Document ppemZyVDjQGOXq4KgqndzeJkX

Malignant Mesothelioma of the Tunica Vaginalis Testis: Report of First Case with Preoperative Diagnosis LEONARD JAPKO, MD,* ANTONIO ALMADA HORTA, MD,* KLAUS SCHREIBER, MD,* SUMI MITSUDO, MD,* GATTU LAL KARWA, MD,t GURMUKH SINGH, MB, BS, PhD,* AND LEOPOLD G. KOSS, MD* The cytologic, histologic and ultrastructural features of a malignant carcinomatous mesothelioma of the tunica vaginalis testis in a 30-year old patient are described. This is the first such case with preoperative diagnosis by cytologic examination of hydrocele fluid and the second with documented history of exposure to asbestos. The identity of the tumor was confirmed by a positive immunoperoxidase reaction directed against mesothelial cells. A review of the previously described ten cases is presented. Cancer 49:119-127, 1982. alignant mesothelioma of the tunica vaginalis aspiration, a slight epididymal nodularity was noted and the M testis is an uncommon tumor of which only ten patient was placed on antibiotic therapy with a presumptive well-documented examples could be found in the lidtiagnosis of epididymitis. Cytologic examination of the hy erature. In all previously recorded instances the diag nosis was established postoperatively and appeared to have been unexpected. For this reason, it was thought worthwhile to report a case of this tumor with a pre operative diagnosis established by cytologic evaluation of the hydrocele fluid. The identity of the tumor could drocele fluid revealed malignant carcinomatous mesothelioma. The patient was readmitted two weeks later for surgery, at which time the fluid had reaccumulated. On admission, except for the scrotal lesion, there were no abnormal physical, bio chemical, or roentgenographic findings. The patient's right scrotal compartment was explored through an inguinal inci sion. The testicle and surrounding hydrocele sac were easily be confirmed by immunohistologic and ultrastructural mobilized: the outer portion of the tunica was smooth and findings. The young patient's prior exposure to asbestos glistening. Upon opening the sac, multiple small yellow nod is of epidemiologic interest. ules were noted on both visceral and parietal surfaces of the tunica. Frozen section of the tunica vaginalis confirmed the Case Report The patient was a 30-year old man who presented with painless right scrotal swelling, first observed three weeks ear lier. He had no other symptoms arid suffered no recent trauma to his testicles. On physical examination, the positive findings were confined to the right scrotum. There was a small hydro cele with a mildly indurated right epididymis. Twenty milli liters of clear hydrocele fluid were aspirated through a 21gauge needle and submitted for cytologic examination. After cytologic diagnosis and a right radical orchiectomy was per formed. Because of the diagnosis of malignant mesothelioma, a de tailed occupational history was obtained. For a period of eight years, until two years prior to admission, the patient was a pipefitter at an oil refinery. His work involved placing thick asbestos insulation around large pipe lines, straddling the pipes and their insulation in the process. The patient was seen again 4'/2 months postoperatively. At that time, the physical examination was unremarkable and his right scrotal wound was well healed. Intravenous pyelogram From the *Department of Pathology, the tDepartment of Urology, Montetiore Hospital and Medical Center, Albert Einstein College of Medicine, Bronx. New York, and the ^Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsyl vania. and abdominal computed tomography (CT) were negative for metastatic disease. There was no evidence of retroperitoneal lymph node enlargement. Six months postoperatively, the pa tient was well and without clinical evidence of disease. Supported in part by Grant no. 5 Rol CA-27081-02 from the Na tional Cancer Institute, DHEW (Dr. Singh). Dr. Japko is a Fellow in Cytopathology, New York City Division of American Cancer Society. Address for reprints: Leopold G. Koss, MD, Department of Pa thology, Montetiore Hospital and Medical Center, 111 East 210th Street, Bronx, NY 10467. The authors thank Ruby Barnett, CT (ASCP), for providing tech nical assistance. Accepted for publication November 19, 1980. Laboratory Findings Cytology Fluid from the right hydrocele was received prefixed in an equal volume of 50% ethanol. Four smears were prepared from the sediment of the centrifuged specimen 0008-543X/82/0I01 /0119 S0.95 American Cancer Society 119 120 Cancer January 1 1982 Vol. 49 Fig. 1. Hydrocele fluid cytology. A. Low power view of spherical clusters of cells (XI40) B. Close-up of a mulberry-shaped cell clus ter. Note several enlarged and hyperchromatic nuclei at the periphery of the clus ter (X350). C. Calcified structures (psammoma bod ies) within a cell cluster (X350). D. Two malignant cells separated from each other by a clear space ("window") (X560), (A, B, C--Papanicolaou stain; D-- cell-block, H & E.) ' and stained by the Papanicolaou technique. Cellular material was abundant and was predominantly com posed of three-dimensional, essentially spherical or "mulberry-shaped" clusters of cells. These clusters ranged from small round balls made up of four to five cells each to very large papillary structures with com plex budding arrangements (Fig. 1A). The cells within the large clusters had a distinctive arrangement. The peripheral cells and their nuclei were generally flattened, and were oriented in a circular fash ion around the core of the cluster (Fig. IB). Within some of the larger structures as well as lying free in the background were numerous round, lamellated calcifications resembling psammoma bodies (Fig. 1C). The background was otherwise clear except for a rare mesothelial cell, occurring singly and in small clus ters (Fig. ID). The cytoplasm of the tumor cells was generally abun dant and eosinophilic and the cell borders were well defined. Many cells displayed cytoplasmic vacuoles, occasionally with peripheral displacement of the nu cleus resulting in a signet ring appearance. The nuclei showed a wide range of atypism. Most cells had a single, centrally placed nucleus, but occa sionally binucleated cells were noted. In general, the nuclei were of moderate size, round or oval, with a smooth nuclear membrane. However, even within the same clusters, some nuclei were markedly enlarged with drastic alteration of the nucleocytoplasmic ratio (Fig. IB). The chromatin pattern was predominantly finely granular but rare, irregularly shaped, coarsely granular, hence hyperchromatic nuclei were also seen (Figs. IB and ID). Some cells had from one to three very small chromocenters while others had one or two large, red dish, round nucleoli. No mitotic figures were observed. A paraffin-embedded cell block was also prepared from residual fluid sediment, and the sections were stained with hematoxylin and eosin. The findings were essentially identical to those described above. Mucicarmine and alcian blue stains performed on the cell block were negative for mucin. Neither the smears nor the cell block contained asbestos bodies. The diagnosis of malignant carcinomatous mesothelioma was ren dered on the strength of the microscopic findings. No. 1 Mesothelioma Tunica Vaginalis Japko et al. 121 Fig. 2. Histologic ap pearance of malignant me sothelioma. A. Low power view showing exophytic, papillary proliferations pro truding into the lumen of the tunica vaginalis (X140). B. Detail of the tumor with an abnormal mitotic figure (X560) C. Gradual transi tion between normal mesothelial cells and tumor. Note superficial extension of the tumor into the con nective tissue stroma (ar row) (X350). D. Plug of tu mor in a lymphatic vessel (H & E, X350) Surgical Pathology Yellow tumor nodules measuring 0.3-0.5 cm in di ameter were located on the parietal and visceral sur faces of the tunica vaginalis, the surface of the epidid ymis, and the base of the segment of the spermatic cord. The epididymis and the testis appeared normal and there was no gross evidence of invasion by tumor. On microscopic examination, each of the multiple tumor nodules was composed of sheets of densely packed, large cells, forming exophytic, papillary prolif erations (Fig. 2A), which were usually attached to the wall of the tunica by only a single, narrow connective tissue pedicle. The tumor was composed of cells bearing strong resemblance to normal mesothelial cells except for moderate variability in size (Fig. 2A). The nuclei were fairly uniform, yet infrequent abnormal mitotic figures were observed (Fig. 2B). The mesothelial sur face of the tunica showed gradual transitions between normal mesothelium and tumor (Fig. 2C). Numerous psammoma bodies were present within the tumor. Mucicarmine and alcian blue stains were negative for mu cin. Periodic acid-Schiff (PAS) stain disclosed posi tively staining cytoplasmic granules which disappeared with prior diastase digestion, indicating the presence of glycogen. The vacuoles seen in many cells did not react with any of the histochemical stains, including colloidal iron. Invasion by tumor cells was observed in the connec tive tissue pedicles supporting papillary structures. Su- 122 Cancer January 1 1982 Vol. 49 Fig. 3. Immunoperoxidase reaction performed on cell-block of hydrocele fluid. A. Negative control (see text) (~ X350). B. There is a strong positive reaction for mesothelial cell anti gens. (~ X500). perficial invasion of the wall of the tunica vaginalis (Fig. 2C) and the presence of a plug of tumor in one lym phatic were also noted (Fig. 2D). The epididymis itself, as well as the testis, were not invaded by tumor and both appeared normal. No asbestos bodies or asbestos fibers were found following digestion of 1.3 g of tumor tissue with household bleach. Immunoperoxidase Reaction A paraffin-embedded cell block of the fluid was sent to one of us (G.S.) for immunoperoxidase staining. Antiserum to mesothelial cells was prepared and ab sorbed according to the protocol described earlier.1 An additional absorption with the homogenates of for malin-fixed colonic and breast carcinomas was carried out prior to immunoperoxidase staining. Immunoper oxidase staining was done according to the method of Pinkus and Said.2 Normal rabbit serum, absorbed in parallel with the antimesothelial cell serum, and rabbit antihuman IgG were used as negative controls (Fig. 3A). The antimesothelial cell serum had been evaluated for its specificity by immunoperoxidase staining of nonmesotheliomatous tumors.3 The tumor cells in the cell block exhibited strong positive reaction for mesothelial cell antigen(s) (Fig. 3B). Electron Microscopy Fresh tumor tissue was minced into 1-mm fragments and fixed in phosphate-buffered 5% glutaraldehyde. Following postfixation in chromate buffer, the sections were rinsed, dehydrated in graded alcohols and embed ded in Epon. Selected ultrathin sections were mounted on copper grids, stained with uranyl acetate and lead citrate, and examined with a Siemens 101 electron microscope. The tumor cells were generally large and polygonal, with abundant cytoplasm; occasional cells were dark and more spindle-shaped. Many slender microvilli of variable length and configuration were present on free surfaces of the cells (Fig. 4A) and within the cleft-like spaces which occurred between cells. Remnants of glycocalix were observed on the surface of the microvilli (Fig. 4B) Numerous well-developed desmosomes be tween tumor cells were observed (Fig. 4A). Occasional cells were accompanied by partial basement mem branes. The cytoplasm contained large, round to oval mito chondria in a perinuclear location. The Golgi apparatus was generally inconspicuous. The rough endoplasmic reticulum was fragmented in some cells, while in others it formed undulating tubules which partially sur rounded mitochondria. Some of the cells contained sparse, peripherally located, smooth vesicles as well as dark, dense bodies. The latter were probably lipid or lysosomal bodies. Numerous tonofilaments and scat tered aggregates of glycogen were present in many of the cells. The nuclei were large and pale, of irregular contour, with angular, shallow or deep indentations (Fig. 4A). The chromatin was aggregated at the nuclear mem brane and around the well-developed nucleoli. The ultrastructural appearance was consistent with an epi thelial tumor of mesothelial origin. Discussion The normal tunica vaginalis testis is an extension of the peritoneum, normally lined by a single layer of mesothelial cells. Primary malignant mesothelioma of No. 1 Mesothelioma Tunica Vaginalis Japko et al. 123 Fig. 4. Electron micrographs of tumor. A. Numerous microvilli of variable length and con figuration cover the outer surface of the cells. Several well-developed desmosomes bind the tu mor cells (arrow). Note the irregularly shaped nucleus (XI2,400). B. Detail of cell surface. Remnants of glycocalix are attached to the ir regular microvilli (small arrows) (X40,000). the tunica vaginalis is an uncommon tumor, analogous to the malignant mesothelioma of the pleura or the peritoneum.4-6 Malignant mesothelioma can be of three histologic types: carcinomatous, fibrosarcomatous, and mixed.7 The differential diagnosis of carcinomatous mesothe lioma comprises mesothelial hyperplasia either spon taneous or secondary to inflammatory processes,4,7-9and metastatic adenocarcinomas either from distant or ad jacent sites.10 124 Cancer January 1 1982 hW" 2 oE* *5 i>_> T3 i'i Q O Qcvo y .3 l/") 5/3 ig =s < Vol. 49 c aCL u> g|CcO5'.s/5 1S5g 4 `c/3 c>o .5 C8O*0+225X-5/5 75 H>- .-5yH/5 (-- ob ; --_-_a *0,,a) *P05-) Ho tyi On .5 a?0 huj C3g/D -S'oS s I. -5C ,T2J H j/j H> sw H >H w> y *5 'c | 2 8' - x 1;! *rCssu .c52/3 ECxO .p5 . {_ " *H> !co2.-y2=>H>o- ^H-o ,2= ay ol. 2a, y 5 E *5 ""OOUO0>n"-l/CCD- wu3>5/5 *1 5H=OJ .t2- X3S --I 8 E __ "a 0 0 'o 0C gg " a5c .E2 quh Is 1 ' ai11 z-j y Co ao CO CO 3'5 H H> Ou *v3 m> 0..0. >.-S ftj -2 ac 2 So -co tau-' 49: cE>, 2 at "ooco =c2fl a uj e4>b 00 " >> C g 0 .15 I -3 5A Oh 00 > <2 " IS S = 'S o o z-3 OX ' O (A J, D so a) -H ,0 ii, -- o . j s | --XV o o3 r>- ^ >-- <t C __y H1- ^ |i 'i CO .2 oI-- CJ ~-Si '.x*5*: t"> 58 .2 c yW5 x*> E * . I a; C/5 z C/5 Z c -0 L E to; 1'C3 y S S JLt* . -.2o a53/3 _>>'*0'3 CaO -y . o >s ^ <cNr "OUo % 2 y 5 .2-5 cl --3 uU>O --<^OX <uy- o .O2 s .*2U OV).QC < Sa >- ^E>N >> >>-r E 5 E S2 *- o c o - g2 .O2 joz -2wac *25oo o CxQ 3 > 3 oEV Ea8oy S 5 CL g S .2 -g o 2 a E V Cl CC/3L jo E o, C? 3L- .3- 3 ~OE >> *5 00 2 E < CkC o y S 3'S 3 c 5 xa"; . >1 6g c >E>oE 75 Z <00 JClL C/DC/DC/5 zzz O Z O ~o >N 75 75 J= z z 0^ 0 00 o 0 a >N x; Oi <N 75 Z 26 -= Tt *s Table 1. Case Summaries V = biopsy; M E T = metastasis; LN = lymph node; neg negative for tumor; PM- = postmortem examination. No. 1 s =8 Mesothelioma Tunica Vaginalis Japko et al. 0 E ors vs TJ1 UUJ. CwO 2^ H E" sJ <*J I ^ 4w 2? 2 125 e-H .> c E ft. >n^2 w u?7 ^0. .o2 Va. 7co J^ 2 i5 z -j H UJ L- "T5 8.1 --iCrO | 4^E= J--0S S r '5"2 o ft-75 w- . J2 e 75 0 5 oo.2 -- .E *o c .E jj E 75 .SESf O 00 75 c . r= OCg 1> oa ". -- i( s <* ; 7o5o--OX= - .22 <5 -- .2 75 -s H UJ s s 2 . sisU '| *5 T3 a, cS >>S SSa- 75 s 7) z c 7) H UJ s -C <*- 0O ^. C3 ^ fOb3> i^> 2 c cM .2 SE ..5I 73 o 75 ^ - C0 <-r S&ee! .2? O 75 x .2PT3 s e2S Jrt CO >c . TO poO t/5 75 V o(N |S ^ 75 -5 f2 . . 00 ? c <u l- o e > ^ .2 H 3> E o L IS M CO *0 st'i's- Z J >v J0D0 u u o o >> o S S H ?3uCO o. (-- S > ' > H co Hs UJ Cl. 2a au 2=a S E 2o ^ JJ U5 ti>> J^= uo CO co "5 -j ^ m 1S E >.a 3 >Jft , x o3 , 2 ~ X/-> i CO oo*-o >rc- **zJ , to. COu 3u g.3.: ,CI O . 3 > _3_ u '> I -2 11! uC2O . o-d.P5-85-E.2 mUE o3 -jz <N -J >N CO .c U o U *6 6 .2 c *o C .*> .2 Z 21 g Su .t2u i ? o(>/), *C3-l oc cko. 'f7t5. < 7c3 . `5oo ^ .5 2 Abbreviations: R = right; L = left; yr. = years; mo. = months; wk. = weeks; NS = not specified; T V T = tunica vaginalis testis; M PM = malignant papillary mesothelioma; Bx 75 Z 4OJ (Jor O *-- 1e -c s; \* ' okO " a) , . t.SoTf 1- o >, E oo ZZ 37) tU- O *j ft- {C 75*2 o mo 2g Xi -o *J oW. yo t>>. -Uo2o.. cCc 0 2.*! > E S oo' ^x: o2 JJ "u 8. 126 Cancer January 1 1982 Vol. 49 The conclusion that we were indeed dealing with a malignant mesothelioma of the tunica vaginalis testis and not with a benign proliferative process affecting the mesothelium was based on several considerations. The cytologic presentation was characteristic and fully com patible with malignant carcinomatous mesotheliomas of other sites such as the pleura, peritoneum and peri cardium.4'5'7'""15 There was evidence of stromal and, more importantly, lymphatic invasion (Fig. 2D). The presence of abundant microvilli of variable length and irregular configuration on the surfaces of the tumor cells demonstrated by electron microscopy (Fig. 4A) was also strongly supportive of the diagnosis of malignant mesothelioma.6,16'17 Benign mesothelium is characterized by regularly spaced, relatively short microvilli.7 The rapid reaccumulation of fluid two weeks after the initial tap of the "hydrocele" has also been recorded in other malignant tumors of tunica vaginalis and has been considered an important clinical indication of a malignant process.18 Other ultrastructural findings, such as the presence of glycogen, tonofilaments, desmosomes, and the perinuclear location of mitochondria, while not specific, were entirely consistent with obser vations recorded in other cases of malignant carcino matous mesothelioma.17 On the other hand, the pres ence of calcified psammoma bodies does not necessarily indicate a malignant process: such structures may be observed in malignant mesotheliomas67,16 but also in benign proliferative processes of the mesothelium.14 The mesothelial derivation of the tumor could be con firmed by immunoperoxidase reaction, using antibodies with previously documented high degree of specificity for mesothelial cells in fluids.1 We undertook a review of the literature on the subject of malignant mesothelioma of the tunica vaginalis testis using the following arbitrary criteria: there should be no evidence of adenocarcinoma elsewhere; the tumor should not be mucicarmine-positive;4,11,14,19-21 there should be in situ changes within the epithelium lining the tunica vaginalis in the surgical material. Specifically excluded were cases of adenomatoid tumors and other clearly benign tumors,22-28 tumors of probable epididymal origin,29-31 and mucin-positive tumors.22,31 Using the above criteria, there were only ten previously de scribed cases,13,16,32:37 that we considered as bona fide malignant mesotheliomas of the tunica vaginalis. The ten case histories and the present case are summarized in Table 1. The ages of the patients were from 21 to 78 years. Seven of the nine cases for which there was adequate description presented with a unilateral hydrocele. The other two cases (Cases 1 and 9) presented with scrotal lumps, wherein fluid-filled cavities were observed on pathologic examination. It is of interest that a very small amount of fluid was present in Case 9 of sarco matous mesothelioma. Contrary to carcinomatous me sotheliomas, such tumors are generally not associated with significant accumulation of fluid.7 The relationship of mesotheliomas to asbestos ex posure is well established for pleural and peritoneal tu mors.38-42 In reference to the cases of malignant me sotheliomas of tunica vaginalis testis, the occupational history was sought in five. Two (Case 8, and this case) provided positive histories of asbestos exposure. Case 835 also had a mesothelioma in the thoracic cavity, pos sibly of pleural origin. To our knowledge, the shortest interval reported between the first exposure to asbestos and the development of mesothelioma is 13 years.40 A more usual period is from 20 to 40 years.38,43Our patient gave a history of initial asbestos exposure dating back only ten years. This probably does not negate a causal relationship. Since the space surrounding the testis is relatively small and easily palpated, it is possible that tumor growth and abnormal fluid accumulation may be observed earlier within the scrotum than within the pleural or peritoneal cavities. Another interesting facet to our patient's occupational history is that he straddled large asbestos-lined pipes. The possibility of exposure through scrotal skin should not necessarily be dis counted. In terms of diagnostic procedures, it is important to note that cytologic examination of hydrocele fluid was not recorded in any of the previously reported cases, even those in which aspirations were performed (Cases 4-6). The efficacy of cytologic evaluation of hydrocele fluids has not been established. However, there is a re port on record in which the diagnosis of a malignant testicular tumor was made, based on the cytologic ex amination of the hydrocele fluid.7 As stated in a large review, "the presence of a hydrocele in association with a paratesticular tumor is usually an indication that the tumor is malignant".15 Failure to perform a cytologic examination of hydrocele fluid may lull the urologist into believing that he is dealing with a benign process. He may either withhold treatment for a long period of time (Cases 4 and 5) or perform a trans-scrotal hydrocelectomy when a radical orchiectomy through an in guinal approach would have been the procedure of choice. Surgical violation of the scrotal skin may lead to tumor implantation into the incision site as recorded in Case 6. Hemiscrotectomy appears to be the proce dure of choice if prior trans-scrotal hydrocelectomy was undertaken. As with malignant mesothelioma of the pleura or peritoneum, distant spread of mesothelioma of the tu nica vaginalis is usually via lymphatics (Cases 5, 7, and 8). Consequently, once the diagnosis is seriously enter tained, preoperative evaluation of the para-aortic and No. 1 Mesothelioma Tunica Vaginalis Japko et al. 127 iliac lymph nodes by lymphangiography and/or com puted tomographic scan appears indicated. Malignant mesothelioma confined to the tunica vag inalis may lend itself to complete surgical extirpation, contrary to mesotheliomas of the pleura, pericardium or peritoneum. Therefore, early diagnosis by cytologic examination of hydrocele fluid may prove to be of major therapeutic and prognostic advantage. REFERENCES 1. Singh G, Whiteside TL, Dekker A. Immunodiagnosis of me sothelioma; use of antimesothelial cell serum in an indirect immu nofluorescence assay. Cancer 1979; 43:2288-2296. 2. Pinkus GS, Said JW. 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