Two Unusual Presentations of Müllerian Adenosarcoma: Case Reports, Literature Review, and Treatment Considerations

GYNECOLOGIC ONCOLOGY

59, 412–422 (1995)

CASE REPORT Two Unusual Presentations of Mu¨llerian Adenosarcoma: Case Reports, Literature Review, and Treatment Considerations RUSSELL GOLLARD, M.D.,* MICHAEL KOSTY, M.D.,*,1 GERALD BORDIN, M.D.,† ARNOLD WAX, M.D.,§ AND CONLEY LACEY, M.D.‡ *Division of Hematology/Medical Oncology, MS217, Ida M. and Cecil H. Green Cancer Center, †Division of Pathology, and ‡Division of Obstetrics and Gynecology, Scripps Clinic and Research Institute, 10666 North Torrey Pines Road, La Jolla CA 92037; and §3920 South Eastern Avenue, Suite 202, Las Vegas, Nevada 89119 Received March 2, 1995

Mu¨llerian adenosarcomas of the uterus usually present as pedunculated endometrial masses in postmenopausal women with vaginal bleeding. Extraendometrial variants (originating in the ovary, adnexa, or myometrium) are much less common, and they tend to present at a more advanced stage due to their location. The sarcomatous portion of mu¨llerian adenosarcoma can vary from low grade to very high grade and the clinical behavior of the tumors can be indolent or aggressive. We present two cases, one of which originated in the adnexa and the other in an apparent focus of uterine adenomyosis. These cases illustrate the difficulty of correct diagnosis and treatment. q 1995 Academic Press, Inc.

INTRODUCTION

Mu¨llerian adenosarcoma is a rare tumor of the uterus first described in 1974 by Clement and Scully [1]. These rare tumors, which are characterized by a mixture of benign glandular epithelium and a malignant sarcomatous stroma resembling that of endometrial stromal sarcoma or mixed mu¨llerian tumors, have been thought to behave clinically like low-grade sarcomas [1–5]. Local recurrences tend to occur frequently, while recurrences distant from the primary site are unusual [1]. Four years after the original description of the uterine adenosarcoma, five cases of extrauterine mu¨llerian adenosarcomas were reported [6]. Adenosarcomas originating from the ovary, adnexa, pelvic sidewall, cervix, or within the myometrium have also been described [6–14]. Despite the original observation that uterine adenosarcomas rarely metastasize outside of the pelvis, there have been 1 To whom correspondence and reprint requests should be addressed at Division of Hematology/Medical Oncology, MS217, Ida M. and Cecil H. Green Cancer Center, Scripps Clinic and Research Institute, 10666 North Torrey Pines Rd., La Jolla, CA 92037. Fax: (619) 554-6941.

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CASE ONE

A 38-year-old Caucasian woman (G1P0Ab1) had been suffering from chronic intermittent pelvic pain and dysmenorrhea for many years. She was noted to have a right-sided ovarian cyst measuring 1.5 1 2 cm at age 26. Over the ensuing 10 years her chronic pelvic pain became worse and more frequent, and at age 35 she underwent a diagnostic laparoscopy with lysis of adhesions. Subsequent to this procedure, she continued to have regular menses. The patient eventually began to complain of constant sharp pain in her right anterior pelvis which persisted through her menstrual cycle. At age 39, in October 1992, a laparoscopic right salpingo-oophorectomy and myomectomy was performed at her local hospital. The laparoscopy revealed an irregular uterus with a large subserosal mass in the right cornual area grossly consistent with a leiomyoma. The suspected leiomyoma was dissected from the uterus and was noted to be highly friable; spillage of some necrotic material into the peritoneal cavity occurred during the resection. Gross inspection revealed a 1.5-cm cavity filled with hemorrhagic material and grey, glistening translucent soft tissue. Histologically, the uterine subserosal mass was found to be composed of irregular glands with benign epithelium surrounded by a spindle cell stroma which was hypercellular

412

0090-8258/95 $12.00 Copyright q 1995 by Academic Press, Inc. All rights of reproduction in any form reserved.

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numerous reported cases of metastases to distant organs, including the lungs, bones, mesentery, and brain [15]. Metastases to the abdominal wall along a laparoscopic trocar tract have not previously been reported. In this paper, we report two new cases of mu¨llerian adenosarcoma, one uterine, the other adnexal in origin, and review all known cases of extrauterine pelvic adenosarcomas in addition to all distant recurrences resulting from uterine adenosarcomas.

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FIG. 1. (Case 1) Myomectomy specimen with cystic space (top right), benign glandular epithelium (small arrow), and polypoid stromal invaginations into cystic space. Note periglandular stromal condensation (large arrow) (801 H&E).

and which had rare mitoses, mild nuclear hyperchromasia, and pleomorphism. Occasional glands were cystically dilated. Within the stroma were foci of rhabdomyoblasts with

FIG. 2.

eosinophilic cytoplasm without well-formed cross-striations. No other heterologous elements were present. Polypoid infoldings of the stromal component into the lumens of the

(Case 1) Abdominal wall recurrence with islands of cartilaginous differentiation (arrow) (801 H&E).

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FIG. 3.

GOLLARD ET AL.

(Case 1) Abdominal wall recurrence with focus of low-grade rhabdomyosarcoma with prominent cross-striations (arrows) (6401 H&E).

larger cystically dilated glands were a prominent histologic feature (Fig. 1). This neoplasm was identified as an adenosarcoma retrospectively after being initially identified as adenomyosis with cystic glands. Four months after her laparoscopy a painless swelling

developed in her left lower quadrant within the laparotomy incision site; clinically, this was consistent with an incisional hernia. A 4-cm suspected hernia sac was excised in April 1993; it contained golden, necrotic gelatinous material. Histologically this was a neoplasm composed of benign cuboidal

FIG. 4. (Case 2) Right pelvic sidewall: polypoid surface with marked stromal cellularity and benign glands (note glandular squamous metaplasia, arrow) (321). Compare stroma cellularity to Fig. 1.

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FIG. 5. (Case 2) Right broad ligament: hypercellular stroma with cytologic atypia and benign glandular epithelium. Stroma lacks high mitotic rate and necrosis (3201).

epithelium with focal mild cytologic atypia lining glands and cystic spaces along with abundant cellular stroma with the appearance of a low-grade stromal cell sarcoma. Heterologous stromal elements with the appearance of cartilage (Fig. 2) and rhabdomyoblasts with well-formed cytoplasmic cross-striations (Fig. 3) were identified. The stroma had 9– 10 mitoses per 10 high power fields (hpf) and demonstrated a tendency to be more cellular immediately adjacent to the glands. This neoplasm was classified as an adenosarcoma of mu¨llerian origin on the basis of these features. CT scan of the abdomen and pelvis at this time was notable only for multiple low-density lesions in the left pelvis at the root of the mesentery. The chest X ray was normal. CA-125 was 45 U/ml (nl õ35 U/ml) at the time of surgery and carcinoembryonic antigen (CEA) and a-fetoprotein (AFP) were normal. Ten days after the left lower quadrant surgery an exploratory laparotomy, total abdominal hysterectomy, left salpingo-oophorectomy, and omentectomy were completed. At surgery no cul-de-sac lesions were present. There were no grossly visible hypogastric, pelvic, or periaortic lymph node abnormalities. The liver edge exhibited no lesions and the peritoneal surfaces were smooth. Pathologic evaluation demonstrated a 128-g uterus with a secretory phase endometrium, and a 2-cm leiomyoma in the posterior inferior myometrium. The left ovary contained a 1.5-cm corpus luteum; the left fallopian tube was normal. The right fallopian tube stump had a 1-cm cyst filled with hemorrhagic fluid. A necrotic nodule in the omentum was not diagnostic of adeno-

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sarcoma. The patient’s CA-125 became undetectable after surgery. The patient received six cycles of adjuvant cisplatin (20 mg/m2, days 1–4), ifosfamide (1.5 g/m2, days 1–4), and mesna (150 mg/m2 intravenous bolus, then 1.5 g/m2/day by continuous infusion over 4 days) at 4-week intervals. In addition, she received 5500 centigray to the abdominal wall. She tolerated her therapy well except for transient neutropenia after her last cycle. She remains disease-free 30 months after treatment. CASE TWO

In January 1994, a 26-year-old woman (G1P0Ab1) presented with an acute abdomen. She underwent an emergency laparotomy and was found to have a ruptured and bleeding 6-cm nodular, pink–tan smooth-surfaced right adnexal mass which was loosely attached to the distal end of the right fallopian tube. The right ovary was normal. Peritoneal implants/metastases were not identified. The right adnexal mass was excised and no additional procedures were performed, awaiting a final pathological diagnosis. The adnexal mass was initially suspected to be an endometrioid adenofibroma because of benign-appearing endometrial-type glands which were surrounded by a moderately cellular stroma. Subsequent expert consultation noted endometrioid glands with mild nuclear atypia and foci of squamous differentiation; the stromal component tended to be more cellular around the glands and demonstrated a tendency for polypoid projections

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into cystically dilated glands (Fig. 4). There were no mitoses and no heterologous components present. The final pathologic diagnosis based on these findings was adenosarcoma (of mu¨llerian origin). Two months later, the patient underwent a restaging laparoscopy and was noted to have a solitary 1-cm nodule on the right posterior aspect of the broad ligament as well as a 3cm bluish-colored nodule on the uterine fundus. The right broad ligament biopsy revealed adenosarcoma; the mass on the uterine fundus was adenomyosis. Histologically, the right sidewall mass was composed of endometrioid-type glands and a cellular stroma (Fig. 5). The glandular epithelium contained cells with enlarged, focally stratified nuclei which were cytologically benign; squamous metaplasia was present. The stroma was cellular with minimal nuclear cytologic atypia and absent mitoses similar to the stroma in the initial right adnexal mass. Two months after the broad ligament biopsy the patient was explored for definitive surgery. The remnants of the broad ligament mass had regrown into a 3- to 4-cm fleshy recurrence on the posterior surface of the broad ligament adjacent to the junction of the uterosacral ligament and the serosa of the uterus. Because of the location of the recurrence, it could not be locally resected with clean margins; therefore, an en bloc modified radical hysterectomy, right salpingo-oophorectomy, left salpingectomy, and complete resection of the right pelvic sidewall recurrence were then completed. A right pelvic, iliac, and para-aortic lymph node dissection and partial omentectomy were also performed. The modified radical hysterectomy specimen was notable for adenosarcoma which involved the right broad ligament, the uterine serosa, and extended into the hilum of the right ovary. The endometrium was proliferative and the myometrium exhibited adenomyosis. There was no metastatic adenosarcoma in any of the lymph nodes. The omentum contained two microscopic foci of cytologically benign stromaltype cells without a glandular component. These foci were interpreted as consistent with adenosarcoma. She was subsequently treated with six cycles of ifosfamide (1.5 g/m2/day 1 5 days), mesna (1.5 g/m2 continuous infusion over 5 days), and cisplatin (20 mg/m2/day 1 5 days). A third-look laparoscopy with biopsies 10 months after the initial diagnosis showed a complete absence of residual disease. DISCUSSION

The original description of the mu¨llerian adenosarcoma in 1974 noted both the difficulty of diagnosis and the dissimilar potentials for locally recurrent as opposed to widely metastatic disease [1]. Distant metastases were felt to be exceptional and were only manifested in 1 of the 10 original cases described, in distinction to the more typically metastatic carcinosarcomas [1]. Adenosarcoma is best thought of as a

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chimera composed of two intermixed neoplastic tissues of differing malignant potential: a benign epithelial component and a sarcomatous stromal component [1, 16]. It occupies a niche between carcinosarcoma (with both a malignant epithelial and a malignant stromal component) and adenofibroma (composed of neoplastic but benign glands and benign stroma) [17–19, 22, 23]. Like mu¨llerian carcinosarcomas, the sarcomatous portion of adenosarcoma may contain heterologous elements including cartilage, smooth muscle, striated muscle, or fat. Recurrences of uterine adenosarcoma have been linked to the presence of myometrial invasion and the presence of sarcomatous overgrowth (pure sarcoma accounting for at least 25% of the tumor volume) [19, 20]. Tumor size has not been linked to development of recurrent disease. Adenosarcoma with heterologous elements may also be a more clinically aggressive neoplasm [7]. The genesis of the tumor is unclear. Some authors have argued for a biclonal origin of the tumor, whereas others see a multipotential stem cell as the cell of origin [21]. The tissue of origin is also controversial. Both the adenomyoma and the endometrioma have been suggested as the histologic precursor [14, 18]. If adenosarcomas do indeed originate in foci of endometriosis, they may potentially occur anywhere in the abdomen or pelvis. Pathologic diagnosis of adenosarcoma is often difficult because the sarcomatous stroma may be very low grade and therefore may have a misleadingly benign appearance. The histologic appearance of low-grade adenosarcoma may be closer to endometriosis than a lowgrade sarcoma. Although the mu¨llerian adenosarcoma was initially described in its uterine endometrial presentation, the extrauterine and intramyometrial variations presented here represent variants of this rare neoplasm prone to local recurrence but exhibiting potential for distant metastasis as well. Only 15 adenosarcomas originating in the adnexa have been previously described (Table 1). The average age at diagnosis was 48. Of these 15 adnexal or ovarian adenosarcomas previously reported, 7 subsequently recurred. Only one of these tumors gave rise to distant metastases. Because of the small number of tumors, no comment can be made about the utility of chemotherapy or radiation therapy after primary surgery. Eighteen distant recurrences have been reported from tumors originating in the uterine body (Table 2). Only half of this number had more than 10 mitotic figures per 10 hpf, and fewer than half had myometrial invasion. The median time to recurrence was 5 years, and survival was variable. Most of the tumors were either completely excised or surgically debulked. Recurrences were almost exclusively sarcomatous. For this reason, palliation of tumors has been attempted with cytotoxic agents employing regimens designed for uterine sarcomas and carcinosarcomas. There has been no demonstrated survival advantage in patients receiving chemotherapy. In a report of four patients with recurrent disease who received cyclophosphamide, vincristine, doxo-

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Clement and Scully [6]

4

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Clement and Scully [6]

Clement and Scully [6]

Bard et al. [7]

Russell et al. [10]

Valdez et al. [12]

5

6

7

8

9

3

Clement and Scully [6] Clement and Scully [6]

This case

Author [reference]

2

1

Case

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29

46

73

45

58

49

43

26

Age (years)

G0P0, 20 year hx. infertility

G0P0

TAH and BSO for uterine leiomyomas and ovarian endometriosis 13 years predating diagnosis TAH and BS for uterine leiomyomas 15 years predating diagnosis TAH and BSO for uterine leiomyomas 38 years previous ABD hysterectomy at age 29 for leiomyomata G0P0

X-ray rx. for endometriosis 13 years previous

Negative

G1P0Ab1

Gynecologic history

Pelvic pain for several years

Right lower extremity pain thrombophlebitis, pulmonary emboli 3 months before diagnosis 2 months hx. dyspareunia, lower abdominal pain

Inability to avoid

None

Urinary urgency

Abnormal vaginal bleeding

Back pain

Acute Abdomen

Presenting symptoms

Left ovary with growth behind uterus onto right pelvic wall compressing right ureter

Left broad ligament

Right pelvic sidewall

Midline pelvis

Right pelvic wall

Left pelvic wall

Left ovary

Right ovary

Right adnexa

Primary site

Local resection, intraperitoneal triethylenethiophosphoramide, 5175 centigray to pelvis, combination chemotherapy with actinomycin D, methotrexate, vincristine for one year followed by 4 years of oral cytoxan, followed by 2 years of chlorambucil

Local resection

Patient refused abdominal surgery, 5000 centigray to tumor

Tumor resection

Partial tumor resection, 5000 centigray to tumor

Partial tumor resection

Right adnexal recurrence; modified radial hysterectomy, right salpingo-oophorectomy, left salpingectomy, resection of right pelvic sidewall recurrence and dissection of right pelvic, right iliac, and aortic lymph node dissection. Six cycles of ifosfamide, mesna, cisplatin Supracervical hysterectomy and BSO TAH and BSO. Intraperitoneal thiotepa

Treatment

TABLE 1 Clinical Features of Extrauterine Mesodermal (Mu¨llerian) Adenosarcomas

Pelvic recurrence 5 months later; subsequent TAH and BSO, postoperative radiation therapy; patient alive and well 18 months after recurrence NED on exploratory biopsy only 5 years after diagnosis; patient alive and well 9 years postdiagnosis

Died 9 months after diagnosis from sepsis; pelvic recurrence and visceral metastases at autopsy Died 2 months after diagnosis from cerebrovascular accident; no autopsy Died from sepsis 2 weeks after 7-week course of radiation treatment

Intra-abdominal recurrence 9 months; palliative chemotherapy (unknown type); died 16 months postdiagnosis; no autopsy Intra-abdominal recurrence 15 months; irradiated; pulmonary metastases 45 months; resected

Alive and well, 12 months

Alive and well 18 months after completion of chemotherapy, no recurrence; negative third-look laparoscopy and biopsies

Follow-up results

CASE REPORT

417

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Kao and Norris [13]

Kao and Norris [13] Kao and Norris [13]

14

15 42

43

44

52

43

49

48

Radium insertion in endometrial cavity for menorrhagia 20 years earlier; right ovary and uterus previously removed for leiomyomas of uterus

Unknown

Unknown

Unknown

Unknown

Unknown

G2P2

Unknown

Abdominal pain

Unknown

Unknown

Unknown

Irregular vaginal bleeding for several months, pelvic pressure, urinary incontinence, increasing abdominal girth Acute abdominal pain (secondary to tumor rupture)

Left round ligament, (left ovary intact); tumor occupied most of pelvis; 2000 cc serous ascites removed

Ovary (not specific)

At least one ovary (not specific) with extension to pelvic wall; adhesions between tumor and omentum intestines

Primary tumor in ovary (not specific) on laparotomy, tumor adherent to lateral pelvic wall, sigmoid colon, and posterior serosal surface of uterus Bilateral ovarian involvement with extension into the omentum, encasement of sigmoid colon, and metastatic nodules in mesentery and liver Ovary (not specific)

Right broad ligament

‘‘Partial excision,’’ actinomycin-D, methotrexate, vincristine for 1 year; cytoxan (resulting in hemorrhagic cystitis after 4 years), leukeran after toxicity described above Hysterectomy bilateral salpingo-oophorectomy Partial resection, cytoxan, 4000 centigray

Hysterectomy bilateral salpingo-oophorectomy

Hysterectomy, subtotal resection of tumor

Hysterectomy, bilateral salpingo-oophorectomy

TAH and BSO

Well 1 year after treatment with no evidence of disease Dead, secondary to complications from tumor, 0.8 year posttreatment

Dead of leiomyosarcoma (felt to be unrelated to original tumor) of bowel 1 day postlaparotomy, 1.6 years after initial presentation; no evidence of residual adenosarcoma at time of death NED on second-look laparotomy 6 years after initial surgery

Alive without tumor after initial therapy, no progression 3.3 years later

Recurrence 5.3 years after initial presentation, treated successfully by resection

NED 1 year, 3 months postsurgery

Note. Table is modeled on that of Clement and Scully [6]. TAH, total abdominal hysterectomy; BSO, bilateral salpingo-oophorectomy; BS, bilateral salpingectomy.

16

Kao and Norris [13]

Kao and Norris [13]

Kao and Norris [13]

Borello et al. [2]

13

12

11

10

TABLE 1—Continued

418 GOLLARD ET AL.

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Clement and Scully [15] Clement and Scully [15]

Clement and Scully [15]

Clement and Scully [15]

6

8

9

10

7

5

Gloor [26]

Clement and Scully [15] Clement and Scully [15] Clement and Scully [15]

3

4

Clement and Scully [15]

This case

1

2

Author

Case

60

40

57

45

74

52

58

32

46

38

Age

NR

Filled cavity

8

5

6

2

13

3

2–6

4

õ10%

No myometrial invasion

8

2

None

0

0

0

0

0

õ2

7

0

ER, C

ER

0

Heterologous

23

30

40

Rare

MF/10 HPF

0

NE

0

0

0

25%

0

0

ú1.5 cm

No residual

Invasion

Size (cm)

Primary tumor

7.25

5.75

4.6

2.2

6

5.2

7

6

5

2.8

2

1

0.5

0.4

Interval (years)a

Abdomen (not otherwise specified)

4 1 1 cm saccular structure of gelatinous tissue in left lower quadrant of abdominal wall Multiple lesions in pelvis, RUQ, subcutis, bone Multiple bone metastases 6-cm mass in omentum 10-cm mass in mesentery, 8-cm mass in pelvis, omental implants Intra-abdominal recurrence Large pelvic mass and multiple peritoneal nodules õ3 cm Same as first recurrence 8.0-cm retroperitoneal mass 11-cm retroperitoneal mass 3.5-cm periumbilical nodule 8-cm mass, left pelvic wall Abdomen, including pelvis and posterior peritoneum

Site and gross appearance

Recurrences

Spindled sarcomatous cells in interlacing bundles; 4–18 mitoses/10 hpf Not reported

Pure sarcoma

Pure sarcoma

Pure sarcoma

Heterologous, MMMT

Pure sarcoma

Adenosarcoma

No biopsy done

Pure sarcoma

Pure sarcoma

Not sampled

Pure sarcoma

Heterologous, with islands of neoplastic cartilage and rhabdomyoblasts

Histology

Treatment

TAH–BSO initially; loop of small intestine, right hemicolon removed at first recurrence

Excision

Excision

Excision

Excision, radiation, CyD

Excision

Excision, debulking procedure, AcCyDV

Excision, CyDV

Debulking procedure

Radiation

Biopsy

Surgical excision, radiation therapy, six cycles of chemotherapy with cisplastin, ifosfamide, and mesna

TABLE 2 Uterine Adenosarcomas with Recurrences Outside of Pelvis: Clinical and Pathologic Features

Dead from second recurrence

NED 7.6 years

DOD 8 years

DOD 8 years

DOD 5 years

DOD 4.8 years

DOD 3 years

DOD 2 years

DOD 0.7 years (after recurrence)

Alive without disease 30 months after recurrence

Final statusa

CASE REPORT

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Zaloudek and Norris [23]

Zaloudek and Norris [23] Zaloudek and Norris [23]

Baker et al. [24]

Baker et al. [24]

Baker et al. [24]

Baker et al. [24]

13

14

16

17

18

19

goa

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NR

NR

NR

39

63

63

54

50

NR

NR

NR

Endometrium; size NR Lower uterine segment; size NR NR

Endometrium; size NR

Mass originated in endometrium and protruded through cervix; additional 7-cm extrauterine mass present in cul-de-sac at presentation Endometrium; size NR

None

None

None

None

Deep

None

None

Indeterminate

Myometrial invasion

13

12

None

None

None

None

õ1

20

C

None

None

None

None

16

5

5

13

14

7

1.4

1.5

2.6

0.75

7

7

5 7

0.5

Pelvis and abdomen

Pelvis and abdomen

Pelvis and abdomen

Pelvis and abdomen

Peritoneum

Lung

Mediastinum

Lung Brain

Omental mass 12 cm in diameter, with multiple peritoneal and diaphragmatic nodules 1–3 cm in diameter

Sarcoma 18 MF/ 10 hpf

Sarcoma 15 MF/ 10 hpf

Sarcoma 30 MF/ 10 hpf

Sarcoma 20 MF/ 10 hpf

Sarcoma 11 MF/ 10 hpf Sarcoma 8 MF/10 hpf

Sarcoma 3 MF/10 hpf Sarcoma 3 MF/10 hpf NR

Sheets of undifferentiated stromal cells, more immature than primary with as many as 60 mitoses/10 hpf

TAH–BSO, vaginal radium; at recurrence, CyVADIC TAH–BSO, vaginal radium; at recurrence; CyVADIC with 12month complete response; cisplatin, and DTIC TAH–BSO, vaginal radium; at recurrence, CyVADIC with 14month complete response; cisplatin and DTIC Vaginal hysterectomy; at recurrence, surgery, cisplatin, DTIC, and adriamycin

Vaginal hysterectomy; treatment for recurrence not reported TAH–BSO; treatment for recurrence not reported TAH–BSO; chemotherapy (type not specified)

TAH–BSO; treatment for recurrence not reported

TAH–BSO, whole pelvis irradiation (5040 centigray)

Alive, NED 93 months

Dead from recurrence 34 months

Dead from recurrence 35 months

Dead from recurrence 1 year after diagnosis Dead from recurrence 36 months

Dead from recurrence 7 years after diagnosis Alive with recurrence

Dead from tumor 9 years after diagnosis

Dead from disease 1–2 years after diagnosis

Note. Table is modeled on that of Clement and Scully [15]. Cy, cytoxan; Ac, Actinomycin-D; D, doxorubicin; V, vincristine; CyVADIC, cyclophosphamide, vincristine, adriamycin, and imidazole carboxamide; DOD, dead of disease; ER, extensive embryonal rhabdomyosarcoma; C, cartilage; NR, not reported; hpf, high power field; MF, mitotic figures. a Presentation to recurrence.

15

Zaloudek and Norris [23]

Katzenstein et al. [17]

12

11

TABLE 2—Continued

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CASE REPORT

rubicin, and imidazole carboxamide (CYVADIC), CYVADIC and cisplatin, or cisplatin, doxorubicin, and DITC, three were dead of progressive disease within 3 years [24]. However, all of the patients survived for at least 1 year. Adenosarcomas of the uterus are uncommon, and extrauterine presentations appear to be even less common. The ovarian or adnexal variants are intrinsically difficult to diagnose clinically because of their location and may also be difficult to diagnose pathologically for the aforementioned reasons. Intrauterine adenosarcoma in postmenopausal women usually presents with vaginal bleeding and a gynecologic examination will often reveal a pedunculated mass in the endometrial cavity. Myometrial and extrauterine tumors are much more difficult to biopsy and diagnose. Moreover, tumors of the myometrium can resemble leiomyomas both grossly and histologically [18]. Women with the extrauterine or intramural variants are often significantly younger (median age 49 years) [6] than those with the intrauterine variety (median age 71 years) [6], and for this reason, their clinical symptoms are often confused with menstrual pain, which may lead to a delay in diagnosis. Histologically, adenosarcoma may superficially resemble endometriosis. Endometriosis is characterized by a benign endometrial-type epithelium forming glands or cysts, a benign endometrial-type stroma, and, usually, evidence of recent or old hemorrhage. Hemosiderin-laden macrophages and fibrosis may replace the initial glands and stroma. The epithelial atypia occasionally present in adenosarcoma is not seen in endometriosis. Also, the stromal hypercellularity, the periglandular stromal cuffing, the frequent mitoses, and the presence of heterologous elements so common in adenosarcoma are not usual in endometriosis. The neoplastic histopathologic differential diagnosis of adenosarcoma includes adenofibroma and carcinosarcoma. Adenosarcoma, rather than adenofibroma, is more likely if there are two to four or more stromal mitoses per 10 hpf [20, 23], marked stromal hypercellularity, more than mild stromal nuclear atypia, periglandular stromal cuffing, and intracystic polypoid projections of stroma. Carcinosarcoma, rather than adenosarcoma, is diagnosed if there is a significant component of carcinoma within a malignant stroma. If the volume of carcinoma is limited in a neoplasm otherwise appearing like adenosarcoma, the clinical behavior may be more like an adenosarcoma than a carcinosarcoma [20]. The two cases presented here illustrate aspects of the malignant potential of the mu¨llerian adenosarcoma. Extrauterine mu¨llerian adenosarcoma is rare; both uterine and extrauterine adenosarcomas are underdiagnosed pathologically because of the benign glandular epithelium and the lowgrade nature of the malignant stromal component which may have a deceptively benign appearance. Ifosfamide and mesna with or without cisplatin are currently being studied in the more common uterine sarcomas and carcinosarcomas and

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may have some utility in the less common adenosarcoma [25]. ACKNOWLEDGMENTS Appreciation is expressed to Jane Hardman, M.D., Department of Gynecologic and Breast Pathology, Armed Forces Institute of Pathology, for her review of histopathology slides from Case 1 and to Robert H. Young, M.D., Department of Pathology, Massachusetts General Hospital, for his review of histopathology slides from Case 2.

REFERENCES 1. Clement, P. B., and Scully, R. E. Mu¨llerian adenosarcoma of the uterus: A clinicopathologic analysis of ten cases of a distinctive type of mu¨llerian mixed tumor, Cancer 34, 1138–1149 (1974). 2. Borello, D. J., Wood, W. G., and Newman, R. L. Mu¨llerian adenosarcoma: Two additional cases with ultrastructural observations, Am. J. Diag. Gynecol. Obstet. 1, 275–282 (1979). 3. Bibro, M. C., Livolsi, V. A., and Schwartz, P. E. Adenosarcoma of the uterus: Ultrastructural observations, Am. J. Clin. Pathol 71, 112–117 (1979). ¨ sto¨r, A. G., and Fortune, D. W. Benign and low-grade variants of 4. O mixed mu¨llerian tumor of the uterus, Histopathology 4, 369–379 (1980). 5. Hajnal-Papp, R., and Szilagyi, D. E. Malignant mu¨llerian tumors of the uterus, Arch. Gynecol. Obstet. 241, 209–219 (1988). 6. Clement, P. B., and Scully, R. E. Extrauterine mesodermal (mu¨llerian) adenosarcoma: A clinicopathologic analysis of five cases, Am. J. Clin. Pathol. 69, 276–283 (1978). 7. Bard, E. S., Bard, D. S., and Vargas-Cortes, F. Extrauterine mu¨llerian adenosarcoma: A clinicopathologic report of a case with distant metastases and review of the literature, Gynecol. Oncol. 6, 261–274 (1978). 8. Fayemi, A. O., Ali, M., and Braun, E. V. Mu¨llerian adenosarcoma of the uterine cervix, Am. J. Obstet. Gynecol. 130, 734–735 (1978). 9. Roth, L. M., Pride, G. L., and Sharma, H. M. Mu¨llerian adenosarcoma of the uterine cervix with heterologous elements, Cancer 37, 1725– 1736 (1976). 10. Russell, P., Slavutin, L., Laverty, C. R., and Cooper-Booth, J. Extrauterine mesodermal (mu¨llerian) adenosarcoma: A case report, Pathology 11, 557–560 (1979). 11. Tang, C. K., Toker, C., and Harriman, B. Mu¨llerian adenosarcoma of the uterine cervix, Hum. Pathol. 12, 579–581 (1981). 12. Valdez, V. A., Planas, A. T., Lopez, V. F., Goldberg, M., and Herrera, N. E. Adenosarcoma of the uterus and ovary: A clinicopathologic study of two cases, Cancer 43, 1439–1447 (1979). 13. Kao, G. F., and Norris, H. J. Benign and low-grade variants of mixed mesodermal tumor (adenosarcoma) of the ovary and adnexal region, Cancer 42, 1314–1324 (1978). 14. Oda, Y, Nakanishi, I., and Tateiwa, T. Intramural mu¨llerian adenosarcoma of the uterus with adenomyosis, Arch. Pathol. Lab. Med. 108, 798–801 (1984). 15. Clement, P. B., and Scully, R. E. Mu¨llerian adenosarcoma of the uterus: A clinicopathologic analysis of 100 cases with a review of the literature, Hum. Pathol. 21, 363–381 (1990). 16. Orenstein, H. H., Richart, R. M., and Fenoglio, C. M. Mu¨llerian adenosarcoma of the uterus: Literature review, case report and ultrastructural observations, Ultrastruct. Pathol. 1, 189–200 (1980). 17. Katzenstein, A. L., Askin, F. B., and Feldman, P. S. Mu¨llerian adenosar-

AP: Gyn Onc

422

18.

19.

20.

21.

GOLLARD ET AL.

coma of the uterus: An ultrastructural study of four cases, Cancer 40, 2233–2242 (1977). Mahoney, A. D., Waisman, J., and Zeldis, L. J. Adenomyoma: A precursor of extrauterine mu¨llerian adenosarcoma? Arch. Pathol. Lab. Med. 101, 579–584 (1977). Morrow, C. P., Curtin, J. P., and Townsend, D. E. Uterine sarcomas and related tumors, in Synopsis of gynecologic oncology, Churchill Livingstone, New York, NY, pp. 189–208 (1993). Silverberg, S. G., and Kurman, R. J. Tumors of the uterine corpus and gestational trophoblastic disease, in Atlas of tumor pathology, third series, fascicle 3, Armed Forces Institute of Pathology, Washington, DC, pp. 156–166 (1992). Fox, H., Harilal, K. R., and Youell, A. Mu¨llerian adenosarcoma of the uterine body: A report of nine cases, Histopathology 3, 167–180 (1979).

/ m4129$4137

10-30-95 19:03:57

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22. Vellios, F., Ng, A. B. P., and Reagan, J. W. Papillary adenofibroma of the uterus: A benign mesodermal mixed tumor of mu¨llerian origin, Am. J. Clin. Pathol. 60, 543–551 (1973). 23. Zaloudek, C. J., and Norris, H. J. Adenofibroma and adenosarcoma of the uterus: A clinicopathologic study of 35 cases, Cancer 48, 354–366 (1981). 24. Baker, T. R., Piver, M. S., Lele, S. B., and Tsukada, Y. Stage I uterine adenosarcoma: A report of six cases, J. Surg. Oncol. 37, 128–132 (1988). 25. Sutton, G. P., Blessing, J. A., Manetta, A., Homesley, H., and McGuire, W. Gynecologic oncology group studies with ifosfamide, Semin. Oncol. 19, 31–35 (1992). 26. Gloor, E. Mu¨llerian adenosarcoma of the uterus: Clinicopathologic report of five cases, Am. J. Surg. Pathol. 3, 203–209 (1979).

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