MULTICYSTIC, PERITONEAL MESOTHELIOMA A Report with Electron Microscopy of a Case Mimicking

Intra-Abdominal Cystic Hygroma (Lymphangzoma)

RALPH MENNEMEYER, MD, A N D MICHAEL SMITH, MD

A 27-year-old Caucasian female complained of persistent, poorly localized abdominal pain of several months' duration, found to be due to a multicystic diffuse lesion involving omentum, peritoneum and pelvic viscera. Three resections were required within a ten-month period for symptomatic control. The tumor showed many of the clinical, operative, gross and light micro- scopic features of intra-abdominal lymphagioma. Tissues removed at the third operation, however, were examined by electron microscopy, and found to con- sist of a myriad of small cysts and channels lined by mesothelial cells. In view of these findings, the lesion was regarded as a cystic peritoneal mesothelioma. Similarities between lymphangioma and peritoneal mesotheli- oma are discussed. It is suggested that electron microscopic examination of lining cells of cystic lesions which are considered grossly consistent with lymphagiomas may yield additional similar cases.

Cancer 44:692-698, 1979.

YMPHANGIOMAS ARE CONSIDERED benign, L although not infrequently recurrent, lesions of the lymphatic system.1,2,5,6,10,12,16-18 They have variable clinical presentations and corresponding morphologic diversity.'~2~'0~- 12,163 While their histogenesis is poorly under- stood and the subject of dispute,1,2,10 they are currently viewed as congenital malformations of the lymphatic vessels.' Although benign and/or solitary peritoneal mesotheliomas do occur, they may pursue an aggressive course and have a poor p r o g n o s i ~ . ~ ~ ' ~

We report a case of a diffuse multicystic intra-abdominal lesion initially considered a lymphangioma in a patient who underwent three operative procedures for removal and symptomatic control within ten months. Elec- tron microscopic examination of tissues re- moved at the third operation revealed cysts and channels lined by well-differentiated mesothelial cells. The significance of cystic intra-abdominal mesothelioma and its mor- phologic and behavioral similarity to lymph- angioma are discussed.

From the Departments of Pathology and Obstetrics and Gynecology, The Mason Clinic, Seattle, Washington.

Electron microscopic studies were performed using an instrument supplied by a grant from the American Cancer Society.

Address for reprints: Ralph Mennemeyer, MD, The Mason Clinic, 1100 Ninth Avenue, Seattle, WA 98101.

Accepted for publication September 7, 1978.

CASE REPORT A Caucasian female was first seen in consulta-

tion at The Mason Clinic in November 1976 (at age 27), with a presenting complaint of poorly de- fined abdominal pains of one year's duration. Evaluation prior to referral had included barium enema, IVP (which suggested a right adnexal mass) and ultrasonography (which suggested multilocular translucency in the right lower quadrant and pelvic ascites). Exploratory lapa- rotomy had been performed elsewhere subsequent to these studies.

Laparotomy (October 1976) revealed numerous filamentous and string-like adhesions involving peritoneum, intestine and pelvic viscera. The cul de sac was obliterated by a mass of small clear cystic structures, and similar implants were scat- tered throughout the pelvis and omentum. The liver, spleen, pancreas, and ovaries were all stated to be free of these implants. The cystic lesions were removed, and postoperative clinical improvement obtained.

Review of tissues obtained at the initial lapa- rotomy revealed portions of omentum and mul- tiple thin-walled cysts with delicate intervening connective tissues, containing clear, serous, straw colored fluid. Aggregate dimensions of the tissues, which weighed 200 g, were 14 x 8 x 6 cm.

Microscopically, tissues showed cystic, honey- combed structures lined by low flattened cells considered consistent with endothelial cells, al- ternating with somewhat taller, more plump cells. The cysts were separated by delicate connective tissues, predominantly mature collagen. No clear evidence of omental invasion was seen micro-

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No. 2 CYSTIC PERITONEAL MESOTHELIOMA . Mennemeyer and Smith 693

scopically. The tissue was interpreted as cystic lymphangioma.

Three months postoperatively (January 1977) similar abdominal pains, again vague, but with some localization to the left upper quadrant, recurred and persisted. In March 1977, diagnostic laparoscopy was carried out at The Mason Clinic. This examination revealed implants of apparent persistent cystic lymphangioma in the cul de sac, as well as a large cystic left upper quadrant mass in the area of the splenic flexure. Again the hepatic surface was described as free of involve- ment. The lesions were removed as far as tech- nically possible translaparoscopically using an electrocoagulating snare technique, and it was elected to await evidence of clinical improvement or recurrence.

Laparoscopic resection yielded globular, clear, cystic structures with an aggregate dimension of 12 X 6 X 3 cm. Microscopic examination again showed dilated channels and cysts of varying sizes with lining varying from flattened to rather regular cuboidal cells with a “picket fence” orientation. Some areas showed intraluminal desquamation of lining cells with an elongated, tadpole-like cyto- plasm. Intervening tissues resembled a mixture of mature collagen and smooth muscle. Again no evi- dence of organ infiltratation by the cysts was seen microscopically. Surgical and pathologic diagnoses were intra-abdominal multicystic lymphangioma.

Five months later (August 1977) the patient again experienced severe abdominal pain in the left upper quadrant, and the following month was readmitted for exploratory laparoscopy and laparotomy .

Laparotomy revealed studding of all pelvic peritoneum and reproductive organs with minute cysts (varying between 1 mm and several cm). The

F I G . 2 . S e c t i o n through omental mass showing cyst walls of varying thickness with connective tissue stroma, and smaller channels. Both types of structures are lined by low, regular flattened to cuboidal cells (H & E, X100).

FIG. 1 . Partial omentectomy, showing multicystic mass diffusely involving omentum. Cysts vary considerably in size, all contain serous clear fluid.

left upper quadrant contained a large, bulky, cystic and partially solid mass, adherent to the antero- lateral peritoneal surface, spleen, stomach and splenic flexure. The majority of the mass was re- sected and partial omentectomy was performed. Innumerable minute residual cysts involved the serosa of the transverse colon, the peritoneum, and the remaining omentum and could not be completely removed.

Postoperatively the patient improved symp- tomatically and continues asymptomatic nine months after the third operation.

Tissues from the third operation consisted of omental and splenic flexure tumors. The former was a segmental omentectomy, 34 x 11 cm, studded with innumerable, thin-walled, fluid filled

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cysts (Fig. 1). Many of the smaller cysts (4-5 mm) were intimately intermingled with the areolar tissues of the omentum. The splenic flexure tumor was of similar gross dimensions and contained numerous grape-like clusters of thin-walled fluid filled cysts with intervening delicate and alternately dense connective tissues.

Microscopic examination of all tissues showed a myriad of cysts and channels lined by alternately flattened and raised cuboidal type cells, many of which had a “picket fence” regularity (Figs. 2-4). Some desquamated cells lay within the cysts. Intervening connective tissues consisted almost entirely of collagen, and varied from sparese to quite abundant. The tissues showed microscopic

FIG. 3. Section of smallest channels, show- ing variation in lining cells from flattened to low cuboidal (H & E, X 250).

evidence of omental infiltration. Special stains were performed on tissues obtained from the second and third operations and were reviewed at this time.s

Small amounts of secretions identified in intra- cytoplasmic vacuoles and within the lumena of larger cysts showed moderate staining with colloidal iron. The majority of this material failed to stain following application of testicular hyal- uronidase. The material was negative on PAS stain after exposure of the sections to diastase, and was also negative with Mayer’s mucicarmine stain. Alcian blue at pH 2.5 showed fairly strong stain- ing of residual intracellular and intracystic fluid.

Tissues for electron microscopy were prepared

FIG. 4. Section of larger cyst wall showing “picket fence” arrange- ment of lining cells with some stratification, par- tial desquamation, as- sociated collagen, fibro- blasts and acute in- flammatory cells (H & E, X400).

No. 2 CYSTIC PERITONEAL MESOTHELIOMA * Mennemeyer and Smith

FIG. 5. Electron photo- micrograph showing uniformity of lining cells with surface microvilli, desmosomes, well-de- veloped basal lamina (X6396).

from the walls of various sized cysts. All of the cysts were lined by cells which, while varying considerably in size, had common features of luminal microvilli, tight desmosomal junctions, numerous intracytoplasmic filaments directly ad- jacent to and continuous with the desmosomes, large ovoid mitochondria, extensive rough- surfaced endoplasmic reticulum and free ribo- somes (Figs. 5-7). The cells, possessing many of the ultrastructural characteristics of mesothelial cell^'^*^^ rested on well-developed basal lamina (Fig. 7). Intercellular stroma consisted almost entirely of mature collagen. The resected tissues were considered to represent multicystic intra- abdominal mesothelioma rather than cystic hy- groma flymphangioma).

DISCUSSION

The case reported concerns a multicystic lesion within and confined to the abdomen which required three operations within ten months for control of recurrences in a young woman with no prior history of abdominal trauma or asbestos exposure. The tumor operatively, grossly, and light microscopically

695

resembled abdominal cystic hygroma (lymph- angioma) and pursued a clinical course of peritoneal, serosal, and omental recurrences consistent with that entity. Because of ultra- structural demonstration of extensive meso- thelial cell proliferation, we chose to regard the tumor as a cystic variation of peritoneal mesothelioma. While there is little similarity between the more classic manifestations of peritoneal mesothelioma and lymphangioma, the two lesions may share some common fea- tures, as this case illustrates.

Lymphangiomas have been regarded as true neoplasms by some authors,‘ and as congenital malformations by others.2”0 They have been classified as simple lymphangioma, cavernous hemangioma and cystic hygroma in an at- tempt to unite their diverse morphologic expressions into a single nosologic entity.1° Numerous case reports and series have es- tablished the clinical and anatomic diversity of these lesions1~5*6*10~12~16~i7 and emphasized the possibility of recurrence following surgical extirpation.2 This latter tendency is not

696 CANCER August 1979 Vol. 44

viewed as inconsistent with the congenital malformation theory of etiology described by Bill and Sumner.2 Their view regards lymphangiomas and cystic hygromas as similar entities etiologically related to lymphatic blockage and proposes that morphologic dif- ferences between them are related to differ- ences in anatomic sites in which they occur. Recurrences following surgical removal are explained by assuming opening and ectasia of pre-existing lymphatic channels due to continued interference with lymphatic drain- age. These authors were not impressed that local tissue infiltration was a significant feature of the lymphangiomas which they reviewed.

The intra-abdominal lesion presented in this case does not represent a true lymph- angioma, since electronmicroscopic exam- ination showed it was composed of numerous cysts lined by mesothelial cells with the same ultrastructural features described in the better differentiated mesotheliomas studied by Suzuki et a1.” Ultrastructural study of lymphangioma, on the other hand, has demonstrated that

F I G . 6. Adjacent mesothelial cells with surface microvilli, des- m o s o m e s , tonofi la- ments, intracytoplasmic filaments, oval mito- chondria, rough-sur- faced endoplasmic re- ticlum. These cells lined all cysts and small chan- nels in the omental and left upper quadrant masses (~26 ,580) .

lesion consists of structures lined by endo- thelial cells,13 essentially identical to those which line normal lymphatic^.^ The absence of endothelial cells from the lesion presented here leads us to conclude that this lesion is not of lymphatic vessel origin.

Kannerstein and Churg’ described many of the clinical, gross, and histologic features of peritoneal mesothelioma, commenting upon the proclivity of that tumor for spread over the peritoneal surfaces without distinct organ invasion. A similar pattern of minimal superficial visceral invasion was also reported by Moertel in his review of the subject.I5 Superficial spread without organ infiltration was observed in this case. Omental infiltration, described by Kannerstein and Churg’ as “con- ceivably present to a degree in virtually all cases” (of peritoneal mesothelioma) was also seen. We have been unable to find a similar case of a tumor diagnosed as a peritoneal mesothelioma which assumed the gross morphology seen in this case, although Winslow and Taylor described one of the

No. 2 CYSTIC PERITONEAL MESOTHELIOMA - Mennemeyer and Smith 697

FIG. 7. Mesothelial cell lining smaller cysts corresponding to cells initially thought to be of endothelial origin light microscopically (x 16,068).

twelve cases of fatal peritoneal mesothelioma which they reviewed as “partially cystic and hemorrhagic.””

While Kannerstein and Churg, in de- scribing the gross characteristics of peritoneal mesothelioma warn that “considerable de- parture from these patterns-particularly in gross morphology-should occasion careful scrutiny of the case and weighing of the diagnosis of me~othelioma,”~ we feel the recognition of mesothelial cells as the only proliferating cellular element in this tumor is sufficient reason to consider the diagnosis valid in this case.13 Rosai and Dehner,lg in describing nodular mesothelial hyperplasia in hernia sacs, review the many causes of benign mesothelial hyperplasia, including hepatic cirrhosis, collagen vascular diseases, and viral infections, none of which were operative factors in this case. Exclusion of any reason- able cause for reactive mesothelial cell pro- liferation in this case led us to regard the de- scribed lesion as neoplastic. McCaughey has listed, among the bases for accurate diagnosis

of peritoneal mesothelioma, “recognition of the capacity of the mesothelial cell to form widely different types of neoplastic

This case, while perhaps unique, is not totally unexpected in view of the diversity of morphologic patterns of mesothelioma stressed by o ~ ~ ~ ~ ~ ~ 7 , 9 , 1 1 , 1 4 . 1 8 ~ 2 0 - 2 2 W e have also been impressed by the gross and light microscopic similarity of reported intra-abdominal lymph- angiomas’O not evaluated electron microscopi- cally to the lesion which we report.

While the electron microscopic findings in this case do not, in and of themselves, help to differentiate between cystic mesothelial hyperplasia and true mesothelioma, the clinical course is more in favor of the latter possibility. We therefore conclude that the lesion reported in this case is neoplastic, capable of aggressive local growth and re- currence, but of considerably less malignant potential than the more classic, plaque-like forms of peritoneal mesothelioma, most of which are associated with a survival of less than one year from the time of d iagn~s is .~ , ’~

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More adequate prognostic evaluation will lymphangiomas. In fact, in the absence of depend upon continued follow-up in this case, electron microscopic evaluation of many as well as the study and reporting of similar previously reported cases thought to repre- cases. We would expect the tumor to pursue sent that entity, we wonder whether some of a course similar to that seen with extensive the lesions so designated may in fact have been (incompletely resectable) intra-abdominal cystic mesotheliomas.

REFERENCES

1. Avigad, S., Jaffe, R., Frand, M., Izhak, Y., and Rotem, Y.: Lymphangiomatosis with splenic involve- ment.JAMA 236:2315-2317, 1976.

2. Bill, A,, and Sumner, D.: A unified concept of lymphangioma and cystic hydroma. Surg. Gynecol. Obstet.

3. Casley-Smith, J. R., and Florey, H . W.: The structure of normal small lymphatics. Q.J. Ex$. Physiol. 46: 101 - 106, 1961.

4. Elmes, P. C., and Simpson, J. C.: The clinical aspects of mesothelioma. Q. J. Med. 179:427-449, 1976.

5. Goetsch, E.: Hygroma colli cysticum and hygroma axillare: Pathologic and clinical study and report of twelve cases. Arch. Surg. 36:394-404, 1938.

6. Kalish, M., Dorr, R., and Hoskins, P.: Retro- peritoneal cystic lymphangioma. Urology 6:503-506, 1975.

7 . Kannerstein, M., and Churg, J.: Peritoneal meso- thelioma. Hum. Pathol. 8:83-94, 1977.

8. Kannerstein, M., Churg, J., and Magner, D.: Histo- chemistry in the diagnosis of malignant mesothelioma. Ann. Clin. Lab. Sci. 3:207-211, 1973.

9. Kannerstein, M., Churg, J., McCaughey, W. T. E., and Hill, D. P.: Papillary tumors of the peritoneum in women: Mesothelioma or papillary carcinoma. Am. J . Obstet. Gynecot. 127:306-3 14, 1977.

10. Kittredge, R., and Finby, N.: T h e many facets of lymphangioma. Radiology 95:56-66, 1965.

1 1 . Komorowski, R. A,, and Robert, D. H.: Peritoneal mesothelioma presenting as an adnexal mass. South. Med. J . 68:83-85, 1975.

12. Larson, D. L., Myhre, B. A,, Schmidt, E. R., and Jaeschke, W. H.: Lymphangioma in unusual sites:

120:79-86, 1965.

Spleen, mesentery, retroperitoneum, mediastinum and the greater omentum. Wzs. M e d . 1 . 60:279-287, 1961.

13. Marcus, J. B., and Lynn, J. A.: Ultrastructural comparison of an adenomatoid tumor, lymphangioma, hemangioma, and mesothelioma. Cancer 25: 17 1 - 175, 1970.

14. McCaughey, W. T. E.: Criteria for diagnosis of diffuse mesothelial tumors. Ann. N.Y. Acad. Sci. 132:

15. Moertel, C. G.: Peritoneal mesothelioma. Gastro- enterology 63:346-350, 1972.

16. Plaut, A.: Locally invasive lymphangioma of adrenal gland. Cancer 15:1165-1169, 1962.

17. Postacchini, F., and Sadun, R.: Lymphangioma of the thigh following acute trauma. Clin. Orthof. 121: 169- 172, 1976.

18. Roberts, G., and Irvine, R. W.: Peritoneal meso- thelioma: A report of four cases. Br. J. Surg. 57:645- 650, 1970.

19. Rosai, J., and Dehner, L. P.: Nodular mesothelial hyperplasia in hernia sacs; a benign reactive condition simulating a neoplastic process. Cancer 35: 165- 175, 1975.

20. Smith, P. G., Higgins, P. McR., and Park, W. D.: Peritoneal mesothelioma presenting surgically. 87. j. Surg. 55:681-684, 1968.

21. Suzuki, Y., Churg, J., and Kannerstein, M.: Ultra- structure of human malignant diffuse mesothelioma. Am. J. Pathol. 85:241-262, 1976.

22. Winslow, D. J., and Taylor, H. B.: Malignant peritoneal mesotheliomas: A clinicopathological analy- sis of twelve fatal cases. Cancer 13: 127-136, 1960.

603-613, 1965.