Primary Angiosarcoma of the Ovary: A Clinicopathologic, Immunohistochemical and Electronmicroscopic Study

Primary Angiosarcoma of the Ovary: A Clinicopathologic, Immunohistochemical and Electronmicroscopic Study

PATHOLOGY :'.; ~ ", .TeaEhlng Case_ RESEARCH AND PRAaJCE © Gustav Fischer Verlag Primary Angiosarcoma of the Ovary: A Clinicopathologic, Immuno...

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PATHOLOGY

:'.;

~

",

.TeaEhlng Case_

RESEARCH AND PRAaJCE

© Gustav Fischer Verlag

Primary Angiosarcoma of the Ovary: A Clinicopathologic, Immunohistochemical and Electronmicroscopic Study* B. Lifschitz-Mercer 1, L. Leider-Trejo 1, G. Messer2 , M. R. Peyser 3 and B. Czernobilsky1 'Institute of Pathology, 2Laboratory for Electronmicroscopy and 3Department of Obstetrics and Gynecology A, Sourasky Medical Center, Tel Aviv, affiliated to the Sackler School of Medicine, University of Tel Aviv, Israel

Summary The present report of a 25 year old woman with a primary ovarian angiosarcoma is supplemented by histochemical and ultrastructural studies and reviews the literature of this extremely rare neoplasm. Since this ovarian tumor, especially in young women, may constitute a diagnostic pitfall, problems relating to differential diagnosis are emphasized. Although the origin of this neoplasm appears to occur most likely from the rich ovarian vasculature, other less conventional histogenetic theories such as a possible origin in mixed mullerian tumor, in teratoma or in other ovarian germ cell tumors have also been proposed and are considered in this paper.

tion ovarian angiosarcoma shows histologic features which are similar to those seen in this neoplasm in other sites, the rare occurrence of this tumor in the ovary and its highly varied histologic features, may, especially in young women, constitute a diagnostic pitfall for the examining pathologist. The present case report supplemented by immunohistochemical and ultrastructural data, emphasizes problems in differential diagnosis, considers histogenetic theories and reviews the literature of this rare tumor. Case Report

Primary angiosarcomas of the ovary are extremely rare, with only about 20 cases reported so far [1, 2, 4, 7, 9, 10, 11, 12, 13, 16, 17}. Since some series include previously reported angiosarcomas and some reports lack illustrations and/or special stains, it is difficult to establish with certainty the exact number of original cases published to date. Although on microscopic examina-

The patient, a 25 year old white woman, gravida 2, para 2, was admitted to the hospital with a three month history of abdominal pain and distention, loss of appetite and weight loss of 8 kg. Her last delivery was 2 months prior to the hospital admission and she was nursing until her hospitalization. Past history was unremarkable. On physical examination there was massive ascites. A large pelvic mass was palpated in the region of the left adnexa. The uterus and the right adnexae were of usual size. The remaining physical examination and laboratory tests yielded no abnormalities. Ultrasonography confirmed the presence of the ascites as well as that of a left pelvic mass which was partially solid and cystic. Paracenthesis of the abdominal fluid revealed sera-sanguinous fluid without malignant cells.

* The present case, in a shortened version without ultrastructural data, is included in a series which has been accepted for publication in the American Journal of Surgical Pathology [Ref. 9].

Address for correspondence: Dr. B. Lifschitz-Mercer, Institute of Pathology, Sourasky Medical Center, 6 Weizmann street, Tel Aviv, 64239, Israel. Tel.: 972-3-6 97 35 30, Fax: 972-3-6973610

Key words: Angiosarcoma - Ovary

Introduction

Pathol. Res. Pract. 194: 183-187 (1998)

0344-0338/98/0194-0183$5.00/0

184 . B. Lifschitz-Mercer et al.

An exploratory laparatomy was performed. The abdominal cavity contained 5 liters of sero-sanguinous fluid and a left ovarian mass which was removed together with the left fallopian tube. The uterus and right adnexa, as well as other abdominal organs showed no gross abnormalities. Postoperatively the patient received three courses of ifosfamide and doxorubicin. Eighteen months following the operation the patient is alive but presents a diffuse spread of intraabdominal tumor. Pathologic Findings A left partially tom adnexal mass weighing 325 gm and measuring 13 x 11 x 5 cm with the adjacent fallopian tube was submitted. The outer surface of the mass was nodular with numerous hemorrhages. Cut section revealed a tan, friable hemorrhagic tumor with cystic areas containing hemorrhagic fluid. On microscopic examination of hematoxylin-eosin stained slides the tumor presented a plethora of histologic features. The predominant picture was that of communicating channels lined by cells ranging from flat to plump with nuclei which were either spindly, pleomorphic or hyperchromatic. In some areas, epithelioid lining cells were prominent. The mitotic rate averaged 8 per 10 high power fields and included atypical mitoses. In some areas the channels created a sinusoidal pattern. Dilated irregular spaces with papillary formations were also present. In addition there were scattered cytoplasmic vacuoles containing isolated erythrocytes as well as microcystic structures. The tumor also showed areas rich in spindle and clear cells. Few eosinophilic round globules were present (Fig. 1-3).

Fig. 1. Ovarian angiosarcoma showing channels lined by plump epithelioid type cells, suggestive of embryonal carcinoma.

Material and Methods Immunohistochemistry

Immunoperoxidase staining was performed on formalin fixed, paraffin-embedded tissues [5]. Primary antibodies used are listed in Table I. Secondary antibodies for immunoperoxidase staining were biotinylated antibodies to mouse or rabbit immunoglobulins and avidin-peroxidase complex supplied as a kit (Vectastain Elite ABC kit, Vector Laboratories, Burlingame, CA, USA). Electronmicroscopy

Tissue fixed in formalin was postfixed in 1% osmium tetroxide. Following dehydration in ethanols and propylene oxide, samples were embedded in epoxy resin. Semithin,

Fig. 2. Dilated, irregular spaces with papillary projections, simulating the pattern encountered in Sertoli-Leydig cell tumor with retiform pattern.

Fig. 3. Hyaline globule (arrow) within cellular area with focal microcystic structures mimicking yolk sac tumor.

Primary Ovarian Angiosarcoma . 185 Table I. Primary antibodies used

Table 2. Immunotyping of tumor cells in ovarian angiosarcoma

Antibody

Source

Antibody

Results

Broad spectrum cytokeratins (AEI/AE3) Vimentin

Zymed (San Francisco, CA, USA) Dakopatts (Glostrup, Denmark) Dakopatts

Cytokeratins (AEI, AE3) Vimentin a-SM actin CD31 CD34 Factor VIII EMA CEA AFP

+ ++ + ++ ++ ++

Alpha-Smooth muscle actin (a-SM actin) CD31 CD34 Von Willebrand factor (factor VIII) Epithelial membrane antigen (EMA) Carcinoembryonic antigen (CEA) Alpha-Feto protein (AFP)

Dakopatts Dakopatts Dakopatts Dakopatts Zymed Dakopatts

I mfl sections stained with toluidine blue were examined by light microscopy with the purpose of selecting samples for electron microscopy. Ultrathin sections stained with uranyl acetate and lead citrate were examined in a leol 100 B electron microscope.

Results

Immunohistochemistry

All the tumor cells, including those forming channels and solid areas, as well as the stromal cells, were strongly labeled with vimentin. Staining with broad spectrum cytokeratin antibody was positive in only very few, isolated epithelioid cells and occasionally in spindle cells. Alpha SM-actin labeled the walls of medium sized blood vessels and occasional cells in the solid parts of the tumor, as well as numerous stromal ele-

Fig. 4. Diffuse staining of vascular tumor cells with antibody CD31, staining vascular endothelium.

- no staining, + focal staining, ++ diffuse staining

ments. CD34 strongly stained tumor cells lining the various sized channels as well as scattered cells in the solid portions of the tumor. CD31 stained both the lining cells of the channels as well as the solid portions of the tumor (Fig. 4). Factor VII related antigen stained the endothelial cells lining blood vessels but only isolated cells in the more solid portions of the tumor. There was no staining for EMA, CEA and AFP (Table 2). Electronmicroscopy

On electronmicroscopic examination, Weibel-Palade bodies were present in the lining cells of the small blood vessel-like structures. The endothelial cells showed intracellular pinocytotic vesicles and junctions, and were surrounded by a basement membrane. Single erythrocytes filled intracellular lumina in some instances (Fig. 5).

186 . B. Lifschitz-Mercer et al.

Fig. 5. Electronmicrograph of Weibel-Palade bodies showing the microtubular structure in cross-section (short arrow) and in longitudinal section (long arrow). An erythrocyte is present in the adjacent lumen (x60,OOO).

Discussion Primary angiosarcomas of the ovary are exceedingly rare. To date only about 20 cases have been recorded [I, 2,4,7,9, 10, 11, 12, 13, 16, 17]. The age of patients with this neoplasm ranges from 19 to 77 years with a mean of about 45 years. Most of the primary ovarian angiosarcomas are unilateral. Bilaterality is usually associated with sarcomas metastatic to the ovary [21]. Symptoms are non-specific and are mostly related to the presence of an abdominal mass and occasionally to intraabdominal bleeding. The prognosis is dismal with all patients beyond stage I dying of their disease between 18 days to 2.5 years after diagnosis [7]. On macroscopic examination ovarian angiosarcoma presents as a large, soft friable, hemorrhagic mass with cystic and necrotic areas. Histologically the tumor is composed of maze-like anastomosing channels lined by atypical cells, papillary formations, solid areas with spindle-shaped cells and necrosis. Cytoplasmic vacuoles containing individual erythrocytes representing the earliest form of vascular differentiation can also be observed. Mitotic activity is usually high. Immunohistochemical studies in the present case showed strong positivity with antibodies against vascular endothelium such as CD34, CD31 and Factor VIII. Focal positivity with broad spectrum cytokeratin antibody was also noted. The latter has been previously re-

ported in some vascular tumors, particularly in those with epithelioid features [3]. Vascular tumors are rare in the ovary in spite of the rich vascularity of this organ. While benign capillary or cavernous hemangiomas only rarely suggest angiosarcoma, ovarian hemangiopericytoma constitutes a more difficult diagnostic problem. According to Prat and Fox [l4J, at least some of these ovarian tumors reported in the past represented most likely endometrioid stromal sarcomas of low grade malignancy. Nevertheless, at least two cases of well documented ovarian hemangiopericytoma have been reported [6,8]. The rare ovarian lymphangiomas are small lesions usually found incidentally. Microscopically they show thin-walled vascular spaces lined by flat endothelial cells lacking blood within the lumen. While these lesions do not constitute a problem of differential diagnosis with angiosarcomas, lymphangiosarcoma of which only one case has been reported [l5J certainly may prove to be difficult to separate from the former. It is a well established fact that especially in poorly differentiated angiosarcoma at any site, a high index of suspicion is required in order to arrive at a correct diagnosis. Among the neoplasms which may mimick angiosarcoma, malignant melanoma and poorly differentiated carcinoma figure prominantly. In the ovary of young women, as in the present case, angiosarcoma must also be differentiated from certain sex-cord stro-

Primary Ovarian Angiosarcoma . 187

mal and germ cell tumors which are much more common than angiosarcomas in these patients. The slit like channels lined by epithelioid endothelial cells, cystic structures and tubules with delicate papillae lined by cells showing nuclear pleomorphism and prominent nucleoli characteristic of angiosarcoma may also suggest, especially within the context of an ovarian malignant neoplasm in a young woman, an embryonal carcinoma, the retiform type of Sertoli Leydig cell tumor or yolk sac tumor. The eosinophilic round globules as seen in the present case are also characteristic of the latter neoplasm. A careful study will reveal, however, typical areas of angiosarcoma which will establish an accurate diagnosis. Furthermore, the widespread labelling of tumor cells with antibodies to endothelium in angiosarcoma will be negative in the tumor cells of the non-vascular neoplasms with which ovarian angiosarcoma may be confused. Although both benign and malignant ovarian vascular neoplasm arise most likely from the rich vasculature of this organ, other less conventional theories have also been advanced. Thus, the association of an ovarian angiosarcoma with a mucinous cystadenoma [10] has given rise to the speculation that the former may constitute part of a mixed mullerian tumor. Furthermore, the report of an ovarian mixed germ cell tumor and a cavernous hemangiomatous lesion [19] suggested that ovarian vascular tumors may share an identical origin with germ cell tumors, a concept which is also supported by the report of Ulbright et al. [20] of angiosarcoma associated with testicular and mediastinal germ cell tumors. Finally, in this context Talerman described an ovarian monodermal purely vascular teratoma [18]. It is also of interest that two out of the 7 cases of ovarian primary angiosarcoma reported by Nielsen et al. [7] arose in a dermoid cyst. In conclusion, the present case report of an ovarian angiosarcoma in a young woman with a review of the literature in which routine histologic examination was supplemented by the use of immunohistochemical stains and electronmicroscopic examination, emphasizes problems in differential diagnosis and discusses various theories concerning the histogenesis of this rare tumor.

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