Ultrastructure of endometrial stromal sarcoma

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An endometrial stromal sarcoma from a 48-year-old woman was studied by light and electron microscopy. Ultrastructurally most of the tumor cells resembled the stromal cells of midproliferative endometrium. There was no evidence of a pericytic differentiation of the tumor cells. These findings lend further support to the concept of an endometrial histogenesis of stromal sarcoma. Cancer 35:406-412, 1975.




tumor which is generally considered to arise from endometrial stroma. Ultrastructure of this tumor has been described in only one previously published report.6 This paper presents the electron microscopic findings in another stromal sarcoma.


A 48-year-old white woman was diagnosed as having endometrial stromal sarcoma following a hysterectomy performed because of dysfunctional uterine bleeding. About 18 months later she was admitted because of right hydroureter and was found to have extensive pelvic involvement by the tumor, which also involved and blocked the right ureter. A segmental resection of the ureter with ureteroplasty was performed. Pathologic examination of the resected segment of the ureter revealed infiltration by stromal sarcoma. A well circumscribed 1.5-cm mass was also discovered in the lower lobe of right lung after a routine chest roentgenogram. A thoracotomy and local resection of the mass was performed. Histologic examination revealed metastatic stromal sarcoma. From the Department of Pathology, Albert Einstein Medical Center, Philadelphia, PA. Staff Pathologist. t Staff Pathologist. t Director of Laboratories. Address for reprints: Mohammed Akhtar, MD, Department of Pathology, Albert Einstein Medical Center, York and Tabor Roads, Philadelphia, PA 19141. The authors thank Chaudhry C. Din for the photography, and Madeline Lang for help in preparation of the manuscript. Received for publication May 13, 1974. +

Light Microscopy T h e tumor from all three sites showed identical histologic features. T h e tumor was composed of irregular compact sheets or masses of uniform spindle-shaped cells resembling endometrial stroma. T h e nuclei were oval and uniform. Mitotic figures were infrequent. T h e tumor contained numerous small blood vessels and a well-developed reticulin network. I n the sections from the uterine wall, extensive permeation of the vascular and lymphatic spaces by the tumor was noted (Fig. 1). Electron Microscopy Tissue from the tumor in the right ureter and the lung was fixed in 2y0 gluteraldehyde, washed in cacodylate buffer (ph 7.3), post-fixed in osmium tetroxide, and embedded in Epon 812; 1-2 p sections were stained with toluidine blue for orientation. Ultrathin sections were stained with uranyl acetate and lead citrate. T h e tumor consisted of randomly disposed cells separated from one another by bundles of collagen fibers. T h e tumor cells were variable in size and shape depending upon the degree of their differentiation. Most of the cells, however, were either spindle-shaped or irregular in outline and contained elongated or irregularly shaped nuclei with prominent nucleoli. T h e cytoplasm was moderate in amount and contained several profiles of rough endoplasmic reticulum, a few round-tooval mitochondria, and one or more welldeveloped Golgi complexes, the latter usually


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FIG. 1 . Section of myometrium showing a vascular space full of tumor. The tumor consists of closely packed spindle-shaped cells and several thin-walled blood vessels (H & E, ~ 1 0 0 ) .

disposed around a centriole (Figs. 2 and 3). Free ribosomes and polyribosomes were frequent. Some of the cells were partly covered by basal laminae (Fig. 2). Desmosomes were infrequent. I n some areas the tumor cells contained prominent dilated cisterns of rough endoplasmic reticulum, margins of condensation, and extracellular and intracellular collagen, thus resembling fibroblasts (Fig. 4). Some of the tumor cells were poorly differentiated and consisted of round-to-oval nuclei and small amounts of cytoplasm, with only a few organelles (Fig. 5 ) . Single cilia were seen in a few cells (Fig. 6). T h e tumor contained a rich net work of well-formed capillaries. These capillaries consisted of a single layer of endothelial cells resting on a basement membrane, which in turn was surrounded by a zone of collagen fibers (Fig. 7). Occasionally the capillary walls also included pericytes. DISCUSSION Komorowskie et al.6 studied the ultrastructure of a stromal sarcoma from a 40-year-old woman. T h e tumor was composed of tightly packed polyhydral cells separated by narrow intercellular spaces. Occasionally larger intercellular spaces containing bundles of collagen

fibers were noted. Most of the tumor cells contained scanty cytoplasm with poorly developed organelles. T h e tumor contained a rich vascular network. T h e ultrastructure of the tumor cells was compared with that of stromal cells of the 6th day proliferative endometrium from a 28-year-old woman. It was concluded that a definite likeness exists between the ultrastructure of endometrial stromal sarcoma and the stromal cells of early proliferative endometrium, thus suggesting an endometrial histogenesis of the tumor.6 Electron microscopic studies of the stromal cells of endometrium have been sparse.6s16v1* Wienke et a1.16 have noted that the structure of stromal cells shows marked variation depending upon the phase of the menstrual cycle, Thus, during the early proliferative phase, the stromal cells are immature and resemble stem cells. During the latter part of the proliferative phase and early part of progestational phase, these cells gradually transform into cells resembling active fibroblasts and show evidence of collagen synthesis. During the late secretory phase the cells transform into predecidual cells.16 In our case the tumor cells vary with regard to their shape, size, and degrees of differentation. A majority of the cells, however, show moderately well-developed cytoplasmic organ-


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FIG.2. Electron micrograph of an area of the tumor showing two irregularly shaped cells with poorly formed desmosomes (small arrows). Cytoplasm contains several mitochondria, occasional profiles of endoplasmic reticulum, and free ribosomes and polyribosomes. Portions of two other cells with prominent cisterns of endoplasmic reticulum are also noted. Intercellular matrix consists of collagen fibers and some amorphous material. One of the cells is partly covered by basal lamina (large arrow) (~13,050, reduced from 15,000).

elles, including profiles of rough endoplasmic reticulum, well-developed Golgi complexes, free ribosomes, and several round-to-ovoid mitochondria. These cells resemble stromal cells in a midproliferative endometrium. Some of the cells are poorly differentiated and are characterized by round-to-oval nuclei and scanty cytoplasm, which shows sparse cytoplasmic organelles. These cells are similar to stromal cells of early proliferative endometrium. Cells with fibroblastic differentiation as seen in this tumor are similar to the superficial stromal cells in late proliferative and early secretory phase.16

I n view of the fact that most of the cells in this tumor closely mimic the structure of normal stromal cells, it can justifiably be concluded that this tumor is probably derived from the endometrial stromal cells. This is in agreement with the findings of Komorowski et al.6 It has been suggested in the past that stromal sarcomas of the uterus are identical to hemangiopericytomas of other organ~.~JO Both tumors have a similar histologic appearance and an identical general architecture, characterized by a rich network of fine

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capillaries surrounded by closely packed, rather uniform tumor cells. A categorical distinction between hemangiopericytoma and stromal sarcoma would, therefore, depend on an ultrastructural differentiation between the cells comprising these tumors. Electron microscopic studies of hemangiopericytoma have failed to establish uniform criteria for the recognition of these tumors. According to these studies some tumors are comprised of uniform, closely packed cells showing ultrastructural features closely resembling those of normal pericyte~.~.597J3 The pericytic histogenesis of such tumors appears well established. By contrast several other tumors are composed of cells which are described as nondescript mesenchymal cells in which no definite evidence of pericytic dif-


ferentiation is noted.lV*Jz These tumors have also been designated as hemangiopericytomas, since they meet the histologic criteria established by Stout,15 although ultrastructural evidence of a pericytic histiogenesis in these cases is not yet forthcoming. Ultrastructure of the cells in stromal sarcoma as described by Komorowski et al.6 and as demonstrated in this study, resembles that of stromal cells of proliferative endometrium and does not show features which usually characterize pericytes (complete investment by basal lamina, numerous pinocytic vesicles, tine cytoplasmic filaments, and scanty endoplasmic r e t i c ~ l u m )Therefore, .~ it is concluded that in spite of the striking histologic resemblance, stromal sarcoma and hemangiopericytoma are distinct entities. Presence of

FIG. 3. Elongated tumor cells each featuring several Golgi complexes, in close proximity to a centriole (X17.400, reduced from 20,000).


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FIG.4. A tumor cell featuring prominent rough endoplasmic reticulum, margins of condensation (small arrows), and extracellular and intracellular collagen (large arrow) (X26,550, reduced from 30,000).

cells with cilia, as noted in this case, has not been observed in previous studies of normal endometrial stroma or stromal sarcoma. However, the presence of occasional cilia in nonepithelial cells, such as smooth muscle cells, astrocytes, and neurons has been well documented.3.ll It is of interest to note that, histologically, our tumor appears to be a low-grade stromal tumor resembling the relatively benign endometrial stromatosis; yet the tumor manifested extensive local recurrence and infiltrative propensity and metastasized to the lung. Such a discrepancy between the histologic appearance and the clinical behavior of endometrial stromal tumors, however, is not unusual. T h e endometrial stromal sarcoma and the less aggressive endometrial stromatosis represent the extremes of invasive stromal lesions. As noted by Wiesbrot and Janovski, there is a large middle ground where morphological criteria alone are not adequate for prognosis.17 In a study of endometrial stromal tumors, Norris and Taylor noted that those stromal tumors which have infiltrative borders and which

manifest propensity for vascular invasion (as noted in our case) showed a high incidence of recurrence and/or metastasis, regardless of the histologic grading.9 Stromal sarcomas are believed to share a common histogenesis with mixed mesodermal tumors, which are comprised of carcinomatous and sarcomatous components, the latter including heterotopic elements such as cartilage, bone, striated muscle, and fat. Ultrastructure of mixed mesodermal tumor has been described in only two relatively recent reports. Silverberg14 studied the ultrastructure of two such tumors and noted that the predominant cell in the sarcomatous areas of the tumors resembled normal endometrial stromal cells. Intermediate forms between the basic stromal cells and cells differentiated as fibroblasts and chondroblasts were also seen. Boram et a1.2 studied the fine structure of another mixed mesodermal tumor in which the sarcomatous component consisted of cells showing various stages of development of differentiated myoblasts from primitive mesenchymal cells. No stromal cells were seen.

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FIG.5. A poorly differentiated tumor cell with ovoid nucleus and scanty cytoplasm with poorly developed organelles ( ~ 1 7 , 4 0 0 , reduced from 20,000).

FIG. 6. A tumor cell with cilium (~30,000).



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FIG. 7. A small capillary consisting of a layer of endothelial cells. A zone of collagen fibers separates the tumor cells from the capillary (~15,000).

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3. Ferenczy, A., Richart, R . M., and Okagaki, T.: A comparative ultrastructural study of leiomyosarcoma, cellular leiomyoma and leiomyoma of the uterus. Cancer 28:1004-1018, 1971. 4. Greene, R. R., and Gerbie, A. B.: Hemangiopericytoma of the uterus. Obstet. Gynecol. 3:150-159, 1954. 5. Hahn, M. J., Dawson, R., Esterly, J. A., and Joseph, D. J.: Hemangiopericytoma-An ultrastructural study. Cancer 31:255-261, 1973. 6. Komorowski, R. A., Garancis, J. C., and Clowry, L. J.: Fine structure of endometrial stromal sarcoma. Cancer 26:1042-1047, 1971. 7. Kuhn, C., and Rosai, J.: Tumors arising from pericytes-Ultrastructure and organ culture of a case. Arch. Pathol. 88:653-663, 1969. 8. Murad, T. M., Von Haam, E., and Murray, M. S. N.: Ultrastructure of a hemangiopericytoma and a glomus tumor. Cancer 22:1239-1249, 1968. 9. Norris, H. J., and Taylor, H . B.: Mesenchymal A clinical and pathologic tumors of the uterus-I. study of 53 endometrial stromal tumors. Cavcer 19: 755-766,1966.

10. Pedowitz, R., Felmus, L. B., and Grayzel, D.: Hemangiopericytoma of the uterus. A m e r . J. Obstel. Gynecol. 67:549-563, 1954. 11. Peters, A., Palay, S. L., and Webster, H de F.: T h e Fine Structure of the Nervous System. New York, Harper an d Row, 1970; pp. 26-30, 108, 114. 12. Ramsey, H. J.: Fine structure of hemangiopericytoma and hemangioendothelioma. Cancer 19:20052017, 1966. 13. Silverberg, S. G., Willson, M. A., and Board,

J. A.: Hemangiopericytoma of the uterus-An ultrastructural study. A m . J. Obstet. Gynecol. 110397-104, 1971. 14. Silverberg, S. G.: Malignant mixed mesodermal

tumor of the uterus-An ultrastructural study. A m . J. Obstet. Gyencol. 110:702-712, 1971. 15. Stout, A. P., and Murray, M. R.: Hemangiopericytoma-A vascular tumor featuring Zimmerman’s pericytes. Ann. Surg. 116:26-33, 1942. 16. Wienke, E. C., Cavazos, F., Hall, D. G., and Lucas, F. V.: Ultrastructure of the human endometrial stroma cell during the menstrual cycle. Am. J . Obstet. Gynecol. 102:65-77, 1968. 17. Weisbrot, I. M., and Janovski, N. A.: Endometrial stromal sarcoma. A m . J. Clin. Pathol. 39273-283, 1963. 18. Wynn, R. M., and Harris, J. A,: Ultrastructural cyclic changes in the human endometrium.-I. Normal preovulatory phase. Fertil. Steril. 18:632-648, 1967.

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