Malignant Granular Cell Tumor

Path. Res. Pract. 172,384-393 (1981)

Case Report

Department of Pathology II, Umverslty of Goteborg, Sweden

Malignant Granular Cell Tumor A Clinico-Pathologic and Ultrastructural Study of a Case L.-G. KINDBLOM and K.-M. OLSSON

Summary The chmcal and light- and electron-microscopic features of a malignant granular cell tumor m a 64-year-old man are reported. The ultrastructural appearance, with abundance of cytoplasmic "phagosomes", may help m the differential diagnosIs. The light-microscopIC fmdmgs and some ultrastructural observatIOns support the suggestIOn that the tumor ongmated from penpheral nerves, and that a close relatIOnship eXists between malignant granular cell tumors and malignant Schwannoma.

Introduction The granular cell tumor, also known as granular cell myoblastoma and AbrikossoH's tumor, is a rare tumor which occurs in all ages and m many locations, includmg the tongue, skin, vulva, breast, larynx, bronchus, oesophagus, stomach, appendix, rectum, uterus, and soft tissues (Ackerman and Rosai, 1974). The tumors are usually small and solitary, although multiplicity of lesions has occasionally been described (Vance and Hudson, 1969). The great maJority of granular cell tumors are benign. However, recurrences after local eXCision are not infrequent. Spontaneous regression of tumors has also been reported (Vance and Hudson, 1969). Malignant metastasizmg granular cell tumors seem to be exceedingly rare. Most cases reported in the literature as mahgnant granular cell tumors or myoblastomas are in reahty examples of alveolar soft part sarcomas (Ackerman and Rosa!, 1974).

Malignant Granular Cell Tumor' 385

In a reView of the hterature, Cadotte (1974) found 22 well-documented malignant granular cell tumors. Smce then a further three cases have been described (USUl et at., 1977; Haustein, 1974; Magon and Szegvan, 1973). Ultrastructural studies of several bemgn granular cell tumors (Fisher and Wechsler, 1962; Moscovic and Azar, 1967; Chnst and Ozzello, 1971; Rosenbloom et at., 1975), and a few malignant ones (Al-Sarraf, 1971; Magon and Szegvari, 1973; USUl et at., 1977) have charactenstically revealed a complex cytoplasmic structure dominated by lysosomes and "phagosomes" with varying contents. The histogenesis of both the benign and the rare malignant granular cell tumor has been debated and an origin from smooth muscle cells, fibroblasts and histiocytes, and Schwann cells has been proposed (Strong et at., 1970). Several examples of both bemgn and malignant granular cell tumors ongmating from nerve structures have been descnbed (BudztlovlCh, 1968; Rosenbloom et at., 1975; Eason et at., 1977; Usui et at., 1977) and most electronmicroscopic studies have favoured a Schwann cell origin. The present paper reports the clinical and light- and electron-microscopic features of a mahgnant granular cell tumor which recurred repeatedly and metastasized to lymph nodes. A neural origm of this tumor is mdlCated by the morphologic observations.

Case-Report A 64-year-old man WIth a prevIOus hIstory of rIckets In 1914, tuberculosIs of the L III-L V vertebrae In 1926 and atrIal fIbrIllatIon In 1967, noted In December 1976 a slowly grOWIng mass In hIs left cheek. In AprIl 1977 he sought medIcal care for thIS at a county hospItal, where the tumor was extIrpated together WIth the superfIcIal part of the parotId gland The pathologIcanatomIC dIagnosIs was "myoblastoma" and the tumor was consIdered to be benIgn. At control In February 1978, a recurrence was dIscovered deep to the anterIor part of the scar, and enlarged lymph nodes were found on the left SIde of the neck. A bIopsy from thIS recurrence was dIagnosed as "mahgnant myoblastoma", and fIne needle aspIratIOn from lymph nodes revealed metastasIS. The patIent was then refered to the ENT department at Sahlgren's hospItal, Goteborg. A WIde local eXCISIon of the tumor area, IncludIng the left submandIbular regIOn, lymph nodes, and branches of the facIal nerve, was performed. Three months later a new recurrence, 2 cm In dIameter, appeared under the mandIble edge and was extIrpated. At follow-up In October 1979, the patIent was well and there were no SIgns of recurrence or metastasIS.

Pathology HIstologic methods The operatIon speCImens were fIxed In 4 percent formaldehyde solutIOn, and embedded In paraffIn. FIve mIcron thIck sectIOns were staIned accordIng to the hematoxylIn - van Gleson

386 . L.-G. Kmdblom and K.-M. Olsson method, with hematoxylm - eosm, with the PAS-method (McManus) and with Masson\ trIchrome. Luxol fast blue was used to demonstrate the myelIn sheaths of perIpheral nerves, and Silver Impregnation, accordmg to the method of Palmgren, was used to study the axons. For electron-microscopy, about 1 mm large pieces of formaldehyde-fixed tumor tissue were washed m 0.1 M sodIUm cacodylate buffer for 24 hours, fixed for 3 hours mice-cold 1 percent OS04 m cacodylate buffer, pH 7.2, dehydrated m ethanol, embedded m Epon 812 and cut m an LKB Ultrotome III. One-mICron thick sections were stamed With tolUldme blue. Ultrathm sllvergrey sectIOns, placed on copper grIds, were stamed With uranyl acetate and lead citrate, and exammed and photographed m a PhilIps EM 400 electron microscope.

Light-microscopic appearance

The tumor was composed of rounded, oval or spindle-shaped cells arranged in solid cords and interlacmg fascIcles, enclosed by delicate fIbrous strands. In some areas the tumor cells formed pseudo alveolar structures, but there were no distinct glandular formatIOns. The cellular appearance vaned within different parts of the tumor: m some areas the tumor cells were rounded or polygonal, fairly umform in SIze, with central, rounded nucleI with one or two dIstmct nucleoli (Fig. 1), while in other areas there was a prominent cellular and nuclear polymorphism, includmg tumor gIant cells WIth one or more large, hyperchromatic nuclei. MitotIC figures were abundant in the polymorphic areas. The cytoplasm of the tumor cells was granular and stained acidophilIc WIth hematoxylin and eosm, pale pink with the PAS-method and brick red with Masson's trichrome stam.

Fig. 1. Granular tumor cells With hyperchromatic central nuclei formmg solId cords separated by delIcate collagen strands. H & E. X 225.

Mahgnant Granular Cell Tumor . 387

FIg. 2. Nerve fascIcles outsIde the tumor mass shoWIng broad sheaths of granular polymorphous tumor cells wIthIn the perIneUrIum. H & E. A X 90, B X 180

Several bundles of penpheral nerve fascicles of up to 5 mm m dIameter were seen to run mto the tumor. These nerve fascIcles outsIde the tumor mass exhibited an mtact penneurium whICh, m many areas, enclosed single or groups of granular, polymorphIC cells SImIlar to those m the tumor (Figs. 2 and 3). In many nerves these cells formed a cuff enclosmg central mtact nerve fascicles. In some nerves the tumor tIssue occupied most of the cut-surfaces, whIle others revealed only a few large, polymorphIC and granular cells beneath the perineurium (FIg. 4). Several nerve fascIcles of varying size were also seen wIthm the tumor mass. The nerve fascicles outsIde and wIthm the tumor appeared to be partly demyelilllzed. In the penpheral part of the tumor mass foci of inflammatory cells, mostly lymphocytes, were seen. The tumor lacked a delimiting capsule and mfIltrated the surrounding muscle and adIpose tIssue. The recurrences had the same morphologIcal appearance as the pnmary tumor, as dId the lymph node metastasIS.

388 . L.-G. Kmdblom and K.-M. Olsson

Fig. 3. Detali showmg the mtlmate relation between the nerve structures (nght) and the tumor cells (left). H & E. X 225.

Fig. 4. A nerve outside the tumor mass showmg occasIOnal granular and moderately polymorphous cells at the penphery beneath the permeunum. A mitotiC figure IS marked With an arrow. H&E. x 225.

Electron-mIcroscopic appearance

The ultrastructural exammation was hampered by the fact that only forma1m-fixed tumor tissue was avaIlable. Although the cytoplasmic membranes were often dIsrupted, most cytoplasmic and nuclear structures were fairly well preserved. The hIghly cellular tumor tIssue revealed closely associated cells with only scant intercellular substance, containing a few collagen and retIculIn fibers. The tumor cells were relatively large, rounded or polygonal, WIth usually a single and rarely two nuclei. The nucleI, often centrally located, vaned in shape from rounded to Irregular and indented, and showed heterochromatin clumps condensed at the periphery, and one or two nucleolI (FIg. 5). The cytoplasm had a complex appearance. It was to a large extent hlled WIth

Mahgnant Granular Cell Tumor . 389

fig. 5. Tumor cell with a central, small nucleus With condensed chromatm penpherally and a nucleolus. The cytoplasm has a complex vacuolar structure. x 8,000. Inserted IS a detail of the cytoplasmIC membrane enclosed by basallammar structure x 20,000.

"phagosomes", which were limIted by dIStIllct membranes and contained very variable structures: numerous small veSIcles, osmIOphilic lIpId-like material, so-called myelin figures, finely granular structures and condensed material which could be recognized as the rough endoplasmic reticulum (RER) and mItochondna (Fig. 6). Between these "phagosomes" there were mitochondna, some of which contained dense, irregular matncal bodies and dIssolved cnstae. The RER was relatively sparse, while free nbosomes and polysomes were abundant and often intImately associated WIth the "phagosomes". Distinct

390

L.-G. Kmdblom and K. -M. Olsson

Fig. 6. Membrane-bound partly coalescmg "phagosomes" filled with vesicles, lammated structures, condensed RER and granular material. X 25,000.

Golgi zones were not seen. Complexes of dense granulae of a size and arrangement compatible with glycogen were found both Within and outside the "phagosomes". Some delicate cytoplasmic filaments were arranged III whirls. Included Within or closely associated With some cells, there were membranebound structures containlllg microtubular formations, fine filaments and vesicles which to some extent resembled non-myelinated axons. No myelinated axons were demonstrated. The cytoplasmic membranes were often disrupted and III some areas with intact cytoplasmic membranes basement membranelike matenal was seen to partly enclose the tumor cells (Fig. 5).

Malignant Granular Cell Tumor

391

Discussion The pnmary tumor In the present case was ongInally considered to be a "myoblastoma". The solId sheaths and anastomosing cords of fairly large, rounded or polygonal cells With aCidophilic and granular cytoplasm and centrally located, rounded nuclei, favored this diagnosIs. SInce the tumor was pnmarily considered to be bemgn, the promment cellular and nuclear polymorphism and mitotIC activity evident m some areas of the Infiltrating tumor was probably not recognized. The maltgnancy of the tumor was first recogmzed at the time of the first recurrence, and defImtely proved by lymph node metastasis. It has previously been stressed by some authors that there do not seem to be any distinct histologic features which are of help for recogmZIng the rare malignant examples of this entity (Gamboa, 1955). However, the polymorphism and mitotic activity, IncludIng some polyploid mItotIC figures,obvious at least In some areas of the pnmary tumor, would hardly be seen in bemgn granular cell tumors. Some of the early reports on metastaslZlng granular cell tumors described an "organoid" or alveolar pattern at Itght-mlcroscoplc examination. These tumors seem to fulftl the histologic cntena for alveolar soft part sarcoma, which was descnbed and defined as an entity In 1952 by Chnstopherson and coworkers. The granular cell tumors and alveolar soft part sarcomas show some slmilanties: the tumor cells of both tumors are granular and partly PASpositive. Moreover, pseudo alveolar structures may be seen In granular cell tumors. However, distInct alveolar patterns, as seen in the alveolar soft part sarcoma, are not found in granular cell tumors, neither are the charactenstIc rod-shaped PAS-positive cytoplasmic granulae whICh, ultrastructurally, correspond to membrane-bound rhomboid crystals (Unni and Soule, 1975). The present tumor grew In the cheek, partly In close viclmty to but not m direct contact with the parotid gland. This locatIOn, the occasIOnal pseudoalveolar structures and the plcrinophlltc cytoplasm of the tumor cells, raised the possibility of a malignant oncocytoma of the parotid gland. The electronmicroscopic examInation, although performed on material not primanly preserved for this study, helped to exclude thiS posslbiltty and confirmed the diagnosis of a granular cell tumor. Oncocytomas of salivary glands usually demonstrate, at least partly, a glandular pattern and, ultrastructurally, the cytoplasm IS filled with mitochondna (Chnstopherson, 1949; Balogh and Roth, 1965; Bazak-Malik and Gupta, 1968). Ultrastructurally, the tumor cells In the present case were characterized by the abundance of cytoplasmIC "phagosomes" of van able size, often contaming so-called myelin figures and remnants of organelles. These cytoplasmic features are very slmtlar to those in prevIOusly reported benign and malIgnant

392 . L.-G. Kmdblom and K.-M. Olsson

granular cell tumors (Moscovic and Azar, 1967; Magori and Szegvari, 1973; Rosenbloom et aI., 1975; Usui et aI., 1977). The concept of a Schwann cell origm has previously gained support from hIstologic and ultrastructural observations (Fisher and Wechsler, 1962; AISarraf et aI., 1971; USUl et aI., 1977). The light-microscopIc observations in this case favor a neural ongin for thIS tumor. Thus, there were small groups or large solId cords of granular tumor cells, some of which were polymorphic and 10 a state of mitosis, situated withm fairly large nerve fascicles outsIde the main tumor mass. Furthermore, there were several nerve fascIcles of vanable SIze withm the tumor mass. The ultrastructural findings in this case are in several respects similar to those described 10 so-called phagocytic forms of Schwann cells (Welser, 1978). Myelinated axons were not demonstrated wlthm the tumor but occasIOnal axon-like, non-myelinated structures were seen, and segments of basallamma enveloped some tumor cells, further supportmg a Schwann cell origin. Granular cell tumors have previously been reported to anse 10 nerves, such as the radIal nerve (Usui et aI., 1977), the vagus nerve (BudzIlovich, 1968) and the thoraCIC sympathetic nerve cham (Rosenbloom et aI., 1975). Malignant tumors of Schwann cell origin have been reported to show variegated hIstologic patterns and several subtypes have been reported, such as malignant epitheliOId Schwannoma (Harkm and Reed, 1969; Alvira et aI., 1976), malignant Schwannoma WIth rhabdomyosarcomatous dIfferentiatIOn (malignant "Tnton" tumor) (Woodruff et aI., 1973), maltgnant mesenchymoma of nerve sheath (Harkin and Reed, 1969) and malignant Schwannoma with epithelial elements (MIChel, 1967). The light- and electron-microscopic observatIOns in the present case and previous reports suggest a close relatIOnship between malignant granular cell tumors and maltgnant Schwannoma.

References Ackerman, L. V., and Rosal, J.: Granular cell tumor. In: Surgical Pathology, Fifth edmon, pp. 1156-1157, C. V. Mosby Company, St. LoUIS 1974 AI-Sarraf, M., Loud, A. V., and ValtkeVIClUs, V. K.: Mahgnant granular cell tumor: histochemical and electron microscoPIC study. Arch. Path. 91. 550-558 (1971) Alvlra, M. M., Mandybur, T. I., and Menefee, M. G.: Light mICroscopIc and ultrastructural observations of a metastaslzmg mahgnant eplthehOid Schwannoma. Cancer 38, 1977-1982 (1976) Balogh, Jr., K., and Roth, S. I.: Histochemical and electron microscoPIc studies of eosmophtllc granular cells (oncocytes) m tumors of the parotid gland. Lab. Invest. 14,310-320 (1965) Bazak-Mahk, G., and Gupta, D. N.: Metastaslsmg (malignant) oncocytoma of the parotid gland. Zeltschr. Krebsforsch. 70, 193-197 (1968) Budzllovlch, G. N.: Granular cell "myoblastoma" of vagus nerve. Acta Neuropath. 10, 162-165 (1968)

Malignant Granular Cell Tumor . 393 Cadotte, M.: Malignant granular-cell myoblastoma. Cancer 33,1417-1422 (1974) ChrISt, M. L., Ozzello, L.: Myogenous ongm of a granular cell tumor of the unnary bladder. Amer. J. clm. Path. 56, 736-749 (1971) ChrIStopherson, W. M. Oncocytoma of the parotId gland. AMA Arch. Path. 48, 96-98 (1949) Chnstopherson, W. M., Foote, Jr., F. W., and Stewart, F. W.: Alveolar soft part sarcomas: structurally charactenstIC tumors of uncertam hIstogenesIs. Cancer 5,100-111 (1952) Eason, A. A., Karol, J., and Collms, E. J.: Granular cell myoblastoma: permeal neoplasm of probable neural ongm. Urology 10, 159-160 (1977) FIsher, E. R., and Wechsler, H.: Granular cell myoblastoma - a mIsnomer. electron mIcroscopIC and hIstochemICal eVIdence concernmg ItS Schwann cell denvatIOn and nature (granular cell Schwannoma). Cancer 15, 936-954 (1962) Gamboa, L. G.: Malignant granular-cell myoblastoma. AMA Arch. Path. 60, 663-668 (1955) Harkm, J. c., and Reed, R. J.: Mahgnant pnmary nerve sheath tumors. In: Tumors of the penpheral nervous system. Atlas of Tumor Pathology, Second senes, FascIcle 3, pp. 107-136, Armed Forces InstItute of Pathology, Washmgton, DC 1969 Haustem, U.-F .. Mallgnes metastasierendes Granularzellmyoblastom Abnkosow mit symptomatIscher DermatomyosItIs. Derm. Mschr. 160,318-328 (1974) Magon, A., and Szegvan, M.: Rezidivierender und metastasierender Abnkossoff-Tumor der Vulva. Zbl. Allg. Path. 117, 265-273 (1973) MIChel, S. H.: EpIthelial elements m a malignant neurogellic tumor of the tibIal nerve. Amer. J. Surg. 113,404-408 (1967) MOSCOVIC, E. A., and Azar, H. A.: Multiple granular cell tumors ("myoblastomas"): Case report WIth electron mICroscopIc observatIOns and reVIew of the literature. Cancer 20, 2032-2047 (1967) Rosenbloom, P. M., Barrows, G. H., Kmetz, D. R., and Canty, T. G.: Granular cell myoblastoma ansmg from the thoracIC sympathetIc nerve cham. J. Pedlatr. Surg. 10, 819-822 (1975) Strong, E. W., McDIVItt, R. W., and BrasfIeld, R. D.: Granular cell myoblastoma. Cancer 25, 415-422 (1970) Unlll, K. K., and Soule, E. H.: Alveolar soft part sarcoma: an electron mICroscopIC study. Mayo ClIn. Proc. 50, 591-598 (1975) USUl, M., Ishu, S., YamawakI, S., Sasaki, T., Mmaml, A., and Hlzawa, K.: Malignant granular cell tumor of the radIal nerve: an autopsy observatIOn WIth electron mICrOSCOPIC and tissue culture studIes. Cancer 39, 1547-1555 (1977) Vance, III, S. F., and Hudson, Jr. R. P.: Granular cell myoblastoma. chlllcopathologic study of forty-two patIents. Amer. J. Chn. Path. 52, 208-211 (1969) Welser, G.: Granularzelltumor (Granulares Neurom Feyrter) und Schwannsche Phagen: ElektronenoptIsche Untersuchung von 3 Fallen. Vlrchows Arch. A. Path. Anat. Hlstol. 380, 49-57 (1978) Woodruff, J. M., Cherlllk, N. L., Smith, M. c., MIllett, W. B., and Foote, Jr., F. W.: Penpheral nerve tumors With rhabdomyosarcomatous dIfferentiation (malignant "Tnton" tumors). Cancer 32, 426-439 (1973) ReceIved November 10, 1980 . Accepted December 18, 1980

Key words: Malignant granular cell tumor - Myoblastoma - Sarcoma Ultrastructure Lars-Gunnar Kmdblom, Department of Pathology, Sahlgren's Hospital, S-413 45 Goteborg, Sweden