Progress in Pathology MuWlerianAdenosarcoma of the Uterus: A Clinicopathologic Analysis of 100 Cases With a Review of the Literature PHILIP B. CLEMENT, MD, AND ROBERT E. SCULLY, MD One hundred encountered

cases of mullerian

adenosarcoma

who usually had the symptom of abnormal enlarged

uterus and tissue protruding

the most common presented were

findings

on multiple

interpreted

in 97 cases, included

site. Histologic

of the excised

in four cases.

disclosed

cut surfaces,

totic figures

filling

the tumors were confined or involved

more than one

cellularity,

formed

intraglandular

or both. The sarcomatous

pol-

stroma was homol-

ogous in 78% of the cases and contained heterologous the remainder.

polypoid

usually

stroma, which typically

cuffs of increased

ypoid projections,

that

Primary

revealed benign or atypical neoplas-

tic glands within a sarcomatous periglandukar

uteri

or the myometrium

examination

polyps”

some form of hysterecresection

cavity; less commonly,

to the endocervix

An

Five patients

as adenosarcomas.

masses, some of which had spongy the endometrial

vaginal bleeding.

with “recurrent

tomy in 93 of them, and conservative examination

compont3~t.’ In contrast to typical malignant mullerian mixed tumors, mullerian adenos,arcomas are usually tumors of low malignant potential. Only a minority of them are clinically malignant, and many of the malignant tumors pursue an indolent course. The closely related mullerian adenofibroma (papillary adenofibroma. cystadenofibroma) is characterized by benign epithelial and benign stromal components. One hundred and sixty uterine adeno-tibromas and adenosarcomas have been reported in the literature;‘-!‘2 the f’ormer term has been applied to ap3x and the latter proximately 30 of‘ them, “--1.,‘I.“X.:~“.‘(ti to most of‘ ;he remainder. 111 some studies. however, the two tumors have been referred to collectively as “benign and low-grade variants of‘ mixed mullerian tumors”‘” or as uterine “cystosarcoma phyllodes”,“’ terms that reflect uncertainty of the criteria for distinguishing these two tumors. An absence of longterm f’ollowup in the majority of‘ the reported cases has also resulted in uncertainty regarding prognostic factors in patients with these tumors. In this report. we document our experience with a Lrge series of mullerian adenosarcomas in which long-term followup data have been obtained in most of the cases, indicate features that are useful in predicting recurrence, and propose histologic criteria f’or the differential diagnosis of adenosarcomas and adenofibromas.

58 years),

from the external OS were

on pelvic examination.

occasions

retrospectively

treatment, known Gross

of the uterus were

in patients 14 to 89 years of age (median,

elements in

The stromal mitotic rate varied from 1 to 40 mi(MFs)

(mean 9) per

10 high-power

fields

(HPFs).

Extensive areas of stromal fibrosis that focally imparted a deceptively benign appearance invasion

was present

Recurrent

to the tumor were common. Myometrial

in 15 cases, but was deep

tumor developed

of 0.5 to 9.5 years (mean interval

with an increased

in combination: stromal

tumor was almost alhematogenous

in only two cases. The only feature associated risk for recurrence

metrial inv,asion. Criteria adenosarcomas

Recurrent

to the vagina, pelvis, or abdomen;

spread occnrred

intervals

3.4); in one third of such cases, the

wa!s 5 years or longer.

ways confiued

in only four.

in 23 cases at postoperative

found

from mullerian

was the presence

useful

in separating

adenofibromas

included, alone or

two or more stromal MFs per 10 HPFs,

celllularity,

PATHOL 21:363-381.

and

significant

stromal

of myo-

mullerian marked

cell atypia.

((‘11990 by W.B. Saunders

HUM

MATERIALS AND METHODS

Company.

One huntlred and twenty-five cases of mixed mullerian tumors of the uterus with a benign or atypical glandular component examined prior to 1986 were obtained from the following sources: 120 cases from the consultation files of one of us (R.E.S.), two cases trom the surgical pathology files of the James Homer Wright Laboratories of the Massachusetts ceneral Hospital, two cases from the Canadian Reference Centre for (lancer Pathology, and one case from the consultation files of the senior author. One hundred ot these cases, interpreted as examples of mttllerian adenosarcoma, form the basis of this report; 20 of‘ the 100 cases additional folhave been previously reported, * although lowup information has been obtained tin most of them.

1974, the term “mullerian adenosarcoma” was introduwd to clesignate an uncommon variant of mullerian mixed tumor of the uterus characterized by ;I benign, hut occasionally atypical, glandular component arid a sarcomatous, usually low-grade, stromal III

__.E’IRJIII the Department of Pathology, Vancouver General Hasi,ital. anti tlhc I.niversity of British Columbia. Vancower, Canada; and

the ,James

1lorner

Wright

Laboratories

ol the hlassachusrtts MA. Ac-

(krreral Hospital. and Harvard Medical School, Boston, cepted for public ation .4uguat 2 I, IWS.

Kq won/~: uterus, endometrium. mixed mullet-ran tumor. at~‘nosarconia. ad~notibroma. Addre\\ col-respondence and reprint request5 to Philip B. (Ilernent. hfl). lkpxtment of Pathology. Vancouvrr (k~x~al lloal)ital. Vanc~~uwr, Can;tda \‘57. 1MS. C lYY0 bv \t’.B. Saunders (impan!. OIM->t I77Wk! 10-1.0001$5.00/0

-I. 6, 8. 16, 17. 22. 23, 11, 33. ,411 the cases in thr cited articles are included in this study with the following exceptions: cabes 2. 3. and 4 ~nly;~ cast 2 onlv:” cat 4 onlv:‘” case 6 0111~;‘:’ taw, 2 and 6 onlv.”

* Kcferences

363

Volume 21, No. 4 (April 1990)

HUMAN PATHOLOGY

TABLE 1.

Uterine Adenosarcoma: Age Distribution

Age Range (y)

Percent

1o- 19 20-29 30-39 40-49 .50-59 tie-69 70-79 80-89

6 7 10 15 15 18 24 5

The remaining cases, consisting of seven adenofibromas, 10 mullerian adenosarcomas with sarcomatous overgrowth, and eight mullerian adenosarcomas with sex cord-like elements (SCEs), have been analyzed separately.“‘-““’ From one to 25 slides of the primary tumor (mean, 6.6) were available for study, and slides of recurrent or metastatic tumor were obtained in 23 cases. In selected cases, additional slides were stained by periodic acid-Schiff with and without diastase predigestion. reticulin, and the peroxidase-antiperoxidase immunohistochemical technique using antibodies directed against myoglobin (Cappel Laboratories, Cooper Biomedical, Malvern, PA). Mitotic activity of the stromal component of each tumor was assessed by counting the number of mitotic figures (MFs) in the 40 most cellular high-power fields (HPFs, HPF = ,159 mmY); the counts were averaged and expressed as MFsilOHPFs. In four cases, mitotic counts could not be performed because of suboptimal material (autolysis, overstained slides, marked

stromal inflammation). Additional clinical information, including followup data. was obtained from the patients’ physicians.

CLINICAL FEATURES, OPERATNE FINDINGS, AND PRIMARY THERAPY The (median,

patients

ranged

in age from

14 to 89 years

58 years). The age distribution by decade is shown in Table 1; 62% of the patients were 50 years of age or older. Of the 57 patients whose race was known, 50 were white, four were black, and three were Oriental. A reproductive history was available in 49 cases: 15 patients were gravida 0; six were gravida 1; 12 were gravida 2; seven were gravida 3; and nine were gravida 4 or more. The presenting clinical features were known in 97 cases. Ninety-two patients went to their physician only once prior to definitive therapy, and five went on multiple occasions. In the former group of patients, the most common symptom was abnormal vaginal bleeding (76 patients): less common symptoms included pelvic pain (five patients), complaints related to uterine prolapse (four patients), and vaginal discharge (two patients). Rare symptoms (one patient each) included an abnormal result of cervicovaginal cytology, dysmenorrhea, dysuria, urinary tract infection, infertility, and abdominal swelling due to ascites. Six patients were asymptomatic. The results of pelvic examination were known in 77 of the 92 patients. The most common finding was tissue protruding from the external cervical OS (41 patients), in some 364

cases partially filling the vagina; a frequent clinical impression in such cases was benign endocervical polyp. Other findings included an enlarged uterus (30 patients), a pelvic mass (four patients), or both (one patient). There was no clinical evidence of extrauterine spread in any case. Sixty-one of the 92 patients underwent a biopsy procedure, usually a polypectomy, a dilatation and curettage (D&C). or both, 1 day to 9 months before the institution of definitive therapy. An initial histologic diagnosis was rendered on 49 of these specimens at the time of referral (Table 2); it was entirely correct in almost one-third of the cases and acceptable but inaccurate in an additional 22%. The five patients who presented on multiple occasions (two to four times) did so during periods ranging from 9 months to 5 years before definitive diagnosis and treatment. These patients were young (21 to 37 years of age) and usually had abnormal vaginal bleeding; in at least three cases, polyps protruded from the external cervical OS on one or more occasions. Polypectomy, a D&C, or both were performed and a pathologic diagnosis of benign endocervical or endometrial polyp was made on each occasion. Retrospective examination of the histologic slides of the “recurrent polyps” in each case revealed adenosarcoma. Fifteen patients had other noteworthy features in their medical histories. Five patients had received abdominal or pelvic radiation therapy. The ovaries of two patients had been radiated 30 and 8 years earlier for the treatment of dysmenorrhea, and three other patients had received radiation treatment 17 years, 10 years, and 7 years previously for the treatment of squamous cell carcinoma of the cervix, clear-cell adenocarcinoma of the endometrium, and an abdominal wall desmoid tumor, respectively. Five patients had a history of estrogen use. One of these patients had ingested estrogens for 16 years after cranial radiation treatment for a chromophobe adenoma,-” TABLE 2.

Uterine Adenosarcoma: Referral Diagnoses on Curettage and Biopsy Specimens Diagnoses (No.)

Benign

Malignant

Benign endometrial or endocervical polyp (6) Adenotibroma (3) Stromal hyperplasia (2) Endometrlal polyp with reactive stroma (1) i\typical endometrial polyp (1) Adenomyomatous polyp (1) Polypoid endometrial hyperplasia (I) Adenosarcoma (16) Endometrial stromal sarcoma (6) Malignant mixed mullerian tumor (-1) Sarcoma botryoides (2) Endometrial stromal sarcoma with benign epithelial inclusions (1) Adenofibroma vs adenosarcoma (1) Endometrial stromal tumor (1) Sarcoma in endometrial polyp (1) Endocervical stromal sarcoma (1) Mesodermal stromal sarcoma (1)

MULLERIANADENOSARCOMA(Clement & Scully) TABLE 4. Uterine Adenosarcomo: Postoperative Follow-up -Status at Follow-up uo. C’i;)

and another patient ingested estrogen for 10 years. In addition to these five cases, there was a history of maternal usage of a hormone of unknown type during the fir:st trimester in one patient and a diagnosis of the Stein-Leventhal syndrome in another. Several patients had a history of previously treated neoplasms, which included bilateral ovarian SertoliLeydig cell tumors treated by bilateral salpingooophorectomy 19 years previously in one patient’7,s” and carcinoma of the breast. treated 5 and 2.5 years earlier, in two patients. Three patients were lost to followup immediately after the diagnosis was established by biopsy, and subsequent treatment, if any, is unknown. The remaining patients underwent primary treatment that included some form of’ hysterectomy in 93 cases and more conservative therapy in four cases (Table 3): some patients also received preoperative or postoperative radiation therapy, chemotherapy. or both (‘I‘able 3). At the time of operation, there was no evidence of extrauterine tumor involvement except in two cases. A T-cm mass in the cul-de-sac adherent to the lefi ovary was excised at the time of hysterectomy in one patient, and in another, a IO-cm left ovarian tumor with a 2-cm serosal implant on the contralatera1 ovary were included in a specimen removed by total abdominal hvsterectomy with bilateral salpingooophorectom\.

Alive, no evidence Dead, no evidence Kerurrenrc

Followup information was available in X8 cases (‘I’able 4). Fifty-three patients (60.2%’ of those with followup) were alive with no evidence of tumor at postoperative intervals of 1.3 to 19 years (mean fol5.9 ! ears). Twelve patients ( 13.676) lowup interval. TABLE 3. Uterine Adenosarcoma: Initial Therapy __.Therapy

:;:3 (60.2) II’(l3.6) ‘?Y (26. I) -__

had no further evidence of tumor hut died ot‘ unrelated causes at postoperative intervals of‘ 2 months to 8.5 years. Recurrent tumor was diagnosed in 23 patients (26.1%); if the two patients with recurrent tumor who had been treated only by locall excision are excluded from analysis, the recurrence rate was 23.9%). Recurrent tumor was diagnosed at postoperative intervals of 0.5 to 9.5 years (mean, 3.4 years); in eight of the 2 1 patients (SS%,j, the first recurrence appeared 5 or more years after hysterectomy (Table 5). The sites of initial recurrence (‘I‘ablle .5) were vagina only (se\:en patients). pelvic cavitv only (six patients), abdomen with or without pelvic involvement (six patients). distant sites with or without abdominopelvic disease (two patients), and the endometrial cavity (in two patients who had only a local resection). Recurrent vaginal tumor took the form of polypoid or papillary lesions, 2 cm to 12 cm in maximum dimension, which were usuall!, attached at the vaginal apex; in one c’ase, the vaginal tumor was described as resembling granulation tissue. Recurrent tumor in the pelvis, ahdomen, or both. varied from large solitarv masses up to 16 cm in diameter, to multiple smkller peritoneal nodules, to a combination thereof. Tumor in the pelvis was found to he adherent to, and in some cases, invasive of pelvic organs (bowel, vagina, bladder). Outside the pelvis. tumor involved the omentum, mesentery of the intestine, periumbilical or the retroperitoneum (‘Table 5); periregion. ureteral lymph nodes were also involved in one case (Table 5. case 13). Blood-borne metastases were found in only two patients (cases 1 and 1). In one of them (case l), a pelvic mass. a right upper quadrant abdominal mass, and a lytic lesion in the right temporal bone that extended into subcutaneous tissue were found 6 months after hysterectomy. In the other case (case 4), multiple bony metastases appeared 1 year after hysterectomy. ‘I‘he intrauterine recurrences in the two patients who had been treated by local excision (cases 20 and 28) consisted of multiple polypoid masses, which were removed by curettage. Recurrent tumor was usually treated by excision or dehulking, sometimes combined with radiation therapy, chemotherapy, or both (Table .5). The two patients with hematogenous spread had only biopsy (case 1) or radiation therapy of the lesions (case 4). One patient (case 8) died shortly after a massive intraahdominal recurrence was diagnosed clinically; the recurrent tumor was neither submitted for biopsy nor treated. In another case, recurrent tumor was first diagnosed at autopsy (Table 5, case 2). Six patients

FOLLOWUP DATA

7 AH and L‘S0 or MO* -I AHI .I AH and BSO 01 I SO. postoperative radiation \Taginal hysterectomy+ ‘I AH, BSO and pelvic Iymphadenectomy Preoperative radiation, TAH and BSO ‘I AH and EZW. pelvic lymphadenertomy. postoperative radiation and c hemotherapyt I.ocal excision cmlv5

of tumor of tumor

NO. .x 11 H 5 5 4 1 -I

Abbreviations: ‘IAH. total abdominal hy,~terectomy; USO. unilateral salpingo-oophorectomy; BSO. bllateral salpingooophorectomy. * One patient rcceivetl preoperative chemotherapv (prorytox. .5 FL!, actinomycin) and one patient received postoperative chemotherapy (P.1~2). t One patiwlt received postoperative radiation. f One patient did not receive postoperative radiation; chemotherapy in these tour patients consisted of DTIC. vincristine. and doxorubicin: vincristine, actinomycin D. and cyctophosphamide; ~incristine. actinomvcin D. and cvclophosphamide; doxorubicin and cisplatin. 5 D&C ( 1). polypecromy (I ). cone biopsy and D&C: (I ). partial myometrectrlmv (I).

365

TABLE 5.

Uterine Adenosarcomas With Recurrences. Clinical and Pathologic Features Primary

Gasc

I.

Size (cnl)

Age

3415

Invasion

Recul-remes

Tumor

Interval

MF/lU HPI:

-

(y)*

0

40

ER

0.5

0

I6

U

1.2

lti

0

0.5

“5%

30

ER. C

1

“0

residual 2.475

I

3.37x9

lj &

.4.145U-t

3

5. 1‘497U

I3

0

“3

U

”

6. 7303

Y

0

4

0

I.5

7. Y49Y

2

u

(I

2.x

8. 86Oh

6

0

9. ‘49HI

5

111..X3]

I

filled cavity

I. “710

.i7

71

i?

of a case. Acta Cytol (Baltimore) 2ti:32%326.

19x2 32. Miles I’:\. Herrera

GA. Greenberg H, et al: Mullerian adenofibroma ot the endometrium: A report of a case with ultrastructural study. Diagn (Gynecol Obstet 4:215-221, 1982 33. (.zernobilsky B. Hohlweg-Majert P, Dallenbach-Hellweg (;: L’cerine adenosarcoma: A clinicopathologic study ot I I cases with a reevaluation c~f histologic criteria. Arch t+necol 233:2X1 291, 19x:+. 34. Harir-i J: Muller-iall adenosarcoma of the endometrium: Rrview of the iitt-rature alld report of two cares. Int ,J Gynecol Path01 ‘L:lH”-191, 1%x:< 3.5. Segura-Fonsec-aJJ. Muikai Ii: Mullerian adenoaarcoma ot the uterus with hrterologous component: Case report uith an immunohistc~chrr~~ic .II study ot mvoglobin. Pathologica 2 I :233-240, 1100 36. Altaras 51, (,ohen I, (:ordoba M. et al: Papillar\ adenofihroma of the rndometrium: Case report and review of the literature. Gvnecol Oncol 19:216-221. 1984 37. Hilton P. ‘Facchi D, Watson A: Mullerian adenofibroma. Case Report. Br J Obstet (iynaecol 91:1261-1265, 1984 3X. Iwai M, Konishi I. Fujii S, et al: A light and electron microscopic study ot mullerian adenofihroma of. the uterus. Nippon Sanka Fuji&a Gakkai Zasshi 36:44-48, 1984 39. i’oncmitsu N. Kakahara M. Sugihara H: A case of mullerian adenosarcoma ot the uterus. Gan No Rinsho 30: lO5- 109. 19X4 40. Oda Y. Nakanishi I. Tateiwa T: Intramural mullerian adenosarcoma of the uterus with adenomyosis. Arch Path01 Lab Med I I~H:79&XOl. 1W-H 11. Press MF. Scull! RF.: Endometrial “sarcomas” complicating ovarian thecoma. polycystir oval-ian disease and estrogen theraI)y. Gvnecol Oncol 21:135-134, 1985 42’. Bjerregaard B. Mall M. Gram NC: Muller-adenl,sarkorrl i uterus. Ugeskr Laeger l-15:2306-2307, 1985 43. (:hen K’TK: Rhabdomyosarcomatous uterine adenosarcoma. lnt .J