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Extrauterine Müllerian adenosarcoma; a clinicopathologic report of a case with distant metastases and review of the literature
GYNECOLOGIC
ONCOLOGY
6, 261-274 (1978)
Extrauterine Miillerian Adenosarcoma; A Clinicopathologic Report of a Case with Distant Metastases and Review of the Literature EVA SPERK BARD, M. D., DAVID S. BARD, M. D., FACOG,’ AND FERNANDO VARGAS-CORTES, M. D. Departments
of Pathology and Obstetrics and Gynecology, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida
Received June 30, 1977 This is a report of a Mtillerian adenosarcoma of homologous type which arose from the right pelvic sidewall and presented as a pelvic hematoma in a 46year-old woman. The tumor was locally aggressive and histologically similar to cases arising in the uterus reported earlier by Clement and Scully. Following her death from B. fragilis septicemia, the autopsy revealed widespread, occult hematogenous metastases composed entirely of the sarcomatous element of the tumor. The problems in diagnosis and management of a pelvic sidewall neoplasm are presented, and the methods of therapy of the homologous and heterologous forms of this new entity are reviewed and discussed in relation to their biologic behavior.
The term Mfillerian adenosarcoma has been proposed by Clement and Scully to designate a distinct type of Miillerian tumor composed of malignant stroma admixed with neoplastic, but histologically benign, epithelial elements [l]. The benign appearance of the neoplastic epithelium differentiates the Miillerian adenosarcoma from the classical malignant mixed Miillerian tumors. The sarcomatous component usually resembles an endometrial stromal sarcoma, but heterologous features have been described [ 1,2]. All tumors reported to date have originated in either the uterine corpus or cervix, but theoretically they could arise from any site where Miillerian tissue has been identified [3, 41. CASE REPORT
A 46-year-old white nulligravida was referred to the University of Florida in January 1975 with an enlarging mass of the right pelvic sidewall of 3-months duration. She had an abdominal hysterectomy in 1958 for leiomyomata and a lumbar laminectomy in 1969 for a herniated disc. There was no history of pelvic irradiation. She was asymptomatic until July 1973 when she developed a gradual onset of weakness and pain in the right lower extremity similar to the disc symptomatology ’ Address reprint requests to David S. Bard, M. D., University of Tennessee Center for the Health Sciences, Memphis, Tennessee 38163. 261 0090~8258/78/0063-0261$01.00/O Copyright @ 1978 by Academic Press, Inc. AU rights of reproduction in any form reservetl.
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in 1969. Repeat myelograms were abnormal and she underwent re-exploration and decompression of the lumbar spine in January and again in May of 1974. The neuropathy progressed and she became bedridden. In September 1974 she developed thrombophlebitis and pulmonary emboli, and anticoagulant therapy was complicated by intermittent bruising and melena. In October 1974 a right hydronephrosis was demonstrated on IVP, and an indistinct mass was palpated against the right pelvic sidewall which was interpreted as a hematoma. By January 1975 the patient had developed urinary incontinence, right vulvar edema, and a painless subcutaneous mass in the right ischiorectal fossa. On examination, a nontender, smooth, rubbery mass occupied over half of the pelvic cavity. At laparoscopy, both ovaries and oviducts were normal, but an extraperitoneal mass filled the right pelvic cavity. The mass was explored through an incision in the right lower vaginal wall just inside the introitus, and 250 g of a partly organized blood clot was removed by suction and forceps. A gray, more solid, tissue fragment was removed with the suction tip and was subsequently interpreted as Miillerian adenosarcoma (Consultant, R. E. Scully). The patient was referred to the University of Florida. On admission her temperature was 39°C; WBC, 19,500; and Hct, 3%. The patient complained of severe hip and thigh pain on motion. The lungs, abdomen, and lymph nodes were unremarkable. A 10 x 8-cm soft, coarsely nodular, and slightly tender mass was firmly attached to the right pelvic sidewall, displaced the vagina and rectum sharply to the left, and extended subcutaneously downward into the right ischiorectal fossa. An 8-cm-deep sinus tract arose from within the mass, terminated on the right introitus, and drained foul-smelling, sero-purulent material. Cultures demonstrated a heavy growth of B. fragilis. The right lower extremity had a foot-drop, absent deep tendon reflexes, and moderate swelling, but had normal sensation and was normal in color. The urinary bladder and rectum were displaced to the left but were free of intrinsic lesions and tumor. Chest X ray and barium enema were normal. The IVP showed that the previous right hydroureter had resolved, but disclosed a 3 x 2-cm erosion of the inner cortex of the right OSilium and OSischium. This pelvic bone involvement was confirmed by bone scan, while other bones, including the spine, were normal. Lymphangiogram and arteriogram could not be performed due to a moderately severe reaction to IVP dye. A low-grade fever persisted during 2 weeks of specific antibiotics and frequent irrigations of the infected pelvic tumor, but after surgical debridement and improvement of drainage, the temperature rapidly returned to normal. The patient was offered, but refused, exploration and possible combined hemipelvectomy and pelvic exenteration. Over the next 7 weeks, 5000-R (of a planned 6500-R split course) cobalt teletherapy was delivered to the tumor through AP, PA, and right lateral pelvic ports which included the right lower buttock and vulva. The overall response was encouraging with 7% reduction in volume of the mass and sufficient pain relief to enable the patient to resume ambulation. She was to return in 2 weeks for the final 1500R. Three days before this appointment, purulent drainage recurred from the sinus tract and her temperature rose to 40°C. She was readmitted, cultured, and started on chloramphenicol, but sepsis progressed
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rapidly and she expired 6 days later. B. fragilis the sinus tract.
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was cultured from the blood and
Pathology
The autopsy material and all antemortem specimens except the uterus were available for review. According to the pathology report of the 1958 hysterectomy specimen, 2 “the uterus was coarsely nodular, measured 13 x 10 x 9 ems, and was distorted by numerous subserosal, intramural, and submucosal, firm, white nodules, the largest of which measured 6 ems. The endometrium was thick, tan, and soft, and measured up to 0.6 ems.” The diagnoses were “endometrium secretory Histologic review of the laminectomy speciphase,” and “fibroleiomyomata.” mens from 1969 and 1974 showed disc material and scar without evidence of tumor. Gross Pathology
The surgical specimens of the paravaginal mass consisted of irregular fragments of nodular, spongy, red-brown tissue resembling partly organized blood clots with firmer, light brown areas and scattered membranous strands. At autopsy, an 8 x 6-cm necrotic, partially cavitated, extraperitoneal mass was fixed to the right pelvic sidewall and created an irregular bony defect in the adjacent ischium. The mass was adherent to the right bladder wall and surrounded, but did not invade or occlude, the right ureter. The pelvic peritoneum, vagina1 walls, and cuff were uninvolved. Both ovaries and Fallopian tubes were normal and the uterus was absent. There was no evidence of pelvic endometriosis, intra-abdominal tumor, or pelvic or paraaortic lymphadenopathy. The left lung contained two firm, graywhite, irregular tumor nodules, the larger measuring 3.0 x 1.0 x 0.5 cm. Most of the second and third lumbar vertebra1 bodies were dark brown, softened, and replaced by tumor. Each of the bodies of the eleventh and twelfth thoracic vertebrae contained a l-cm pale gray, firm, round lesion which suggested tumor. Lymph nodes were sampled from all major groups but were grossly unremarkable. Microscopic
Pathology
The surgical specimens contained neoplastic mesenchymal and epithelial elements intermixed with extensive hemorrhage and necrosis. The tumor tended to form coarse papillary projections covered with epithelium. Multiple glands permeated the underlying stroma and ranged from branching tubular and cleft-like to round and small. The glands were widely separated by variable amounts of malignant stroma and were in no place back-to-back (Fig. 1). The epithelium of the glands and surface was polymorphic and moderately atypical and, in most areas, was simple to pseudostratified columnar with focal cilia resembling endometrial epithelium (Fig. 2). Foci of clear cells (Fig. 3) and squamous epithelium (Fig. 4) were present. The nuclei were round to oval and vesicular with small nucleoli and focal hyperchromasia. Mitoses were rare. The predominant component of the tumor was a moderately cellular stroma that 2 Courtesy of Dr. R. Monaco, Bay Memorial Hospital, Panama City, Florida 32401.
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FIG. 1. Pelvic tumor. Widely separated, benign-appearing, branching tubular, and cleft-like glands. Periglandular condensation of stromal cells in lower right corner (H and E, x 40).
resembled endometrial stroma and consisted of stellate to plump spindle cells in a fibrillary matrix (Fig. 5). Their mildly hyperchromatic nuclei were round to ovoid and vesicular. In the most active areas, there were five mitoses per 10 high-power fields (hpf). The stroma tended to be more compact around the glands and immediately beneath the surface epithelium (Fig. I), while in other areas it appeared myxomatous. Some areas had an abundance of prominent capillaries and resembled granulation tissue. In the autopsy material, the irradiated, residual pelvic tumor contained fewer glands than the antemortem surgical specimens. These glands were atypical,
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FIG. 2. Simple to pseudostratified columnar epithelium of glandular elements. Insert shows presence of cilia (H and E, x 400).
distorted, and degenerating. The tumor involved the right ischium, the bodies of the tenth and eleventh thoracic and the second and third lumbar vertebrae (Fig. 6), the lung (Fig. 7), and the perinodal adipose tissue of several mediastinal and porta hepatic lymph nodes (Fig. 8). All metastatic sites consisted of pure sarcoma without the glandular component and were similar to that in the antemortem material, but tended to be more compact with a mitotic rate of 8’10 hpf. In the lung, the tumor cells were more elongated with oval nuclei and prominent nucleoli (Fig. 9). DISCUSSION
Although pelvic tumors with similar histologic appearance have been described by other authors [4-61, the Miillerian adenosarcoma was only recently defined and proposed as a distinct type of malignant mixed Miillerian tumor by Clement and Scully [I]. The tumor is unique because its epithelial component, while neoplastic, appears and behaves benign. As with other tumors of Miillerian origin, the morphologic appearance of the elements comprising the adenosarcoma is variable with a general relationship of the stroma and glands similar to that of the cystosarcoma phyllodes of the breast.
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FIG. 3.
BARD,
AND
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Atypical glandular epithelium with vacuolated columnar cells (H and E, x 400).
The mesenchymal component is usually homologous and resembles a low-grade endometrial stromal sarcoma, but three cases with heterologous differentiation have been reported; one with an embryonal rhabdomyosarcoma-like stroma [ll, another with focal rhabdomyoblasts [l], and another with an embryonal rhabdomyosarcoma and foci of cartilage [21. The distinctive histologic feature of both the homologous and heterologous types is the presence of benign, but frequently atypical-appearing, glandular epithelium of Mtillerian type. This epithelial component is considered to be an integral part of the neoplasm because of its diffuse and extensive presence throughout the primary tumors and in local recurrences following hysterectomy [l]. The Miillerian adenosarcomas, therefore, can be defined as a group of Mtillerian-derived tumors consisting of a homologous or heterologous malignant stroma admixed with atypical but benign neoplastic glands and should be classified in the spectrum of mixed Mulletian tumors somewhere between the benign adenofibroma [7,8] and the malignant mixed Miillerian tumors of homologous and heterologous types [9]. The biological behavior of the homologous type of adenosarcoma can be as-
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FIG. 4.
MiiLLERIAN
267
ADENOSARCOMA
Focus of squamous epithelium
(H and E,
x
100).
sessed from eight cases arising in the uterus reported by Clement and Scully [II. Of five Stage I cases followed from 2 to 10 years after hysterectomy, none have demonstrated clinical evidence of distant metastases, but two have developed recurrence in the upper vagina; one at 2.5 years (mitotic rate, 6/10 hpf) and the other at 4 years (mitotic rate, 4/10 hpf). The latter patient died of extensive pelvic recurrence 6 years later. No case has, as yet, received a postmortem examination. Local recurrence, therefore, is relatively frequent following surgical excision and when discovered it is usually over 2 years later. This pattern of biologic behavior is similar to the “low-grade” endometrial stromal sarcomas [5,9,101. From experience with other heterologous tumors of Mtillerian origin, the biological behavior of the heterologous type of adenosarcoma would be expected to be more aggressive [9]. Three cases have been reported to date [1,2]. The sarcomatous component of one tumor had features consistent with embryonal rhabdomyosarcoma and had a mitotic rate of 40/10 hpf. The patient developed skin and bone metastases and intra-abdominal recurrence within 7 months following intracavitary radium and hysterectomy [l]. Another tumor contained an area suggestive of rhabdomyoblasts and had 10 mitoses per hpf. The patient developed vaginal recurrence 18 months after hysterectomy [ 11.Roth reported an adenosar-
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FIG. 5. Stroma of pelvic tumor. Fibrillary matrix with stellate and plump spindle cells (H and E, x 250).
coma with heterologous elements arising in the endocervix of a 14-year-old girl [2]. The sarcomatous portion consisted of embryonal rhabdomyosarcoma with numerous mitoses and foci of pleomorphic rhabdomyosarcoma and cartilage. The patient was still free of disease 42 months following radical hysterectomy, vaginectomy, and pelvic lymphadenectomy, whole abdominal irradiation, a 2000-R pelvic boost, and 1 year of combination chemotherapy utilizing vincristine, dactinomycin, and cyclophosphamide. When compared with the homologous type of adenosarcoma, therefore, an adenosarcoma containing definite, or suspected, heterologous elements may be a more aggressive neoplasm with a greater, and earlier, probability of local recurrence and distant, primarily hematogenous, metastases. The case presented herein is a Miillerian adenosarcoma of homologous type which appears to have arisen form the pelvic sidewall. Although an occasional low-grade endometrial stromal sarcoma has been reported to recur 27 years after initial therapy [IO], it seems unlikely that this case represents a recurrence of a primary uterine adenosarcoma 16 years following hysterectomy because: (a) the
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FIG. 6. Vertebral bone marrow replaced by metastatic tumor (H and E, x 40).
original pathology report described a uterus that contained grossly and microscopically typical leiomyomata but no other lesions; (b) all reported recurrences of the homologous type of adenosarcoma of uterine origin have involved the upper vagina and cuff [ 11;(c) the tumor’s mitotic rate of WY10 hpf, when analyzed with previous cases [ 11,corresponds with an expected time of recurrence at 2-4 years, rather than 16 years, following treatment; and (d) other neoplasms of Mtiilerian origin are known to arise in extrauterine sites such as the pelvic lymph nodes, endometriotic deposits, the Fallopian tubes, and even the ovary [ 1,3,4]. Although all reported Miillerian adenosarcomas have arisen in the uterine corpus or cervix, several histologically similar tumors described in the literature may have had an extrauterine origin [ 1,111. The primary pelvic tumor in our case contained the distinctive histopathologic features of a homologous adenosarcoma with a diffuse admixture of atypicalappearing epithelial elements in a sarcomatous stroma. Only the sarcomatous element, however, was identified in the small, but widespread, hematogenous metastases to lung, bone, and perinodal adipose tissue. These findings are consis-
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FIG. 7. Lung metastasis. Predominant location in interlobular septum. Alveoli present in left upper and right lower corners (H and E, x 40).
tent with the thesis that the neoplastic glands in the pelvic tumors are benign and that the malignant behavior of the homologous adenosarcoma is fundamentally a reflection of the sarcomatous element. From a clinical standpoint, our case presented with the classical symptoms of a neoplasm involving the pelvic sidewall: unilateral sciatic pain and neuropathy, venous occlusion, and hydronephrosis. The clinical diagnosis was obscured, however, because of the patient’s previous history of lumbar disc surgery and her severe bleeding problems during anticoagulation for thromboembolism. The mass presented as a hematoma, but as time, symptoms, and its size progressed a neoplasm was considered. Exploration of the mass through the lower vagina revealed a small fragment of tissue containing the adenosarcoma, but the predominant component of the mass consisted of partly organized, hematoma-like material. The association of extensive hemorrhage with the pelvic sidewall tumor is interesting and important, but of uncertain etiology. Possible explanations include vascular or marrow invasion by tumor, uncontrolled anticoagulation, stromal
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FIG. 8. Anterior mediastinal lymph node. Pericapsular location of metastatic tumor. Uninvolved node parenchyma on the left (H and E, x 40).
necrosis within the tissue from cyclic hormone withdrawal similar to endometriosis or menses [12], extensive necrosis and hemorrhage of proliferating tumor, or combinations of the above. While the hemorrhagic component undoubtedly enhanced the size and symptoms of the neoplasm resulting in its earlier detection, it later served as the nidus for uncontrollable infection and fatal septicemia. Although our understanding of the Miillerian adenosarcomas is limited and optimal therapy has not been determined, it is clear that current management should be directed at the sarcomatous element in the tumor because this component appears to dictate the overall clinical course and response to therapy. Surgical resection should, in most cases, be part of the initial management of both the homologous and heterologous forms of the tumor. When the diagnosis is known before exploration, some form of preoperative radiation may be used. An exenterative procedure might be considered in cases with extension of uterine tumor to bladder or rectosigmoid or tumors involving the sidewall. Peritoneal cytology, histologic assessment of the periaortic and pelvic lymph nodes, a search
272
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FIG. 9. Lung metastasis. More pronounced spindle shape and prominent nucleoli of tumor cells (H and E, x 400).
for heterologous elements in the tumor and determination of its mitotic rate, as well as routine staging and histologic assessment of the surgical specimen are important factors in analyzing the extent and behavior of these tumors and in planning any adjunctive radiation and/or chemotherapy on an individual basis. Since the sarcomatous element of the homologous tumors histologically resembles, and behaves similarly to, a low-to-medium grade endometrial stromal sarcoma and some stromal sarcomas appear to be moderately radiosensitive [5,131, a course of pre- or postoperative radium and/or whole pelvis irradiation may reduce the incidence of local recurrence in these cases. The amount and type of adjunctive irradiation would be tailored to the particular situation. Cases with positive peritoneal cytology, tumor involvement of the uterine serosa, or “cut-through” tumor might benefit from a course of whole abdominal irradiation, a pelvic boost, and a vaginal cuff radium. Cases with common iliac or aortic node involvement may be considered for extended held irradiation. Since high-dose progestins have yielded long-term remissions of recurrent low-grade stromal sarcomas [ 141,these
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agents may be helpful in cases with widespread or recurrent adenosarcoma of homologous type. Isolated vaginal recurrences have been managed successfully by en bloc surgical excision, irradiation, or combination of both modalities [l]. The heterologous forms of adenosarcoma, on the other hand, appear to be highly aggressive lesions and similar to malignant mixed Miillerian tumors of heterologous type 191.It appears that management should likewise be aggressive, since the only known survivor received radical surgical excision and pelvic lymphadenectomy combined with whole abdominal and whole pelvic irradiation and 12 months of vincristine, cyclophosphamide, and dactinomycin 123.Some patients with widespread metastases or extensive recurrence of the heterologous forms of malignant mixed Mtillerian tumors have appeared to respond to intensive combination chemotherapy [ 15,161. The Miillerian adenosarcomas of homologous and heterologous types are relatively new, but distinct, histopathologic entities. Detailed analysis of additional cases will assist in understanding their biologic behavior and response to therapy.
ACKNOWLEDGMENTS The authors are grateful to Dr. R. E. Scully, Boston Massachusetts, for his review of the pathologic material; to Dr. C. Cooper and Dr. W. Burgert, Jr., of Tallahassee, Florida, for their referral and contribution of pertinent information; to Mrs. B. Fant and Mrs. E. E. Salt for their clerical assistance; and to Mr. Fernando Solares for his technical assistance.
REFERENCES 1. Clement, P. B., and Scully, R. E. Mulletian adenosarcoma of the uterus--A clinicopathologic analysis of ten cases of a distinctive type of Miillerian mixed tumor, Cancer 34, 1138-1149 (1974). 2. Roth, L. M., Pride, G. L., and Sharma, H. M. Miillerian adenosarcoma of the uterine cervix with heterologous elements. A light and electron microscopic study, Cancer 37, 1725-1736 (1976). 3. Javert, C. T. The spread of benign and malignant endometrium in the lymphatic system with a note on coexisting vascular involvement, Amer. J. Obstet. Gynecol. 64, 780-802 (19.52). 4. Palladino, V.S., and Trousdell, M. Extrauterine Miillerian tumors-A review of the literature and the report of a case, Cancer 23, 1413-1422, (1969). 5. Norris, H. J., and Taylor, H. B. Mesenchymal tumors of the uterus. I. A clinical and pathological study of 53 endometrial stromal tumors, Cancer 19, 755-766 (1%6). 6. Teilum, G. Special tumors of ovary and testis, Lippincott, Philadelphia, 1971. 7. Abell, M. R. Papillary adenofibroma of the uterine cervix, Amer. J. Obstet. Gynecol. 110, 990-993 (1971). 8. Vellios, F., Ng, A. B. P., and Reagan, J. W. Papillary adenofibroma of the uterus: A benign mesodermal mixed tumor of Miillerian origin, Amer. J. Clin. P&IO/. 60, 543-551 (1973). 9. Kempson, R. L., and Bari, W. Uterine sarcomas: Classification, diagnosis, and prognosis, Hum. Pathol.
1, 331-349 (1970.
10. Koss, L. G., Spiro, R. H., and Brunschwig, A. Endometrial stromal sarcoma, Surg. Gynecol. Obstet. 121, 531-537 (1965). 11. Scully, R. E. Personal communication, Massachusetts General Hospital, Boston, Mass. 12. Baggish, M. S., and Woodruff, J. D. Uterine stromatosis-Clinicopathologic features and hormone dependency, Obstet. Gynecol. 40, 487-498 (1972). 13. Gilbert, H. A., Kagan, A. R., LaGasse, L., Jacobs, M. R., and Tawa, K. The value of radiation therapy in uterine sarcoma, Obstet. Gynecol. 45, 84-88 (1975).
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14. Pellillo, D. Proliferative stromatosis of the uterus with pulmonary metastases. Remission following treatment with a long-acting synthetic progestin: A case report, Obstet. Gynecof. 31, 33-39 (1968). 15. Rivard, G., Ortega, J., Hittle, R., Nitschke, R., and Karon, M. Intensive chemotherapy as primary treatment for rhabdomyosarcoma of the pelvis, Cancer 36, 1593-1597 (1975). 16. Smith, J. P. and Rutledge, F. Advances in chemotherapy for gynecologic cancer, Cancer 36, 669-674 (1975).
ONCOLOGY
6, 261-274 (1978)
Extrauterine Miillerian Adenosarcoma; A Clinicopathologic Report of a Case with Distant Metastases and Review of the Literature EVA SPERK BARD, M. D., DAVID S. BARD, M. D., FACOG,’ AND FERNANDO VARGAS-CORTES, M. D. Departments
of Pathology and Obstetrics and Gynecology, J. Hillis Miller Health Center, University of Florida, Gainesville, Florida
Received June 30, 1977 This is a report of a Mtillerian adenosarcoma of homologous type which arose from the right pelvic sidewall and presented as a pelvic hematoma in a 46year-old woman. The tumor was locally aggressive and histologically similar to cases arising in the uterus reported earlier by Clement and Scully. Following her death from B. fragilis septicemia, the autopsy revealed widespread, occult hematogenous metastases composed entirely of the sarcomatous element of the tumor. The problems in diagnosis and management of a pelvic sidewall neoplasm are presented, and the methods of therapy of the homologous and heterologous forms of this new entity are reviewed and discussed in relation to their biologic behavior.
The term Mfillerian adenosarcoma has been proposed by Clement and Scully to designate a distinct type of Miillerian tumor composed of malignant stroma admixed with neoplastic, but histologically benign, epithelial elements [l]. The benign appearance of the neoplastic epithelium differentiates the Miillerian adenosarcoma from the classical malignant mixed Miillerian tumors. The sarcomatous component usually resembles an endometrial stromal sarcoma, but heterologous features have been described [ 1,2]. All tumors reported to date have originated in either the uterine corpus or cervix, but theoretically they could arise from any site where Miillerian tissue has been identified [3, 41. CASE REPORT
A 46-year-old white nulligravida was referred to the University of Florida in January 1975 with an enlarging mass of the right pelvic sidewall of 3-months duration. She had an abdominal hysterectomy in 1958 for leiomyomata and a lumbar laminectomy in 1969 for a herniated disc. There was no history of pelvic irradiation. She was asymptomatic until July 1973 when she developed a gradual onset of weakness and pain in the right lower extremity similar to the disc symptomatology ’ Address reprint requests to David S. Bard, M. D., University of Tennessee Center for the Health Sciences, Memphis, Tennessee 38163. 261 0090~8258/78/0063-0261$01.00/O Copyright @ 1978 by Academic Press, Inc. AU rights of reproduction in any form reservetl.
262
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BARD,
AND
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in 1969. Repeat myelograms were abnormal and she underwent re-exploration and decompression of the lumbar spine in January and again in May of 1974. The neuropathy progressed and she became bedridden. In September 1974 she developed thrombophlebitis and pulmonary emboli, and anticoagulant therapy was complicated by intermittent bruising and melena. In October 1974 a right hydronephrosis was demonstrated on IVP, and an indistinct mass was palpated against the right pelvic sidewall which was interpreted as a hematoma. By January 1975 the patient had developed urinary incontinence, right vulvar edema, and a painless subcutaneous mass in the right ischiorectal fossa. On examination, a nontender, smooth, rubbery mass occupied over half of the pelvic cavity. At laparoscopy, both ovaries and oviducts were normal, but an extraperitoneal mass filled the right pelvic cavity. The mass was explored through an incision in the right lower vaginal wall just inside the introitus, and 250 g of a partly organized blood clot was removed by suction and forceps. A gray, more solid, tissue fragment was removed with the suction tip and was subsequently interpreted as Miillerian adenosarcoma (Consultant, R. E. Scully). The patient was referred to the University of Florida. On admission her temperature was 39°C; WBC, 19,500; and Hct, 3%. The patient complained of severe hip and thigh pain on motion. The lungs, abdomen, and lymph nodes were unremarkable. A 10 x 8-cm soft, coarsely nodular, and slightly tender mass was firmly attached to the right pelvic sidewall, displaced the vagina and rectum sharply to the left, and extended subcutaneously downward into the right ischiorectal fossa. An 8-cm-deep sinus tract arose from within the mass, terminated on the right introitus, and drained foul-smelling, sero-purulent material. Cultures demonstrated a heavy growth of B. fragilis. The right lower extremity had a foot-drop, absent deep tendon reflexes, and moderate swelling, but had normal sensation and was normal in color. The urinary bladder and rectum were displaced to the left but were free of intrinsic lesions and tumor. Chest X ray and barium enema were normal. The IVP showed that the previous right hydroureter had resolved, but disclosed a 3 x 2-cm erosion of the inner cortex of the right OSilium and OSischium. This pelvic bone involvement was confirmed by bone scan, while other bones, including the spine, were normal. Lymphangiogram and arteriogram could not be performed due to a moderately severe reaction to IVP dye. A low-grade fever persisted during 2 weeks of specific antibiotics and frequent irrigations of the infected pelvic tumor, but after surgical debridement and improvement of drainage, the temperature rapidly returned to normal. The patient was offered, but refused, exploration and possible combined hemipelvectomy and pelvic exenteration. Over the next 7 weeks, 5000-R (of a planned 6500-R split course) cobalt teletherapy was delivered to the tumor through AP, PA, and right lateral pelvic ports which included the right lower buttock and vulva. The overall response was encouraging with 7% reduction in volume of the mass and sufficient pain relief to enable the patient to resume ambulation. She was to return in 2 weeks for the final 1500R. Three days before this appointment, purulent drainage recurred from the sinus tract and her temperature rose to 40°C. She was readmitted, cultured, and started on chloramphenicol, but sepsis progressed
EXTRAUTERINE
MijLLERIAN
rapidly and she expired 6 days later. B. fragilis the sinus tract.
ADENOSARCOMA
263
was cultured from the blood and
Pathology
The autopsy material and all antemortem specimens except the uterus were available for review. According to the pathology report of the 1958 hysterectomy specimen, 2 “the uterus was coarsely nodular, measured 13 x 10 x 9 ems, and was distorted by numerous subserosal, intramural, and submucosal, firm, white nodules, the largest of which measured 6 ems. The endometrium was thick, tan, and soft, and measured up to 0.6 ems.” The diagnoses were “endometrium secretory Histologic review of the laminectomy speciphase,” and “fibroleiomyomata.” mens from 1969 and 1974 showed disc material and scar without evidence of tumor. Gross Pathology
The surgical specimens of the paravaginal mass consisted of irregular fragments of nodular, spongy, red-brown tissue resembling partly organized blood clots with firmer, light brown areas and scattered membranous strands. At autopsy, an 8 x 6-cm necrotic, partially cavitated, extraperitoneal mass was fixed to the right pelvic sidewall and created an irregular bony defect in the adjacent ischium. The mass was adherent to the right bladder wall and surrounded, but did not invade or occlude, the right ureter. The pelvic peritoneum, vagina1 walls, and cuff were uninvolved. Both ovaries and Fallopian tubes were normal and the uterus was absent. There was no evidence of pelvic endometriosis, intra-abdominal tumor, or pelvic or paraaortic lymphadenopathy. The left lung contained two firm, graywhite, irregular tumor nodules, the larger measuring 3.0 x 1.0 x 0.5 cm. Most of the second and third lumbar vertebra1 bodies were dark brown, softened, and replaced by tumor. Each of the bodies of the eleventh and twelfth thoracic vertebrae contained a l-cm pale gray, firm, round lesion which suggested tumor. Lymph nodes were sampled from all major groups but were grossly unremarkable. Microscopic
Pathology
The surgical specimens contained neoplastic mesenchymal and epithelial elements intermixed with extensive hemorrhage and necrosis. The tumor tended to form coarse papillary projections covered with epithelium. Multiple glands permeated the underlying stroma and ranged from branching tubular and cleft-like to round and small. The glands were widely separated by variable amounts of malignant stroma and were in no place back-to-back (Fig. 1). The epithelium of the glands and surface was polymorphic and moderately atypical and, in most areas, was simple to pseudostratified columnar with focal cilia resembling endometrial epithelium (Fig. 2). Foci of clear cells (Fig. 3) and squamous epithelium (Fig. 4) were present. The nuclei were round to oval and vesicular with small nucleoli and focal hyperchromasia. Mitoses were rare. The predominant component of the tumor was a moderately cellular stroma that 2 Courtesy of Dr. R. Monaco, Bay Memorial Hospital, Panama City, Florida 32401.
264
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FIG. 1. Pelvic tumor. Widely separated, benign-appearing, branching tubular, and cleft-like glands. Periglandular condensation of stromal cells in lower right corner (H and E, x 40).
resembled endometrial stroma and consisted of stellate to plump spindle cells in a fibrillary matrix (Fig. 5). Their mildly hyperchromatic nuclei were round to ovoid and vesicular. In the most active areas, there were five mitoses per 10 high-power fields (hpf). The stroma tended to be more compact around the glands and immediately beneath the surface epithelium (Fig. I), while in other areas it appeared myxomatous. Some areas had an abundance of prominent capillaries and resembled granulation tissue. In the autopsy material, the irradiated, residual pelvic tumor contained fewer glands than the antemortem surgical specimens. These glands were atypical,
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FIG. 2. Simple to pseudostratified columnar epithelium of glandular elements. Insert shows presence of cilia (H and E, x 400).
distorted, and degenerating. The tumor involved the right ischium, the bodies of the tenth and eleventh thoracic and the second and third lumbar vertebrae (Fig. 6), the lung (Fig. 7), and the perinodal adipose tissue of several mediastinal and porta hepatic lymph nodes (Fig. 8). All metastatic sites consisted of pure sarcoma without the glandular component and were similar to that in the antemortem material, but tended to be more compact with a mitotic rate of 8’10 hpf. In the lung, the tumor cells were more elongated with oval nuclei and prominent nucleoli (Fig. 9). DISCUSSION
Although pelvic tumors with similar histologic appearance have been described by other authors [4-61, the Miillerian adenosarcoma was only recently defined and proposed as a distinct type of malignant mixed Miillerian tumor by Clement and Scully [I]. The tumor is unique because its epithelial component, while neoplastic, appears and behaves benign. As with other tumors of Miillerian origin, the morphologic appearance of the elements comprising the adenosarcoma is variable with a general relationship of the stroma and glands similar to that of the cystosarcoma phyllodes of the breast.
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FIG. 3.
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Atypical glandular epithelium with vacuolated columnar cells (H and E, x 400).
The mesenchymal component is usually homologous and resembles a low-grade endometrial stromal sarcoma, but three cases with heterologous differentiation have been reported; one with an embryonal rhabdomyosarcoma-like stroma [ll, another with focal rhabdomyoblasts [l], and another with an embryonal rhabdomyosarcoma and foci of cartilage [21. The distinctive histologic feature of both the homologous and heterologous types is the presence of benign, but frequently atypical-appearing, glandular epithelium of Mtillerian type. This epithelial component is considered to be an integral part of the neoplasm because of its diffuse and extensive presence throughout the primary tumors and in local recurrences following hysterectomy [l]. The Miillerian adenosarcomas, therefore, can be defined as a group of Mtillerian-derived tumors consisting of a homologous or heterologous malignant stroma admixed with atypical but benign neoplastic glands and should be classified in the spectrum of mixed Mulletian tumors somewhere between the benign adenofibroma [7,8] and the malignant mixed Miillerian tumors of homologous and heterologous types [9]. The biological behavior of the homologous type of adenosarcoma can be as-
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FIG. 4.
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Focus of squamous epithelium
(H and E,
x
100).
sessed from eight cases arising in the uterus reported by Clement and Scully [II. Of five Stage I cases followed from 2 to 10 years after hysterectomy, none have demonstrated clinical evidence of distant metastases, but two have developed recurrence in the upper vagina; one at 2.5 years (mitotic rate, 6/10 hpf) and the other at 4 years (mitotic rate, 4/10 hpf). The latter patient died of extensive pelvic recurrence 6 years later. No case has, as yet, received a postmortem examination. Local recurrence, therefore, is relatively frequent following surgical excision and when discovered it is usually over 2 years later. This pattern of biologic behavior is similar to the “low-grade” endometrial stromal sarcomas [5,9,101. From experience with other heterologous tumors of Mtillerian origin, the biological behavior of the heterologous type of adenosarcoma would be expected to be more aggressive [9]. Three cases have been reported to date [1,2]. The sarcomatous component of one tumor had features consistent with embryonal rhabdomyosarcoma and had a mitotic rate of 40/10 hpf. The patient developed skin and bone metastases and intra-abdominal recurrence within 7 months following intracavitary radium and hysterectomy [l]. Another tumor contained an area suggestive of rhabdomyoblasts and had 10 mitoses per hpf. The patient developed vaginal recurrence 18 months after hysterectomy [ 11.Roth reported an adenosar-
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FIG. 5. Stroma of pelvic tumor. Fibrillary matrix with stellate and plump spindle cells (H and E, x 250).
coma with heterologous elements arising in the endocervix of a 14-year-old girl [2]. The sarcomatous portion consisted of embryonal rhabdomyosarcoma with numerous mitoses and foci of pleomorphic rhabdomyosarcoma and cartilage. The patient was still free of disease 42 months following radical hysterectomy, vaginectomy, and pelvic lymphadenectomy, whole abdominal irradiation, a 2000-R pelvic boost, and 1 year of combination chemotherapy utilizing vincristine, dactinomycin, and cyclophosphamide. When compared with the homologous type of adenosarcoma, therefore, an adenosarcoma containing definite, or suspected, heterologous elements may be a more aggressive neoplasm with a greater, and earlier, probability of local recurrence and distant, primarily hematogenous, metastases. The case presented herein is a Miillerian adenosarcoma of homologous type which appears to have arisen form the pelvic sidewall. Although an occasional low-grade endometrial stromal sarcoma has been reported to recur 27 years after initial therapy [IO], it seems unlikely that this case represents a recurrence of a primary uterine adenosarcoma 16 years following hysterectomy because: (a) the
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FIG. 6. Vertebral bone marrow replaced by metastatic tumor (H and E, x 40).
original pathology report described a uterus that contained grossly and microscopically typical leiomyomata but no other lesions; (b) all reported recurrences of the homologous type of adenosarcoma of uterine origin have involved the upper vagina and cuff [ 11;(c) the tumor’s mitotic rate of WY10 hpf, when analyzed with previous cases [ 11,corresponds with an expected time of recurrence at 2-4 years, rather than 16 years, following treatment; and (d) other neoplasms of Mtiilerian origin are known to arise in extrauterine sites such as the pelvic lymph nodes, endometriotic deposits, the Fallopian tubes, and even the ovary [ 1,3,4]. Although all reported Miillerian adenosarcomas have arisen in the uterine corpus or cervix, several histologically similar tumors described in the literature may have had an extrauterine origin [ 1,111. The primary pelvic tumor in our case contained the distinctive histopathologic features of a homologous adenosarcoma with a diffuse admixture of atypicalappearing epithelial elements in a sarcomatous stroma. Only the sarcomatous element, however, was identified in the small, but widespread, hematogenous metastases to lung, bone, and perinodal adipose tissue. These findings are consis-
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FIG. 7. Lung metastasis. Predominant location in interlobular septum. Alveoli present in left upper and right lower corners (H and E, x 40).
tent with the thesis that the neoplastic glands in the pelvic tumors are benign and that the malignant behavior of the homologous adenosarcoma is fundamentally a reflection of the sarcomatous element. From a clinical standpoint, our case presented with the classical symptoms of a neoplasm involving the pelvic sidewall: unilateral sciatic pain and neuropathy, venous occlusion, and hydronephrosis. The clinical diagnosis was obscured, however, because of the patient’s previous history of lumbar disc surgery and her severe bleeding problems during anticoagulation for thromboembolism. The mass presented as a hematoma, but as time, symptoms, and its size progressed a neoplasm was considered. Exploration of the mass through the lower vagina revealed a small fragment of tissue containing the adenosarcoma, but the predominant component of the mass consisted of partly organized, hematoma-like material. The association of extensive hemorrhage with the pelvic sidewall tumor is interesting and important, but of uncertain etiology. Possible explanations include vascular or marrow invasion by tumor, uncontrolled anticoagulation, stromal
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FIG. 8. Anterior mediastinal lymph node. Pericapsular location of metastatic tumor. Uninvolved node parenchyma on the left (H and E, x 40).
necrosis within the tissue from cyclic hormone withdrawal similar to endometriosis or menses [12], extensive necrosis and hemorrhage of proliferating tumor, or combinations of the above. While the hemorrhagic component undoubtedly enhanced the size and symptoms of the neoplasm resulting in its earlier detection, it later served as the nidus for uncontrollable infection and fatal septicemia. Although our understanding of the Miillerian adenosarcomas is limited and optimal therapy has not been determined, it is clear that current management should be directed at the sarcomatous element in the tumor because this component appears to dictate the overall clinical course and response to therapy. Surgical resection should, in most cases, be part of the initial management of both the homologous and heterologous forms of the tumor. When the diagnosis is known before exploration, some form of preoperative radiation may be used. An exenterative procedure might be considered in cases with extension of uterine tumor to bladder or rectosigmoid or tumors involving the sidewall. Peritoneal cytology, histologic assessment of the periaortic and pelvic lymph nodes, a search
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FIG. 9. Lung metastasis. More pronounced spindle shape and prominent nucleoli of tumor cells (H and E, x 400).
for heterologous elements in the tumor and determination of its mitotic rate, as well as routine staging and histologic assessment of the surgical specimen are important factors in analyzing the extent and behavior of these tumors and in planning any adjunctive radiation and/or chemotherapy on an individual basis. Since the sarcomatous element of the homologous tumors histologically resembles, and behaves similarly to, a low-to-medium grade endometrial stromal sarcoma and some stromal sarcomas appear to be moderately radiosensitive [5,131, a course of pre- or postoperative radium and/or whole pelvis irradiation may reduce the incidence of local recurrence in these cases. The amount and type of adjunctive irradiation would be tailored to the particular situation. Cases with positive peritoneal cytology, tumor involvement of the uterine serosa, or “cut-through” tumor might benefit from a course of whole abdominal irradiation, a pelvic boost, and a vaginal cuff radium. Cases with common iliac or aortic node involvement may be considered for extended held irradiation. Since high-dose progestins have yielded long-term remissions of recurrent low-grade stromal sarcomas [ 141,these
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agents may be helpful in cases with widespread or recurrent adenosarcoma of homologous type. Isolated vaginal recurrences have been managed successfully by en bloc surgical excision, irradiation, or combination of both modalities [l]. The heterologous forms of adenosarcoma, on the other hand, appear to be highly aggressive lesions and similar to malignant mixed Miillerian tumors of heterologous type 191.It appears that management should likewise be aggressive, since the only known survivor received radical surgical excision and pelvic lymphadenectomy combined with whole abdominal and whole pelvic irradiation and 12 months of vincristine, cyclophosphamide, and dactinomycin 123.Some patients with widespread metastases or extensive recurrence of the heterologous forms of malignant mixed Mtillerian tumors have appeared to respond to intensive combination chemotherapy [ 15,161. The Miillerian adenosarcomas of homologous and heterologous types are relatively new, but distinct, histopathologic entities. Detailed analysis of additional cases will assist in understanding their biologic behavior and response to therapy.
ACKNOWLEDGMENTS The authors are grateful to Dr. R. E. Scully, Boston Massachusetts, for his review of the pathologic material; to Dr. C. Cooper and Dr. W. Burgert, Jr., of Tallahassee, Florida, for their referral and contribution of pertinent information; to Mrs. B. Fant and Mrs. E. E. Salt for their clerical assistance; and to Mr. Fernando Solares for his technical assistance.
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14. Pellillo, D. Proliferative stromatosis of the uterus with pulmonary metastases. Remission following treatment with a long-acting synthetic progestin: A case report, Obstet. Gynecof. 31, 33-39 (1968). 15. Rivard, G., Ortega, J., Hittle, R., Nitschke, R., and Karon, M. Intensive chemotherapy as primary treatment for rhabdomyosarcoma of the pelvis, Cancer 36, 1593-1597 (1975). 16. Smith, J. P. and Rutledge, F. Advances in chemotherapy for gynecologic cancer, Cancer 36, 669-674 (1975).