysis demonstrated proteinuria. Chest x-ray was interpreted as consistent with "mild interstitial inflammatory changes." A rudimentary drug screen was sent, which had negative results for acidic, basic, or neutral drug substances. No specific analysis for paraquat was performed. He was transferred to the Medical University Hospital in Charleston on the sixth day following his toxic ingestion, where physical examination revealed an alert, afebrile black man, with a supine blood pressure of 140/ 100 mmHg and a pulse of 92 beats per minute. His sclerae were markedly icteric, and examination of his oral cavity revealed extensive palatal, lingual, and posterior pharyngeal ulcerations covered with clotted blood. Chest examination revealed scattered bibasilar rales and shallow respirations. Abdominal examination was significant for voluntary guarding to the right upper quadrant (with moderate shock tenderness) and liver span of 10-12 cm by percussion. Stool was heme positive by guaiac testing. Laboratory hematologic and chemistry values essentially were unchanged from initial determinations. Arterial blood gas results determined while the patient inspired room air were as follows: pH, 7.42; Po;, 55 mmHg; PCOi, 25 mmHg; serum bicarbonate, 16 mEq/L; and an oxygen saturation, 90%. A repeat chest x-ray demonstrated a bilateral basilar reticular pattern of unknown origin, and repeat serum and urine drug screen was remarkable only for the presence of nicotine. Other pertinent laboratory studies included a negative urine myoglobin, negative Hepatitis B surface antigen, a urinary fractional sodium excretion of 12.3%, and negative urine and blood cultures. An abdominal ultrasound revealed slightly increased kidney size bilaterally, with no obvious obstruction, and normalappearing pancreas and liver. A nasogastric tube was placed to ensure esophageal patency, and intravenous aqueous penicillin G and dexamethasone were started. Because of his acute renal failure and rapidly 0002-9173/83/1100/0771 $01.10 © American Society of Clinical Pathologists