CALIFORNIA TUMOR TISSUE REGISTRY
95TH SEM\-ANNUAL CANCER SEM\NAR
ON TUMORS OF THE FEMALE GENITAL TRACT
CASE HISTORIES
MODERATORS:
WILLIAM R. HART, M.D. Cleveland Clinic Foundation
and
PHILIP B. CLEMENT, M.D~ Vancouver General Hospital
December 5, 1993 Ritz Carlton Hotel San Francisco, California
CHAIRMAN:
ROGER TERRY, M.D. ... Emeritus Professor of Pathology LAC·USC School of Medicine CONTRIBUTOR: William R. Hart, M.D. CASE NO. 1 -DECEMBER 1993 Cleveland, OH
TISSUE FROM: Vulva ACCESSION NO. 27353
A 75 year-old, nulligravld woman had a 7-year history of recurrent vulvar lesions. Several biopsies, including a wide local excislonal biopsy, had been performed. She also had vulvar lichen sclerosus for which she was being treated with topical testosterone cream. On examination, raised lesions Involving the right labium majus were seen. A wide local excision was performed.
The submitted specimen was an 1.6 x 0.5 em ellipse of skin with 0.7 em of attached subcutaneous adipose tissue. Multiple pi nk-white papular lesions ranging from 0.1 to 0.4 em involved the cutaneous surface.
CONTRIBUTOR: William R. Hart, M.D. CASE NO. 2- DECEMBER 1993 Cleveland, OH
TISSUE FROM: Vulva ACCESSION NO. 27354
This 87 year-old, nulligravid woman had a history of a local excision for a bleeding vulvar mass one year ago. She subsequently presented with a recurrent vulvar lesion which bled with mild trauma. On examination, a 4 x 6 em polypoid velvety mass Involving the left labium minus with some attachment to the clitoris was found. Following biopsy, a radical vulvectomy was performed.
The vulvectomy specimen was 15 x 10 x 1.5 em. Arising from the left labium minus and Involving the left lateral aspect of the clitoris was an exophytic nodular tumor that measured 4 em in diameter and projected 1.2 em above the cutaneous surface. Sectioning of the tumor revealed tan-white, glistening and focally hemorrhagic tissue. The tumor extended 0.8 em Into the subcutaneous adipose tissue. CONTRIBUTOR: Edwar.d Farber, M.D. CASE NO.3· DECEMBER 1993 Midland, Ml
TISSUE FROM: Vagina ACCESSION NO. 27355
At the time of an otherwise normal obstetrical vaginal delivery, a 20 year-old woman was found to have a small "cyst" in the posterior aspect of the vaginal introitus. The lesion was excised.
The submitted specimen consisted of a solid, ovoid nodule 0.3 em in diameter. The cut surface was tan-white and appeared edematous.
CONTRIBUTOR: Atllia Martinez, M.D. CASE NO.4· DECEMBER 1993 Tustin, CA ·
TISSUE FROM: Uterus ACCESSION NO. 27240
A 44 year-old woman presented with a mass in the lower abdomen that had been gradually increasing for the last three years. She had not been taking any hormonal medications. A CA-125 value of 86 (normal: <35) led her clinicians to believe that there was a possibility of an ovarian cancer. A lower abdominal mass arising from the central portion of the pelvis, about the size of an 18-week pregnancy, was noted on physical examination. A total abdominal hysterectomy with bilateral salpingo-oophorectomy and pelvic washings were performed.
Gross examination revealed an enlarged and distorted multinodular 16 x 10.5 x 9 em uterus weighing 710 grams. The largest mass measured 6.5 x 7.1 em and was found in the dome of the uterus. Sectioning of the mass revealed a mucoid violet parenchyma with hemorrhagic discoloration In Its· center. The periphery of the nodule consisted of a rim of paler white tissue. The mass appeared well-circumscribed grossly. On the left lateral wall ofthe myometrium a second nodular mass measuring 3. 7 em in greatest dimension was Identified. The sectioned surface consisted of white, whorled parenchyma which bulged above the cut surface and had a central, hemorrhagic, necrotic area. The remainder of the uterine nodules had a white whorled appearance typical of ieiomyomas.
2 CONTRIBUTOR: Arthur Koehler, M.D. CASE NO.5 · DECEMBER 1993 Pasadena, CA
TISSUE FROM: Uterus ACCESSION NO. 27229
A 47 year-old woman presented with fibroids, anemia, menometrorrhagia and dysmenorrhea Physical examination revealed a large, palpable abdominal mass the size of a 16-we.ek pregnancy. A hysterectomy was performed.
The resected uterus was 11 x 8 x 9.5 em and weighed 656 grams. The external surface was smooth and glistening_ with a posterior bulge. The endometrial cavity measured 7.5 x 3.5 em, with a 2 mm thick endometrium. The myometrium had a single large, well-demarcated mass approximately 8 em in diameter. Sectioning revealed a bulging tan, soft, solid leiomyoma-like lesion with cystic areas. The myometrium, where not involved by the tumor, was 1.5 em in thickness.
C.ONTRIBUTOR: Michael D. McCoy, M.D. CASE NO.6· DECEMBER 1993 Cleveland, OH
TISSUE FROM: Uterus ACCESSION NO. 27356
This 46 year-old, G3P1, female presented with menorrhagia and an enlarged uterus. An ultrasound of the pelvis showed an enlarged uterus with a fundal mass which had not been present at the time of a previous ultrasound examination performed one year earlier. Pelvic examination revealed a "fibroid uterus." A total abdominal hysterectomy and right salpingo-oophorectomy were performed.
The uterus was 12 x 11.8 em and weighed 387 grams. A spherical intramural mass, 8 em In diameter, bulged from the posterior wall of the corpus. The mass had a well-demarcated periphery. The cut surface was gelatinous; glistening and moderately soft. The tumor had a variegated appearance with yellow and pink-tan areas. Areas of degeneration and necrosis were seen grossly.
3 CONTRIBUTOR: Philip Clement, M.D. CASE NO.7- DECEMBER 1993 Vancouver, BC
TISSUE FROM: Retropubic area ACCESSION NO. 27348
A 39 year-old woman presented With crampy lower abdominal pain. Pelvic examination, ultrasonography, and CT-scan revealed a right pelvic mass. At laparotomy, a 9 em in maximum dimension, soft, solid retropubic mass was found, displacing the urinary bladder to the left. The tumor extended deeply into the pelvis as far as the obturator foramen. The mass was excised, and the seminar slides are from this specimen. Six months later, the patient noticed a gradual swelling of the right side of the vulva, which increased In size over the next two years. A CT -sc.an found a large right pelvic mass involving the Ischiorectal fossa. A second operation using a combined abdominal-perineal approach was performed to remove the mass that was 17 em in maximum dimension.
Gross examination of the first specimen revealed a 9 x 6 x 4 em, solid, soft, non-encapsulated mass. Its sectioned surface was glistening, gray-tan and myxoid. The specimen removed three years later had a similar appearance.
CONTRIBUTOR: Arthur Koehler, M.D. CASE NO. 8- DECEMBER 1993 Pasadena, CA
TISSUE FROM: Cervix ACCESSION NO. 27266
A 42 year-old woman presented with menorrhagia of three months duration. She also experienced an episode of syncope and pain. Physical examination revealed the vagina to be completely filled by a 9 em mass. The mass was necrotic with a foul smelling discharge. The mass was palpable Into the right cardinal ligament and right uterosacral ligament but did not extend to the pelvic sidewall. CT-scan showed no lymphadenopathy and no metastases to chest, liver or brain. A bone scan was negative. A cervical biopsy was performed.
Gross examination of the cervical biopsy material revealed multiple fragments of soft, glistening tan tissue admixed with blood clot measuring 6 x 5.4 x 1.5 em In aggregate. Sectioning revealed much of the tissue to be necrotic, although occasional fragments of apparent tumor appeared viable.
4 CONTRIBUTOR: Philip Clement, M.D. CASE NO.9· DECEMBER 1993 Vancouver, BC
TISSUE FROM: Cervix ACCESSION NO. 27350
A 53 year-old woman presented with vaginal discharge; pelvic examination revealed a bulky uterus. A dilatation and curettage yielded purulent material consistent with pyometra. Pathologic examination of this specimen revealed inflamed endometrial and endocervical tissue; the latter exhibited atypia which was considered reactive, consistent with the degree of inflammation. S.imilar findings were found on a repeat curettage one month later. Three mol)fhs after presentation, a total abdominal hysterectomy was performed because of persistent symptoms. The cervix was noted to be firm in consistency at the time of operation; there was no evidence of extrauterine spread.
Gross examination of the hysterectomy specimen revealed a submucosal leiomyoma within the lower uterine segment. The cervix was firm but not enlarged, and there was no obvious tumor on gross examination.
CONTRIBUTOR: Philip Clement, M.D. CASE NO. 10 ·DECEMBER 1993 Vancouver, BC
TISSUE FROM: Uterus ACCESSION NO. 27352
A 74 year-old woman presented with a three·month history of post-menopausal bleeding. There was no history of hormone intake. The uterus was only slightly enlarged on pelvic examination. Following a dilatation and curettage, a total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed. Tumor nodules were noted on the uterine serosa at the time of operation, but there was no evidence of extrauterine spread.
Gross examination revealed an enlarged, 245 gram uterus. The endometrium was completely replaced by a friable, tan-white, polypoid tumor that measured up to 1 em In thickness. There was deep myometrial invasion and gross involvement of the cervix.
5 CONTRIBUTOR: Steven B. Jobst, M.D. CASE N0. 11 · DECEMBER 1G93 San Luis Obispo, CA
TISSUE FROM: Uterus ACCESSION NO. 26112
A 38 year-old woman presented with severe dysmenorrhea which had progressively gotten worse. A sonogram showed a cystic and solid mass In the left adnexal region. Physical examination revealed a uterus approximately 7-weeks In gestational size and slightly Irregular. An 8 em, tensely cystic, very tender mass was also noted on the left. Laparoscopy revealed a mass In the left adnexal region, and a total abdominal hysterectomy ar:'d bilateral salpingo-oophorectomy were performed.
The resected uterus and cervix together weighed 160 grams and measured 11 .6 x 7.4 x 5.9 em. The endometrial cavity was entirely filled with a soft, yellow to yellow-tan mass which was attached near the fundus but did not appear to Invade the underlying myometrium. The mass measured 5.5 x 4.5 x 4.0 em. Each tube and ovary was submitted separately. One was a 9.1 x 6.2 x 4.5 em mass of hemorrhagic, gray tan to reddish-tan tissue with blood clot, hemorrhage, ecchymosis and petechiae over the surface. Cut sectioning revealed a dilated fallopian tube with blunted fimbria which ended In a hemorrhagic and necrotic ovarian mass. Sectioning of the ovary revealed a central area of necrosis and hemorrhage, with a greenish-yellow color throughout.
CONTRIBUTOR: Farooq All, M.D. CASE NO. 12 ·DECEMBER 1993 Ventura, CA
TISSUE FROM: Pelvis and bilateral ovaries ACCESSION NO. 27235
A 43 year-old woman presented with syncope, left leg pain and paresthesiae in January 1993, and was noted to have a peri-umbilical, 3 x 2 em mass. ACT-scan of the pelvis showed uterine flbroids and a large 15 x 16 em tumor that involved both ovaries that contained solid, cystic and necrotic areas, and possible tumor masses that involved the left lower abdominal wall and extended to the umbilical cystic mass. A hysterectomy, bilateral saJplngo-oophorectomy, tumorectomy and omentectomy were perfonned.
Two lobular, encapsulated, ovoid masses were received. Both had a similar pale pink-tan, edematous, predominantly solid cut surface that contained small cysts with green-brown material. The larger mass measured 5.5 x 4.0 x 3.0 em, and the smaller measured 3.0 x 2.0 x 1.5 em. The ovarian remnants contained multiple red and yellow cysts. In addition, a large, lobula~ed, fleshy, yellow-pink mass with multiple gray tan cystic areas, 0.5 x 2.0 em In diameter, measured 21 x 12 x 6 em and weighed 775 grams.
6 CONTRIBUTOR: William R. Hart, M.D. CASE NO. 13- DECEMBER 1~3 Cleveland, OH
TISSUE FROM: Right ovary ACCESSION NO. 27357
This 66 year-old, G4P4, woman had a chief complaint of fullness, bloating and abdominal distention of two month's duration. On examination, a massive abdominal mass which extended almost to the zyphoid was palpated. Ultrasound also showed a large abdominal mass. At operation, a large mass Involved the right ovary. Multiple mucinous deposits throughout the peritoneal cavity, including the cul-de-sac, sigmoid serosa, right colic gutter and sub-diaphragmatic surface of the liver, were found. A total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, appendectomy and multiple perltone~ biopsies were performed.
The resected right ovarian mass consisted of a large cystic gelatinous tumor, 24 x 23 x 16 em and 3018 grams. The cysts were lined by thin fibrous walls and contained abundant yellow mucinous material. The left ovary was grossly normal. The uterus contained small myomas. The appendix was 6 em In length and had a slightly dilated distal portion. The dilated area was 1.5 em in diameter, about twice the diameter of the resected base of the appendix. The dilated lumen contained clear mucus. A rupture site was Identified which was in continuity with a mucinous implant on the serosa
CONTRIBUTOR: William R. Hart, M.D. CASE NO. 14 ·DECEMBER 1993 Cleveland, OH
TISSUE FROM: Left ovary ACCESSION NO. 27358
A 54 year-old woman complained of severe abdominal and low-back pain for six months. The pain had been especially severe during the previous two weeks. Recently she had experienced post-menopausal bleeding. On examination, she had a tender abdomen and there was a questionable mass in the right uterine adnexal area The differential diagnosis was peritonitis with an inflammatory mass vs. a pelvic tumor. A CT·scan showed a large pelvic mass in the region of the left ovary of approximately 14 em, a questionable mass Involving the right ovary, an upper abdominal mass and a right hydroureter. The patient underwent an exploratory laparotomy at which time a 20 em left ovarian mass along with a 6 em cystic right ovary and a 4 em metastatic nodule In the right lobe of the liver were found. A retroperitoneal nodular mass was also palpated in the upper abdomen. There were no enlarged lymph nodes and the omentum was normal. 200 cc of free fluid was in the pelvis. A bilateral salplngo· oophorectomy and needle biopsy of the upper abdominal mass were performed.
The resected left ovarian mass was 495 grams, 16.5 x 10.8 x 5.4 em, and had a smooth extemal surface. On sectioning, the tumor was multlcystic with firm white areas up to 3 em In greatest dimension. The right ovary was 4.2 x 2.8 x 1.5 em. The external surface was smooth. Cut surface showed a smooth-walled cyst occupying most of the ovarian parenchyma
7 CONTRIBUTOR: Robert Rosser, M.D. CASE N0.15 ·DECEMBER 1993 Palm Springs, CA
TISSUE FROM: Right ovary ACCESSION NO. 27359
This 28 year-old, G1 P1, woman had a three-day history of pelvic pain and was found to have a large pelvic mass. Five months previously, she had an uneventful pregnancy with a normal delivery. At the time of hospital admission, the pelvic mass had grown to approximately 16-week size and was present below the umbilicus. Serum calcium level was 9.1 mg/dl (normal range 8.5 • 10.5) and a CA·1251evel was 284. At operation, an 18 em solid, friable right ovarian mass was found along with enlarged para-aortic lymph nodes and ascites (1;ooo ml). A right salpingo-oophorectomy, omentectomy, biopsy of the left ovary and para-aortic lymph node biopsy ware performed.
The right ovary consisted of a 20 x 20 x 12 em multinodular tumor. The cut surface of the tumor was solid, soft and nodular. Creamy tan, "brain-like" areas alternated with granular red and yellow areas. No papillary structures were seen.
CONTRIBUTOR: Joseph Boccia, M.D. CASE NO. 16 ·DECEMBER 1993 Cleveland, OH
TISSUE FROM: Left ovary ACCESSION NO. 27360
This 21 year-old female had abnormal bleeding and an adnexal mass which was thought to be an ectopic pregnancy, possibly ovarian. A O&C was performed. No chorionic villi were identified in a frozen section of the endometrial curettings. An exploratory laparotomy was performed to further explore the possibility of an ectopic pregnancy. A mass was found in the region of the left ovary and a left salpingo oophorectomy was performed.
The submitted specimen was labeled •tube, ovary and products of conception. • It consisted of multiple fragments of yellow, coarsely bosselated and slightly mucoid tissue fragments. The fragments ranged in size from 1.5 to 3.0 em. Recognizable ovarian tissue with a corpus luteum was attached to some of the fragments. The fallopian tube was grossly normal.
8 ,
CONTRIBUTOR: Mark J. Beck, M.D. CASE NO. 17 ·DECEMBER 1993 Rancho Mirage, CA
TISSUE FROM: Right ovary ACCESSION NO. 26977
A 90 year-old woman presented with occasional vaginal spotting and abdominal disfigurement noticed by the patient's daughter. Ultrasound revealed a large cystic pelvic mass with septa, suggestive of malignancy. A D&C was performed, followed by an exploratory laparotomy, hysterectomy and bilateral salpingo-oophorectomy.
The right ovary consisted of a. cystic mass, weighing 3,500 grams and measuring 23 x 18 x 14 em. The cortical surface was nodular along one aspect. Most of the tumor was cystic with honey-comb areas and Intervening solid areas. The cysts contained yellow-green, viscous mucous. The left ovary and tube measured 6.6 x 5.8 x 2.5 em and weighed 35 grams. The left ovary contained multiloculated mucinous cysts that measured up to 1. .8 em in diameter.
CONTRIBUTOR: Mark J. Beck, M.D. CASE NO. 18 ·DECEMBER 1993 Rancho Mirage, CA
TISSUE FROM: Right ovary ACCESSION NO. 27233
A 41 year-old woman presented with chronic pelvic pain, progressive pelvic fullness and urinary Incontinence. She had a known history of fibroids for many years. Ultrasound of the pelvis revealed a large, irregular, mobile uterus about 1o-weeks In size. The adnexae were difficult to palpate due to the large size of the uterus. An exploratory laparotomy was performed, and the uterus was found to be irregular with obvious pedunculated fibroids. The right ovary was enlarged, and the walls of the ovaries were very thick. A total abdominal hysterectomy and bilateral salplngo oophorectomy were performed.
Gross examination of the 122 gram uterus revealed multiple fibroids which ranged from 0.6 to 1.0 em in greatest dimension. The right ovary weighed 45 grams and measured 7 x 4 x 3 em. Sectioning revealed three cysts, one that measured 2 em and grossly appeared to be a hemorrhagic corpus luteum, and the other two which measured 3.5 and 2.5 em with fatty and hairy contents. The left ovary measured 3.5 x 2.5 x 1.5 em. Sectioning revealed multiple subcortical follicular and h,Jteal cysts with two central cysts, 0.6 and 0.9 em in diameter, containing slightly grumous contents.
9 CONTRIBUTOR: Philip Clement, M.D. CASE N0.1 II- DECEMBER 10113 Vancouver, BC
TISSUE FROM: Left ovary ACCESSION NO. 27351
A 28 year-old woman presented at 18 weeks' gestation with markedly elevated maternal serum alpha-fetoprotein levels (29,902 ng!ml). Investigation revealed a large left adnexal mass. Laparotomy revealed a hemorrhagic left ovarian tumor that had undergone partial torsion, and a left salplngo.oophorectomy was performed.
On gross examination, ~he left ovary was replaced by an 18.5 em In maximum dimension, solid and cystlc, markedly hemorrhagic tumor.
CONTRIBUTOR: Usha Garg, M.D. CASE NO. 20- DECEMBER 1993 Oxnard, CA
TISSUE FROM: Ovary ACCESSION NO. 27308
A 20 year-old woman presented with an irregular uterus or adnexal mass. Pelvic ultrasound revealed a small uterus displaced to the left by a large pelvic mass. A laparoscopy was performed, and a large 9 em smooth·walled, solid ovarian tumor was visualized. A laparotomy was subsequently performed to remove the left tube and ovary.
Grossly, the ovarian tumor consisted of a smooth, ovoid, grayish·tan nodular mass which measured 12 x 6 x 6 em and weighed 360 grams. Sectioning revealed it to be partially cystic and exuding mucinous fluid. Most of the mass was solid, fleshy and quite soft with microcysts containing yellow material.
10 CONTRIBUTOR: Philip Clement, M.D. CASE NO. 21 ·DECEMBER HKI3 Vancouver, BC
TISSUE FROM: Left ovary ACCESSION NO. 27349
A 71 year-old woman was admitted to the hospital for congestive heart failure. Physical examination and ultrasonography revealed a large cystic mass in the region of the left ovary. A bilateral salpingo-oophorectomy was performed. There was no evidence of extra-ovarian tumor.
On gross examination, the le~ ovary was replaced by a multiloculated cyst that was 20 em in maximum dimension. The contents of the locules varied from serosanguineous fluid to tenacious mucus. In the wall of one of the cyst locules, a predominantly solid white mass was present that contained small cystic spaces. The Ipsilateral tube and the contralateral tube and ovary were unremarkable.
CONTRIBUTOR: Keith England, M.D. CASE NO. 22 ·DECEMBER 1993 West Covina, CA
TISSUE FROM: Right ovary ACCESSION NO. 26956
A 37 year-old woman presented with right lower quadrant pain radiating to the back. The pain appeared at the onset of menses and had been present for two to three months. Upon examination, a 6 to 7 em mass was noted in the pelvic area and located to the right of the uterus. The retroverted small uterus appeared to be fixed to the posterior aspect of the mass. The left adnexa was negative. Ultrasound examination revealed the uterus to be 17.7 plus 10.9 to 9.5 em in diameter. The right ovary was not visualized. The left adnexa showed a funnel lucency suggestive of fluid in the intestinal tract vs. ovarian cyst. An exploratory laparotomy was done, and a 10 x 8 x 1 0 em firm mass was noted arising from the right ovary with large dilated blood vessels. A total abdominal hysterectomy, bilateral salplngo-oophorectomy and omental biopsy were performed.
Gross examination of the right adnexal mass and ovaiy revealed a 15.1 x 13.4 x 8.4 em ovoid, soft, encapsulated mass. The external aspect was smooth, glistening, gray-white with scattered thin-walled blood vessels which coursed over the external aspect. The cut surface was soft, slightly nodular, yellow-orange, and predominantly solid with focal cystic degeneration. An edematous, well-delineated, elongated ovary was Identified attached to one external aspect, measuring 5.7 x 2.5 x 1.9 em.
11 CONTRIBUTOR: Frank Pezzlo, M.D. CASE NO. 23- DECEMBER 1993 Orange, CA
TISSUE FROM: Left ovary ACCESSION NO. 26405
A 33 year-old woman presented with a six-month history of amenorrhea and left lower quadrant paln. An adnexal mass was discovered on physical examination. At surgery, the left ovary was enlarged to 5 em. The uterus and right adnexa were normal. A hysterectomy and left salpingo-oophorectomy was performed.
Gross examination revealed a 5.3 x up to 3.2 em round structure. Stretched over segments of the structure was a segment of oviduct-like tissue. . Sectioning through the central portion of the mass revealed a circumscribed, bright yellow, 3.3 x 2.6 em tumor mass. The tumor had a solid appearance throughout.
CONTRIBUTOR: Philip Clement, M.D. CASE NO. 24- DECEMBER 1993 Vancouver, BC
TIS.SUE FROM: Left uterine adnexa ACCESSION NO. 27347
A 42 year-old woman presented with a six-week history of left lower quadrant pain. A left pelvic mass was palpable on pelvic examination. A total abdominal hysterectomy had been performed seven years earlier for uterine leiomyomas. At laparotomy, an 8 em hemorrhagic, multicystic mass in the region of the left ovary was densely adherent to the surrounding pelvic peritoneum. A left salpingo-oophorectomy was performed.
On gross examination, the specimen consisted of a spherical mass measuring 7 x 6 x 3 em that was covered by fibrous adhesions. Sectioning the mass revealed a multilocular cyst With thin septa and contents that varied from serous to hemorrhagic. No solid or papillary areas were noted.
12 CALIFORNIA TUMOR TISSUE REGISTRY
95TH SEMI-ANNUAL CANCER SEMINAR
ON TUMORS OF THE FEMALE GENITAL TRACT
ADDENDA
MODERATORS:
WILLIAM R. HART, M.D. Cleveland Clinic Foundation
and
PHILIP B. CLEMENT, M.D. Vancouver General Hospital
Decamb!l( 5, 1993 Ritz Cartton Hotel San Francisco, California
CHAIRMAN:
ROGER TERRY, M.D. Emeritus Professor of Pathology LAC.USC School of Medicine 95th Semi-Annual Cance.r Seminar "Tumors of the Female Genital Tract"
TABLE OF CONTENTS
Case #1 (27353) Squamous cell carcinoma in-situ of differentiated (simplex) type (YIN Ill) Pages 2-5
Case #2 (27354) Malignant melanoma of vulva Pages 6,7
Case #3 (27355) Benign mixed tumor of vagina ("spindle cell epithelioma") Pages 8,9
Case #4 (27240) Mitotically active leiomyoma of uterus Pages 10-14
Case #5 (27229) Bizarre leiomyoma of uterus Page 15
Case #6 (27356) Myxoid leiomyosarcoma of uterus Pages 16,17
Case #7 (27348) Aggressive angiomyxoma of pelvic soft tissues Pages 34-36
Case #8 (27266) Small cell undifferentiated carcinoma of the cervix Pages 37-44
Case #9 (27350) Adenoma malignum of cervix (minimal deviation adenocarcinoma) Pages 45-48
Case #10 (27352) Serous papillary adenocarcinoma of the Pages 49-53 endometrium
Case #11 (26112) Uterine tumor resembling ovarian sex-cord tumor Pages 54-56
Case #12 (27235) Extrauterine mesodermal adenosarcoma Pages 57-66
Case #13 (27357) Cystic mucinous borderline tumor of ovary of pseudomyxoma type, secondary to mucin- producing adenoma of appendix Pages 18-21
Case #14 (27358) Metastatic pancreatic adenocarcinoma in ovary Pages 22,23
Case #15 (27359) Small cell carcinoma of ovary, "hypercalcemic Pages 24,25 type"
Case #16 (27360) Juvenile granulosa cell tumor of ovary Pages 26,27
a TABLE OF CONTENTS CONTINUED
Case #17 (26977) Clear cell adenofibroma of low malignant potential (borderline clear cell adenofibroma) of ovary Pages 28,29
Case #18 (27233) Struma! carcinoid tumor of ovary Pages 30-32
Case #19 (27351) Endometrioid-like yolk sac tumor of the ovary Pages 67-71
Case #20 (27308) Sertoli-Leydig cell tumor of ovary, poorly differentiat~d, with heterologous (mucinous) elements Pages 72-75
Case #21 (27349) Brenner tumor of borderline malignancy Pages 76-79
Case #22 (26956) Ovarian tumor of probable wolffiao origin Pages 80-82
Case #23 (26405) Steroid cell tumor (NOS) of ovary Pages 83-91
Case #24 (27347) Multilocular peritoneal inclusion cyst Pages 92-94
b CALIFORNIA TUMOR TISSUE REGISTRY CANCER SEMINAR
TUMORS OF TilE FEMALE GENITAL TRACT
ADDENDUM
CASES 1 - 6, 13 - 18
WILLIAMR. HART, M.D. Chainnan, Division of Pathology and Laboratory Medicine The Cleveland Clinic Foundation Cleveland, Ohio
DECEMBER S, 1993
SAN FRANCISCO, CALIFORNIA CASE 1 (CTIR II 27353)
DIAGNOSIS: SQUAMOUS CELL CARCINOMA IN-SITU OF DIFFERENTIATED (SIMPLEX) TYPE (VIN Ill)
The designation vulvar intraepithelial neoplasia (YIN) is the currently recommended rubric for all types of squamous epithelial dysplasia and in~situ squamous cell carcinoma (CIS) of the vulva. (4- 6) According to this unitary approach, such terms as Bowen's disease, Bowenoid papulosis, CIS, erythroplasia of Queyrat, intraepithelial carcinoma of simplex type, dysplasia, and dystrophy (hyperplastic or mixed types) with atypia should be abandoned and replaced by the term VIN. VIN lesions are then graded as YIN I (mild dysplasia), YIN ll (moderate dysplasia) or VIN ill (severe dysplasia/carcinoma in-situ) depending on the degree and extent of intraepithelial atypia, as is often done for cervical intraepithelial neoplasia (CIN). The majority of YIN lesions have the microscopic changes of severe dysplasia or carcinoma in-situ, although a spectrum of changes, including lesser degrees of dysplasia, may be found in the same lesion or in other biopsies from the same patient. It is unusual to find VIN I (slight dysplasia) unassociated with higher grade lesions and care must be taken not to overdiagnose inflammatory, degenerative and reparative epithelial changes, including those due to podophyllin therapy. (9)
In our opinion there are two main clinicopathologic forms of vulvar squamous cell carcinoma in situ (VIN III): 1) Bowenoid CIS and 2) differentiated (simplex) CIS. (9) In some instances, there is a mixture of the two types. Most pathologists are very familiar with the Bowenoid variant which is more common and the type most often referred to when YIN lesions are reported. Th.e differentiated (simplex) form is less well known, although it has occassionally been illustrated in studies of YIN. (8) Recently, it seems to have been "rediscovered."
In the 1960's Abell drew attention to a highly differentiated form of in-situ squamous cell carcinoma which he designated "intraepithelial carcinoma of simplex type. • (1) This important lesion differs clinically and histologically from YIN of Bowenoid type. (9) Most of the patients with the simplex variant are postmenopausal with a mean age of 66 years (1), more than two decades older than the typical patient with YIN. This variant is relatively infrequent in its pure form, but is often seen adjacent to or overlying superficially invasive squamous cell carcinoma. The histologic features are more subtle with atypia most marked in the basilar portions of the epidermis and in expanded bulbous rete ridges. The bizarre nuclear changes of Bowenoid CIS are absent and full thickness loss of differentiation does not occur. Parakeratosis commonly is on the epidermal or mucosal surface. Characteristically, the atypical squamous cells are enlarged and may have premature keratinization or maturation, including attempts at keratin pearl formation. Loss of intercellular cohesion with accentuation of intercellular bridges and increased numbers of mitotic figures are commonly seen. Intraepithelial carcinoma of simplex type is not characterized by a full-thickness proliferation of uniform neoplastic basaloid cells, as has sometimes been stated by those insufficiently familiar with the original description of this lesion. When YIN is found in patients with lichen sclerosus and hyperplastic vulvar "dystrophies," it usually is of this type. (9) It is extremely important for pathologists to recognize this highly differentiated histologic variant of VIN, lest it be mistaken for a reactive hyperplasia. We su.spect this lesion is the precursor of many, if not most, squamous cell carcinomas of the vulva.
2 The most common type of VIN Ill is the Bowenoid type. This is the classical CIS of the vulva. Grossly,the lesions usually are thickened plaques which may be whitish ("leukoplakic"), erythematous or both. Some are pigmented. Bowenoid lesions are easily recognizable because of their obvious cytologic atypia, prominent mitotic activity and lack of differentiation. They typically have a highly disorganized architecture, the so-called "wind-blown• appearance, and contain multinucleated tumor giant cells, "corps ronds," and koilocytotic cells. They may have a warty papillomatous surface. These latter features have given rise to the term "warty" or •condylomatous• YIN. Some Bowenoid lesions consisting predominantly of uniform, small, undifferentiated parabasal-type cells with scanty cytoplasm have been described as "basaloid" VJN. ln our opinion, the "warty• and "basaloid" VIN lesions are both morphologic variants of Bowenoid VIN. HPV has been consistently found in the vast majority of Bowenoid VIN lesions, regardless of whether they have warty or basaloid features. DNA hybridization studies have demonstrated several different HPV types; however, HPV-16 has emerged as the predominant type detected. (2,3,7) Typical condylomas may be seen adjacent to Bowenoid VIN lesions and transitional forms with features of both condyloma and VIN are sometimes encountered. The role of herpes simplex viruses (HSY) and their interaction with HPV remains uncertain. HSV-2 may be a co-factor in the development of vulvar as well as cervical neoplasia.
Bowenoid YIN lesions consisting of multiple papules or small condyloma-like areas in young patients tend to be hyperpigmented or violaceous. Often these small papular lesions have occurred in pregnant patients, and some have undergone spontaneous regression. Such lesions have been designated "Bowenoid papulosls" (13, 15) or "Bowenold dysplasia." (10, 14) Although it is argued whether a diagnosis of "Bowenoid papulosis" can be reliably made on purely histologic grounds, the current consensus amongst gynecologic pathologists is to regard this lesion as a form of YIN and not to use Bowenoid papulosis as a diagnostic histopathologic term. We generally designate such lesions as Bowenoid dysplasia (VIN I or II) and indicate in a comment that there are histologic features suggestive of so-called Bowenoid papulosis. Correlation with clinical findings is advised.
There is renewed support for the thesis that YIN, as well as invasive squamous cell carcinoma of the vulva, is not a single clinicopathologic entity, since it seems to occur in at least two clinical subsets of patients. (10-12) In young women, YIN is frequently multifocal and multicentric, is often associated with clinical HPV infection, is consistently found to contain HPV-DNA, has a low frequency of progression to invasive carcinoma and may occassionally spontaneously regress. The invasive squamous cell carcinomas associated with this subset often have condylomatous and/or basaloid histologic features, contain HPV and often are accompanied by Bowenoid VIN in the adjacent epidermis. (10) Contrariwise, YIN in the older woman is more often unifocal, is less often associated with clinical HPV infection, is less likely to spontaneously regress and is more likely to progress to invasive carcinoma. The invasive squamous cell carcinomas in this subset are usually keratinizing carcinomas, are more often associated with vulvar "dystrophy," are devoid of HPV and lack adjacent Bowenoid VIN. (11) Instead, the adjacent and overlying epidermis is more likely to show features of the differentiated (simplex) form of YIN or show no recognizable intaepitheliallesion at all. In general, invasive carcinoma is more likely to develop in elderly or immunosuppressed women with VIN than in young women.
3 REFERENCES
1. Abell MR: Intraepithelial carcinomas of epidermis and squamous mucosa of vulva and perineum. Surg Clin No Amer 45(5):1179-1198, 1965.
2. Beckmann AM, Kiviat NB, Daling JR, Sherman K1 and McDougalL JK: Human papillomavirus type 16 in multi focal neoplasia of the female genital tract. Int J Gynecol Pathol 7:39-47, 1988.
3. Buscema J, Naghashfar Z, Sawada E, Daniel R, Woodruff JD and Shah K: The predominance of human papillomavirus type 16 in vulvar neoplasia. Obstet Gynecol 71:601, 1988.
4. Crum CP: Vulvar intraepithelial neoplasia: The concept and its application. Hum Pathol 13(3): 187-189, 1982. .
5. Crum CP, Fu YS, Levine RU, Richard RM, Townsend DE and Fenoglio CM: Intraepithelial squamous lesions of the vulva: Biologic and histologic criteria for the distinction of condylomas from vulvar intraepithelial neoplasia. Am J Obstet Gynecol 144:77-83, 1982.
6. Crum CP, Liskow A, Petras P, Keng WC and Frick HC: Vulvar intraepithelial neoplasia (severe atypia and carcinoma in-situ): A clinicopathologic analysis of 41 cases. Cancer 54:1429-1434, 1984.
7. Crum CP, Braun LA, Shah KV, Fu YS, Levine RU, Fenoglio CM, Richart RM and Townsend DE: Vulvar intraepithelial neoplasia: Correlation of nuclear DNA content and th.e presence of a human papilloma virus (HPV) structural antigen. Cancer 49:468-471, 1982.
8. Fu YS, Reagan JW, Townsend DE, Kaufman RH, Richart RM and Wentz WB: Nuclear DNA study of vulvar intraepithelial and invasive squamous neoplasms. Obstet Gynecol 57:643, 1981.
9. Hart WR: Case 19. Squamous cell carcinoma in-situ of vulva. pll4-121 IN, Hart WR, Young RH and Dail DH: Tumors and Related Lesions of the Female Genital Tract. Proceedings of the 56th Annual Anatomic Pathology Slide Seminar of the American Society of Clinical Pathologists, ASCP Press, 1991, Chicago, ppl28.
10. Kurman RJ, Told T and Schiffman MH: Basaloid and warty carcinomas of the vulva: Distinctive types of squamous cell carcinoma frequently associated with human papillomaviruses. Am J Surg Patholl7(2):133-145, 1993.
11. Told T, Kurman RJ, Park JS, Kessis T, Daniel RW and Shah KV: Probable nonpapillomavirus etiology of squamous cell carcinoma of the vulva in older women: A clinicopathologic study using in situ hybridization and polymerase chain reaction. Int J Gynecol PathollO: 107-125, 1991.
4 12. Park JS, Jones RW, McLean MR et al: Possible etiologic heterogeneity of vulvar intraepithelial neoplasia. Cancer 67:1599-1607, 1991.
13. Patterson JW, Kao GF, Graham JH and Helwig EB: Bowenoid papulosis: A clinicopathologic study with ultrastructural observations. Cancer 57:823-836, 1986.
14. Ulbright TM, Stehman FB, Roth LM, Ehrlich CE and Ransburg RC: Bowenoid dysplasia of the vulva. Cancer 50:2910-2919, 1982.
15. Wade TR, Kopf AW and Ackerman AB: Bowenoid papulosis of the genitalia. Arch Dermatol 115:306-308, 1979.
5 CASE 2 (CTI'R II 27354)
DIAGNOSIS: MALIGNANT MELANOMA OF VULVA
Malignant melanomas of the vulva .are uncommon tumors. (1 ,2,4,7-15) About 3 to 5% of melanomas in females originate in the vulva. While melanomas account for only about 5 to 10% of all vulvar cancers, they are second in relative frequency only to invasive squamous cell carcinoma. They occur predominantly in white women. The r~rted age range is 15 to 94 years with an average age of 55 years. About 80% of vulvar melanomas involve the labia minora and clitoris. Most of the types of cutaneous melanoma may be found, including nodular melanoma and superficial spreading melanoma. Vulvar melanomas, as well as vaginal melanomas, however, often have features of "mucous membrane (acrallentiginous) melanoma." In one study, 63% of vulvar melanomas were classified as the mucous membrane melanoma type of acrallentiginous melanoma. (1) · ·
The melanoma cells may be epithelioid, spindled or nevoid, and are often present in mixtures. Intraepidermal melanoma cells often are arrayed in a lentiginous pattern along the basilar epidermis. A neurotropic pattern with involvement of peripheral nerve bundles is sometimes prominent, occliring in 31 % of cases in one series. (1) Sparsely pigmented tumors are easily mistaken for undifferentiated carcinomas or spindle cell sarcomas. In fact, a good rule-of-thumb is to never diagnose ·spindle cell carcinoma or undifferentiated carCinoma of the vulva or vagina without first excluding the diagnosis of melanoma! Positive immunohistochemical staining for S- 100 protein, or HMB-45, and negative staining for cytokeratin should make this an easy differential diagnosis once the possibility of melanoma is considered. Electron microscopic examination for melanosomes is rarely needed.
Prognosis is very poor, since most vulvar melanomas are relatively deeply invasive when initially diagnosed, extending several millimeters, if not centimeters, into the dermis or submucosal connective tissue. Only very thin lesions, generally those which to not exceed Level II of Clark or Chung, have been reported to have a very low rate of metastasis, and the maximum tumor thickness among disease-free survivors has varied from l.OOmm to 1.75mm, depending on the study. (2,4,7,8,9,11,12) The overall survival rate at 5 years is only about 30 to 35%, (2,4,9,11,13,15), although rates up to 54% have also been reported. (12)
Nevi in pregnancy have been reported to have a mild degree of "atypia," or activation, when compared to controls consisting of nevi removed from non-pregnant women, although no differences were found when compared to male controls. (5) ·Occasional mitotic figures were seen in such nevi, but these lesions did not cause confusion with melanoma. Some unusual nevi of the vulva have also been repprted. (3,6) In one study, 60% of vulvar nevi were described as "distinctive" lesions which the authors considered "prototypical for atypical melanocytic proliferations of the vulva. • (6) These nevi were said to differ from. dysplastic nevi and to be easily distinguishable from melanoma.
6 REFERENCES
1. Benda JA, Platz CE and Anderson B: Malignant melanoma.of the vulva: A clinical pathologic review of 16 cases. lnt I Gynecol Pathol5:202-216, 1986.
2. Bradgate MG, Rollason TP, McConkey CC aild Powell J: Malignant melanoma of the vulva: A clinicopathological study of 50 women. Brit J Obstet Gynecol 97:124-133, 1990.
3. Christensen WN, Friedman KJ, Woodruff JD and Hood AF: Histologic characteristics of vulvar nevocellular nevi. J Cutaneous Pathol 14:87-91, f987.
4. Chung AF, Woodruff JM and Lewis JL: Malignant melanoma of the vulva: A report of 44 cases. Obstet Gynecol45(6):638-646, 1975.
S. Foucar E, Bentley TJ, Laube DW and Ros3i J: A histopathologic evaluation of nevocellular nevi in pregnancy. Arch Dermatoll21:350-354, 1985.
6. Jampel RM, Friedman KF, Hood AF and Clark WH: Atypical melanocytic lesions of the. vulva. J Cutaneous Pathol 15:316, 1988.
7. Jaramillo BA, Ganjei, Averette HE, Sevin BU and Lovecchio JL: Malignant melanoma of the vulva. Obstet Gynecol 66:398-401, 1985.
S. Johnson TL, Kumar NB, White CD and Morley GW: Prognostic features of vulvar melanoma: A clinicopathologic analysis. Int J Gynecol Pathol5:110-118, 1986.
9. Look KY, Roth LM, Sutton GP: Vulvar melanoma reconsidered. Cancer 72:143-146, 1993.
10. Morrow CP and Rutledge FN: Melanoma of the vulva. Obstet Gyneco139(5):745-752, 1972.
II. Phillips GL, Twiggs LB and Okagaki T: Vulvar melanoma: A microstaging study. Gynecol Oncol 14:80-88, 1982.
12. Podratz KC, Gaffey TA, Symmonds RE, Johansen KL and O'Brien PC: Melanoma of the vulva: An update. Gynecol Oncol 16:153-168, 1983.
13. Ragnarsson-Olding B, Johansson H, Rutqvist LE and Ringoorg U: Malignant melanoma of the vulva and vagina. Cancer 71:1893-1897, 1993.
14. Warner TF, Hafez Rand Buchler DA: Neurotropic melanoma of the vulva. Cancer 49:999-1004, 1982.
15. Yackel DB, Symmonds RE and Kempers RD: Melanoma of the vulva. Obstet Gynecol 35(4):625-631' 1970.
? CASE 3 (CTTR # 27355)
DIAGNOSIS: BENIGN MIXED TUMOR OF VA GINA ("SPINDLE CELL EPITHELIOMA")
The tenn benign mixed tumor of the vagina has historically been applied to a rare type of primary vaginal neoplasm composed of bland spindled cells admixed with a minor component of squamous cells and/or glandular elements. (1-6) Other than a few single cases reports, only two series of more than a few cases have been reported. (1 ,4) The tumors occur in adult women (age range, 20 to 69 years) and usually are located on or just inside the the hymeneal ring within the introitus. Their size has ranged from 1.5 to 6.0 em. in greatest dimens.ion (mean, 2.6 em). Typically, the tumors are submucosal, beneath an. intact and unremarkable vaginal mucosa. They are well circumscribed solid nodular lesions which do not incorporate peripheral nerve bundles or adipose tissue. Histologically, theft cellularity is variable. Areas of collagenization and edema often alternate with sheets ·and fascicles of uniform small oval and spindled cells with bland nuclei, often referred to as "stromal cells." Rosettes of tumor cells around collagenous hyaline cores are often found. These may simulate glandular spaces. Well-differentiated epithelial structures, usually consisting of islands of squamous epithelium and less commonly of mucinous epithelium are typically also present, but may be inconspicuous. •
Branton and Tavassoli ( 1) convincingly demonstrated that the neoplastic cells are of epithelial type with irnmunostaining for cytokeratins in the "stromal cells" as well as in the more obvious epithelial structures. Actin was coexpressed in tumor cells, but most of the actin immunoreactivity was in noll-neoplastic cells Electron microscopy revealed epithelial features in the tumor cells. No good evidence of myoepithelial differentiation, as would be expected in benign mixed tumors of salivary gland type, was found. Consequently, they proposed the term "spindle cell epithelioma • as a more appropriate designation than benign mixed tumor. The histogenesis of these tumors is unknown. An origin from the minor vestibular glands, or paravestibular glands, was postulated at one time. Currently, 'there is speculation that they arise from epithelium derived from the urogenital sinus. The tumors are benign. A few have recurred locally but have been cured following re-excision. (1,5)
REFERENCES
I. Branton PA and Tavassoli FA: Spindle cell epithelioma, the so-called mixed tumor of the vagina. A clinicopathologic, immunohistochemical, and ultrastructural analysis of 28 cases. Am J Surg Pathol 17(5):509-515, 1993:
2. Brown CE. Mixed epithelial tumor of vagina. Am J Clin Pathol 23:237, 1953.
3. Chen KTK. Benign mixed tumor of the vagina. Obstet Gynecol 57:89S, 1981.
4. Sirota RL, Dickersin ·oR and Scully RE. Mixed tumors of the vagina. A clinicopathologic analysis of eight cases. Am J Surg Pathol 5:413, 1981.
5. Whelton JA. Mixed tumor arising in vagina. Obstet Gynecol 19:803, 1962.
8 6. Wright RG, Buntine DW, Forbes KL. Recurrent benign mixed tumor of the vagina. Gynecol Oncol40:84-86, 1991.
9 CASE 4 (CITR # 27240)
DIAGNOSIS: MITOTICALLY ACTIVE LEIOMYOMA OF UTERUS
The diagnosis of leiomyoma and leiomyosarcoma of the ut~:rus is usually straightforward. Some types of smooth muscle tumors, however, cause difficulty in diagnosis because they have soine, but not all, of the features of a sarcoma. It is important to remember that leiomyosarcomas of the uterus are uncommon tumors. Christopherson et al. reported an average yearly incident rate of only 0.67 per 100,000 women 20 years of age or ol4er in Jefferson County, Kentucky. (3) Hysterectomies and myomectomies performed for "fibroids" produce a large number of specimens for the surgical pathology laboratory. Fortunately, the incidence of leiomyosarcoma in uteri removed with a preoperative diagnosis of benign leiomyoma is only about 0.5%. (16)
Careful gross examination is very helpful in evaluating myomatous uterine tumors. Leiomyosarcomas often are solitary uterine tumors, but they also may be associated with other myomatous tumors. When leiomyosarcoma occurs in a multinodular uterus, the largest tumor is almost invariably the malignant one. (20) Leiomyosarcomas tend to be less well circumscribed, softer, less trabeculated or whorled and more variegated when compared to benign Jeiomyomas. Obvious invasion into adjacent tissues or organs may be found. Areas of necrosis and hemorrhage are extremely common in leiomyosarcomas, although they also occur in leiomyomas. Thorough sampling of uterine smooth muscle tumors with necrosis, hemorrhage or nuclear atypia is essential. Markedly gelatinous tumors also require close scrutiny. One block of tissue slrould be taken for each 1 to 2 em of the greatest dimension of the tumor when any unusual gross or microscopic features are encountered.
Microscopically, leiomyosarcomas almost always display the combination of hypercellularity, moderate or marked nuclear atypia and high mitotic activity. (1 0) The importance of determining the level of mitotic activity in distinguishing between benign and malignant uterine smooth muscle tumors was documented in the important study in 1966 by Taylor and Norris.(22) After reviewing a series of 63 highly cellular uterine tumors suspected or diagnosed as leiomyosarcoma on file at the Armed Forces Institute of Pathology, they concluded that the number of mitotic figures in the most active areas proved to be a reliable basis for separating clinically benign from clinically malignant neoplasms. In their study, tumors with fewer than 10 mitotic figures (MF) per 10 high-power fields (HPF) proved benign regardless of the degree of cytologic atypism, whereas those with 10 or more MF in 10 HPF recurred or metastasized in 86% of patients with followup information. Subsequent studies in the 1970's corroborated the diagnostic value of performing accurate mitosis counts and provided additional data on the levels of mitotic activity found in clinically benign and malignant tumors. Occasional examples of leiomyosarcoma with fewer than 10 MP/10 HPF were reported, and the minimum level of mitotic activity for clinically malignant uterine smooth muscle tumors was reduced to 5 MF/10 HPF.(3,10, 11,13)
Although some investigators questioned the reproducibility of mitosis counts (21), the counting of mitotic figures in uterine smooth muscle tumors became a standard practice during the ensuing 15 to 20 years. (5 ,24) A consensus developed for employing stringent criteria for the diagnosis of uterine smooth muscle neoplasms, with a requirement of at least 5 MF/10 HPF for a diagnosis of leiomyosarcoma. Except for the controversial entity of benign metastasizing leiomyoma, only rare
10 examples of clinically malignant uterine smooth muscle tumors with less than 5 MF/10 HPF were discovered. Of five such cases reported by Burns et al, each tumor had 2+ or 3+ cytologic atypia and all of the tumors were judged to have been"inadequately sampled. • (2) These cases serve to re-emphasize the need to adequately sample smooth muscle tumors, especially those with significant atypia.
Theoretically, variations in mitosis counts also may result from delays in fixation. Several studies have analyzed mitotic activity in animal and human tumors following fixation delays ranging from 5 minutes to over 12 hours. (1 ,4, 7-9) The results of these studies have not been uniform. Several have found decreased counts (1,9), especially after prolonged delays in fixation. (8) With increasing periods of delay, the microscopic identifiability of mitoses may become more difficult due to the formation of "pyknotic" mitoses. (4) Well-preserved mitotic figures may be observed even after 9 and 12 hours of fixation delay, however, suggesting that tumor cells remain capable of proliferation for several hours after biopsy. (4) Therefore, total completion of mitoses with conversion to interphase cells within short periods of time is unlikely. (4) The decrease in mitotic activity is marked only for those tumors with very high mitotic rates and is minimal for those with lower mitotic rates. (4) Fortunately, the vast majority of uterine leiomyosarcomas have very high mitosis counts with more than 90% having at least IS MF/10 HPF. (10) It is doubtful that the relatively short delays in fixation which usually occur in modem surgical pathology laboratories would produce clinically significant errors in estimating mitotic activity by the presently employed methods.
It is important to realize that different methods of counting mitotic figures may yield different results depending on whether the mitosis count is expressed as the averaee number of MF/10 HPF after counting 40 or 50 HPF or as the hiehest count in a single set of 10 HPF after counting 4 to 5 sets of 10 HPF. The latter method will produce higher estimates than the former with the magnitude ranging from less than I MF/10 HPF in tumors with the lowest mitotic activity to almost 4 MF/10 HPF in those with highest activity. (19) Differences in the area of an HPF obtained with microscopes with different oculars and objectives also may cause variations in counts. (6) Nonetheless, careful performance of mitosis counts remain one of the most important tasks in the proper assessment of malignant potential in uterine smooth muscle tumors. Equally important is the assessment of nuclear atypia which must be done before a tumor can be diagnosed as benign or malignant. In my opinion the minimum histologic criteria for the diagnosis of uterine leiomyosarcoma require the presence of both significant nuclear atypia and mitotic activity of at least 5 MF/ 10 HPF. There are exceptions to this "rule," with some modifications for epithelioid (IS) and myxoid tumors. (1 4) The prognosis for patients whose tumors meet these stringent criteria is dismal with about 75% of patients dying of metastatic leiomyosarcoma within 18 months after hysterectomy (10) and 5-year survival rates of only 20% or less. (3,10,11, 13,22)
While the degree of mitotic activity has proven to be an extremely important criterion of malignancy, it is not the only one. In 1978, Hart and Billman indicated they had not seen clinically malignant smooth muscle tumors that did not have ominous histologic features of hypercellularity and nuclear atypism in addition to high mitotic activity. (10) In some classi fications, however, tumors with 5 to 9 MF/10 HPF without nuclear atypia were designated "smooth muscle tumors of uncertain malignant potential" while those with 10 or more MF/10 HPF were interpreted as leiomyosarcoma even when nuclear atypia was absent. (11,24)
11 Subsequent studies have clarified this issue by identifying clinically benign leiomyomas with unusually high mitosis counts. Recent reports have documented that uterine smooth muscle tum-ors which have histologic appearances of ordinary leiomyomas but have mitosis counts exceeding 4 MF/10 HPF are clinically benign, provided they are devoid of significant cytologic atypia. These tumors are termed mitotically active leiomyoma or "leiomyoma with increased mitotic activity. • (17-19)
Mitotically active benign leiomyomas typically occur in women of reproductive age (median age 37 years). (19) They seem to be associated with the secretory phase of the menstrual cycle (19) or hormonal medication usage such as oral contraceptives or progestational agents. (17-19) These associations may be related to the increased mitotic activity reported in typicalleiomyomas removed during the secretory phase of the menstrual cycle (12) and in patients receiving progestins. (23) Mitotically active leiomyomas are generally small (less than 10 em. in maximum dimension). In our experience, they frequently have a submucosal location. (19) Usually, these .neoplasms do not arouse suspicion of malignancy when removed by the surgeon or examined grossly by the pathologist. Grossly, they resemble banalleiomyomas, with or without degenerative changes. Areas of hemorrhage or necrosis are, however sometimes present, either grossly or microscopically. (17) When present, the necrosis usually has histologic features of an jnfarct, often with a peripheral zone of fibrosis or granulation tissue. This contrasts with the abruptly necrotic areas typically seen in leiomyosarcomas which are usually devoid of a "healing zone• and result from rapid growth of the neoplasm exceeding it's local blood supply. Cellularity is variable in mitotic3lly active leiomyomas. Most are only moderately cellular, but some are diffUSillY hypercellular or have hypercellular perihemorrhagic zones. Nuclear atypia is absent or only of very mild degree with slight pleomorphism or nuclear enlargement Mitosis counts usually are in the 5 to 9/10 RPF range (17-19), but sometimes are are as high as 15/10 HPF. (18,19) Were. it not for the prominent numbers of mitotic figures, however, these tumors would be quickly diagnosed as ordinary leiomyomas.
REFERENCFS l. Bullough WS: Mitotic activity in the tissue of dead mice, and in tissue kept in physiological salt solution. Exper Cell Res I :410-420, 1950.
2. Bums B, Curry RH and Bell MEA: Morphologic features of prognostic significance in uterine smooth muscle tumors; A review of eighty-four cases. Am J Obstet Gynecol 135:109-114, 1979.
3. Christopherson WM, Williamson EO and Gray LA: Leiomyosarcoma of the uterus. Cancer 29:1512-1517, 1972.
4. Donhuijsen K, Schmidt U, Hirche H, van Beuningen D and Bucash V; Changes in mitotic rate and cell cycle fractions caused by delayed fixation. Hum Pathol21:709-714, 1990.
5. Editorials: Mitosis counting -1, -II, -III. Human Pathol 7'481-484, 1976.
12 6. Ellis PSJ, Chir B, Whitehead R: Mitosis counting- a need for reappraisal. Human Pathol 12:3-4, 1981.
7. Evans N: Mitotic figures in malignant tumors as affected by time before f1xation of tissues. Arch Pathol 1:894-898, 1926.
8. Franzini DA, Silva EG, Maize! A: Variability of mitotic count dependent on fixation time. Lab Invest 44:20A-21A, 1981.
9. Graem N, Helweg-Larsen K: Mitotic activity and delay in fixation of tumour tissue. Acta Path Microbial Scand 87:375-378, 1979.
10. Hart WR and Billman 1K : A reassessment of uterine neoplasms originally diagnosed as leiomyosarcomas. Cancer 41:1902-1910, 1978.
II. Hendrickson MR and Kempson RL: Surgical Pathology of the Uterine Corpus, Volume 12. Major Problems in Pathology. JL Bennington (editor). WB Saunders, Philadelphia, Pennsylvania, 1980.
12. Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogalci Hand Mori T: Mitotic activity in uterine leiomyomas during tile menstrual cycle. Am 1 Obstet Gynecol 160:637-641, 1989.
13. Kempson RL and Bari W: Uterine sarcomas: Classification, diagnosis and prognosis. Human Pathol 1:331-349, 1970.
14. King ME, Dickersin GRand Scully RE: Myxoid leiomyosarcoma of the uterus: A report of six cases. Am 1 Surg Pathol 6:589-598, 1982.
15. Kurman RJ and Norris HJ: Mesenchymal tumors of the uterus: VI. epithelioid smooth muscle tumors including leiomyoblastoma and clear-cell leiomyoma: A clinical and pathologic analysis of 26 cases. Cancer 37:1853-1865, 1976.
16. Leibsohn S, d'Ablaing G, Mishell DR and Schlaerth JB: Leiomyosarcoma in a series of hysterectomies performed for presumed uterine leiomyomas. Am J Obstet Gynecol 162:968-976, 1990.
17. O'Connor DM and Norris HJ: Mitotically active leiomyomas of the uterus. Hum Pathol 21:223-227, 1990.
18. Perrone T and Dehner LP: Prognostically favorable "mitotically active" smooth-muscle tumors of the uterus: A clinicopathologic study of ten cases. Am J Surg Pathol 12:1-8, 1988.
19. Prayson RA and Hart WR: Mitotically active leiomyomas of the uterus. Am J Clin Pathol 97:14-20, 1992.
13 20. Schwartz LB, Diamond MP and Schwartz PE: Leiomyosarcomas: Clinical presentation. Am I Obstet Gynecol168:180-183, 1993.
21. Silverberg SG: Reproducibility of the mitosis count in the histologic diagnosis of smooth muscle tumors of the uterus. Human Pathol 7:451-454, 1976.
22. Taylor HB and Norris, HI: Mesenchymal tumors of the uterus: IV. Diagnosis and prognosis of leiomyosarcomas. Arch Pathol 82:40-44, 1966.
23. Tiltman AJ: The effect of progestins on the mitotic activity of uterine fibromyomas. Int 1 Gynecol Pathol 4:89-96, 1985.
24. Zaloudek CJ and Norris HI: Mesenchymal Tumors of the Uterus. IN: Progress in Surgical Pathology, Volume ill. C. Fenoglio & M. Wolff (editors). Masson Publishing USA, Inc. 1981, pp. 1-35.
14 CASES CCTI'R # 27229)
DIAGNOSIS: BIZARRE LEIOMYOMA OF UTERUS
The term bizarre leiomyoma was introduced by Christopherson et al in 1972 (1) for benign uterine smooth muscle tumors with bizarre nuclear atypia but mitotic activity Jess than 5/ 10 HPF. Others have referred to these tumors as symplastic leiomyoma, symplasmic leiomyoma, atypical leiomyoma and pleomorphic leiomyoma. (2-5) Grossly, bilarre leiomyomas usually appear as ordinary leiomyomas, with or without degenerative changes. Their size generally is less than 10 em. The bizarre tumor cells are immediately recognizable on low power microscopic examination. They may be focally aggregated in an otherwise typical leiomyoma or may comprise the entire tumor. Multinucleated cells or cells with multilobulated nuclei are often plentiful and may reach huge size. The atypicality may be so alarming to the unwary observer that a diagnosis of leiomyosarcoma is immediately suggested.
Characteristically, the nuclei have smudged chromatin with a degenerated appearance. Pyknotic and karyorrhectic nuclei are common. The cytoplasm frequently is dense and brightly eosinophilic with a degenerative quality which makes it difficult to distinguish from hyalinized collagen or intercellular matrix. Intranuclear cytoplasmic invaginations produce large, eosinophilic pseudonucleoli. Tumor necrosis is not present. In spite of their ominous microscopic appearance, however, they have very low mitotic activity. Care must be taken not to misinterpret degenerating nuclei as mitotic figures, although at times this can be extremely difficult. Unequivocal mitotic figures usually are difficult to find and, by defmition, must be fewer than 5110 HPF. Of the 13 cases in Christopherson's study with followup of at least 5 years (average, 11.2 years), none of the tumors recurred. ( 1)
REFERENCES
I. Christopherson WM, Williamson EO and Gray LA: Leiomyosarcoma of the uterus. Cancer 29:1512-1517, 1972.
2. Hart WR and Billman JK: A reassessment of uterine neoplasms originally diagnosed as leiomyosarcomas. Cancer 41:1902-1910, 1978.
3. Kempson RL and Bari W: Uterine sarcomas: Classification, diagnosis and prognosis. Human Pathol1:331-349, 1970.
4. Taylor HB and Norris, IU: Mesenchymal tumors of the uterus: lV. Diagnosis and prognosis ofleiomyosarcomas. Arch Pathol 82:40-44, 1966.
S. Zaloudek CJ and Norris IU: Mesenchymal Tumors of the Uterus. IN: Progress in Surgical Pathology, Volume III. C. Fenoglio & M. Wolff (editors). Masson Publishing USA, Inc. 1981, pp. 1-35.
15 CASE 6 (CTI'R /127356)
DIAGNOSIS: MYXOID LEIOMYOSARCOMA OF UTERUS
In 1982, King et al (3) reported a series of six uterine myxoid leiomyosarcomas with very low mitotic activity, ranging from 0 to 2 MF/10 HPF. In spite of their low mitotic activity, recurrences and metastases developed. The tumors ranged in size from 5 to 15 em and were characterized by a grossly gelatinous appearance due to a massive accumulation of acid mucopolysaccharide ground substance. In spite of their apparently circumscribed borders, these tumors characteristically show irregular myometrial invasion and vascular invasion when the periphery of the tumors is examined microscopically. The tumor cells are widely separated by large pools of mucoid material While bland cells predominate in some cases, pleomorphic cells with nuclear irregularity and hyperchromatism are not uncommon.
The tumor cells may not have easily reCognizable smooth muscle features. Often, the histologic appearance of the tumor resembles a myxoid sarcoma of soft tissues, and immunostains for actin and desmin may be required to confirm their smooth muscle nature The low mitosis count in some cases may be due to the abundant myxoid material which widely separates the tumor cells and dramatically reduces the concentration of tumor cells in a microscopic field. Mitotic figures, however, are often evident after careful search. Some myxoid leiomyosarcomas contain areas with high cellularity and high mitotic activity, allowing easy recognition as a sarcoma. (4,5); others may be uniformly paucicellular and more difficult to diagnose. (1) As mentioned before, the presence of irregular myometrial invasion and vascular invasion which are generally found in myxoid leiomyosarcomas are useful diagnostic aids.
Myxoid leiomyosarcomas with low mitotic activity are extremely rare. Much more common are benign leiomyomas with prominent edema and pools of fluid due to hydropic change and liquefactive degeneration. Unfortunately, there is a tendency to overinterpret these degenerative changes and mistalce them for the pronounced myxoid change seen in myxoid leiomyosarcomas. (2) Unlike myxoid change, however, these pools of fluid fail to stain positively with alcian blue (ph 2.5) and colloidal iron stains, because they are not composed of acid mucopolysaccharides. It is also important to understand that foci of myxoid change may also be found in otherwise typical uterine leiomyomas, occurring in 3.4% to 13% of cases in some series. (3) Leiomyomas of the vulva and vagina have a greater tendency for myxoid change, especially during pregnancy. (6, 7)
REFERENCES
I. Chen KTK: Myxoid leiomyosarcoma of the uterus. Int 1 Gynecol Pathol 3:389-392, 1984.
2. Clement PB, Young RH and Scully RE: Diffuse, perinodular, and other patterns of hydropic degeneration within and adjacent to uterine leiomyomas. Problems in differential diagnosis. Am J Surg Pathol 16(1):26-32, 1992.
3. King ME, Dickersin GR and Scully RE: Myxoid leiomyosarcoma of the uterus: A report of six cases. Am I Surg Pathol 6:589-598, 1982.
16 4. Pounder D1 and Iyer PV: Uterine leiomyosarcoma with myxoid stroma. Arch Pathol Lab Med 109:762-764, 1985.
5. Salm Rand Evans DJ: Myxoid leiomyosarcoma. Histopathol9:159-169, 1985.
6. Tavassoli FA and Norris HJ: Smooth muscle tumors of the vulva. Obstet Gynecol53:213- 217, 1979.
7. Tavassoli FA and Norris HJ: Smooth muscle tumors of the vagina. Obstet Gynecol53:689- 693, 1979.
17 CASE 13 (CTIR # 27357)
DIAGNOSIS: CYSTIC MUCINOUS BORDERLINE TUMOR OF OVARY OF PSEUDOMYXOMA TYPE SECONDARY TO MUCIN-PRODUCING ADENOMA OF APPENDIX
The presence of abundant intraperitoneal mucus deposits, or gelatinous ascites, is commonly referred to as pseudomyxoma peritonei. It is an enigmatic and controversial condition, especially in terms of histogenesis. Most patients with pseudomyxoma peritonei are in the age range of SO to 70 years; however, cases occurring in younger patients and even in children have been described. (1-5) The disease affects both men and women. Pseudomyxoma peritonei is relatively rare in females, occurring in only O. A wide variety of mucinous lesions ranging from benign omphalomesenteric cysts to adenocarcinoma have been implicated in the origin of pseudomyxoma peritonei. (3) Primary mucinous tumors of diverse organs, including the ovary, appendix, uterus, bowel, common bile duct, fallopian tube and pancreas have been associated with pseudomyxoma peritonei. (3,6-8) Historically, the predominant view has been that pseudomyxoma peritonei usually results from rupture or spillage of a primary mucinous tumor of either the appendix or ovary. About 3.5 to 12% of all mucinous ovarian tumors and from 10.6 to 29% of appendiceal mucinous tumors have been reported to be associated with pseudomyxoma peritonei. (1) Recent studies have refocused attention on the appendix as the source of pseudomyxoma peritonei in both men and women, including those patients who also have an ovarian tumor. (4,9) The most common primary tumor of the appendix associated with pseudomyxoma peritonei is an adenoma, or cystadenoma, which often resembles an ovarian mucinous tumor of low malignant potential (cystadenoma of borderline malignancy). A smaller number of patients are found to have an appendiceal adenocarcinoma which is often associated with an adenoma. (9). Unfortunately, the definition of appendiceal adenoma and adenocarcinoma in patients with pseudomyxoma peritonei is controversial, particularly when neoplastic epithelial cells are present in extra-appendiceal mucinous deposits. Some investigators insist that the presence of epithelial cells in peritoneal implants justifies the diagnosis of carcinoma. (10) Others (4,11), including ourselves (9), disagree. We maintain that the criteria for distinguishing adenomas from adenocarcinomas of the appendix should be the same as those used in the diagnosis of tumors of the large intestine and that the presence of adenomatou~ epithelial cells in extra-appendiceal mucinous deposits does not by itself indicate the tumor is an appendiceal carcinoma. The ovarian tumors found in patients with pseudomyxoma peritonei usually have distinctive features. (4,9,13) They are multicystic gelatinous tumors in which many of the cysts are lined by epithelium resembling either mucinous cystadenoma, mucinous borderline (LMP) tumor of intestinal type or both. Characteristically, the epithelial cysts are accompanied by irregular pools of mucus dissecting through the ovarian stroma. This histologic pattern of ovarian tumor has been termed pseudomyxoma ovarii. (13) The association ofpseudomyxoma ovarii with 18 pseudomyxoma peritonei was highlighted by Hart & Norris in 1973 who felt that ovarian mucinous tumors of this type were more aggressive neoplasms than the usual mucinous borderline tumor.(l3) Up to one-third of patients with pseudomyxoma peritonei have both ovarian and appendiceal mucinous tumors. (1) Even in these patients, the pseudomyxoma is believed to originate from the appendix in the vast majority of cases. (4,9) In 1991, Young and his coworkers presented a series of 22 patients with mucinous appendiceal tumors associated with mucinous ovarian tumors and pseudomyxoma peritonei. (4) Their findings, along with recent work done at our institution (9), support the contention that the mucinous ovarian tumors found in patients with pseudomyxoma peritonei probably represent secondary rather than primary neoplasms. Young et al based their conclusion on several observations. Bilateral ovarian tumors were observed in almost a third of their patients, a much higher frequency of bilaterality than occurs in patients with Stage I primary ovarian mucinous carcinomas and borderline tumors. (13) In unilateral tumors, they found a right-sided predominance, suggesting a diicct route of spread from the appendix to the neaxby right ovary. (4) A histologic similarity of the mucinous epithelium found in the ovarian tumors, the peritoneal implants and the primary appendiceal mucinous tumors was observed in their study, (4) as well as in our study. (9) Ovarian tumors do not occur in all women with pseudomyxoma peritonei; however, women with pseudomyxoma peritonei who have ovarian tumors almost always also have primary appendiceal mucinous neoplasms. (9) In addition, mucinous implants are commonly found on the surface of ovaries without gross tumor. Rupture of the appendix was observed in more than half the patients reported by Young et al . (4),and in several of our patients (9), providing a mechanism for spillage of mucinous epithelium into the peritoneal cavity and onto the surface of the ovaries. Subsequent incorporation of proliferating mucinous epithelium into the ovary at sites of ovulation in a premenopausal ovary, or into surface crevices in a postmenopausal ovary, could then produce a grossly evident mucinous tumor simulating a primary ovarian neoplasm. Some investigators, however, maintain that both the appendiceal and ovarian tumors in such patients are separate primary tumors. In the recent study, Seidman et al (12) described histologic dissimilarities of the appendiceal, peritoneal and ovarian tumors and contended that the synchronous ovarian and appendiceal tumors are both primary independent neoplasms. They resurrected the theory that the ovarian, appendiceal and peritoneal lesions arise de novo as part of a multifocal process. Regardless of whether the ovarian tumors are primary or secondary neoplasms, we concur with Young and his associates (4) on the need to remove the appendix in patients with pseudomyxoma peritonei, whenever technically possible, because a primary mucinous tumor of the appendix is almost always present in such patients. (9) The prognosis for patients with pseudomyxoma peritonei is extremely variable. Extra-abdominal spread of pseudomyoxma peritonei is rare, as are metastases to the liver or lymph nodes. Patients often deteriorate over a course of years and die of infection, inanition, or complications of bowel obstruction. (9,14) One large surgical series reported actuarial survival rates of 54% at S years and 18% at 10 years. (15) A smaller, more recent series reported survival rates of 75% at S years and 60% at 10 years. (16) Treatment of pseudomyxoma peritonei is primarily surgical, with removal of the appendix, ovaries, and debulking of the intraperitoneal mucinous deposits. The 19 roles of chemotherapy and radiation therapy have been unclear. Systemic chemotherawutic regimens have generally been ineffective but may be of value in treating patients with proven recurrence. (16) Mucolytic agents to facilitate removal of the intraperitoneal mucus have also been used. (14) The standard of treatment'continues to be aggressive surgical resection with repeat laparotomies to relieve intestinal obstruction. Hyperalimentation support in patients with long-term disease or with bowel obstruction has also been found to be of some benefit. (14) REFEREJilCES I. Hart WR. Pathology of Malignant and Borderline (Low Malignant Potential) Epithelial Tumors of Ovary. IN: Gynecolo~:ic Oncolo&y, 2nd Edition. Chapter 55. M. Coppleson, JM Mon~~ghan , CP Morrow and MHN Tattersall (editors), Churchill-Livingstone, Edinburgh, 1992. p. 875.-876. 2. Sandenbergh HA, Woodruff JD. Histogenesis of pseudomyxoma peritonei: Review of 9 cases. Obstet Gynecol 1977;49:339-345. 3. Osburn CL. Pseudomyxomaperitonei: A report of seven cases. Gynecol Oncol 1973; 1:195-202. 4. Young RH, Gilks CB, Scully RE. Mucinous tumors of the appendix associated with mucinous tumors of the ovary and pseudomyxoma peritonei. A clinicopathological analysis of22 cases supporting an origin in the appendix. Am I Surg Patholl991;15:414- 429. 5. Long RTL, Spratt JS, Dowling E. Pseudomyxoma peritonei. New concepts in management with a report of seventeen patients. Am J Surg 1969;117: 162-169. 6. Jones DH. Pseudomyxoma peritonei. Br J Clin Prac 1965;19:675-679. 7. McCarthy JH, AgaR. A fallopian tube lesion of borderline malignancy associated with pseudomyxoma peritonei. Histopathol 1988;13:223-225. 8. Chejfec G, Rieker WJ, Jablokow VR, Gould VE. Pseudomyxoma peritonei associated with colloid carcinoma of the pancreas. Gastroent 1986;90:202-205. 9. Prayson RA, Hart WR, Petras RE. Pseudomyxoma·peritonei: A clinicopathologic study of 19 cases with emphasis on site of origin and nature of associated ovarian tumors. Am J Surg .Pathol (accepted for publication) 10. Higa E, Rosai J, Pizzimbono CA, Wise L. Mucosal hyperplasia, mucinous cystadenoma, and mucinous cystadenocarcinoma of the appendix. A re-evaluation of appendiceal "mucocele. • Cancer 1973;32: 1525-1541. 20 11. Wolff M, Ahmed N. Epithelial neoplasms of the vermiform appendix (exclusive of carcinoid). I. Adenocarcinoma of the appendix. Cancer 1976;37:2493-2510. 12. Seidman JD, Elsayed AM, Sobin LH, Tavassoli FA. Association of mucinous tumors of the ovary and appendix. A clinicopathologic study of 25 cases. Am J Surg Pathol 1993;17:22-34. 13. Hart WR, Norris HJ. Borderline a:nd malignant mucinous tumors of the ovary: Histologic criteria and clinical behavior. Qmcer 1973;31: 1031-1045. 14. Mann WJ, Wagner J, Chumas J, Chalas E. The management of pseudomyxoma peritoneL Cancer 1990;60:1636-1640. 15. Fernandez RN, Daly JM. Pseudof!lyxoma peritonei. Arch Surg 1980;115:409-413. 16. Smith JW, Kemeny N, Caldwell C, Banner P, Sigurdson E and Huvos A. Pseudomyxoma peritonei of appendiceal origin. The Memorial Sloan-Kettering Cancer Center experience. Cancer 1992;70:396-40. 21 CASE 14 (CTfR 1127358) DIAGNOSIS: METASTATIC PANCREATIC ADENOCARCINOMA IN OVARY Metastatic tumors to the ovary account for about 6% to 7% of ovarian neoplasms enCountered clinically during investigation of a pelvic mass. Not infrequently, the metastasis masquerades as a primary tumor, even after the neoplasm has been eJtamined microscopically. Usually the patient has a known primary tumor, but in some instances the ovarian tumor is the first manifestation of the patient's cancer. It is intriguing how often a prir,nary tumor that is solid in its site of origin produces metasll!Ses to the ovary which are cystic. The grossly cystic appearance of some metastases and the presence of seemingly-benign or borderline epithelium lining some of the cysts greatly contribute to their misdiagnosis. The most common tumor to simulate a primary ovarian neoplasm is adenocarcinoma of the large intestine, which often is mistaken for an endometrioid adenocarcinoma and sometimes for a muc~nous cystadenocarcinoma. (2) Metastases from the pancreas are another typical ellample of this pitfall in ovarian pathology. About 3.5% to 6% of pancreatic adenocarcinomas are found at autopsy to have metastasized to the pancreas. (3) Occasionally, pancreatic metastases produce a clinically recognizable ovarian mass which is resected during surgical ellploration. Although the number of such reported cases is very small, we suspect this occurs more often than is generally appreciated. In 1989, we reported a series of seven such cases of metastatic carcinoma from the pancreas with features resembling primary mucinous tumors of the ovary. (3) The patients' ages ranged from 29 to 87 years (average, 63 years). The ovarian and pancreatic tumors were discovered synchronously in five patients. In two patients, the pancreatic tumor preceded the ovarian tumor by 9 months and 8:5 years, respectively. In four cases, the clinical presentation simulated primary ovarian cancer. All seven patients also had metastases in other sites. The ovarian tumors were typically large, multiloculated neoplasms which were grossly indistinguishable from primary mucinous cystadenocarcinoma. They ranged in size from 7 to 21 em (average, 12.5 em) in greatest dimension. Six of them were bil~teral; the status of the opposite ovary was not known in one case. Microscopically, the tumors manifested varying degrees of differentiation, usually containing areas resembling mucinous cystadenoma, mucinous LMP tumor and well-differentiated mucinous cystadenocarcinoma. The primary pancreatic tumors were typical invasive ductal adenocarcinoma in six patients and mucinous cystadenocarcinoma in the seventh. A noteworthy aspect of all the ovarian tumors was the' presence of desmoplastic surface implants, consisting of nodular to plaquelike aggregates of small irregular glands or clusters of infiltrating carcinoma cells within a prominent fibroblastic stroma. These implants appeared to be "plastered" on the cortical surface, suggesting transperitoneal spread to the ovary. Such lesions, as well as the presence of lymphatic invasion, are eJttremely helpful clues in determining that an epithelial ovarian tumor is a metastatic rather than a primary carcinoma. Other helpful features pointing away from the diagnosis of primary ovarian mucinous cystadenocarcinoma include bilaterality of the ovarian tumors and eJttraovarian spread of tumor at the time of discovery of the ovarian tumors, since primary ovarian mucinous carcinomas and LMP tumors are bilateral in less than 10% of Stage I tumors (1) and the vast majority are confined to the ovary when diagnosed. 22 Before diagnosing bilateral ovarian tumors as either primary mucinous cystadenocarcinoma or primary endometrioid adenocarcinoma, be sure the possibility of a metastatic carcinoma has been considered and excluded. REFERENCES I. Hart WR and Norris HI: Borderline and malignant mucinous tumors of the ovary: histologic criteria and clinical behavior. Cancer 31:1031-1045, 1973. 2. Lash RH and Hart WR: Intestinal adenocarcinomas metastatic to the ovaries: a clinicopathologic evaluation of22 cases. Am J Surg Patholll:ll4-121, 1987. 3. Young RH and Hart WR: Metastases from carcinomas of the pancreas simulating primary mucinous tumors of the ovary: A report of seven cases. Am J Surg Pathol 13(9):748-756, 1989. 23 CASE 15 (C'ITR # 27359) DIAGNOSIS: SMALL CELL CARCINOMA OF OVARY, "HYPERCALCEMIC TYPE" In 1982, Dickersin eta! (1) reported a series of 11 cases of a distinctive type of undifferentiated carcinoma of the ovary associated with hypercalcemia which they designated •small cell carcinoma. • Previously, many of these tumors had been diagnosed as undifferentiated malignant sex cord or gonadal stromal tumors. (4) Recently, Scully (6) has extensively reviewed his experience with over 100 cases of this neoplasm. The tumor is characteristically found in young females ranging in age from 9 to 44 years, with an average age of 23 years. Hypercalcemia has been found in about two-thirds of the cases in which the serum calcium level has been measured pteoperatively. It is the most common type of primary ovarian tumor to be associated with paraendocrine hypercalcemia in young females. This ovarian tumor is now referred to as small cell carcinoma of the hypercalcemic t~ . At initial operation, the tumor is almost invariably unilateral and about 40% of them have been Stage IA (6). They typically are large tumors with obvious hemorrhage and necrosis. Microscopically, they consist of sheets, nests, and occasionally cords, of malignant small undifferentiated epithelial cells in a scanty fibrous stroma. In over 75% of cases, there are rounded follicle-like structures containing eosinophilic fluid . (6) The tumor cells are small with scanty cytoplasm and relative!y uniform oval or round hyperchromatic nuclei. Mitotic figures are abundant. A confounding feature found in about 50% of cases is the presence of larger cells witlt more abundant eosinophilic cytoplasm and large nuclei with prominent nucleoli. (6) The large cell component may comprise a significant portion of the tumor ("larL!e cell variant of sma11 cell carcinoma") or be more apparent in the metastases than in the primary tumor. Another peculiar feature. in 8% of cases is the presence of epithelial cells with abundant intracytoplasmic mucin, usually forming either small cysts lined by endocervical-type mucinous cells or signet cells. (6) Ultrastructurally, the neoplastic cells have epithelial features and consistently contain prominent vesicles composed of dilated cisterns of rough endoplasmic reticulum filled with granular proteinaceous material. (5) Immunohistochemically, the tumor cells almost always stain with at least one cytokeratin marker while about one-third are EMA positive and half are positive for vimentin. (6) Interestingly, all 25 tumors in one study analyzed by flow cytometry were DNA diploid, a feature which may be of valudn the differential diagnosis with primary and metastatic neuroendocrine small cell carcinomas of the ovary. (2) The prognosis for patients with small cell carcinoma of hypercalcemic type is dismal with only a 30% survival rate in stage IA cases and practically all patients with extraovarian spread of tumor dying within a few years. (6) The differential diagnosis includes the juvenile granulosa cell tumor, lymphoma, "small blue cell tumors" of childhood, and the rare small cell carcinoma of pulmonary type which has only been -recently described. (3) In contrast to the small cell carcinoma of hypercalcemic type, the small cell carcinoma of pulmonary type occurs mostly in menopausal and postmenopausal women, is more often bilateral, commonly has an associated endometrioid or Brenner component and is DNA-aneuploid by flow cytometry in over half the cases studied. (3) Histologically, ultrastructurally, and immunohistochemically, they resemble small cell neuroendocrine carcinoma 24 of the lung. In fact, origin in the ovary can only be assigned after exclusion of a metastasis from primary small cell neuroendocri.ne carcinoma of the lung or other organs. REFERENCFS 1. Dickersin GR, Kline IW & Scully RE (1982) Small cell carcinoma of the ovary with hypercalcemia: A report of eleven cases. Cancer 49: 188 2. Eichhorn JH, Bell DA, Young RH, Swymer CM, Flotte TJ, Preffer FI & Scully RE (1992) DNA content and proliferative activity in ovarian small cell carcinomas of the hypercalcemic type: Implications for diagnosis, prognosis and histogenesis. Am 1 Clin Pathol 98: 579 3. Eichhorn JH, Young RH & Scully RE (1992) Primary ovarian small cell carcinoma of pulmonary type: A clinicopathologic, immunohistologic, and flow cytometric analysis of 11 cases. Am J Surg Pathol 16(10): 926 4. Holtz G, Johnson TR and Schrock ME (1979) Paraneoplastic hypercalcemia in ovarian tumors. Obstet & Gynecol 54: 483 5. McMahon JT & Hart WR ( 1988) Ultrastructural analysis of small cell carcinomas of the ovary. Am J Clin Pathol90: 523 6. Scully RE (1993) Small cell carcinoma of hypercalcemic type. Int J Gynecol Pathol 12: 148 25 CASE 16 (CTTR # 27360) DIAGNOSIS: JUVENU,.E GRANULOSA CELL TUMOR OF OVARY Ovarian granulosa cell tumors are of two histologic types: 1) adult aranulosa cell tumor (AGCf) and 2) juvenile granulosa cell tumor (JGCf). While either type of tumor may be found in patients of a wide age range, about 90% of tumors occuiring in prepubertal girls and many of those encountered in women less than 30 years of age are JGCT. (7) About 3% of JGCT occur in women older than 30 years. The clinical manifestations of JGCT are similar to those of AGCT with signs and symptoms of hyperestrinism the most common. In children, isosexual pseudoprecocity may result from the estrogenic stimulation due to the tumor's hormonal secretions. An association with Oilier's disease and Maffucci's syndrome has been found in some patients. (6, 7) The JGCT may also arise in the testis, and is one of the gonadal tumors that has occurred in infants with abnormal chromosomes and ambiguous genitalia. (9) Trisomy 12 has been detected by fluorescence in situ hybridization (FISH) studies of several JGCTs. (4) As with AGCTs, the tumors are usually unilateral and confined to the ovary at the time of discovery (Stage lA ). (1, 7, 10) Grossly, they are usually relatively large tumors (average diameter, 12 em) with only a small percentage less than 5 em. (1,7) The tumors are usually cystic or semicystic, but are solid in about one-third of cases. (7). Their sectioned surfaces often have tan or yellow areas, often with hemorrhagic zones. The tumors may be friable and rupture spontaneously or when handled. Microscopically, the tumors have a nodular or diffuse pattern in which poorly-formed, irregular follicles are found. The follicles vary in size and shape. They do not have the uniform appearance of the classic microfollicular pattern seen in AGCTs and Cali Exner bodies are absent. There often is considerable hyaluronic acid-rich myxoid material in the interstitial spaces between cells and mucoid fluid in the follicular spaces. (1, 7) Myxoid change and edema may be especially abundant during pregnancy. (1,8) The neoplastic granulosa cells are poorly differentiated and spindled cells resembling thecal cells are often present. Luteinization of the granulosa cells is common. The nuclei frequently are hyperchromatic and atypical with marked nuclear atypia seen in 10% to 15% of cases. (7) They lack the angular, grooved or folded nuclear membranes typically seen in AGCTs. Mitotic figures are easily found in most tumors and are often plentiful. Ultrastructural studies have shown features similar to those seen in AGCTs. (1,3) DNA-aneuploidy has been found in about half of the JGCTs studied by flow cytometry. (2,5) The prognosis for patients with JGCT is very good. The recurrence rate is only about 8% with a mortality rate for Stage I tumors of 3%. (7) Unlike AGCTs, in which late recurrences are not unusual, most recurrences of JGCT develop within two years. Generally recommended treatment is unilateral salpingo-oophorectomy for Stage IAl tumors in young patients. The relatively favorable clinical behavior of JGCT underscores the need to carefully distinguish JGCT from the highly-aggressive, and often fatal, ovarian small cell carcinoma of hypercalcemic type. 26 REFERENCES 1. Biscotti CV and Hart WR: Juvenile granulosa cell tumors of the ovary. Arch Pathol Lab Med 113:40-46, 1989. 2. Jacoby AF, Young RH, Colvin RB, Flotte TJ, Preffer F, Scully RE, Swymer CM and Bell DA: DNA Content in juvenile granulosa cell tumors of the ovary: A study of early- and advanced-stage disease. Gynecol Oncol. 46:97-103, 1992. 3. Roth LM, Nicholas TR and Ehrlich CE: Juvenile granulosa cell tumor: A clinicopathologic study of three cases with ultrastructural observations. Cancer 44:2194- 2205, 1979. 4. Schofield DE and Fletcher JA: Trisomy 12 in pediatric granulosa-stromal cell tumors. Demonstration by a modified method of fluorescence in in-situ hybridization on paraffin embedded material. Am J Pathol 141:1265-1269, 1992. S. Swanson SA, Norris HJ, Kelsten ML and Wheeler JE: DNA content of juvenile granulosa tumors determined by flow cytometry. Int J Gynecol Pathol9:101-109, 1990. 6. Tanaka Y, Sasaki Y, Nishihira H, Izawa T and Nishi T: Ovarian juvenile granulosa cell tumor associated with Maffucci's syndrome. Am J Clin Pathol 97:523-527, 1992. 7. Young RH, Dickersin GRand Scully RE: Juvenile granulosa cell tumor of the ovary: A clinicopathological analysis of 125 cases. Am J Surg Pathol 8:575-596, 1984. 8. Young RH,. Dudley AG and Scully RE: Granulosa cell, Sertoli-Leydig cell and unclassified sex cord-stromal tumors associated with pregnancy: A clinicopathological analysis of thirty-six cases. Gynecol Oncol 18:181-205, 1984. 9. Young RH, Lawrence WD and Scully RE: Juvenile granulosa cell tumor- another neoplasm associated with abnormal chromosomes and ambiguous genitalia. A report of three cases. Am J Surg Pathol 9(10):737-743, 1985. 10. Zaloudek C and Norris HJ: Granulosa tumors of the ovary in children: A clinical and pathologic study of 32 cases. Am J Surg Pathol6:513-522, 1982. 27 CASE 17 (CITR I 26971) DIAGNOSIS: CLEAR CELL ADENOFIBROMA OF LOW MALIGNANT POTENTIAL (BORDERLINE CLEAR CELL ADENOFIBROMA) OF OVARY Practically all clear cell tumors of the ovary are carcinoma. Benign and low malignant potential (LMP), or borderline, clear cell tumors occur, but they are extreme! y uncommon. They typically are adenofibromatous or cystadenofibromatous tumors. The criteria for classification of clear cell adenofibromatous tumors are controversial and there is no consensus at present. The classification advocated by Bell and Scully includes: 1) benign clear cell adenofibroma, 2) clear cell adenofibroma of borderline malignancy, 3) malignant clear cell adenofibroma, including those with microinvasive carcinoma and 4) mixed clear cell adenofibroma and invasive clear cell carcinoma. (1) Clear cell tumors of borderline malignancy (LMP) have been reported to account for 5 to 8% of all clear cell neoplasms. The mean age of patients with LMP tumors is 62 years, intermediate between the mean age of those patients with benign adenofibromas and those with adenofibromas with microinvasive carcinoma. (1) Grossly, clear cell adenofibromatous neoplasms are semisolid tumors, sometimes with a few large cysts. Their sectioned surfaces often have a sieve-like or sponge-like appearance with numerous small cysts within firm, fibrous tissue. The tumors are usually unilateral. Microscopically, the tumors consist of abundant fibromatous stroma with widely separated tubules and small cysts lined by flat cells, hobnail cells and/or clear cells. In benign tumors (clear cell adenofibroma), the cysts are lined by a single layer of epithelial cells which have bland nuclei or display only slight cytologic atypia, usually characterized by slightly enlarged nuclei with smudged chromatin. {l ,3) LMP (borderline) adenofibromatous tumors contain noninvasive glands or small solid nests of atypical clear cells or hobnail cells with cytologic features of a low-erade malignancy. (1) When the epithelium has features of a noninvasive hieh-mde carcinoma, the tumor is termed "malignant adenofibroma," according to Bell and Scully who also classify predominantly borderline tumors with microinvasion as "malignant adenofibroma. • Slightly differe.nt criteria were used by Roth and his associates (3) whose classification included clear cell adenofibroma, clear cell adenofibromaous tumor of LMP, and clear cell adenofibromatous tumor of LMP with invasive carcinoma. In their schema, noninvasive tumors with moderate to marked nuclear atypia with an occasional mitotic figure were included in the LMP category. Because of the small number of reported cases in each category in the reported series, it is difficult to reconcile the criteria cited by various investigators for distinguishing between 1) an "adenofibroma with epithelial atypia • (2) and an LMP tumor when the degree of atypia is slight to-moderate, and 2) an LMP tumor and a "malignant adenofibroma" when the atypia is severe. It is common to find a spectrum of atypicality within the same tumor which ranges from clearly benign cystadenofibroma to well-differentiated clear cell carcinoma. Problems in the identification of early stromal invasion, or microinvasion, in adenofibromatous tumors add to the difficulties. 28 There are two especially important aspects of clear cell adenofibromatous tumors, regardless of the criteria used for distinguishing between adenofibromas, adenofibromas with epithelial atypia, LMP (borderline) adenofibromatous tumors, and malignant adenofibromas. Firstly, all tumors without obvious areas of invasive clear cell carcinoma have an excellent prognosis, with only exceptional instances of documented recurrences. Secondly, it must be understood that ~ benign or borderline clear cell tumors are rare. Many adenofibromatous clear cell tumors also contain areas of clear cell carcinoma. Hence, careful gross examination and extensive sampling must be performed before a reliable diagnosis of either benign or LMP clear cell tumor can be safely made. REFERENCFS I. Bell DA & Scully RE (1985) Benign and borderline clear cell adenofibromas of the ovary. Cancer 56: 2922 2. Kao GF & Norris HJ (1978) Cystadenofibromas of the ovary with epithelial atypia. Am J Surg Pathol 2: 357 3. Roth LM, Langley RA, Fox H, Wheeler JE & C:z.emobilsky B (1984) Ovarian clear cell adenofibromatous tumors: Benign, of low malignant potential, and associated with invasive clear cell carcinoma. Cancer 53: 1156 29 CASE 18 (CITR II 27233) DIAGNOSIS: STRUMAL CARCINOID TUMOR OF OVARY Strumal carcinoid tumor is classified as a primary germ cell tumor of the ovary. It consists of an intimate mixture of teratomatous benign thyroid follicles and carcinoid tumor. The histogenesis of struma! carcinoid is ascribed to endodermal derivation within a teratoma. (3) In the past, struma! carcinoids were often misinterpreted as malignant struma ovarii. Patients with strumal carcinoid tumor range in age from 21 to 77 years. (3,5,7) They may be asymptomatic or present with a pelvic mass. In about 8% of patients there is clinical evidence of a functioning thyroid component. (3) The carcinoid syndrome is not a feature of struma! carcinoids. A case associated with Sipple's syndrome (MEN, type llA) has been reported. (9) The prognosis for patients with struma! carcinoid is excellent; only one patient has died as a result of the tumor. (3) · Struma! carcinoid tumors are almost always unilateral. Their size is highly variable, ranging from a microscopic nodule to 26 em in greatest dimension. (3) The gross appearance of the tumor depends on whether or not it is associated with a mature cystic or semisolid teratoma, usually a dermoid cyst (about 60% of cases). In such cases, it occurs as a nodule or thickening of the walls of a cyst. (3) In its pure, or almost pure, form without grossly obvious teratomas structures, the tumor is a solid mass. The carcinoid component appears as a solid, firm, white or pale yellow-tan mass, often resembling a thecoma or Brenner tumor. When the thyroid component is sufficiently , prominent to be grossly visible, it usually has a tan-red appearance. Teratomatous elements, such as are routinely seen in dermoid cysts and other varieties of mature teratoma, are present microscopically in over 80% of tumors. (3) In 46% of cases, mucinous glands or cysts are present (3); occasional tumors have occured as a nodule within a cystic mucinous LMP (borderline) tumor. (7) Pure struma! carcinoids without any demonstrable teratomatous elements, other than thyroid follicles, comprise Jess than 20% of cases. These are regarded as monodermal teratomas. The carcinoid component almost always has a prominent trabecular or ribbon pattern, either alone or mixed with an insular pattern. (3) The thyroid component consists of follicles filled with colloid and lined by typical thyroidal epithelium. Calcium oxalate crystals are often present in the colloid. (3, 7) These merge with thyroid follicles I in which partial to complete replacement of the thyroidal epithelial cells by carcinoid cells has occurred. The thyoid epithelial cells and colloid stain for thyroglobulin while the carcinoid cells are reactive with the usual battery of immunostains for carcinoid tumors, including chromogranin, synaptophysin and a vari.ety of polypeptide hormones. (5,7) Immunohistochemically, the carcinoid element typically is multi hormonal. (5-7) Interestingly, the carcinoid cells also stain positively for prostatic acid phosphatase, a feature shared by trabecular rectal carcinoids. (7) Luteinized non-neoplastic ovarian stromal cells are found focally in 31% of cases, and 8% of patients have clinical evidence of steroid hormone production. (3) The struma! carcinoid is only one type of primary ovarian carcinoid tumor. Typical insular carcinoid tumors also occur (4,8), and rare examples of mucinous (goblet cell) carcinoid arise in the ovary. (1,10) Distinction between these types of primary ovarian carcinoid tumor and 30 metastatic carcinoid tumor in the ovary can be challenging. Robboy and his associates studied 35 carcinoid tumors metastatic'to the ovary and compared them to 34 primary ovarian carcinoids. (4) 'The most helpful features in this differential diagnosis are: 1) primary carcinoids are almost invariably unilateral, while metastatic carcinoids are usually bilateral; 2) metastatic carcinoids are not found in association with a teratoma, while primary carcinoids commonly are; 3) primary carcinoids often have a trabecular pattern, while metastatic carcinoids usually have an insular pattern; and 4) metastatic carcinoids usually are accompanied by metastases to lymph nodes, liver or other sites, while primary carcinoids are almost always confined to the ovary (Stage 1). Thyroid tissue occurs in 5% to 15% of mature ovarian teratomas. To qualify for the designation of struma ovarll, the thyroid tissue must comprise at least 50% of the tumor. According to this criterion, 1.4% to 2% of ovarian teratomas can be considered struma ovarii. (2) Struma ovarii may be solid or cystic. They may have a variety of histologic patterns, including colloid nodules, hyperplastic nodules and markedly hypercellular prolferative areas ("proliferative struma ovarii"). (2) The term malignant struma ovarii'is restricted to those rare tumors containing either papillary carcinoma or follicular carcinoma as typically seen in the cervical thyroid gland. (2,11) Well-differentiated follicular carcinomas may be particularly difficult to diagnose, since the partially investing capsule found in the thyroid tumors is absent in the ovarian tumors. REFERENCFS l. Alenghat·E, Okagaki T and Talerman A: Primary mucinous carcinoid tumor of the ovary. Cancer 58:7TI-783, 1986. 2. Devaney K, Snyder R, Norris HJ and Tavassoli FA: Proliferative and histologically malignant struma ovarii: A clinicopathologic study of 54 cases. lnt J Gynecol Pathol 12:333-343, 1993. 3. Robboy SJ and Scully RE: Struma! carcinoid of the.ovary: An analysis of 50 cases of a distinctive tumor composed of thyroid tissue and carcinoid. Cancer 46:2019-2034, 1980. 4. Robboy SJ, Scully RE and Norris HJ: Carcinoid metastatic to the ovary: A clinicopathologic analysis of35 cases. Cancer 33:798-811, 1974. 5. Snyder RR and Tavassoli FA: Ovarian struma! carcinoid: Immunohistochemical, ultrastructural, and clinicopathologic observations. lnt J Gynecol Pathol 5:187-201, 1986. 6. Sporrong B, Falkmer S, Robboy SJ, Alumets J, Hakanson R, Ljungberg 0 and Sundler F: Neurohormonal peptides in ovarian carcinoids: An immunohistochemical study of 81 primary carcinoids and of intraovarian metastases from six mid-gut carcinoids. Cancer 49:68-74, 1982. 7. Stagno PA, Petras RE and Hart WR: Struma! carcinoids of the ovary: An immunohistochemical and ultrastructural study. Arch Pathol Lab Med 111:440-446, 1987. 31 8. Talerman A: Carcinoid tumors of the ovary. J Cancer Res Clin Oncol 107:125-135, 1984. 9. Tamsen A and Mazur MT: Ovarian struma! carcinoid in association with multiple endocrine neoplasia, type IlA. Arch Pathol Lab Med 116:200-203, 1992. 10. Wolpert HR, Fuller AF and Bell DA: Primary mucinous carcinoid tumor of the ovary: A case report. lntJ Gynecol Patho18:156-162, 1989. II. Young RH: New and unusual aspects of ovarian germ cell tumors. Am J Surg Pathol 17:1210-1224, 1993. 32 .. CALIFORNIA TUMOR TISSUE REGISTRY CANCER SEMINAR TUMORS OF THE.FEMALE GENITAL TRACT ADDENDUM CASES 7 - 12, 19 - 24 PHILIP B. CLEMENT, M.D. Consultant Pathologist Vancouver General Hospital Vancouver, British Columbia DECEMBERS, 1993 SAN FRANCISCO, CALIFORNIA 33 CASE 7 (Ace #27348) DIAGNOSIS: AGGRESSIV$ ANGIOMYXOMA OF PELVIC SOFT TISSUES DISCUSSION: Clinical Features In 1983, Steeper and Rosail proposed the designation "aggressive angiomyxoma" for a distinctive tumor that appears to arise from the soft tissues of the pelvic floor; approximately 35 cases have. been reported.l-9 Over 90% of the tumors occur in women, who are usually in the reproductive age group (mean age, 32 yrs; range 15 to 63). The typical presentation is that of a mass or an ill-defined swelling of one or more sites that are typically vulvar, perineal, vaginal, inguinal, gluteal, or ischiorectal in location. The initial clinical impression is often that of a Bartholin cys.t or hernia. The tumors may reach large sizes, filling the pelvis, but usually grow along tissue planes, displacing, rather than invading, the pelvic organs. The rare examples that have occurred in men have been perineal, inguinal., or scrotal masses; two case in men were associated with inguinal hernias. 2,9 Fatbological Features On gross examination, the tumors are typically bulky (up to 60 em in diameter), soft to rubbery, solid masses with a lobulated contour that appear partially or completely encapsulated. Their sectioned surface has a glistening, gelatinous, relatively homogeneous appearance, although small cysts or areas of hemorrhage may be present. Recurrent tumor has a similar gross appearance, although hemorrhagic and fibrotic areas may be more prominent. The tumors are composed of a sparse population of small, spindle and stellate cells lying in a loose, myxoid background that contains a dense network of delicate collagen fibrils. The nuclei of the tumor cells are small and uniform, with small, indistinct nucleoli; rare multinucleated cells may be present. Mitotic figures have not been observed. There is a prominent vascular component with thin and thick-walled blood vessels of varying sizes distributed haphazardly throughout the myxoid stroma. The latter shows weak positivity with alcian blue at pH I. 0 and 2. 5 and with colloidal iron. Extravasated erythrocytes and sparsely distributed mast cells are common!y preserit within the stroma. The tumors lack a capsule, and infilt.rqte the surrounding soft tissue, usually fat and skeletal muscle; small nerves are commonly entrapped. The tumor cells are immunoreactive for vimentin and actin;2,3 in some studies3 blit not otherslO the tumors have also been positive for desmin. Estrogen and progesterone receptors have been demonstrated within the tumor in one case. 4 The microscopic appearance of the recurrent tumor is usually identical to that of the primary neoplasms, although it may be focally more cellular with larger, more polygonal cells. Ultrastructural studies of the spindle cells have shown features consistent with fibroblastic and/or myofibroblastic differentiation.! ,2 Behavior and Treatment The tumors are typically indolent with a tendency to recur locally, in most cases likely a result of incomplete excision. One or more local recurrences, at postoperative inte!Vals ranging 34 from 9 months to 14 years, have appeared in almost all of the patients who have been followed for at least one year; distant metastases or death from tumor have not been described. The treatment of aggressive angiomyxoma as well as that of recurrent tumor is wide surgical excision to the extent that is technically feasible. Differential Diagnosis The differential diagnosis is long and includes a variety of benign and malignant myxoid tumors such as myxoma, spindle cell lipoma, myxoid neurofibroma, fibroepithelial polyp, fibromatosis, myxoid liposarcoma, myxoid leiomyosarcoma, embryonal rhabdomyosarcoma (sarcoma botryoides), and the myxoid variant of malignant fibrous histiocytoma.l,2 Aside from a myxoid stroma, all of these tumors Jack the characteristic histologic appearance, including the distinctive vascular component, of the aggressive angiomyxoma. In addition, the variety of sarcomas that may have a myxoid appear'!flce will usually contain nonmyxoid areas and cells with greater degrees of nuclear .pleomorphism and mitotic activity than seen in the aggressive angiomyxoma. One recently described benign soft tissue tumor of the vulva that also merits consideration in the differential diagnosis of aggressive angiomyxoma is the angiomyolibroblastoma.lO,l l Patients with the latter tumor, who are in the same age range as those with aggressive angiomyxoma, present with a vulvar mass that clinically may mimic a Bartholin cyst. The tumors, which are well circumscribed both grossly and microscopically, range in size from 0.5-12 em. They are characterized by alternating hypercellular and hypocellular edematous zones in which abundant blood vessels (predominantly capillaries) are irregularly distributed.lO Spindled, plump spindled, or oval stromal cells, separated by wavy strands or thick bundles of collagen, are aggregated around blood vessels, sometimes forming solid compact foci, or are loosely dispersed in the hypocellular areas. In rate cases, the cells have a distinctly epithelioid ·appearance.! 1 Fat has been present in rare cases. 11 The nuclei of the tumor cells are bland, but in 40% of the cases, rare nuclei are enlarged and hyperchromatic. Some cells have abundant eosinophilic hyaline cytoplasm and eccentrically placed nuclei. Mitotic figures are absent or sparse. The cells are immunore;~.ctive for vimentin and desmin, but not cytokeratin, actin, or S-100, and ultrastructurally have features consistent with myofibroblasts. None of the tumors recurred following local excision. The angiomyofibroblastoma can be distinguished from the aggressive angiomyxoma by its circumscribed borders, higher cellularity, more numerous blood vessels (which lack prominent hyalinization), frequent presence of plump stromal cells that are occasionally overtly epithelioid, and perivascular condensation of the stromal cells.lO Immunoreactivity for desmin but not actin also favors the diagnosis of angiomyofibroblastoma over aggressive angiomyxoma.l 0 35 REFERENCES I. Steeper TA, Rosai J: Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. Am J Surg Pathol 1983;7:463-475. 2. Begin LR, Clement PB, Kirk ME, Jothy S, McCaughey WTE, Ferenczy A: Aggressive angiomyxoma of pelvic soft parts: A clinicopathological study of nine cases. Hum Pathol 1985;16:621-628. 3. Manivel C, Steeper T, Swanson P, Wick M: Aggressive angiomyxoma of the pelvis. An immunoperoxidase study (abstract). Lab Invest 1987;56:46A. 4. Sutton GP, Rogers RE, Roth LM, Ehrlich CE: Aggressive angiomyxoma first diagnosed as levator hernia. Am J Obstet Gynecoll989;16l:73-75. 5. Hilgers RD, PaiR, Bartwo SA, Aisenbrey G, Bowling MC. Aggressive angiomyxoma of the vulva. Obstet Gynecol1986;68:60S-62S. 6. Simo M, Zapata C, Eqquius J, Domingo J: Aggressive angiomyxoma of th female pelvis and perineum. Report of two cases and review of the literature. Br J Obstet Gynaecol 1992;99:925-927. 7. Cheung TH, Chan KS, Chang A: Aggressive angiomyxoma of the female perineum: Case reports. Aust NZ J Obstet Gynaecol ~991;31:285-287. 8. Elchalal U, Lifschitz-Mercer B, Dgani R, Za.lel Y: Aggressive angiomyxoma of the vulva. Gynecol Oncol 1992;47:260-262. 9. Clatch RJ , Drake WK, Gonzalez JG. Aggressive angiomyxoma in men. A report of two cases associated with inguinal hernias. Arch Pathol Lab Med 1993;117:911-913. 9a Mascarenhas L, Knaggs J, Clark J et al. Aggressive angiomyxoma of the pelvis and perineum: Case report and literature review. Am J Obstet Gynecol 1993; 169:555-556. 10. Fletcher CDM, Tsang WYW, Lee KC, Chang JKC: Angiomyofibroblastoma of the vulva. A benign neoplasm distinct from aggressive angiomyxoma. Am 1 Surg Pathol 1992; 16:373-382. 11. Hiruki T, Thomas MJ, Clement PB. Vulvar angiomyofibroblastoma (letter). Am J Surg Pathol 1993; 17:423-424. 36 CASE 8 (Ace #27266) DIAGNOSIS: SMALL CELL UNDIFFERENTIATED CARCINOMA OF THE CERVIX DISCUSSION: Small cell carcinomas of the cervix were originally considered a rare subtype of squamous cell carcinoma characterized by a highly malignant behavior. Although small cell squamous carcinomas exist, it has become apparent during the past 15 years that the majority of small cell carcinomas of the cervix express neuroendocrine differentiation. I-59 In a minority of such tumors, squamous differentiation may also be present, as discussed below. The designations small cell undifferentiated carcinoma, neuroendocrine carcinoma, oat cell carcinoma, argyrophiliC carcinoma, endocrine carcinoma, malignant carcinoid tumor, and malignant APUDoma have been applied to these tumors. .Because they are classified primarily on the basis of their appearance on routine light microscopy and because not all of them exhibit neuroendocrine differentiation, the term ·"small cell undifferentiated carcinoma" (SCUC) has generally been preferred. Conversely, occasional cervical carcinomas not of small cell type, such as rare adenosquamous carcinomas, 37,60 have exhibited neuroendocrine differentiation on immunohistochemical or ultrastructural examination. The term "carCinoid tumor" should be avoided except to refer to a well differentiated tumor, resembling typical carcinoid tumors within the intestinal tract, with uniform nuclei and infrequent mitotic figures. It is questionable if such a tumor has been described within the cervix. Some tumors composed of larger cells arranged in insular and trabecular patterns (and with argentaffin granules in some cases) have resembled so-called poorly differentiated carcinoids. The "endocrine carcinomas of intermediate cell type" described by Silva et al appear to fall into this category.27 However, the prognosis cif such tumors is similar to typical small cell carcinomas, and both are considered together in this discussion. SCUCs may arise from argyrophilic cells which have been demonstrated within the ectocervical or endocervical epithelium in 2-43% of normal subjects61,62 and as many as 35% of patients with SCUCs. 6 Some tumors, however, particularly those with an admixed squamous or adenocarcinomatous component, may originate from subcolumnar reserve cells. Clinical Features Approximately 250 SCUCs of the cervix have been described in the literature. I-59 In most studies, they have accounted for approximately 2% of ce[\(ical carcinomas (range, 0.5 to 5 percent).26 The clinical features of patients with SCUCs are similar to those with squamous cell carcinomas. The age of individual patients has ranged widely (21 to 87 years), although in most series the median and mean ages are in the fifth decade. Four SCUCs have been encountered in pregnant women.48 Most patients present with abnormal vaginal bleeding and have an obvious cervical mass on pelvic examination. Rare patients have presented with abdominal symptoms related to the presence of ovarian metastases. 56 The proportion of patients with SCUCs that have an abnormal Papanicolaou smear is smaller than in patients with 37 squamous cell carcinoma, a feature which has been attributed to the frequent absence of an associated in situ component, rapid growth of the tumor, or both.43 An elevated serum ' wcinoembryonic antigen (CEA) level at the time of presentation has been found in occasional patients. II Approximately 75% of patients with SCUCs are clinical stage I or n, a figure similar to that for patients with squamous cell carcinoma. Many such patients, however, are of a higher stage if operative findings are considered. In one study of patients with clinical stage IB or IIA SCUCs undergoing pelvic lymph node dissection, 57% were found to have lymph node metastases; all patients with positive nodes had tumors > 2 em.41 In another series, however, 40% of stage m tumors < 3 em had positive nodes.42 In the most recent large study of SCUCs in the literature, 60% of patients were surgical stage Ill or IV. 48 Some patients, as noted above, have had ovarian metastases at pre_sentation. 9,56 Despite the wide variety of hormones detectable immunohistochemically in SCUCs (see below), clinical or biochemical evidence of hormone production is rare. This observation suggests that the hormonal polypeptides are secreted in an inactive form, in insufficient levels to produce clinical syndromes, or are rapidly inactivated in the circulation.27 Six patients have had Cushing's syndrome, some with documented elevations in serum ACTH, and in one, antidiuretic hormone (ADH); I, 7,14,18,21,59 two patients have had hypoglycemia (one with elevated serum insulin);31,33 three patients have had the carcinoid syndrome, one of whom had elevated serum levels of ACTH, cortisol, and hCG, and in another, there were elevated levels of somatostatin, ACTH, and serotonin;2,34,56 one patient has had the syndrome of inappropriate ADH secretion (with elevated serum levels of ADH);50 one patient has had elevated serum and tumor levels of serotonin (but not the carcinoid syndrome);49 and one patient has bad elevated serum levels of calcitonin. 45 The tumor from one of the patients with Cushing's syndrome was found to contain high levels of serotonin, ACTH, beta-MSH, ACTH, histamine, and amylase.l4 Tumor extracts from four other SCUCs that were clinically nonfunctioning have contained one or more hormones including somatostatin, pancreatic polypeptide, cal.citonin, vasointestinal polypeptide (VIP), ACTH, beta-MSH, NSE, and insulin.25,58 Gross and Microscopic Features On gross examination, SCUCs of the cervix are indistinguishable from squamous cell carcinomas. Many tumors are large ulcerating masses that frequently encompass and destroy the cervix and extend into the parametria, vagina, and occasionally, the corpus. On microscopic examination, the tumors are typically densely cellular and exhibit a variety of \)attems, frequently admixed, including solid sheets, ill-defined or sharply outlined nests, trabetulae, and single cells. Small rosette-like or acinar structures, sometimes containing PAS-positive material, may be present and when numerous impart a pseudoglandular pattem.6,27 As in pulmonary small cell undifferentiated carcinomas, both small (oat) and 38 intermediate-type cells can be identified, with usually one ce11 type predominating. The small cells are oval to spindle in sh~pe and contain scanty cytoplasm and hyperchromatic., molded nuclei with finely dispersed chromatin and indistinct nucleoli. Nuclear detail is often obscured by intense hyperchromasia, smudged chromatin, and crush artifact. 39 The ceHs of intermediate type; are round to polygonal and medium-sized with moderate amounts of pale, eosinophilic cytoplasm and ill-defined cell borders; the cells may exhibit peripheral palisading. 8,27 Their round to oval nuclei are more uniform that those of the small cells and exhibit a more coarse chromatin pattern; nucleoli may be prominent. Mitotic figures are numerous within both the small and intermediate-type cells;27,30,39,48 in one study, two-thirds of the cases had 20-50 mitotic figures per 10-high-power-fields (MFs/10 HPFs), whereas the remaining cases had >50 MFs/10 HPFs.48 Nuclear fragmentation ("hematoxylin bodies")53 and single cell or confluent necrosis are frequently present. Foci of typical squamous cell carcinoma or adenocarcinoma (either of which may be in situ, invasive, or both) are present in as many as one-half of the cases; these invasive components may be discrete or intimately admixed with the neoplastic small cells. The tumors typically have a delicate, fibrovascular stroma; a desmoplastic stromal response may occur but is uncommon. An inflammatory response is usually inconspicuous. Perivascular hematoxylin staining39 and amyloid-like material within the stroma have been present in occasional cases. Lymphatic and vascular invasion is often prominent. The histologic appearance of metastatic or recurrent tumor is typically indistinguishable from that of the primary; occasional adenocarcinomas of the cervix have had a component of SCUC in recurrent or metastatic tumor that was not demonstrable within the primary tumor. 27 Findings with Special Techniques Most recent studies of SCUCs have shown that the majority of cases exhibit evidence of neuroendocrine differentiation as determined by one or more techniques. The frequency with which the tumor cells contain arygyrophilic granules has varied from only a minority of cases to all of the tumors in a particular series; the staining may be very focal and require prolonged search.39 Argentaffin cells have been demonstrated in only very rare cases,l4,17,56 and appear to more common in tumors of int~rmediate cell type. SCUCs have been shown to be variably immunoreactive for a wide variety of antigens, including cytokeratins (low and high molecular weight), epithelial membrane antigen (EMA), CEA, neuron-specific enolase (NSE), chromogranin, HNK-1, Leu-7, and synaptophysin, as well as for a variety of polypeptide and amine hormones, including ACTH, calcitonin, gastrin, serotonin, substance P, VIP, pancreatic polypeptide, and somatostatin.l3,25,27,28,35,39,46,53 One example of a cervical SCUC was found to have an associated hyperplasia of benign appearing cells within adjacent normal endocervical glands and glands showing adenocarcinoma in situ; the cells were argyrophilic and immunoreactive for NSE and chromogranin. 47 The ultrastructural features of SCUCs have been well described elsewhere.30,39 As with similar tumors in the lung, the heterogeneity noted at the light microscopic level is reflected by electron microscopic examination. Dense-core granules can be demonstrated in most, but not -all, S.CUCs; they vary from s<;anty to numerous, and are often concentrated within dendritic cell processes. Absence of dense core granules may reflect sampling error, cyclic granule ptoduction and depletion, or dedifferentiation of the cells. 39 Microvilli, microfilaments, and poorly formed desmosomes with or without tonofilaments have also been observed, reflecting variable degrees of glandular or squamous differentiation that may not be appreciable nisto\o~ica\\'j.6 , 14,30,39 \n rue cases, bot\\ endocrine and exocrine ~eatutes ma.'j be \dentlf\ed within the same neoplastic ce\\s (" amphicr:ine carcinoma"). 57 Recently, an association between cervical SCUCs and human papilloma virus type 18 has been found in most53,63,64 but not all65 studies. Combining the results of three studies, HPV 18 DNA or messenger RNA has been found in 62% of the cases; in one study, the corresponding figure for SCUCs with ne~roendocrine differentiation was 78%.63 In another series, the presence of HPV 18 DNA was associated with a high frequency of lymph node metastases, and a significant association was found between the presence of aneuploidy, mitotic activity, and HPV 18 DNA. 53 HPV 16 has also been detected, but only in small minority of cases,81,88 and in one series was confined to SCUCs showing squamous differentiation.63 DNA ploidy analysis of 16 cases in one study .revealed that 5 tumors were diploid and 11 were hyperploid, 48 whereas in another study of 6 cases, four tumors were peridiploid and two were aneuploid. 53 In a third study, all 14 cases were aneuploid.54 Differential Diagnosis The differential diagnosis of cervical SCUCs includes other small cell malignant neoplasms that may involve the cervix, including small cell squamous carcinoma, lymphoepithelioma-like carcinoma, adenoid basal carcinoma, lymphoma and leukemia, endometrial stromal sarcoma, and metastatic small cell carcinoma. Although their distinction from SCUCs on histological grounds alone may occasionally b.e difficult, particularly on a small biopsy specimen, routine light microscopic findings are usually diagnostic, and the histochemical, immunohistochemical, and ultrastructural findings will facilitate the diagnosis in problem cases. With respect to the differential diagnosis with small cell squamous carcinomas (SCSC), a recent study found that a number of features favored a diagnosis of scuc over sese, including a younger age (mean 36 years vs 50 years for SCSC), an absence of squamous intraepithelial neoplasia (vs 60% for SCSC), immunoreactivity for neuroendocrine markers combined with nonreaetivity for cytokeratin (all tumors with this immunoprofile were SCUC), and the presence of HPV 18 DNA (60% vs 36% for SCSq.53 Despite these findings, significant overlap existed between the two groups of tumors, and the authors concluded that the distinction between SCUC and sese should be based primarily on their histologic features. Behavior and Prognostic Factors SCUCs, of both small and intermediate-cell types, are highly aggressive neoplasms; this behavior appears independent of the presence or absence of neuroendocrine differentiation as 4n 48 demonstrated by special techniques. 39• The tumors have a propensity to metastasize early and widely by both lymphatic and hematogenous routes, and involvement of regional and distant lymph nodes, lung, bone, brain, and liver is common. The disease-free interval is usually less than two years and almost 70% of recurrences were noted within 12 months of therapy in one study.42 Approximately three-quarters of the patients reported in the literature have died from tumor progression or were alive with tumor at the time of reporting. The best indicator is the surgical (pathologic) stage. 48 In one study, 8 of 11 patients with pathological stage I or n disease survived four years (a survival rate similar to that of squamous cell carcinoma or adenocarcinoma in this site), whereas 22 of 23 patients with stage m or IV disease died of tumor. 48 Other potential adverse prognostic factors include lymph node involvement35 and aneuploidy, 48,53 although whether these factors have a prognostic effect independent of stage is not clear. 48 The presence of an admixed squamous or glandular component was associated wiih a better survival rate (35 vs 8%) in one study, 48 but was not prognostically significant in two others.39,43 A DNA index of< 1.5 was associated with prolonged survival in a recent series. 54 Factors not affecting prognosis in one study included mitotic rate, the presence of vascular invasion, and the number of quadrants involved by tumor. 48 Another study has shown a correlation between disease-free intervals and survival with primary tumor size. Median disease-free intervals and survival were 6 months and 13 months for patients with tumors > 2 em; the corresponding figures for patients with tumors < 2 em were 30 months and 37 months.41 REFERENCES I. Berthelot P, Benhanou JP, Fauver! R: Hypercorticisme et cancer de 1'uterus. Presse Med 69:189-190, 1961 2. Driessens J, Clay A, Adenis L, Demaille A. Tumeur cervico-uterine et syndrome biologique de carcinoidose. Arch Anat Patho1 12:200-203, 1964 3. Shames JM, Dhurandhar NR, Blackard WG: Insulin-secreting bronchial carcinoid tumor with widespread metastases. Am J Med 44:632-637, 1968 4. Albores-Saavedra J, Poucell S, Rodriguez-Martinez HA: Primary carcinoid of the uterine cervix. Pato1ogia 10:185-193, 1971 §.Kiang DT, Bauer GE, Kennedy BJ: lmmunoassayable.insulin .in carcinoma of the cervix associated with hypoglycemia. Cancer 31:801-805, 1973 6. Tateishi R, Wada A, Hayakawa Ketal: Argyrophil cell carcinomas (apudomas) of the uterine cervix. Light and electron microscopic observation of 5 cases. Virchows Arch [Pathol Anat) 366:257-274, 1975 7. Jones HW Ill, Plymale S, Gluck FB et al: Small cell nonkeratinizing carcinoma of the cervix associated w.ith ACTH production. Cancer 38:1629-1635, 1976 8. Albores-Saavedra J, Larraza 0, Poucell S, Rodriguez Martinez HA: Carcinoid of the uterine cervix. Additional observations on a new tumor entity. Cancer 38:2328-2342, 1976 9. Daw E: Carcinoid of the cervix. Postgrad Med I 53:272-273, 1977 10. Van Nagell JR Jr, Donaldson ES, Wood EG et al: Small cell cancer of the uterine cervix. Cancer 40:2243-2249, 1977 11. Warner TFCS: Carcinoid tumor of the uterine cervix. J Clin Pathol 31:990-995, 1978 12. Mackay B, Osborne B, Wharton IT: Small cell tumor ofcervix with neuroepithelial features . Ultrastructural observations in two cases. Cancer 43:1138-1145, 1979 41 13. Albores-Saavedra J, Rodriguez-Martinez HA, Larraza-Hemandez 0: Carcinoid tumors of the cervix. Pathol Annu 14:273-291, 1979 14. Matsuyama M, Inoue T, Ariyoshi Yet al: Argyrophil carcinoma of the uterine cervix with ectopic production of ACTH, beta-MSH, serotonin, histamine, and amylase. Cancer 44:1813-1823, 1979 15. Habib A, Kaneko M, Cohen CJ, Walker G: Carcinoid of the uterine cervix. A case report with light and electron microscopic studies. Cancer 43:535-538, 1979 16. Jacobs AJ, Marchevsky A, Gordon RE, DeppeG, Cohen CJ. Oat cell carcinoma of the uterine cervix in a pregnant woman treated with cis-diamminedichloroplatinum. Gyneco1 Oncol 9:405-410, 1980 17. Johannessen N, Capella C, Solcia E et al: Endocrine cell carcinoma of the uterine cervix. Diagn Gynecol Obstet 2:127-134, 1980 18. Lojek MA, Fer MF, Kasselberg AG et al: Cushing's syndrome with small cell carcinoma of the uterine cervix. Am J Med 69:140-144, 1980 19. Hsu C, MaL, Wong LC, Chan CW: Non-endocrine carcinoid tumour of the uterine cervix: Aspects of diagnosis and treatment. Case Report. Br J Obstet Gynaecol 88:1056-1060, 1981 , 20. Mullins JD, Hilliard GD: Cervical carcinoid ("argyrophil cell" carcinoma) associated with an endocervical adenocarcinoma: A light and ultrastructural study. Cancer 47:785-790, 1981 21. Pazdur R, Bonomi P, Slayton Ret al: Neuroendocrine carcinoma of the cervix: Implications for staging and therapy. Gynecol Oncoll2: 120-128, 1981 22. Stahl R, Demopoulos RI, Bigelow B: Carcinoid tumor within a squamous cell carcinoma of the cervix. Gynecol Oncol II :387-392, 1981 23. Stassart J, Crum CP, Yordan EL et al: Argyrophilic carcinoma of the cervix: A report of a case with coexisting cervical intraepithelial neoplasia. Gynecol On col 13:247-251, 1982 24. Hariri J, Rasmussen EA, HageE: Carcinoid tumor of the uterine cervix. Acta Obstet Gynecol Scand 62:539-540, 1983 25. Inoue T, Yamaguchi K, Suzuki H et al: Production of immunoreactive polypeptide hormones in cervical carcinoma. Cancer 53: 1509-1514, 1984 26. Scully RE, Aguirre P, DeLellis RA. Argyrophilia, serotonin, and peptide hormones in the female genital tract and its tumors. lnt J Gynecol Pathol 3:51-70, 1984 27. Silva EG , Kott MM, Ordonez NG: Endocrine carcinoma intermediate cell type of the uterine cervix. Cancer 54:1705-1713, 1984 28. Yamasaki M, Tateishi R, Hongo Jet al: Argyrophil small cell carcinomas of the uterine cervix. IntI Gynecol Pathol 3:146-152, 1984 29. Yoshida A, Yoshida H, Fukunishi R, Inohara R: Carcinoid tumor of the uterine cervix. A light and electron microscopic study. Virchows Arch [Pathol Anal] 402:331-336, 1984 30. Groben P, Reddick R, Askin F. The pathologic spectrum of small cell carcinoma of the cervix. Int J Gynecol Pathol 4:42-57, 1985 31. Inoue M, Ueda G, Nakajima T: Immunohistochemical demonstration of neuron-specific enolase in gynecologic malignant tumors. Cancer 55:1686-1 690, 1985 32. Miles PA, Herrera GA, Mena H, Trujillo I: Cytologic findings in primary malignant carcinoid tumor of the cervix, including immunohistochemistry and electron microscopy performed on cervical smears. Acta Cytol 29:1003-1008, 1985 33. Fujii S, Konishi I, Ferenczy A et al: Small cell undifferentiated carcinoma of the uterine cervix: Histology, ultrastructure, and immunohistochemistry of two cases. Ultrastruct Pathol 10:337-346, 1986 34. Stockdale AD, Leader M, Phillips RH , Henry K: The carcinoid syndrome with multiple hormone secretion associated with a carcinoid tumour of the uterine cervix. Case report. Br J Obstet Gynaecol93:397-401, 1986 35. Ulich TR, Liao S, Layfield Let al: Endocrine and tumor differentiation markers in poorly differentiated small-cell carcinoids of the cervix -and vagina. Arch Pathol Lab Med 110:1054-1057' 1986 42 36. Turner W A, Gallup DG, Talledo OE et al: Neuroendocrine carcinoma of the uterine cervix complicated by pregnancy: Case repon of review of the literature. Obstet Gynecol 67:80S-83S, 1986 37. Barrett RJ ll, Davos I, Leuchter RS, Lagasse LD. Neuroendocrine features in poorly differentiated and undifferentiated carcinomas of the cervix. Cancer 60:2325-2330, 1987 38. Muraoka S, Takahashi T, Ando Metal: Minute carcinoid tumor of the uterine cervix associated with microinvasive adenocarcinoma, with reference to its histogenesis. Acta Pathol Jpn 37: 1183-1198, 1987 39. Gersell DJ, Mazoujian G, Mutch DG, Rudloff MA: Small-cell undifferentiated carcinoma of the cervix. A clinicopathologic, ultrastructural, and immunocytochemical study of 15 cases. Am J Surg Pathol 12:684-698, 1988 40. Seidel R Jr, Steinfeld A. Carcinoid of the cervix: Natural histo.ry and implications for therapy. Gynecol Oncol30:114-119, 1988 41. Sheets EE, Berman ML, Hrountas CK et al: Surgically treated, early-stage neuroendocrine small-cell cervical carcinoma. Obstet Gynecol 71:10-14, 1988 42. Van Nagell JR Jr, Powell DE, Gallion HH et al: Small cell carcinoma of the uterine cervix. Cancer 62:1586-1593, 1988 43. Walker AN, Mills SE, Taylor PT: Cervical neuroendocrine carcinoma: A clinical and light microscopic study of 14 cases. Int J Gynecol Pathol 7:64-74, 1988 44. Husain AN, Gattuso P, Abraham K, Castelli MJ: Synchronous adenocarcinoma and carcinoid of the uterine cervix: Immunohistochemical study of a case and review of literature. Gynecol Oncol 33: 125-128, 1989 45. Tsukamoto N, Hirakawa T, Matsukuma K, et al: Carcinoma of the uterine cervix with variegated histological patterns and calcitonin production. Gynecol Oncol 33:395-399, 1989 46. Ueda G, Shimizu C, Shimizu H, et al: An immunohistochemical study of small-cell and poorly differentiated carcinomas of the cervix using neuroendocrine markers. Gynecol Oncol34: 164-169, 1989 47. Chang JKC, Tsui WMS, Tung SY, Ching RCT: Endocrine cell hyperplasia of the uterine cervix. A precursor of neuroendocrine carcinoma of the cervix? Am J Clin Pathol 92:825-830, 1989 48. Silva EG, Gershenson D, Sneige N et al: Small cell carcinoma of the uterine cervix: "Pathology and prognostic factors". Surg Pathol 2:105-115, 1989 49. Hirahatake K, Hareyama H, Kure Ret a1: Cytologic and hormonal findings in a carcinoid tumor of the uterine cervix. Acta Cytol 34:119-124, 1990 50. Kothe MJC, Prins JM, De Wit Ret al: Small cell carcinoma of the cervix with inappropriate antidiuretic hormone secretion. Case report. Br J Obstet Gynaecol 97:647-648, 1990 51. Miller B, EI-Torky M, Photopulus G: Simultaneous small cell carcinoma of the cervix and adenocarcinoma of the ovary. Gynecol Oncol 39:99-102, 1990 52. Ramsay IN, Gardiner DS: Small cell undifferentiated carcinoma of the cervix. Case report. Br J Obstet Gynaecol 97:1046-1048, 1990 53. Ambros RA, Park J, Shah K, Kurman RJ: Evaluation of histologic, morphometric, and immunohistochemical criteria in the differential diagnosis of small cell carcinomas of the cervix with particular reference to human papillomavirus types 16 and 18. Mod Pathol 4:586-593, 1991 54. Miller B, Dockter M, El Torky M, Photopulos G. Small cell carcinoma of the cervix: A clinical and flow-cytometric study. Gynecol Oncol 42:27-33, 1991 55. O'Hanlan KA, Goldberg GL, Jones JG et al: Adjuvant therapy for neuroendocrine small cell carcinoma of the cervix: Review of the literature. Gynecol Oncol43:167-172, 1991 56. Young RH, Gersell DJ, Roth LM, Scully RE: Ovarian metastases from cervical carcinomas other than pure adenocarcinoma: A report of 12 cases. Cancer 71 :407-4 18, 1993 57 . Hammar SP, Insalaco SJ, Lee RB et al: Amphicrine carcinoma of the uterine cervix. Am J Clin Pathol 97:516-522, 1992 43 58. Ueda G, Yamasaki M: Neuroendocrine carcinoma of the uterus, p.309. In: Sasano N (ed): Current Topics in Pathology, Vol. 85, Gynecological Tumors. Springer-Verlag, New York, 1992 59. Iemura K, Sonoda T, Hawakawa A et al: Small cell carcinoma of the uterine cervix showing Cushing's syndrome caused by ectopic adrenocorticotropin hormone production. Jpn J Clin Oilcol 21:293-298, 1991 60. Miles PA, Herrera GA , Greenberg H, Rawding-Patterson G: Primary carcinoid tumor of the uterine cervix presenting as an adenosquamous carcinoma. Diagn Gynecol Obstet 4:327-337, 1982 61. Fox H, Kazza B, Langley FA: Argyrophil and argentaffm cells in the female genital tract and in ovarian mucinous cysts. J Pathol Bact 88:479-488, 1964 62. FetissofF, Serres G, Arbeille Bet al: Argyrophilic cells and ectocervical epithelium. Int J Gynecol Pathol 10:177-190, 1991 63. Stoler MH, Mills SE, Gersell DJ, Walker AN. Small-cell neuroendocrine carcinoma of the cervix: A human papillomavirus type IS-associated cancer. Am J Surg Pathol15:28-32, 1991 64. Wolber RA, Clement PB: In situ DNA hybridization of cervical small cell carcinoma and adenocarcinoma using biotin-labeled human papillomavirus probes. Mod Pathcil4:96-100, 1991 65 . Pao CC, Lin C, Tseng C et al: Human papillomaviruses and small cell carcinoma of the uterine cervix. Gynecol Oneal 43:206-210, 1991 66. Ueda G, Yamasaki M, Inoue M, et al: Immunohistochemical demonstration of HNK-1-defmed antigen in gynecologic tumors with argyrophilia. Inr J Gynecol Pathol5: 143-150, 1986 CASE 9 (Ace #27350) DIAGNOSIS: ADENOMA MALIGNUM OF CERVIX (MINIMAL DEVIATION ADENOCARCINOMA) DISCUSSION: In 1963 McKelvey and Goodlin I described the first cases of this tumor in the English language literature in a report of five cases with a generally poor prognosis .. A decade later, a report of five additional cases by Silverberg and Hurt,2 who preferred the term "minimal deviation adenocarcinoma" found that the tumors had a good prognosis. Sixty-five additional examples of adenoma malignum have now been reported. 3-6 The prognosis in some of these • reports has varied markedly,3,4 but the results in the largest series strongly supports the contention that this is a highly aggressive tumor. 6 Some have included cervical endometrioid and clear cell tumors in the category of adenoma malignum. 4, 7 These tumors occasionally have deceptively benign features, but we prefer to restrict the designation "adenoma malignum• to mucinous tumors wjth these features. Clinical Features Adenoma malignum has occurred throughout adult life with an average age of the reported patients of approximately 42 years. Ten to 15% of the patients have had the Puetz-Jeghers syndrome; 60% of such patients have also had ovarian sex cord tumors wjth annular tubules. 8-Jla The most common presenting symptom is menometrorrhagia but a vaginal discharge which is often mucoid is also common, as is postmenopausal bleeding. Positive Pap smears are rare. Occasional patients present because of abdominal swelling as a result of the presence of an ovarian mucinous tumor (see below). As many as 75% of the patients have spread beyond the cervix at presentation (Stage IT-IV). Pathological Features On gross inspection by either the gynecologist or pathologist the cervix usually appears abnormal (typically firm or indurated), but occasional specimens are grossly unremarkable. Sectioning of the cervical wall may show mucoid tissue, and in occasional cases, cysts. The characteristic microscopic feature Is the presence of infiltrating glands, the majority of which are lined by bland appearing columnar mucinous epithelial cells with basally located nuclei exhibiting minimal atypia. The glands are typically deeply invasive, usually into the outer third of the cervical wall, are typically associated with a desmoplastic stromal response, at least focally, and are often irregularly shaped. Although by definition the majority of the tumor must have a well differentiated appearance, minor foci of tumor with a less well differentiated appearance are present in most cases. In the largest study, 6 one-half of the cases were associated with vascular invasion and almost one-sixth with perineural invasion. When silver stains are performed, approximately 40% of the tumors are shown to contained argyrophil cells, a frequency similar to that of cervical adenocarcinomas NOS. 6 Most but not all of the tumors contain cells in which the cytoplasm is positive for carcinoembryonic antigen, although the 45 staining is often only focal. 6 Differential Diagnosis The deceptively benign appearance of the neoplastic cells in adenoma malignum results in frequent difficulties in histological diagnosis. This is illustrated by one study in which biopsies of 9 of 26 patients were misinterpreted as benign; in another case, the tumor was not appreciated, except retrospectively, in a hysterectomy specimen.6 In the distinction of adenoma malignum from abnormally-shaped benign endocervical glands, the presence of a stromal response, which may be desmoplastic or loose and edematous, is very helpful in indicating the infiltrative nature of the glands, although this change is not seen around every neoplastic gland and may be absent in small biopsies. The finding of glands with clearly malignant lining epithelium or vascular or perineural invasion, is obviously helpful. Clinical information such as a gross appearance ~ompatible with carcinoma, a mucoid vaginal discharge or the presence of the Peutz-Jehgers syndrome should increase the suspicion for adenoma malignum. It is possible to misdiagnose several benign glandular lesions as adenoma malignum: this differential diagnosis has been recently reviewed elsewhere. 20 Michael et al5 reported five cases in which abnormal gland contours secondary to mechanical distortion, or rupture of glands with mucin extravasation and entrapment of epithelial cells, were mistaken for evidence of invasion. These changes were usually focal and not present on subsequent biopsy or hysterectomy specimens, emphasizing the importance of repeated biopsies in equivocal cases. Mesonephric remnants, particular! y when hyperplastic, 12 may also be mistaken for adenoma malignum because of their deep location in the cervical wall. However, the glands in mesonephric hyperplasia are usually small and regular in contrast to the large irregular glands of adenoma malignum, are not associated with a stromal response and most importantly, are not lined by mucinous epithelium. Other benign conditions that may be confused with adenoma malignum include tunnel clusters,13 deep Nabothian cysts,l4 and diffuse laminar hyperplasia of tbe endocervical glands. IS Tunnel clusters are characterized by irregularly-shaped dilated glands, which may surround smaller proliferating glands, arranged in lobulated groups.13 In contrast to adenoma malignum, the epithelium in the dilated glands is flattened, the glands are superficially located and they are arranged in lobulated clusters. The designation "deep Nabothian cysts" has been used to refer to the presence of Nabothian cysts deep in the~ cervical waJ1.14 These cysts are lined by mucinous epithelium that is ofte,n flattened and lack an associated stromal response. It is also exceptional for the glands in adenoma maljgnum to be as prominently and extensively dilated as in this condition. Diffuse laminar hyperplasia of the endocervical glands, in contrast to .adenoma malignum. is characterized by a diffuse distribution of closely packed glands, typically appearing as a discete layer sharply demarcated from the underlying stroma, confined to the inner one.-third of the cervical wall. Reactive cytologic atypia was seen in some cases, but significant atypia was absent; a marked inflammatory 4/i response was seen in the majority of the cases. 15 Michael et a15 found immunohistochemical staining for carcinoembryonic antigen (CEA) to be focally positive in all 5 cases of adenoma malignum studied while only areas of reserve cell hyperplasia were positive in five benign lesions. Steeper and Wick16 found that cases of adenoma malignum were all CEA-positive and cases of microglandular hyperplasia were all negative and also concluded that CEA positivity favors a diagnosis of adenocarcinoma in these cases. However, others have found CEA staining of adenoma malignum so focal as to severely limit its diagnostic utility. 6 In a small biopsy composed entirely of glands lined by cytologically bland epithelium, positive cytoplasmic staining for CEA supports a diagnosis of adenoma malignum, but a negative result does not exclude that diagnosis. It should also be noted that even normal endocervical glands may exhibit CEA-immunoreactivity in a glycocalyceal pattern. Behavior As noted earlier, controversy has surrounded the prognosis of adenoma malignum. Only one of the five patients in the series of McKelvey and Goodlin! survived for a long period, whereas four of the five patients in the series of Silverberg and Hurt2 were disease-free for at least three years. The latter authors suggested that the poor prognosis in the early literature was due to inadequate therapy. However, the results of the recent large study support this tumor being very aggressive. Thirteen of 22 patients with follow-up data died of tumor and four others had recurrences;6 only three were disease-free for at least two years. An analysis of 57 cases in the literature followed for at least two years indicates only a 28% survival (all stages); survival is 50% for stage I tumors. A high frequency of mucinous tumors of the ovary in cases of adenoma malignum has recently been apparent.l7-l9 In some of these cases, the ovarian tumors are metastases whereas in others they appear to be independent primaries. Mucinous epithelium has been present in the endometrium in six cases and in the fallopian tubes in three. cases of adenoma malignum. 6 This is probably the result of direct spread from the adenoma malignum in most of the cases, rather than a metaplastic process, alth.ough the latter may explain some cases. 47 REFERENCFS 1. McKelvey JL, Goodlin RR. Adenoma ma!ignum of the cervix. Cancer 16:549-557, 1963. 2. Silverberg SG, Hurt WG. Minimal deviation adenocarcinoma ("adenoma malignum") of the cervix. Am J Obstet Gynecol 123:971-975, 1975. 3. Kaku T, Enjoji M. Extremely well-differentiated adenocarcinoma ("adenoma malignum") of the cervix. lot J Gynecol Pathol 2:28-41 , 1983. 4. Kaminski PF, Norris HJ. Minimal deviation carcinoma (adenoma malignum) of the cervix. lnt J Gynecol Pathol2:141-152, 1983. 5. Michael H, Grawe L, Kraus FT. Minimal deviation endocervical adenocarcinoma: Clinical and histologic features, immunohistochemical staining for carcinoembryonic antigen, and differentiation from confusing benign lesions. lnt 1 Gyoecol Pathol 3:261-276, 1984. 6. Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE. Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases. Am J Surg Pathol 13:717-729, 1989. 7. Young RH, Scully RE. Minimal-deviation endometrioid adenocarcinoma of the uterine cervix. A report of five cases of a distinctive neoplasm that may be misinterpreted as benign. Am J Surg Patholl7:660-665, 1993 8. McGowan L, Young RH, Scully RE. Peutz-Jeghers syndrome with "adenoma malignum" of the cervix. A report of two cases. Gynecol Oncol 10:125-133, 1980. 9. Young RH, Welch WR, Dickersin GR, Scully RE. Ovarian sex cord tumor with annular tubules. Review of 74 cases including 27 with Peutz-Jeghers syndrome and four with adenoma malignum of the cervix. Cancer 50: 1384-1402, 1982. 10. Chen KTK. Female genital tract tumors in Peutz-Jeghers syndrome. Hum Pathol 17:856-861, 1986. II. Kaku T, Hachisuga T, Toyoshima S, Enjoji M, Mori T, Nagaoka M. Extremely well-differentiated adenocarcinoma ("adenoma malignum ") of the cervix in a patient with Peutz-Jeghers syndrome. lnt 1 Gynecol Pathol 4:266-273, 1985. !Ia Choi CG, Kim SH, Kim Jet al. Adenoma malignum of uterine cervix in Peutz-Jeghers syndrome: CT and US features. 1 Comput Assis Tomog 17:819-821, 1993. 12. Ferry JA, Scully RE. Mesonephric remnants, hyperplasia and neoplasia in the uterine cervix. A study of 49 cases. Am J Surg Pathol 14:1100-1111, 1990. 13. Segal GH, Hart WR. Cystic endocervical tunnel clusters. A clinicopathologic study of 29 cases of so-called "adenomatous hyperplasia". Am J Surg Pathol14:895-903, 1990. 14. Clement PB, Young RH. Deep Nabothian cysts of the uterine cervix. A possible source of confusion with minimal-deviation adenocarcinoma (adenoma malignum). lnt J Gynecol Pathol 8:340-348, 1989. 15. Jones MA, Young RH, Scully RE. Diffuse laminar endocervical glandular hyperplasia: A report of seven cases. Am J Surg Pathol 15:1123, 1991 16. Steeper TA, Wiele MR. Minimal deviation adenocarcinoma of the uterine cervix ("adenoma ma!ignum"). Cancer 58:1131-1138, 1986. 17. LiVolsi VA, Merino M1, Schwartz PE. Coexistent endocervical adenocarcinoma and mucinous adenocarcinoma of ovary: A clinicopathologic study of four cases. Int 1 Gynecol Pathol1:391-402, 1983. 18. Kaminski PF, Norris HJ. Coexistence of ovarian neoplasms and endocervical adenocarcinoma. Obstet Gynecol 64:553-556, 1984. 19. Young RH, Scully RE. Mucinous tumors of the ovary associated with mucinous adenocarcinomas of the cervix. A clinicopathologic analysis of 16 cases. Int J Gynecol Pathol 7:99-111, 1988. 20. Young RH, Clement PB. Pseudoneoplastic glandular lesions of the uterine cervix. Semin Diagn Pathol 8:234-249, 1991. CASE 10 (Ace #27352) DIAGNOSIS: SEROUS PAPILLARY ADENOCARCINOMA OF TilE ENDOMETRIUM DISCUSSION: Clinical Features Although papillary carcinomas of the endometrium resembling serous carcinomas of the ovary had been described sporadically in the literature over the past 25 years, it was not until 1981 and 1982 that Lauchlan7 and Hendrickson et al,l respectively, drew major attention to these tumors (SPECs). SPECs accounted for 10% of pathologic stage I carcinomas in the series of the latter authors, although as noted below, some tumors in that study might have been interpreted as pllpillary clear cell carcinomas by other authorities.! In other centers the frequency has varied from 1.1 to 7.8%.2-4,6,8-10 The presenting clinical features of the patients with SPECs are in general similar to those with typical endometrial carcinoma, although some differences have been noted.1-33 The patients tend to be a decade older (mean age late sixties to early seventies) than patients with typical endometrial carcinoma,1,2,8,10,19 are less apt to have a history of estrogen use,l,21 and are more likely to have an abnormal Papanicolaou smear, which may contain psammoma bodies.l,5,9,28 One study has noted a higher frequency in blacks.2 The patients typically present with postmenopausal bleeding, but occasionally a serous or serosanguinous vaginal discharge is the initial manifestation of the disease.7,12 Some tumors may be a late complication of pelvic radiation: in one study, three of eight cases of postradiation endometrial carcinomas were SPECs. 21 In another series of six postradiation SPECs, the mean interval between the radiation and the development of the SPEC was 16.1 years (range, 4 to 25 years).31 Patients with SPEC frequently present with high stage disease: in some of the earlier studies, as many as 25% had clinical stage Ill or IV tumors at the time of diagnosis,2 with this figure rising as high as 75% if intraoperative findings are considered (surgicopathological stage).2,3,6,8,12,16,17,21 ,33 When lymph node dissections are performed, the pelvic and para-aortic lymph nodes are involved in 25 to 57% of the cases.ll,l3, 19,20 Intraoperative peritoneal washings contain malignant cells in 35 to 75% of the cases. 6,8,9, 19,20 The serum CA 125 level may be elevated at presentation and may be useful in monitoring the effects of therapy.5,23 Elevations of serum carcinoembryonic antigen (CEA), l8 alpha-fetoprotein (AFP), 29 NB/70K, 23 and lipid-associated sialic acid23 have also been reported. Pathological Features On gross examination, SPECs do not differ significantly from typical endometrial carcinoma except that the uterus may be small and atrophic in the l)resence of extensive myometrial and myometrial lymphatic involvement. I On histological examination, SPECs resemble ovarian serous carcinomas, and are characterized by a complex papillary pattern composed of papillae with thin (or rarely broad) fibrovascular stalks that are covered by stratified epithelial cells 49 associated with cellular buds. The tumor cells and cellular buds may also line irregular slit-like glandular spaces, and occasionally such a pattern may predominate. The tumor cells are usually high grade with nuclear pleomorphism, hyperchromasia, macronucleoli and frequent mitotic figures. Hobnail-type cells and giant cells with bizarre nuclear features may be present. Psammoma bodies have been observed in I 0 to 59% of cases.! ,33 Tumor necrosis is frequent. In occasional cases, SPECs appear to arise within an endometrial polyp, and may be confined to it or invade the underlying myometrium.25,30,33 SPECs may be admixed with other types of endometrial carcinoma, including endometrioid (typical and villoglandular forms) and clear cell carcinoma. 30,33 In contrast to endometrioid adenocarcinomas which are frequently associated with endometrial hyperplasia elsewhere in the same uterus, the endometrium uninvolved by SPEC was atrophic in over 90% of the cases in one study ,33 Microscopic examination reveals a high frequency of local invasion, metastasis, or both, manifested by deep myometrial invasiol\ in 40 to 70% of the casesl ,5,8,19 and permeation of myometrial lymphatics in 37 to 87% of the cases.1,5, 16 The lower uterine segment, cervix, adnexa, and peritoneal surfaces are more commonly involved than by endometrioid carcinomas.! Cervical and adnexal involvement is often within lymphatics and is often inapparent grossly. The papillary pattern is typically preserved in the invasive and metastatic tumor. Changes suggestive of in situ serous papillary carcinoma have been noted on the surface of the endometrium, endocervix, endosalpinx, omentum, and ovary, 1, 12,20,25,30,33,34 although it is unclear if these findings reflect luminal and peritoneal spread of exfoliated tumor cells or multicentric neoplasia. Because of the high frequency of microscopic involvement of the myometrium, cervix, and adnexa, extensive pathological sampling of these areas should be performed. SPECs do not differ significantly from other endometrial carcinomas on immunohistochemical examination32 and do not have distinctive ultrastructural features.l4 A high frequency of aneuploidy,24,35 C-myc amplification,24 and p53 expression have been found in SPECs. Behavior and Management SPECs have a much worse prognosis than typical endometrial carcinoma, and are more aggressive than even poorly differentiated and deeply invasive examples of the latter. In the series by Hendrickson et al, 50% of the patients with surgical stage I tumor had a relapse, a frequency five times that of patients with endometrioid endometrial adenocarcinoma. I Although SPECs accounted for only 10% of the surgical stage I endometrial carcinomas in that study, they accounted for 50% of the cases with relapse, with 6 of 7 cases with relapse in the upper abdomen. Only 15% of the patients with higher stage disease were alive with no evidence of tumor at the time of the last follow-up examination. In another series of SPECs, 10 the 5 and 10 year survival rates were 27% and 14% respectively. In additional series, overall survival rates have been 27%8 and 34%,6 and for surgical stage I tumors, 33%16 and 47%.6 One study 50 found tllat when a SPEC is admixed with another histologic subtype and accounts for at least 25% of tlle tumor, the tumor typically behaves as a pure SPEC.33 However, we have seen occasional otherwise typical or villoglandular endometrioid adenocarcinomas tllat contained only microscopic foci of SPEC in which the latter component extensively invaded myometrial lymphatics, and we therefore suspect that any component of SPEC in a mixed carcinoma may adversely affect the prognosis. Further studies are needed to clarify this problem. Altllough an absence of myometrial invasion has been a good prognostic factor in some series, I, 21 tumors that were apparently confined to the endometrium or an endometrial polyp were associated with peritoneal spread at presentation or on follow-up in other studies.25,30,33,34 These observations may reflect, as noted earlier, multicentric origin of tumor or, more likely in our opinion, transtubal spread of tumor. In the study by Sherman et al, tumors with vascular invasion were more commonly associated with extrauterine dissemination than tumors lacking this feature (84 vs 56%).33 Occasional patients with clinical or pathologic stage I disease may have a recurrence outside the pelvis and abdomen.l7 ,21 Because SPECs exhibit a propensity to spread transperitoneally in a manner similar to that of surface epithelial carcinomas of the ovary, it has been recommended that if the diagnosis is made by curettage, peritoneal washings, inspection of the peritoneum including that of the upper abdomen, biopsy of suspicious lesions, sampling of para-aortic lymph nodes (which may harbor microscopic tumor in the absence of grossly evident extrauterine tumorS), and omentectomy should be performed at the time of hysterectomy. Grossly evident extrauterine disease should be resected as completely as possible. Current postoperative treatment recommendations include adjuvant abdominopelvic irradiation for stage I cases witll any degree of myometrial invasion; one recent study27 has suggested the irradiation should also be given to the vaginal apex to decrease the risk of recurrence at this site. In some centers, chemotherapy is also added to the treatment regimen.21 Complete, but often only temporary, remission after combination chemotherapy has been observed in some patients with higher stage disease.l5,18 As noted above, because patients with no demonstrable myometrial invasion may also experience recurrence, there may be a role for similarly aggressive treatment in these patients. Differential Diagnosis Involvement of the uterine corpus by a serous carcinoma arising in other sites, especially the ovary and fallopian tube, should be excluded before rendering a diagnosis of SPEC. With respect to cases with synchronous ovarian involvement, the tumor was considered a SPEC in the Stanford series only when the dominant disease was in the uterus and the ovarian involvement was confined to lymphatics within the hilus or was limited to microscopic disease within the cortex as part of widespread peritoneal disease.l The differential diagnosis of SPEC also includes villoglandular endometrioid carcinoma (VGEC), which in contrast to SPECs, are characterized by an orderly pattern composed of villus-like papillae and glands lined by a pseudostratified layer of columnar cells that usually have low-grade nuclear features and form 51 few or no cellular buds. The complex papillarity, the marked cellular stratification, and the high-grade nuclear features of SPECs are absent. Clear cell carcinomas may be papillary, and when accompanied by high-grade nuclear features, have an appearance that overlap with that of SPECs. Indeed, one-third of the SPECs in two series contained foci of clear cells,l,33 and the authors of one of these studies I indicated that some of these tumors would be regarded as clear cell carcinomas by other investigators. The presence of papillae with hyalinized cores, a tubulocystic pattern and a prominent component of clear cells or hobnail cells, or combinations thereof, strongly support or are diagnostic of a diagnosis of clear cell carcinoma. Psammoma bodies may occur in both tumors, but are more common in SPECs. In some cases, the distinction between the two tumors may be arbitrary. As both tumors have a similar behavior, their histologic distinction is not crucial. Finally, SPECs should be distinguished from •papillary syncytial metaplasia". This distinction should not be problematic as this type of metaplasia is typically a microscopic finding confined to the endometrial surface, and is characterized by the presence of cytologically bland cells, and is generally considered a regenerative phenomenon in a late menstrual or postcurettage endometrium. REFERENCES I. Hendrickson MR, Ross J, Eifel P, Martinez A, Kempson R: Uterine papillary serous carcinoma. A highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol 6:93-108, 1982 2. Chen JL, Trost DC, Wilkinson EJ: Endometrial papillary adenocarcinomas: Two clinicopathological ty~s. Int J Gynecol Pathol 4:279-288, 1985 3. Sutton GP, Brill L, M1chael H, Stehman FB, Ehrlich CE: Malignant papillary lesions of the endometrium. Gynecol Oncol 27:294-304, 1987 4. Burke TW, Heller PB, Woodward JE et al: Treatment failure in endometrial carcinoma. Obstet Gynecol 75:96-101, 1990 S. O'Hanlan KA, Levine PA, Harbatkin D et al: Virulence of papillary endometrial carcinoma. Gynecol Oncol37:112-119, 1990 6. Ward BG, Wright RG, Free K: Papillary carcinomas of the endometrium. Gynecol Oncol 39:347-351, 1990 7. Lauchlan SC: Tubal (serous) carcinoma of the endometrium. Arch Pathol Lab Med 105:615-618, 1981 8. Jeffrey JF, Krepart GV, Lotocki RJ: Papillary serous adenocarcinoma of the endometrium. Obstet Gynecol 67:670-674, 1986 9. Kuebler DL, Nikrui N, Bell DA: Cytologic features of endometrial papillary serous carcinoma. Acta Cytol 33:120-126, 1989 10. Abeler VM, Kjorstad KE: Serous papillary carcinoma of the endometrium: A histopathological study of 22 cases. Gynecol Oncol 39:266-271, 1990 II. Burrell MO, Franklin EW, Powell JL: Endometrial cancer: Evaluation of spread and follow-up in one hundred eight-nine patients with stage I or stage II disease. Am J Obstet Gynecol 144:181-185, 1982 12. Walker AN, Mills SE: Serous papillary carcinoma of the endometrium. A clinicopathological study of II cases. Diagn Gynecol Obstet 4:261-267, 1982 13. Chen SS, Lee L: Retroperitoneal lymph node metastases in stage I carcinoma of the endometrium: Correlation with risk factors. Gynecol Oncol 16:319-325, 1983 14. Sato N, Mori T, Orenstein JM, Silverberg SG: Ultrastructure of papillary serous carcinoma of the endometrium. Int J Gynecol Pathol 2:337-348, 1984 15. Fitzgerald D, Rosenthal S: Uterine papillary serous carcinoma. Complete response to combination chemotherapy. Cancer 56:1023-1024, 1985 52 16. Chambers IT, Merino M, Kohom EI et al: Uterine papillary serous carcinoma. Obstet Gynecol69:109-113, 1987 17. Christman JE, Kapp DS, Hendrickson MR eta!: Therapeutic approaches to uterine papillary serous carcinoma: A preliminary report. Gynecol Oncol 26:228-23:5, 1987 18. Fukuma K, Miyarnura S, Thoya T eta!; Uterine papillary serous carcinoma with high levels of serum carcinoembryonic antigen. Response to combination chemotherapy. Cancer 59:403-405, 1987 19. Rarnirez-Gonzalez CE, Adamsons K, Mangual-Vazquez TY, Wallach RC: Papillary adenocarcinoma in the endometrium. Obstet Gynecol 70:212-215, 1987 20. Bitterman P, Potkul RK , Lewandowski GS, Kurman RJ: Papillary serous carcinoma of the endometrium and ovary: A comparative study of 40 cases. Lab Invest 58: lOA, 1988 21. Gallion HH, Van Nagell JR Jr, Powell DF eta!: Stage I serous papillary carcinoma of the endometrium. Cancer 63:2224-2228, 1989 22. Rosenberg P, Risberg B, Askmalm L, Simonsen E: The prognosis in early endometrial carcinoma. The importance of uterine papillary serous carcinoma (UPSC), age, FIGO grade and nuclear grade. Acta Obstet Gynecol Scand 68:157-163, 1989 23. Tseng PC, Sprance HE, Carcangiu ML eta!: CA 125, NBnOK, and lipid-associated sialic acid in monitoring uterine papillary serous carcinoma. Obstet Gynecol 74:384-387, 1989 24. Sasano H, Comerford J, Willdnson DS et al: Serous papillary adenocarcinoma of the endometrium. Analysis of proto-oncogen amplification, flow cytometry, estrogen and progesterone receptors, and immunohistochemistry. Cancer 65: 1545-1551, 1990 25. Silva EG, Jenkins R: Serous carcinoma in endometrial polyps. Mod Pathol 3: 120-128, 1990 26. Wilson TO, Podratz KC, Gaffey T A et al: Evaluation of unfavorable histologic subtypes in endometrial adenocarcinoma. Am I Obstet Gynecol 162:418-426, 1990 27. Frank AH, Tseng PC, Haffty BG et al: Adjuvant whole-abdominal radiation therapy in uterine papillary serous carcinoma. Cancer 68:1516-1519, 1991 28. Kern SB: Prevalence of psammoma bodies in Papanicolaou-stained smears. Acta Cytol 35:81-, 1991 29. Kubo K, Lee G, Yamauchi K, Kitagawa T: Alpha-fetoprotein-producing adenocarcinoma orignating from a uterine body. Acta Pathol Jpn 41 :399-403, 1991 30. Lee KR, Belinson JL: Relationship to noninvasive endometrial carcinoma. Relationship to uterine papillary serous carcinoma. Am J Surg Pathol 15:965-973, 1991 31. Parkash V, Carcangiu ML: Uterine papillary serous carcinoma after radiation therapy for carcinoma of the cervix. Cancer 69:496-501, 1992 32. Swanson PE, Wick MR, Mills SE: Serous papillary endometrial carcinoma. An immunohistochemical comparison with endometrioid carcinoma. Mod Pathol4:62A, 1991 33. Sherman ME, Bitterman P, Rosenshein NB et al: Uterine serous carcinoma. A morphologically diverse neoplasm with unifying clinicopathologic features . Am I Surg Pathol 16:600-610, 1992 34. Lee KR, Belinson JL: Papillary serous adenocarcinoma of the endometrium: A clinicopathological study of 19 cases. Gynecol Oncol 46:51, 1992 35. Rosenberg P, Wingren S, Simonsen E eta!: Flow cytometric measurements of DNA index and S-phase on paraffin-embedded early stage endometrial cancer. An important prognostic factor. Gynecol Oncol 35:50, 1989 53 CASE II (Ace #261U) DIAGNOSIS: UTERINE TUMOR RESEMBLING OVARIAN SEX-CORD TUMOR DISCUSSION: We have applied the term "uterine tumor resembling ovarian sex-cord tumor" (UTROSCI') to a heterogeneous group of rare neoplasms characterized by pure or prominent microscopic patterns that resemble those of ovarian sex-cord tumors (granulosa cell and Sertoli ceU tumors).l-10 Several tumors reported as "granulosa cell tumors• of the uterus belong in this category.ll,12 The histologic appearance of these neoplasms merges almost imperceptibly with that of endometrial stromal tumors exhibiting less than predominant epithelial differentiation. Clinical Features The patients are in the reproductive and postmenopausal age groups, with an age range of 16 to 73 years (mean, 47 years)lO The presenting clinical manifestations are usually abnormal vaginal bleeding, uterine enlargement ascrib~ to "fibroids" or a pelvic mass, or both; occasional patients have had pelvic pain or discomfort or have been asymptomatic. Unique presentations have included uterine rupture, tumor prolapse through the externa.l os, and masculinization.lO In approximately 25% of the cases, tumor tissue has been obtained by curettage, biopsy, or polypectomy prior to hysterectomy; rarely, no residual tumor has been found in the hysterectomy specimen in these cases.lO At the time of hysterectomy, the tumors are almost invariably confined to the uterus (Stage I). Extrauterine tumor, however, has been documented intraoperatively in four patients, involving bowel, ovary, omentum, and liver, alone or in combination .1 0 One of these four patients had serosal involvement by the primary tumor, a finding that was present in three additional cases that were not associated with extrauterine spread. Gross Appearance On gross examination, UTROSCTs are generally solid, round, well-circumscribed myometrial masses that range from 0.7 em to 20 em in diameter (mean, 5.7 em); rare tumors have been predominantly cystic. I, 10 Occasional tumors have had infiltrative margins or foci of vascular invasion that were macroscopically visible.IO UTROSCTs are usually mural, but are occasionally submucosal or subserosa!; the submucosal and subserosa! tumors may be polypoid, and in such cases, focal hemorrhage is sometimes encountered within them. Rare tumors have been located predominantly within the endometrium or endocervix. The cut surfaces are often yellow, but occasionally grey to tan , and are soft, fleshy and homogeneous without the whorled pattern of a leiomyoma. Microscopic Appearance The cardinal feature of UTROSCTs on microscopic examination is a variety of epithelial and stromal patterns that create a resemblance to those of ovarian sex-cord tumors, especially granulosa cell and Sertoli cell tumors. ln the largest series of UTROSCTs (92 cases), the tumors were separated into two groups. IO Group I (25 cases) was characterized by a 54 predominant component of cells resembling endometrial stromal or smooth muscle cells and a minor component (10 to 50%) of sex-cord-like elements (SCLEs), whereas in Group II tumors (67 cases), the latter component predominated. Almost 60% of Group I tumors and 10% of Group II tumors had an infiltrating border similar to that of low-grade endometrial stromal sarcomas (ESSs), despite being grossly well demarcated.10 The SCLEs typically consist of, alone or in combination, anastomosing cords one to two cells in width or broader trabeculae, small nests, and sertoliform tubular structures. Call-Exner-like bodies were found in 8% of Group I tumors and 17% of Group II tumors. The epithelial-like cells within the SCLEs vary from small, round and regular with scanty cytoplasm to large with abundant eosinophilic, clear, or foamy cytoplasm that is often lipid-rich. The nuclei are generally small and regular with little pleomorphism and indistinct nucleoli. Nuclear grooves are rare or absent and mitotic figures are typically scarce. The stroma ranges from scanty to ab~ndant and from moderately cellular to hypocellular and hyalinized. Twelve percent of Group I tumors and 22% of the Group II tumors in the series cited above were considered to have a stromal component of smooth muscle, characterized by bundles of cells with elongated nuclei, and occasionally cells with ample eosinophilic cytoplasm resembling the cells of typical and epithelioid smooth muscle tumors, respectively.10 Leydig cell-like or theca cell-like differentiation has not been observed in UTROSCTs, although lipid-laden stromal cells of questionable origin have been present in some cases.5,10 Vascular invasion was observed in 32% of Group I tumors and 19% of Group II tumors.lO In one immunohistochemical study of UTROSCTs, the majority of the tumors were immunoreactive for both mesenchymal and epithelial markers.9 The SCLEs were immunoreactive for vi men tin in all the cases, for cytokeratin in 55% of the cases, for EMA in 10% of them, and for desmin in 43% of them.9 Other immunohistochemical studies of SCLEs in UTROSCTs (and ESSs) have also reported frequent immunoreactivity for smooth muscle antigens.l3-15 Ultrastructural study of one tumor revealed cells with features of both endometrial stromal and smooth muscle cells, 2 and in another case, cells with desmosomes, tonofilaments and microvilli lining glandular spaces. 5 Histogenesis Because of the close resemblance of these tumors to ovarian sex-cord tumors, a possible origin from displaced ovarian tissue has been considered. However, the neoplastic cells lack the characteristic pale nuclei with grooves and typical Call-Exner body formation of ovarian granulosa cell tumors, and with one exception, lO there has been no clinical evidence of endocrine function in the reported cases. In one case, however, structures resembling Charcot-Bottcher filament-bundles, characteristic inclusions of testicular Sertoli cells, were enigmatically present. 7 The histologic heterogeneity of these tumors suggests the possibility of more than a single cell of origin. The content of endometrial stromal-type cells in some of the tumors and the similarity of the SCLEs to those seen focally in otherwise typical endometrial 55 stromal tumors strongly support a derivation from endometrial stromal cells in most cases. Similarly, the content of smooth muscle cells in some UTROSCTs and the plexiform pattern in some cases, which may be similar to that seen in epithelioid smooth muscle tumors and plexiform tumorlets, favor a smooth muscle origin in other cases.16,17 Some UTROSCTs may represent combined smooth muscle-endometrial stromal tumors ("stromomyomas").2,13 Behavior Most UTROSCTs are clinically benign. In the study cited above, recurrent tumor developed in ten patients (15%) at an average of 6 ye 56 CASE 12 (Ace 1127235) DIAGNOSIS: EXTRAUTERINE MESODERMAL ADENOSARCOMA DISCUSSION: As the vast majority of adenosarcomas in the female genital tract involve the uterus ("mullerian" adenosarcomas), tumors in the latter site will be the major focus of this discussion, concluding with a briefer discussion of similar, but extrauterine, tumors ("mesodermal" adenosarcomas). Mullerian adenosarcomas are much less common·than malignant mullerian mixed tumors (MMMTs; carcinosarcomas); approximately 275 uterine adenosarcomas have been reported in the literature.l-62 The term "adenofibroma" or a variation thereof has been applied to approximately 10% of them, and "adenosarcoma" to most of the remainder. In some studies, however, the two tumors have been referred to collectively as "benign and low-grade variants of mixed mullerian tumors•22 or as uterine "cystosarcoma phyllodes" ,23 terms that reflect uncertainty regarding prognostic factors in patients with these tumors. Clinical Features The tumors usually occur in postmenopausal women; the median age of patients with adenosarcoma in the largest series was 58 years. 54 In contrast to MMMTs, however, approximately 30% of adenosarcomas are found in patients under 50 years of age, and 11 cases have occurred in the second decade. The occasional association of adenosarcomas with hyperestrinism (exogenous estrogen, ovarian thecoma, Stein-Leventhal syndrome)54 or prior pelvic radiation54 suggests their possible etiologic role in some cases. Tamoxifen therapy may have played a role in the development of an adenosarcoma from an adenomyoma in one recently described case. 61 The most common symptom is abnormal vaginal bleeding, often accompanied by lower abdominal or pelvic pain. Pelvic examination typically reveals an enlarged uterus, and in about half the cases, tumor protruding through the external os. The diagnosis can frequently be made prior to hysterectomy by biopsy or dilatation and curettage. Patients with typical adenosarcomas are almost always stage I at presentation, and the presence of extrauterine tumor suggests multicentricity (see below) or metastases from an adenosarcoma with sarcomatous overgrowth. 51,60 lt is noteworthy that occasional patients have presented on two or more occasions with lesions misinterpreted microscopically as benign polyps. 54 The most striking example of this type of presentation was the case of a patient who underwent II curettages over a ?-year period for recurrent polyps that were subsequently reinterpreted as adenosarcoma. 25 Recurrent endocervical or endometrial polyps are uncommon, particularly in young women, and their occurrence should therefore suggest the possibility of adenosarcoma. Gross Appearance Adenofibromas and adenosarcomas form typically polypoid, but sometimes villous masses that are usually broad-based, but occasionally their mucosal attachment is by a narrow stalk. 57 Almost 90% of them arise from the endometrium and frequently fill the endometrial cavity; prolapse of the tumor through the external os is common. Approximately 10% of the tumors originate in the endocervix.l,6,18,27 ,29,54 In rare cases, both the corpus and endocervix are involved by separate primary tumors, 54 or the tumor may be confined to the myometrium without mucosal involvement. 40,54 The cut surface is frequently spongy, with by cystic spaces filled with a watery or mucoid fluid, surrounded by white to tan tissue. Myometrial invasion, which is present in approximately one-sixth of adenosarcomas of mucosal origin, may be appreciable on gross examination of the hysterectomy specimen. As noted above, rare cases with extraovarian adenosarcoma (ovary, cul-de-sac) at presentation may represent multicentric origin rather than metastatic tumor.54 Microscopic Appearance Adenofibromas and adenosarcomas have an epithelial component characterized by glands that are frequently cystically dilated and that are scattered regularly or irregularly throughout the mesenchymal component of the tumor. Occasional tumors have a villous pattern, with the neoplastic epithelium lining thin papillae or broad polypoid fronds, and only a minor component of glands. The glands are lined by a variety of benign or atypical mullerian epithelia, most commonly of proliferative-endometrial type, although endocervical (mucinous), tubal (ciliated), secretory-endometrial (with subnuclear vacuoles), hobnail, or indifferent epithelia may also be seen. Metaplastic squamous epithelium, typically nonkeratinizing, is often present and may fill the gland lumens. In approximately one-third of adenosarcomas, the glandular epithelium exhibits foca.l architectural or cytological atypia, and small foci of endometrial adenocarcinoma have been rarely encountered in otherwise typical adenosarcomas2,33,54 and even adenofibromas. 2,62 In such cases, the endometrium elsewhere in the uterus may be atypically hyperplastic or carcinomatous.26,43,54 The commonly observed mitotic activity of the epithelial component, which is often in contrast to the inactivity or atrophy of the glandular epithelium of the adjacent endometrium, the variety of epithelial cell types, the extensive distribution of glands throughout the stromal component and the occasional presence of glands within recurrent adenosarcoma are evidence of the neoplastic nature of the epithelial component of the tumor. The stromal component of the adenofibroma has a benign appeara11ce on histologic examination, with a composition of cells resembling fibroblasts or endometrial stromal cells. These cells exhibit no or minimal nuclear pleomorphism and are mitotically inactive (see belo~). Smooth muscle may be present focally in the stroma, but heterologous elements have not been described. The degree of stromal ceiJularity can vary widely from tumor to tumor or from one area of a tumor to another, depending on the amount of intercellular collagen, although the stroma is typically less cellular than that of an adenosarcoma and typically lacks the periglandular condensation characteristic of the latter. In contrast, the stromal component of the adenosarcoma typically has the appearance of a 58 low-grade sarcoma, usually an endometrial stromal sarcoma, fibrosarcoma, or combinations thereof. 54 Minor foci of smooth muscle differentiation of typical or epithelioid type have been encountered in occasional cases. 28,54 In one recently reported case, the stromal component of an adenosarcoma consisted exclusive! y of angiosarcoma. 58 The stromal cells exhibit nuclear atypia that is usually mild or moderate, but occasionally marked. Stromal mitotic figures are an almost constant finding, and >80% of tumors exhibit a mitotic rate of 4 or more per 10HPF.54 The mitotic rates are highly variable from one tumor to another, however, with a range of 1 to 40 MF/lOHPFs (mean 9) in the largest series in the literature. 54 Characteristically the stroma is more cellular around the glands, creating a cuff-like appearance, and intraluminal polypoid or papillary stromal projections are common. The stroma at a distance from the glands is often less cellular, and in some tumors, the stroma is composed predominantly of sparsely cellular, myxoid or hyalinized fibrous tissue, imparting a deceptively benign appearance to large areas of the tumor. Approximately 20% of adenosarcomas contain heterologous elements, which have varied from minor foci of fat, cartilage, or rhabdomyoblaslS to embryonal rhabdomyosarcoma occupying most or all of the stroma.54,60 Some of the cases with the latter type of stroma have also contained nodules of fetal-type cartilage54 similar to those occurring in some cases of embryonal rhabdomyosarcoma of the vagina and cervix. One adenosarcoma contained stromal elements suggestive of neuroepithelial differentiation.l3 Adenofibromas are usually noninvasive, but three examples have invaded the endocervical wall or the myometrium, and in one of them, myometrial vessels were also invaded.22,55 Approximately one-sixth of adenosarcomas invade the myometrium, although in only 20% of such cases does the invasion extend beyond the inner one-half of the myometrium. 54 The invasive borders are usually well-circumscribed but occasional tumors invade in irregular tongues. Rare adenosarcomas invade myometrial vessels in a pattern similar to that of low grade endometrial stromal sarcoma. 54 Occasional adenosarcomas are focally overgrown by the stromal component ("mullerian adenosarcoma with sarcomatous overgrowth)" (MAS0).51,60 In one series of ten cases, a pure homologous sarcoma, typically of higher grade and with a higher mitotic rate than those of the associated adenosarcoma, focally replaced the tumor. 51 In contrast to typical adenosarcomas, myometrial invasion was present in six of the ten cases, reaching the serosa in three of them. Pure sarcoma occupied at least 25% of the tumor volume in the reported cases. MASOs accounted for less than 10% of adenosarcomas in one series of consultation cases51,54 but for 55% of adenosarcomas in another series based on a gynecologic oncology group (GOG) study. 60 The MASOs in the GOG study were also associated with a much higher frequency of myometrial (and lymphatic) invasion than in cases of typical adenosarcoma. 60 In contrast to the other series of MAS0s,51 the pure sarcoma in almost 60% of the MASOs in the GOG study consisted of a prominent component of rhabdomyosarcoma. A second type of stromal proliferation in adenosarcomas was documented in a series of eight 59 adenosarcomas that contained foci of sex cord-like elements (SCLEs) within their stromal component;52 two other similar cases have been reported.44 ,59 The SCLEs, which accounted for 5-50% of the tumors, were composed of benign-appearing cells of epithelial type that were arranged in solid nests, trabeculae, and solid or hollow tubules. The cells often contained abundant eosinophilic or foamy, lipid-rich cytoplasm. The appearance of the SCLEs was similar to that of those encountered in some endometrial stromal tumors and in the rare uterine tumors resembling ovarian sex cord tumors. Criteria for Distinguishing Adenofibromas and Adenosarcomas The histologic dividing line between adenofibromas and adenosarcomas has not been clearly established. Zaloudek and Norris have stated that the stromal mitotic rate is the most reliable criterion in the differential diagnosis. 28 Because all the clinically malignant tumors in their series of cases had stromal mitotic counts of 4 or more MFs/10 HPFs, they concluded that only tumors with that degree of mitotic activity ~hould be designated adenosarcomas. Four of the 10 clinically malignant adenosarcomas in their series, however, had mitotic rates of only 4 or 5/lOHPF; the difference between such counts and a "benign" count of 3 MF/ 10 HPF is within interobserver variation. Also, counting mitotic figures in these tumors may be difficult because of variations in cellularity; in some cases, for example, the mitotically active areas are confined to thin rims around the glands. Finally, those authors reported a five-year follow-up on only 4 of the 10 tumors they designated as adenofibromas, all of which were treated by hysterectomy. Even a five-year follow-up is inadequate to evaluate the behavior of these tumors since adenosarcomas often recur betweeen 5 and 10 years postoperatively. We have encountered in our series, 54 as well as in the literature, 33 a number of tumors with 2 or 3 MF/ IOHPF and extrauterine disease at the time of presentation or that recurred after hysterectomy. Thus it appears that almost any measurable degree of stromal mitotic activity in these tumors can be associated with a malignant behavior. We currently diagnose as adenosarcoma tumors with 2 or more MF/IOHPF, a mitotic rate that will detect almost all tumors with a malignant potential. Because rare essentially amitotic tumors with marked stromal cellularity, stromal atypia or both have recurred after hysterectomy, we also consider tumors with these features low-grade adenosarcomas. If these criteria are applied, adenofibromas account for only 5% of tumors in tbe adenofibroma-adenosarcoma group, and the former diagnosis is rendered only after the tumor has been extensively sampled to exclude foci exhibiting mitotic activity, marked cellularity, or stromal cell atypia. This evaluation usually requires hysterectomy. Differential Diagnosis The differential diagnosis of adenofibroma and adenosarcoma include benign endomet.rial polyps as well as other tumors characterized by a mixture of epithelial and mesenchymal elements. In endometrial polyps, the stroma may resemble that of the adjacent endometrium or may be less cellular and often sclerotic. If its stromal component is unusually cellular or 60 mitotically active, if its glandular cells differ in appearance from those of the adjacent endometrium, or if periglandular cuffing or intraglandular stromal papillae are present, the diagnosis of adenosarcoma should be seriously considered. Polypoid adenomyomas are distinguished from adenofibromas by their predominent component of smooth muscle and typical absence of intraglandular papillae, and the former lesions lack the stromal cellularity, mitotic activity, and atypia of adenosarcomas. The atypical polypoid adenomyoma has a stromal component that consists predominantly of fascicles of benign, cellular smooth muscle, which may show mitotic activity, and a glandular component that is less cystic and generally more atypical than that of an adenosarcoma and usually contains prominent numbers of squamous morules. Occasional MMMTs have foci in which the glandular component lacks frankly malignant features, but most of the glands are frankly carcinomatous and focally confluent. Endometrial stromal sarcomas typically lack the integral glandular component of the adenosarcoma, although their periphery may contain occasional entrapped glands, or in a minority of cases, there may be focal prominent glandular differentiation within the tumor. Unlike adenosarcomas, endometrial stromal sarcomas typically have highly infiltrative borders with extensive myometrial and vascular penetration. A final consideration in the differential diagnosis of adenosarcoma is the very rare uterine Wilms' tumor. Behavior Tumors fulfilling our criteria for adenofibroma are associated with a benign postoperative course, although they may recur after local excision.22 Similarly, the follow-up was uneventful at the time of reporting in the three cases of invasive adenofriboma referred to above.22,55 In contrast to MMMTs, adenosarcomas typically have a low malignant potential, manifested primarily by vaginal or abdominopelvic recurrence in approximately one-quarter of the cases; hematogenous spread occurs in less than 5%.28,54 Even in the clinically malignant cases, the recurrent tumor has often been indolent. In one-third of cases with recurrences in one large series, the recurrent tumor appeared 5 or more years after hysterectomy, and rare tumors recurred 10 or more years after hysterectomy. 54 Longterm clinical follow-up is therefore essential in these patients. The recurrent tumor has been a pure sarcoma in 70% of the cases, an adenosarcoma in almost 30%, and a carcinosarcoma in a single case. 54 Rarely recurrent tumor has contained heterologous elements or foci of carcinoma that were not present in the primary tumors. 54 Blood-borne metastases have been pure sarcomas. The mitotic rate and grade of the recurrent tumor may be lower than, similar to, or in one-half the cases, higher than those of the original adenosarcoma. In some of the cases in which the initial recurrence was an adenosarcoma, subsequent recurrences have been pure sarcomas. The risk of recurrence in adenosarcomas correlates with the presence of myometrial invasion.28,54,60 In the largest literature series, the risk of recurrence in the absence of invasion was 12.7% and the risk in the presence of invasion 46%.54 Although such cases are rare, there is a suggestion that the risk for recurrence may be even higher in tumors with deep 61 28 54 58 myometrial invasion. • • The only other feature that correlates with an increased risk of recurrence is sarcomatous overgrowth.51 ,60 In the aforementioned study of 10 cases of adenosarcomas with sarcomatous overgrowth, recurrent tumor, hematogenous mewtases, and death from tumor occurred in 70%, 40%, and 60% of patients, respectively.51 Corresponding figures for recurrence and death from tumor in the GOG series of adenosarcomas with sarcomatous overgrowth were 44% and 31%.60 Two of 17 tumors with sarcomatous overgrowth in that study were also associated with pelvic lymph node metastases. As already noted , the areas of sarcomatous overgrowth accounted for at least 25% of the tumor volume in these series, but it was noted in another study that even smaller foci ofpure high-grade sarcoma may indicate an increased likelihood of aggressive behavior. 54 Adenosarcomas with sarcomatous overgrowth therefore have a malignant potential similar to that of other high grade uterine sarcomas such as MMMT and leiomyosarcoma. When tumors fulfilling the criteria pr~nted above for adenofibroma are excluded, the stromal mitotic rate does not appear to be of prognostic importance. The presence of heterologous elements was not associated with an increased risk of recurrence in one large study of typical adenosarcomas. 54 Extensive rhabdomyosarcomatous differentiation was accompanied by a higher rate of recurrence in another srudy, but all such tumors also had sarcomatous overgrowth by the rhabdomyosarcoma.60 Treatment In young patients with endometrial or endocervical adenofibromas, in whom the preservation of fertility is a consideration, local excision by curettage or polypectomy may be curative. 54 It is important, however, that the specimen be thoroughly examined to exclude adenosarcoma, and that the patient be followed closely for evidence of local recurrence. Adenofibromas in older patients are most easily managed by hysterectomy unle~~ such an operation is contraindicated. The recommended therapy for adenosarcomas is almost always hysterectomy, usually accompanied by bilateral salpingo-oophorectomy. Although typical adenosarcomas are almost always stage I at presentation, the GOG study concluded that a staging procedure (including peritoneal washings) should be performed. 60 Staging would be particularly important if sarcomatous overgrowth is diagnosed or suspected in a curettage specimen. As adjuvant postoperative radiation or chemotherapy appears to have had no demonstrable value in reducing the likelihood of recurrent tumor,54 such therapy should probably be reserved, if it it to be used at all, for patients with invasive tumors or tumors with sarcomatous overgrowth. Recurrent tumor was successfully treated by local excision in 50% of the cases in one series, 54 although in another series, all but two patients with recurrent tumor died of tumor progression or were alive with tumor at the time of reporting.28 Extrauterine Mesodennal Adenosarcomas Extrauterine adenosarcomas, which are more appropriately referred to as "mesodermal" than fi? •mullerian", are less than one-tenth as common as their uterine counterparts. Only 21 such cases have been reported in the literature, although there are a greater number of unreported cases in the consultation files of Dr. Scully. The reported cases most commonly have occurred in the ovary (12 cases), less commonly from the "pelvis" or "pelvic wall" (4 cases), broad ligament (2), retroperitoneum (1), and urinary bladder (I). 63-70 Several of the unreported cases noted above have arisen within the vagina. The adenosarcoma originating in the bladder was contiguous with vesical endometriosis, and several other extrauterine adenosarcomas arose in patients with a history of endometriosis. Analysis of the literature cases indicates a median age of 49 years, which is somewhat younger than the correspondin.g median age of patients with uterine adenosarcomas (58 years). The presenting manifestations are usually those relating to a mass. In contrast to uterine adenosarcomas, which are almost always stage I at presentation, one-third of the extrauterine tumors had spread locally at the time of the initial operation. On gross examination, the extrauterine tumors are generally solid or solid and cystic, often bulky tumors, and have a microscopic appearance that does not differ significantly from their uterine counterparts. Of the 17 cases with follow-up information, 4 have died of disease, five are alive with disease, and 8 are alive with no evidence of disease. This data suggests that extrauterine adenosarcomas are somewhat more aggressive than their uterine counterparts, although study of a larger number of cases will be needed to confirm this. Even if this more aggressive behavior is confirmed, extrauterine adenosarcomas appear to have a better prognosis than extrauterine malignant mixed mesodermal tumors (carcinosarcomas), from which they should be distinguished on microscopic examination. 63 REFERENCES I. Abell MR: Papillary adenofibroma of the uterine cetvix. Am J Obstet Gynecol 110:990-993, 1971 2. Vellios F, Ng ABP, Reagan JW: Papillary adenofibroma of the uterus: A benign mesodermal mixed tumorofmullerian origin. Am J Clin Pathol60:543-551, 1973 3. Clement PB, Scully RE: Mullerian adenosarcoma of the uterus: A Clinicopathologic analysis of ten cases ofa distinctive type of mullerian mixed tumor. Cancer 34:1138-1149, 1974 4. Grimalt M, Arguelles M , Ferenczy A: Papillary cystadenofibroma of endometrium: A histochemical and ultrastructural study. Cancer 36:137-144, 1975 5. Silverberg SG: Adenomyomatosis of endometrium and endocervix- a hamartoma? Am J Clin Pathol64:192-199, 1975 6. Roth LM, Pride GL, Sharma HM: Mullerian adenosarcoma of the uterine cetvix with heterologous elements: A light and electron microscopic study. Cancer 37:1725-1736, 1976 7. Sakamoto A, Sugano H: Mixed mesodermal tumor of the uterine lxxly: Relationship between histology and survival. Gann 67:263-273, 1976 8. Katzenstein AA, Askin FB, Feldman PS: Mullerian adenosarcoma of the uterus: An ultrastructural study of four cases. Cancer 40:2233-2242, 19TI 9. Philippe E, Schoetter F: A propos de l'adenosarcome mullerian et de l'adenofibrome uterin. Annales d'anat Pathol 22:263-268, 1977 10. Damjanov I, Casey MJ, Maenza RM et al: Mullerian adenosarcoma of the uterus: Ultrastructure before and after radiation therapy. Am J Clin Pathol 70:96- 103, 1978 11. Bibro MC, Livolsi VA, Schwartz PE: Adenosarcoma of the uterus: Ultrastructural obsetvations. Am 1 Clin Pathol71:112-117, 1979 12. Borello DJ, Wood WG, Newman RL: Mulle.rian adenosarcoma: Two additional cases with ultrastructural obsetvations. Diagn Gynecol Obstet 1:275-282, 1979 13. Fox H, Harilal KR, Youell A: Mullerian adenosarcoma of the uterine body: A report of nine cases. Histopathology 3: 167-180, 1979 14. Gloor E: Mullerian adenosarcoma of the uterus: Clinicopathologic report of five cases. Am J Surg Pathol 3:203-209, 1979 15. Okagaki T, Brooker DC, Adcock LL et al: Mullerian adenosarcoma of the ute.rus with rapid progression: An ultrastructural study. Gynecol Oncol 7:361-370, 1979 16. Sampat MB, Krishnamurthy SC, Talwalkar GV: Mullerian adenosarcoma philloides of uterus. Report of a case and literature review. Ind 1 Cancer 16:74-97, 1979 17. Valdez VA, Planas AT, Lopez VF et al: Adenosarcoma of uterus and ovary: A clinicopathologic study of two cases. Cancer 43:1439-1447, 1979 18. Ali M, Fayemi AO. Mullerian adenosarcoma of uterine cetvix. Report of a case with rapidly fatal outcome. Diagnostic Gynecol Obstet 2:135- 138, 1980 19. Baratz M, Gitstein SZ, David MP et al: Papillary cystadenofibroma of the endometrium. Acta Obstet Gynecol Scand 59:467-470, 1980 20. Martinelli G, Pileri S, Bazzocchi Fetal: Mullerian adenosarcoma of the uterus: A report of 5 cases. Tumori 66:499-506, 1980 21. Orenstein HH, Richart RM, Fenoglio CM: Mullerian adenosarcoma of the uterus: Literature review, case report, and ultrastructural obsetvations. Ultrastruct Patholl: 189-200, 1980 22. Ostor AG, Fortune DW: Benign and low grade variants of mixed mullerian tumour of the uterus. Histopathology *:369-369, 1980 23. Vellios F: Papillary adenofibroma - adenosarcoma; the uterine cystosarcoma phyllodes in Fenoglio CM, Wolff M (eds): Progress in Surgical Pathology, Vol I. New York, Masson Publishing USA, Inc. 1980, pp 205-219 24. Dietze 0, Hopfe1-Kreiner I, Scharf 0, Ortner A. Heterologes Mullersches Adenosarkom des uterus - ein seltener Tumor: Licht und elektronenmikroskopische Befunde, klinische Dignitat. Arch Gynecol 231 :75-85, 1981 25. Mills SE, Sugg NK, Mahnesmith RC: Endometrial adenosarcoma with pelvic involvement following uterine perforation. Diagn Gynecol Obstet 3: 149· 154, 1981 26. Street B, Du Toit JP: Uterine adenosarcoma: Report of a case with two further primary malignant tumors. Gynecol Oncolll:252-258, 1981 64 27. Tang C, Toker C, Harriman 8: Mullerian adenosarcoma of the uterine cervix. Hum Pathol 12:579-581, 1981 28. Zaloudek CJ, Norris HI: Adenofibroma and adenosarcoma of the uterus: A clinicopathologic study of 35 cases. Cancer 48:354-366, 1981 29. Edinger DD, Safaii H, Tak W, eta!: Cervical mullerian adenosarcoma: case report. Eur J Gynecol Oncol3:69-73, 1982 30. Hanchard 8 , Coard K, Persaud V: Mullerian adenosarcoma of the uterus. West Indian Med J 31:41-44, 1982 31. Hidvegi DF, DeMay RM, Sorensen K: Uterine mullerian adenosarcoma with psammoma bodies. Cytologic, histologic and ultrastructural studies of a case. Acta Cytol 26:323-326, 1982 32. Miles PA, GreenburgH, Herrera GA, eta!: Mullerian adenofibroma of the endometrium: A report of a case with ultrastructural study. Diagn Gynecol Obstet4:215-221, 1982 33. Czemobilsky B, Hohlweg-Majert P, Dallenbach-Hellweg G: Uterine adenosarcoma: A clinicopathologic study of II cases with a reevaluation of histologic criteria. Arch Gynecol 233:281-294, 1983 34. Hariri J: Mullerian adenosarcoma of the endometrium: Review of the literature and report of two cases. Int J Gynecol Pathol 2:182-191, 1983 35. Segura-Fonseca JJ, Muikai K. Mullerian adenosarcoma of the uterus with heterologous component: Case report with an immunohistochemical study of myoglobin. Pathologica 21:233-240, 1983 36. Altaras M, Cohen I, Cordoba M, eta!: Papillary adenofibroma of the endometrium: Case report and review of the literature. Gynecol Oncol 19:216-221, 1984 37. Hilton P: Mullerian adenofibroma. Case Report. Br J Obstet Gynecol91: 1261-1265, 1984 38. 1wai M, Konishi I, Fujii S, et a!: A light and electron microscopic study of mullerian adenofibroma of the uterus. Acta Obstet Gynaecol Japonica 36:44-48, 1984 39. Yonemitsu N, Nakahara M, Sugihara H, eta!: A case of mullerian adenosarcoma of the uterus. Gan No Rinsho 30:105-109, 1984 40. Oda Y, Nakanishi I, Tateiwa T: Intramural mullerian adenosarcoma of the uterus with adenomyosis. Arch Pathol Lab Med 108:798-801, 1984 41. Bjerregaard B, Moll M, Gram NC: Muller-adenosarkom i uterus. Ugeskr Laeger 147:2305-2306, 1985 42. Chen KTK: Rhabdomyosarcomatous uterine adenosarcoma. Int J Gynecol Pathol 4:146-152, 1985 43. Bahari CM, Gorodeski IG, Avidor I: Case report of two primary tumors: Mullerian adenosarcoma and endometrial adenocarcinoma. Isr 1 Med Sci 22:127-130, 1986 44. Hirschfield L, Kahn LB , Chen S, et a!: Mullerian adenosarcoma with ovarian sex cord-like differentiation: A light- and electron-microscopic study. Cancer 57: 1197-1200, 1986 45 . Piura B, Hagay ZJ, Goldstein J: Infected mullerian adenosarcoma of the endometrium. J Surg Oncol 34:235-238, 1987 46. Agdal N, Wilken-Jensen C. Adenosarcoma uteri. Acta Obstet Gynecol Scand 66:183-184, 1987 47. Baker TR, Piver MS , Lele SB, Tsukada Y. Stage I uterine adenosarcoma: a report of six cases. J Surg Oncol 37: 128-132, 1988 48. Dekel A, Dicker D, Kugler 0 eta!. Mullerian adenosarcoma of the uterus: Report of a rare case and review of the literature. Gynecol Oneal 30:291-297, 1988 49. Hajnal-Papp R, Szilagyi I. Malignant mullerian tumours of the uterus. Arch Gynecol Obstet 241:209-219, 1988 50. Gal D, Kerner H, Beck D, Peretz BA, Eyal A, Paldi E. Mullerian adenosarcoma of the uterine cervix. Gynecol Oncol 31 :445-453, 1988 51. Clement PB. Mullerian adenosarcomas of the uterus with sarcomatous overgrowth. A clinicopathological analysis of 10 cases. Am J Surg Pathol 13:28-38, 1989 52. Clement PB, Scully RE. Mullerian adenosarcomas of the uterus with sex cord-like elements. A clinicopathological analysis of eight cases. Am J Clin Pathol 91:664-672, 1989 53. Gast MJ, Radkins LV, Jacobs AJ, Gersell 0: Mullerian adenosarcoma with heterologous elements: diagnostic and therapeutic approach. Gynecol Oncol 32:381-384, 1989 65 54. Clement PB, Scully RE: Mullerian adenosarcoma of the uterus: A clinicopathological analysis of 100 cases witlt a review of the literature. Hum Pathol21:363-381, 1990 S5. Clement PB, Scully RE. Mullerian adenofibroma of the uterus with invasion of myometrium and pelvic veins. Int J Gynecol Pathol 9:363-371, 1990 56. Seltzer VL, Levine A, Spiegel G et aL Adenofibroma of the uterus: Multiple recurrences following wide local excision. Gynecol Oncol 37:427-431, 1990 57. Agarwal PK, Husain N, Chandrawati (sic). Adenofibroma of uterus and endocervix. Histopathol 18:79-80, 1991 58. Lack EE, Bitterman P, Sundeen IT: Mullerian adenosarcoma of the uterus with pure angiosarcoma: Case report. Hum Pathol22:1289-1291, 1991 59 . .Raymundo Garcia C, Toro Rojas M, Morales Jill'\inez CM et al. Uterine mullerian adenosarcoma wtth histiocytic (xanthomatous) mesenchymal component. 'Histol Histopath 6:363-367, 1991 60. Kaku T, Silverberg SG, Major FJ et al. Adenosarcoma of the uterus: A gynecologic oncology group clinicopathologic study of 31 cases. Int J Gynecol Patholll:75-88, 1992 61. Bocklage T, Lee KR, Belinson JL: Uterine mullerian adenosarcoma following adenomyoma in a woman on Tamoxifen therapy. Gynecol Oncol44: 104-109, 1992 62. Miller KN, McClure SP: Papillary adenofibroma of the uterus. Report of a case involved by adenocarcinoma and review of the literature. Am J Clin Pathol 97:806-809, 1992 63. Mahoney AD, Waisman J, Zeldis U ..Adenomyoma. A precursor of extrauterine mullerian adenosarcoma? Arch Pathol Lab Med 101:579-584, 1977 64. Clement PB, Scully RE: Extrauterine mesodermal (mullerian) adenosarcoma. A clinicopathological analysis of five cases. Am J Clin Pathol69:276-283, 1978 65. Kao GF, Norris HJ. Benign and low grade variants of mixed mesodermal tumor (adenosarcoma) of the ovary and adnexal region. Cancer 42:1314-1324, 1978 66. Russell P, Slavutin L, Laverty CR, Cooper-Booth J. Extrauterine mesodermal (mullerian) adenosarcoma. A case report. Pathology 11:557-560, 1979 67. Czemobilsky B, Gillespie JJ, Roth LM. Adenosarcoma of the ovary. Diagn Gynecol Obstet 4:25-36, 1982 68. Kerner H, Lichtig C, Beck D. Extrauterine mullerian adenosarcoma of the peritoneal mesothelium: A clinicopathologic and electron microscopic study. Obstet Gyneco173:510-513, 1989 69. Vara AR, Ruzics EP, Moussabeck 0, Mart.in DC. Endometrioid adenosarcoma of the bladder arising from endometriosis. J Urol 143:813-815, 1990 70. Roman LD, Mitchell MF, Tornos C, Glover A, Kavanagh JJ. Dedifferentiated extrauterine adenosarcoma responsive to chemotherapy. Gynecol Oncol 49:389-394, 1993 66 CASE 19 (Ace #27351) DIAGNOSIS: ENDOMETRIOID-LIKE YOLK SAC TUMOR OF THE OVARY DISCUSSION: The yolk sac tumor (YST) or endodermal sinus tumor is one of the tumors that Schiller designated "mesonephroma" because of the presence of structures resembling renal glomeruli. Later Teilum recognized these structures to be identical in histologic appearance to the so-called endodermal sinuses (of yolk sac origin) present in the rat placenta. The YST is now considered a primitive germ cell tumor composed of extraembryonic endoderm (and mesoderm) that recapitulates embryonic development of the yolk sac (8,12,14,18,19,22,23). The typical Jlaltems of YST and their associated production of alpha-fetoprotein (AFP) are considered to represent "visceral" yolk sac differentiation. In contrast, "parietal" yolk sac differentiation is characterized by the presence of AFP-negative basement membrane-like material analagous to Reichert's membrane (of parietal yolk sac origin) in the rat placenta (5,23). The presence of enteric and hepatic differentiation in some YSTs indicates embryonal, as well as extraembryonal, differentiation, consistent with origin of the primitive gut from the yolk sac during embryogenesis, and the subsequent development of the hepatobiliary anlage from the former (3,4,12,17,21,23). Clinical Features Although relatively rare, YSTs are the second most common malignant germ cell tumor in the ovary, and are almost as common as dysgerminomas in females <20 years of age. YSTs are most common in childhood and adolescence (mean age, 19 years) and are rare over the age of 40; exceptional cases, however, have been reported in postmenopausal women (15). Patients typically present with abdominal pain, frequently of sudden onset, and a large abdominal or pelvic mass. Serum AFP is almost invariably elevated, and in contrast to other AFP-secreting ovarian tumors, may reach very high levels; its measurement is also useful in monitoring therapy and detecting recurrent tumor. Less specific serum markers, such as lactic dehydrogenase, may also be elevated (I0). YST is a rapidly growing tumor, with evidence of extraovarian spread to the peritoneum or retroperitoneal lymph nodes, or both, in approximately one-third of patients. Before the use of combination chemotherapy, survival was poor (12); more recently however, such treatment has achieved survivals of over 80% with stage I YST and over 50% with higher-stage tumors (7). Gross Appearance The tumors are typical! y large with a median diameter of 15 em. The external surface is usually smooth and glistening although 25% have capsular tears due to preoperative or intraoperative rupture. The sectioned surfaces are typically solid and cystic and composed of soft, friable, yellow to grey tissue; very rare tumors are entirely cystic (2). Extensive areas of hemorrhage and necrosis are common. A honeycomb appearance due to the presence of many small cysts may indicate the presence ofa polyvesicular-vitelline pattern (see below). Gross 67 evidence of other germ cell elements, most commonly a benign cystic teratoma, may be seen. YSTs are virtually never bilateral unless the opposite ovary is involved as part of generalized peritoneal spread. Histologic Features Almost all YSTs have one or more of three cardinal histologic features: a reticular pattern, Schiller-Duval bodies, and hyaline droplets (12, 14,23). The reticular pattern consists of a loose meshwork of communicating spaces lined by primitive tumor cells with cytoplasm that is typically clear, containing glycogen, and occasionally, lipid. The hyperchromatic, irregular, large nuclei contain prominent nucleoli; mitotic figures are numerous. Schiller-Duval bodies (SDB), which are present in up to 75% of yolk sac tu.mors in some series (12), consist of single papillae that vary from rounded to elongated depending on the plane. of section, with a connective tissue core containing a single central vessel. These structures are covered typically by primitive columnar cells and lie in a space lined by cells that are cuboidal, flattened, or of hobnail type. SDB are usually sparsely distributed, but when numerous and closely packed, a distinctive papillary pattern is created (12). Variably sized; eosinophilic, PAS-positive, diastase resistant, hyaline. droplets are present in most YSTs, and are most numerous in areas with a reticular or hepatoid pattern (see below). Other less common, but characteristic, patterns, may occur in YSTs, usually admixed with reticular foci, but rarely they predominate or occur in pure form. The polyvesicular-vitelline pattern (PVV) is characterized by the presence of cysts lined by columnar, cuboidal, or flattened cells and separated by a dense spindle-cell stroma (12,19). The cysts may exhibit eccentric constrictions simulating the division of the primary yolk sac vesicle into a larger component corresponding to the vestigial yolk sac of the embryo and a smaller component, which is the forerunner of the primitive gut. A hepatoid pattern, characterized by the presence of large polygonal cells with abundant eosinophilic cytoplasm growing in compact masses separated by thin lo thick fibrous bands, resembles hepatocellular carcinoma (21). YSTs may contain glands lined by nonspecific or vacuolated cells, and rare tumors exhibit a predominant glandular pattern ("glandular YSTs"). Some of the latter have been referred to as "intestinal" YSTs because of glandular spaces lined by cells with the ultrastructural features of intestinal cells. In our experience, glandl!lar YSTs- exemplified by the seminar case - may simulate typical or secretory endometrioid carcinoma, so-called "endometrioid-Jike" YSTs (2). Foci of hepatoid differentiation within the glands in such cases can resemble squamous differentiation, enhancing the resemblance of the tumor to endometrioid carcinoma. Similarly, the endometrioid-like glands can be surrounded by an abundant fibrous stroma or a cellular mitotically active stroma, tesulting in possible confusion with an endometrioid adenofibroma or carcinosarcoma, respectively (2). As previously noted, "parietal" differentiation is characterized by small extracellular accumulations of basement-membrane material, typically within reticular foci (5,23). Recently, Michael et al (6, 16) have aescrlbed a mesenchyme-like component in some 68 YSTs, characterized by mitotically-inactive spindle cells in a vascular myxoid background. It is often prominent, and may be the exclusive component, in YSTs after chemotherapy, and may give rise to sarcomas occurring in some patients with treated germ cell .tumors. Nonspecific patterns that may .occur in YSTs include solid, papillary, myxoid, and adenofibromatous. Occasional foci in YSTs are composed of tumor cells with large intracellular vacuoles that displace the nucleus, creating an appearance resembling liposarcoma. Enteric-type glands occur in as many as 50% of YSTs and appear as glands lined by bland mucinous columnar cells, goblet cells, and rarely, Paneth cells (12,23). Rare tumors contain small numbers of syncytiotrophoblastic giant cells (SGCs). Luteinized stromal cells, granulomatous inflammation, and erythropoetic foci are occasionally found within the stroma of YSTs (12). Immunohistochemical findings may be useful in confirming a diagnosis of YST, particularly in tumors with unusual or nonspecific histologic patterns. The cytoplasm of the tumor cells is almost always immunoreactive for alpha-fetoprotein (AFP), alpha-1-antitrypsin (AAT), and cytokeratin, although the staining may be focal. The luminal contents of the glands and cysts in tumors with polyvesicular-vitelline, hepatoid, and endometrioid-like patterns are also positive for these antigens. Most hyaline droplets are immunoreactive for AAT; the droplets stain for AFP in only occasional cases. The enteric glands and their luminal contents are typically immunoreactive for carcinoembryonic antigen (23). Leu-Ml immunoreactivity can lie seen in occasional YSTs as discussed below (26). Differential Diagnosis The differential diagnosis varies with the pattern of YST. Typical and PVV patterns may be oonfused with clear cell carcinoma (CCC) (II). The following table outlines their major differences: FEATURE 'YST CCC age typically < 30 yr typically > 40 yr elevated serum AFP typical absent papillae SDB with vessel hyalinized hyaline bodies typical uncommon AFP immunoreactivity* typical uncommon Leu-MI immunoreactivity* uncommon typical other germ cell elements common absent *A recent study (26) found that 94.1% of CCCs and 28.5% of YSTs stained for Leu-Ml, whereas 85.7% of YSTs and 17.6% of CCCs stained for AFP. Since an occasional example of either tumor may be positive or negative for both antigens, these staining patterns are not diagnostically useful, but staining for only Leu-MJ was found confmed to CCCs and staining for only AFP was confined to YSTs. The differential diagnosis of typical YST also includes embryonal carcinoma (EC), a closely related tumor that may be admixed with YST (13). EC, however, lacks the characteristic patterns of YST, typically exhibiting the more nonspecific papillary, solid, and glandular patterns as seen in the much more common ECs of the testis. In addition, hCG+ SGCs (and 69 elevated serum hCG levels) are typically present in ECs in contrast to their rarity in YSTs. YSTs with prominent endometrioid-like glandular patterns must be distinguished from endometrioid and other surface epithelial carcinomas, carcinosarcomas, and metastatic carcinomas (2). Features including a young patient age, elevated serum AFP, primitive appearance of the nuclei lining the glands, immunoreactivity for AFP, and admixture of other YST elements, present alone or in combination, will usually facilitate the diagnosis. Because of their component of cells with abundant eosinophilic cytoplasm, the differential diagnosis of a hepatoid YST is with a number of other. tumors which generally do not enter the differential diagnosis of YSTs. The ovarian tumor which most characteristically has such cells is the steroid cell tumor (see Case 23). However, these tumors are generally readily distinguished from YSTs because of their much more monomorphic pattern and the lack of a primitive appearance of their nuclei. The uncommon oxyphilic variant of clear cell carcinoma (24) is also generally easily diagnosed because of the presence of typical foci of clear cell carcinoma, although sometimes small in amount. Another tumor to be distinguished from the hepatoid YST is the hepatoid carcinoma (9). These tumors, however, generally occur in an older, typically postmenopausal, age group, and are not associated with other patterns of yolk sac neoplasia that are helpful in establishing a diagnosis of hepatoid YST. Similar features would also help distinguish hepatoid YST from ovarian involvement by metastatic hepatoid carcinoma arising in other sites (stomach, lung) or metastatic hepatocellu.lar carcinoma from the liver (9a). Hepatic tissue may occasionally occur within other ovarian tumors, including immature teratomas (20), polyembryomas (17), and Sertoli-Leydig cell tumors (1,25). AFP-immunoreactivity of the hepatic tissue, elevated serum levels of AFP, or both may be encountered in such cases. In contrast to hepatoid YSTs, however, the hepatic tissue in these tumors takes the form of small nests of benign-appearing fetal or adult-type hepatocytes. REFERENCES General Reference: Human Yolk Sac and its Tumors. Nogales F, editor. Springer-Verlag 1993. I. Chadha S, Honnebier WJ, Schaberg A: Raised serum alpha-fetoprotein in Sertoli-Leydig cell tumor (androblastoma) of ovary: report of two cases. Int J Gynecol Pathol 1987;6:82-88. 2. Clement PB, Young RH, Scully RE. Endometrioid-like variant of ovarian yolk sac tumor. A clinicopathological analysis of eight cases. Am J Surg Pathol 1987; i l :767-778. 3. Cohen MB, Mulchahey KM, Molnar JJ. Ovarian endodermal sinus tumor with intestinal differentiation. Cancer 1986;57: 1580-1583. 4. Cohen MB, Friend DS, Molnar JJ, Talerman A: Gonadal endodermal sinus (yolk sac) tumor with pure intestinal differentiation: a new histologic type. Path Red Pract 1987;182:609-616. 5. Damjanov I, Amenta PS, Zarghami F. Transformation of an AFP-positive yolk sac carcinoma into an AFP-negative neoplasm. Evidence for in vivo cloning of the human parietal yolk sac carcinoma. Cancer 1984;53:1902-1907. 6. Dehner LP. Yet another face on the yolk sac tumor. Arch Pathol Lab Med 1989;113: 1115-1119. 7. Gershenson DM, Del Junco G, Herson J, Rutledge FN. Endodermal sinus tumor of the ovary: theM. D. Anderson experience. Obstet Gyneco1 1983;61: 194-202 .. 70 8. Gonzalez-Crussi F, Roth LM. The human yolk sac and yolk sac carcinoma. Human Pathol 1976;7:675-691. 9. Ishikura H, Scully RE: Hepatoid carcinoma of the ovary. A newly described tumor. Cancer 1987;60:2775-2784. 9a. Young RH, Gersell DJ, Clement PB, Scully RE: Hepatocellular carcinoma metastatic to the ovary: A repon of three cases discovered during life with discussion of the differential diagnosis of hepatoid tumors of the ovary. Human Pathol 1992;23:574-580. 10. Kinumaki H, Takeuchi H, Nakamura Ketal. Serum lactate dehydrogenase isoenzyme-! in children with yolk sac tumor. Cancer 1985;56: 178-181. II. Klemi PJ, Meurman L, Gronroos M, Talerman A. Clear cell (mesonephroid) tumors of the ovary with characteristics resembling endodermal sinus tumor. Int J Gynecol Pathol 1982;1:95-100. 12. Kurman RJ, Norris HJ. Endodermal sinus tumor of the ovary. A clinical and pathologic analysis of 71 cases. Cancer 1976;38:2404-2419. 13. Kurman RJ, Norris HJ. Embryonal carcinoma of the ovary. A clinicopathologic entity distinct from endodermal sinus tumor and resembling embryonal carcinoma of the adult testis. Cancer 1976;38:2420-2433. 14. Langley FA, Govan ADT, Anderson MC, Gowing NFC, Woodcock AS, Harilal KR. Yolk sac and allied tumours of the ovary. Histopathology 1981;5:389-401. 15. Mazur MT, Talbot WH, Talerman A. Endodermal sinus tumor and mucinous cystadenofibroma of the ovary. Cancer 1988;62:011-2015. 16. Michael H, Ulbright TM, Brodhecker CA. The pluripotential nature of the mesenchyme-like component of yolk sac tumor. Arch Pathol Lab Med 1989;113:1115-1119. 17. Nakashima N, Fukatsu T, Nagasaka T, Sobue M, Takeuchi J: The frequency and histology of hepatic tissue in germ ceiJ tumors. Am J Surg Pathol 1987;11:682-692. 18. Nogales-Femandez F, Silverberg SG, Blaustein PA, Maninez-Hemandez A, Pierce GB. Yolk sac carcinoma (endodermal sinus tumor). Ultrastructure and histogenesis of gonadal and extragonadal tumors in comparison with normal human yolk sac. Cancer 1977;39: 1462-1474. 19. Nogales FF, Matilla A, Nogales-Ortiz F, Galera-Davidson HL. Yolk sac tumors with pure and mixed polyvesicular vitelline patterns. Hum Pathol 1978;9:553-566. 20. Perrone T, Steeper T, Dehner LP. Alpha-fetoprotein localization in pure ovarian teratoma. An immunohistochemical study of 12 cases. Am J Clin Pathol 1987;88:713-717. 21. Prat J, Bhan AK, Dickersin RG, Rob boy SJ, Scully RE. Hepatoid yolk sac tumor of the ovary (endodermal sinus tumor with hepatoid differentiation). A iight microscopic ultrastructural and immunohistochemical study of seven cases. Cancer 1982;50:2355-2368. 22. Takashina T, Kanda Y, Hayakawa 0, Kudo R, Ito E, Sagae S. Yolk sac tumors of the ov~ and the human yolk sac. Am J Obstet Gynecoll987; 156:223-229. 23. Ulbnght TM, Roth LM, Brodhecker CA. Yolk sac differentiation in germ cell tumors. A morphologic study of SO cases with emphasis on hepatic, enteric, and parietal yolk sac features. Am J Surg Pathol 1986;10: 151-164. 24. Young RH, Scully RE: Oxyphilic clear cell carcinoma of the ovary. A repon of nine cases. Am J Surg Pathol 1987;11:661-667. 25. Young RH, Perez-Atayde AR, Scully RE: Ovarian Sertoli-Leydig cell tumor with retiform and heterologous components. Report of a case with hepatocytic differentiation and elevated serum alpha-fetoprotein. Am J Surg Pathol 1984;8:709-718. 26. Zirker TA, Silva EG, Morris M, Ordonez NG. Immunohistochemical differentiation of clear-cell carcinoma of the female genital tract and endodermal sinus tumor with the use of alpha-fetoprotein and Leu-M I. Am J Clin Pathol1989;9 1:51 1-514. 71 CASE 20 (Ace #27308) DIAGNOSIS: SERTOLI-LEYDIG CELL TUMOR OF OVARY, POORLY DIFFERENTIATED, WITH HETEROLOGOUS (MUCINOUS) ELEMENTS DISCUSSION: Sertoli-Leydig cell tumors (SLCTs) are classified into five major categories: well differentiated, of intermediate differentiation, poorly differentiated, retiform, and mixed. As exemplified by the seminar case, any of the last four categories may be associated with heterologous elements. Clinical Features SLCTs account for less than 0.2% of ovarian neoplasms (1-9). They may be seen at any age but typically occur in young women and have an overall average age of 25 years (5). Retiform SLCTs usually occur at a younger age (average age 15 years). Approximately half of the patients present with hirsutism or virilization, whereas the corresponding figure for the retiform tumors is 28%. Occasional tumors, however, are associated with estrogen-related manifestations. The tumors secrete a variety of androgens alone or in combination; the testosterone level is usual! y markedly elevated when the tumors are androgenic. It has recently been appreciated that occasional SLCTs are associated with elevations of serum alpha-fetoprotein (9), but the latter rarely reach the high levels typically seen in YSTs. Gross Features The diameter of SLCTs varies greatly, averaging 10 em. Typically, they form a firm, lobulated, yellow or tan mass with a smooth external surface. Cysts may be conspicuous, particularly if the tumor contains heterologous elements or has retiform component. The retiform tumors are often soft, spongy, or cystic with edematous intraluminal polypoid excrescences. Areas of hemorrhage and necrosis are uncommon, except in poorly differentiated subtypes. Only 2% of tumors are bilateral. Microscopic Features Well-differentiated SLCTs are composed of hollow or solid tubules similar to those of a pure Senoli cell tumor, but the surrounding fibrous stroma contains cells resembling Leydig cells. Reinke crystals have been identified within the latter in only a minority of cases. The tubules are usually small and round to oval but are occasionally large, varying in size and shape. They may be lined by stratified cells and, rarely, resemble the glands of a low-grade endometrioid adenocarcinoma. Tumors of intermediate differentiation often have a lobulated appearance with densely cellular areas intersected by acellular fibrous or edematous connective tissue. The latter often contains nests, small clusters, and cords of cells compatible with immature Sertoli cells, as well as single cells or nests of cells consistent with Leydig cells. Leydig cells are most often conspicuous at the periphery of the lobules, as well as at the periphery of the tumor ali a whole. The cells resembling immature Sertoli cells have small round to oval nuclei, and typically scanty cytoplasm. 72 Occasionally they contain abundant, pale or vacuolated cytoplasm, and in rare cases, eosinophilic cytoplasm. Sertoli cells are separated by variable numbers of Leydig cells and indifferent stromal cells. Some tumors contain foci of small, spindle-shaped cells with appreciable mitotic activity. Cysts of varying size, sometimes containing eosinophilic secretion, may be present and mimic thyroid tissue. Rarely, SLCTs, like granulosa-cell tumors and thecomas., may contain cells with bizarre nuclei. SCLTs from pregnant patients in the third trimester, as with other sex-cord-stromal rumors at this time, typically show distinctive changes, particularly edema; large sheet-like aggregates of Leydig cells may also be seen. Poorly differentiated SLCTs are characterized by a diffuse growth of highly mitotically active cells that are usually spindle shaped, suggesting a fibrosarcoma. They may, however, be rounded and simulate an undifferentiated carcinoma. Tubules, sex-cord-like formations, and Leydig cells, as well as other, more distinctive patterns of Sertoli-Leydig cell neoplasia, are necessary to establish the diagnosis but may be minor in extent. Retiform SLCTs, characterized by growth patterns that simulate those of the rete testis, account for 10% to 15% of SLCTs (2-6). Retiform SLCTs have not received much attention until recently and in the past, these tumors have undoubtedly been confused with a variety of other tumors. As noted above, there are some noteworthy clinical and gross differences between retiform and nonretiform SLCTs. On microscopic examination the retiform pattern is. characterized by an irregular network of elongated, often slit-like tubules and cysts which often contain papillae. The papillae in these tumors may be short and rounded or blunt, often containing hyalinized cores, or are larger with fibrous or edematous cores. The tubules are usually lined by a single layer of cuboidal epithelial cells with round to oval nuclei although stratification is conspicuous in some cases. The cytoplasm is typically scanty and mitotic activity variable, but sometimes marked. Similar cells typically line the papillae and cysts, but large cysts may be lined by flattened cells. The stromal component varies from moderately cellular fibrous tissue (which is occasionally focally hyalinized) to markedly edematous (accounting for the soft, spongy consistency) to very cellular, immature mesenchymal tissue. Heterologous elements occur in approximately 20% of SLCTs (1, 7). The most common heterologous component seen in these tumors, present in almost 90% of them, is mucinous epithelium of gastrointestinal type (7). The epithelium contains goblet cells in over half of the cases and argentaffin cells in one-third. The mucinous epithelium is usually benign, but is occasionally borderli.ne or a low-grade carcinoma. In approximately half of the cases with argentaffin cells, microscopic foci of carcinoid are present, typically in the form of small nests which are easily overlooked. Occasionally, more conspicuous foci of insular or mucinous carcinoid are present. Diagnostic confusion due to the presence of these elements is particularly likely to occur when they are extensive and when the sex cord elements admixed within the tumor are relatively minor. ln approximately 25% of heterologous SLCTs, the heterologous elements are mesenchymal, in the form of cartilage, which typically appears fetal , or skeletal muscle cells in the form of rounded 73 rhabdomyoblasts or strap cells. Mesenchymal heterologous elements are usually found in tumors with a sarcomatoid background. Rarely, cells resembling hepatocytes or neuroectodermal elements have been seen in SLCTs. Behavior Approximately I 2% of SLCTs are clinically malignant. Almost all of the malignant tumors have been, alone or in combination, poorly differentiated, retiform, or contained heterologous mesenchymal elements. To what extent the last feature contributes to the poor prognosis in these tumors is difficult to determine as heterologous mesenchymal elements typically occur in poorly differentiated tumors, which have a poor prognosis even in the absence of the heterologous elements. Differential Dlaenosis Because SLCTs exhibit a wide range of patterns, the differential diagnosis is long; this topic has been reviewed in detail elsewhere (5,10), and only the differential diagnosis of the retiform and heterologous tumors will be considered here. Retiform SLCTs may be misinterpreted as a variety of other tumors. Because of the young age of the patient and presence of papillae in many cases the diagnosis of yolk sac tumor is often considered. Resemblance to a serous borderline tumor may be imparted by the presence of small papillary clusters in the cyst lumens. The clefts, papillae and a complex branching pattern associated with cellular stratification and atypicality may suggest a serous adenocarcinoma. The admixture of retiform tubules with immature mesenchymal tissue which may show heterologous differentiation can suggest the diagnosis of a malignant mixed mesodermal tumor. The presence in most cases of typical foci of SLCT, although sometimes very small in amount, and other clinical and pathologic features of the tumors usually enable the diagnosis of a retiform SLCT to be established. Most other patterns of SLCT may co-exist with the retiform pattern but typically the retiform foci merge with long, thick ribbons of immature cells consistent with Senoli cells. When a tumor is entirely retiform, knowledge of the existence of this distinctive subtype of SLCT is essential in enabling the pathologist avoid a serious error in diagnosis. Heterologous SLCTs are most often misdiagnosed as teratomas, but the common constituents of teratomas, such as squamous epithelium, skin appendages, and respiratory epithelium, have not been reported in SLCTs. In addition, neuroectodermal tissues are very rare in these neoplasms in contrast to their frequency in teratomas. Heterologous SLCTs containing prominent amounts of mucinous epithelium may be confused with pure mucinous cystic tumors on gross and microscopic examination. Although a history of virilization is much more suggestive of a SLCT, occasional mucinous tumors containing luteinized stromal cells are masculinizing. The diagnosis of heterologous SLCT rests on finding a Sertoli-Leydig cell component, which is almost always of intermediate differ:ntiation, between the glands and cysts or at the periphery of the tumor. Heterologous SLCTs with mesenchymal elements may be confused with sarcoma when recognizable Sertoli-Leydig cells are scarce. Before a pure ovarian sarcoma is diagnosed, particularly in a young woman, heterologous SLCT should be excluded by thorough sampling. 74 REFERENCES 1. Prat J, Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors with heterologous elements. II. Cartilage and skeletal muscle: A clinicopathologic analysis of twelve cases. Cancer 50:2465-2475, 1982. 2. Roth LM, Slayton RE, Brady LW, Blessing JA, Johnson G. Retiform differentiation in ovarian Sertoli-Leydig cell tumors. A clinicopathologic study of six cases from a gynecologic oncology group study. Cancer 55: 1093-1098, 1985. 3. Roth LM, Anderson MC, Govan ADT, Langley FA, Gowing NFC, Woodcock AS. Sertoli-Leydig cell tumors: A clinicopathologic study of 34 cases. Cancer 48:187-197, 1981. 4. Talerrnan A. Ovarian Sertoli-Leydig cell tumor (androblastoma) with retiform pattern. A clinicopathologic study. Cancer 60:3056-3064, 1989. 5. Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors. A clinicopathological analysis of 207 cases. Am J Surg Pathol 9:543-569, 1985. 6. Young RH, Scully RE. Ovarian Sertoli-Leydig cell tumors with a retiform pattern: A problem in histopathologic diagnosis. A report of 25 cases. Am J Surg Pathol 7:755-771, 1983. 7. Young RH, Prat J, Scully RE. Ovarian Sertoli-Leydig cell tumors with heterologous elements. I. Gastrointestinal epithelium and carcinoid: A clinicopathologic analysis of thirty-six cases. Cancer 50:2448-2456, 1982. . 8. Zaloudek C, Norris HJ. Sertoli-Leydig tumors of the ovary. A clinicopathologic study of 64 intermediate and poorly differentiated neoplasm. Am J Surg Pathol 8:405-418, 1984. 9. Gagnon S, Tetu B, Silva E, McCaughey WTE. Frequency of alphafetoprotein production by Sertoli-Leydig cell tumors of the ovary: An immunohistochemical study of eight cases. Mod Pathol 2:63-67, 1989. 10. Young RH, Scully RE. Ovarian sex cord-stromal tumours: Recent advances and current status. Clin Obstet Gynaecol 11:93-134, 1984 75 CASE 21 (Ace #27349) DIAGNOSIS: BRENNER TUMOR OF BORDERLINE MALIGNANCY DISCUSSION: This is an example of an uncommon tumor, a Brenner tumor of borderline malignancy (BLBT) (3,5,8,10), and is used as a focal point for a discussion of the category of transitional cell tumors of the ovary (Table I), including transitional cell carcinoma (TCC) of the ovary, which has been the subject of recent attention in the literature (1,2,6,7). In the evaluation of any ovarian tumor which resembles a TCC, thorough sampling is important in an attempt to identify a benign Brenner component. The presence of the latter establishes the diagnosis of Brenner tumor (benign, borderline, or malignant depending on the presence of other fmdings discussed below), thereby excluding not only a primary ovarian TCC (which, by definition, lacks a benign Brenner component) but also a metastatic TCC from the urinary tract. Borderline Brenner Tumors The BLBT typically takes the form of a noninvasive, papillary proliferation of transitional cells lining cystic spaces, the appearance resembling that of a low-grade papillary TCC of the urinary tract; by definition, a benign Brenner component must also be present (3,5,8,10). Mucin-rich cells may also be encountered, typically in the innermost layer. Although such tumors with grade 1, 2, or 3 nuclear features are considered BLBTs by W.H.O. criteria, tumors with grade 1 or 2 nuclear features would be considered a "proliferating" BT by some authors, or if it had grade 2 or 3 nuclear features, a malignant BT by others (Table II). BLBTs account for 3-5% of BTs according to some investigators, although the corresponding figure estimated by Stanford workers in only 0.5% (4). These tumors have occurred in patients 30-87 (mean 66) years of age. All of the tumors have been stage I. On gross examination, they have been usually cystic or solid and cystic and have varied from 8·31 (mean 18) em in diameter; some have had grossly visible intracystic papillae. Rarely cases have been bilateral. No tumor related deaths have been reported, regardless of the grade of the carcinoma lining the cystic spaces. Malignant Brenner Tumor A malignant BT is characterized by the presence of a benign BT accompanied by an invasive carcinoma that may be TCC, squamous cell carcinoma, or undifferentiated carcinoma; any of these cypes may be associated with an adenocarcinoma (1 ,3,5,9,10). Stromal invasion in these tumors may sometimes be difficult to recognize, given that even typical BTs are characterized by epithelial nests within a fibrous stroma. Invasion, however, can usually be recognized by the presence of a reactive stroma (in contrast to the fibromatous stroma of a benign BT), a disorderly growth pattern, an irregular epithelial-stromal interface, and a crowding out of the stromal component by the epithelial component (9). As already noted, some investigators diagnose malignant BT, even in the absence of stromal invasion, when the degree of atypia exceeds that of a grade I TCC (Table II). Because the probability of stromal 76 invasion is high in a BT in which a high-grade carcinoma lines cystic spaces, tumors with these features should be thoroughly sampled to exclude invasion. Malignant BTs account for 5% of BTs, but the corresponding figure according to Stanford workers in only 0.5% (4). These tumors have occurred in women 34-87 y (median 60) of age. In contrast to TCCs (see below), only 19% of these tumors have spread beyond the ovary at presentation (>Stage 1). On gross examination, the tumors have ranged from 5-22 (mean 15) em in diameter; rare bilateral tumors have been reported. In contrast to TCCs, gross or microscopic calcification is present in the majority of cases (1). Patients with malignant BTs have an 88% survival in stage 1 tumors; the corresponding figure for TCCs of the same stage is only 43% (I). Transitional Cell Carcinomas TCC has recently been established as a specific subgroup within the category of surface epitheUal carcinomas. Although there is a degree of inherent subjectivity in the classification of many surface epithelial tumors, this is particularly so with TCCs. In poorly differentiated carcinomas, particularly those of serous and endometrioid types, and undifferentiated carcinomas, one often sees foci that resemble to some extent TCC of the urinary bladder; the point at which one of these neoplasms should be designated TCC is not clearly established. That notwithstanding, there is no doubt that some ovarian carcinomas have a striking resemblance to TCCs of the bladder and accordingly, designating them TCCs is justifiable. In the experience of the workers at the Armed Forces Institute of Pathology (1), the resemblance of TCC to typical bladder carcinoma was seen most overtly in areas of cystic change where the tumor cells formed papillae or had an undulating surface. Those workers found small areas of squamous differentiation or adenocarcinoma in from one-third to one-half of the cases. As noted above, the calcification commonly present in malignant BTs is not typically present in TCCs (1). TCCs were found to be stage n or higher in 69% of cases in the AFIP study; the corresponding figure for malignant BTs, as noted above, was only 19%. The survival for stage I TCCs in the same study was only 43%, compared to 88% for malignant BTs of the same stage (1). More recently, Silva and colleagues from the M.D. Anderson Cancer Center have published a series of articles that have focussed on the chemosensitivity of TCCs (2,6,7). In the most recent article from this center (2), tumors with any component ofTCC accounted for 9% of stage JII and IV ovarian carcinomas; 1% were pure TCC, 5% were TCC-predominant (>50% TCC), and 3% were TCC-nonpredominant (<50% TCC). Tumors that were not pure TCC were usually admixed with serous, endometrioid, or undifferentiated carcinoma. Silva's criteria for TCC include (a) thick blunt papillae with smooth luminal borders and fibrovascular cores extending into empty cystic spaces; irregular nests within a fibrous stroma may also be present; (b) tumor cells with at least moderate amounts of cytoplasm and distinct cell borders; (c) nuclear features that are grade 2 or 3 but that are not typically highly pleomorphic; (d) 77 glandular or squamous differentiation may also be present, and (e) an absent benign Brenner component. It was found in this study that TCC-predominant primary tumors were significantly more chemosensitive and had a much better prognosis than serous carcinomas of similar stage and grade: 45% vs 10% 5ys Stage. m & IV (2). Moreover, it was found that any component of TCC in the metastatic tumor was associated with chemosensitivity and an improved survival as compared to serous carcinomas (2). Primary TCC of the ovary must be distinguished not only from malignant BT but from the very rare TCC of the urinary tract metastatic to -the ovary. Young and Scully found that features favoring a metastatic nature of ovarian tumors in patients with a TCC involving both the ovary and urinary tract were deep invasion of the urothelial tumor and the presence of features typically associated with metastatic spread to the ovary, including extraovarian peritoneal tumor, bilaterality, multinodularity, and prominent lymphatic/vascular invasion. On the other hand, when there were some differences in the histologic appearance of the two tumors, an absence of invasion or only superficial invasion of the urothelial tumor, a long interval between the detection of the urothelial and ovarian tumors, an associated benign BT, and an absence of extra-urinary tract tumor for three years or more after treatment of the ovarian tumor, independent primaries were favored. TABLE I W .H.O. CLASSIFICATION OF TRANSITIONAL CELL TUMORS BRENNER TUMORS BENIGN BORDERLINE MALIGNANT TRANSITIONAL CELL CARCINOMA TABLE II CLASSIFICATION OF BRBHNER TUMORS FEATURES W.H.O. BELL & SCULLY ROTH ET AL Benign epithelium benign benign benign No invasion Atypical epithelium gr l-3 = gr l = borderline gr 1+2 = proliferative No invasion border-line gr 2+3 = malignant gr 3 = borderline Atypical epithelium malignant malignant malignant Invasion 78 REFERENCES I. Austin RM, Norris HJ. Malignant Brenner tumor and transitional cell carcinoma of the ovary: A comparison. Int J Gynecol Patbol 6:29-39, 1987. 2. Gershenson DM, SDva EG, Mitchell MF, Atkinson EN, Wharton IT. Transitional cell carcinoma of the ovary: A matched control study of advanced-stage patients treated with cisplatin-based chemotherapy. Am J Obstet Gynecol168:1178-1ll87, 1993. 3. Halgrimsson J, Scully RE. Borderline and malignant Brenner tumors of the ovary. A report of 15 cases. Acta Pathol Microbiol Scand A 80: suppl 233:56-66, 1972. 4. Hendrickson MR, Longacre TA. Classification of surface epithelial neoplasms of the ovary, page 234. In: Surface epithelial neoplasms of the ovary. Hendrickson MR (ed). State of the Art Reviews, volume 1, #2. Hanley and Belfus Inc. Philadelphia 1993. 5. Miles PA, Norris HJ. Proliferative and malignant Brenner tumors of the ovary. Cancer 30:174-186, 1972 6. Silva EG, Robey-Cafferty SS, Smith TL, eta!. Ovarian carcinomas with transitional cell carcinoma pattern. Am J Clin Pathol 93:457-465, 1990. 7. Robey SS, Silva EG, Gershenson DM, McLemore D, El-Naggar A, Ordonez NG. Transitional cell carcinoma in high-grade high-stage ovarian carcinoma. Cancer 63:839-847, 1989. 8. Roth LM, Dallenbach-Hellweg G, Czemobilsky B. Ovarian Brenner tumors. I. Metaplastic, proliferating, and of low malignant potential. Cancer 56:582-591, 1985. 9. Roth LM, Czemobilsky B. Ovarian Brenner tumors. II. Malignant. Cancer 56:592-601, 1985. 10. Roth LM, Gersell DJ, Ulbright TM. Ovarian Brenner tumors and transitional cell carcinomas: Recent developments. IntJ Gynecol Pathol l993;12:128-133. II. Young RH, Scully RE. Urothelial and ovarian carcinomas of identical cell types: Problems in interpretation. A report of three cases and review of the literature. Int J Gynecol Pathol7:197-211, 1988. 79 CASE 22 (Ace #26956) DIAGNOSIS: OVARIAN TUMOR OF PROBABLE WOLFFIAN ORIGIN DISCUSSION: This is an ovarian example of a distinctive female genital tract tumor that was designated •female adnexal tumor of probable wolffian origin" (FATWO) by Karirninejad and Scully who described nine cases in 1973 (9). Those tumors arose within the broad ligament or hung on a pedicle from it or the fallopian tube. They were judged to be of probable wo1ffian origin because their features were unlike those of mullerian type tumors and because of a location predominantly in sites where wolffian remnants are distributed. Another prominent feature in some of these cases was the presence of conspicuous basement membranes around the epithelial aggregates, a feature consistent with a wolffian derivation. The designation wolffian was given to these tumors to differentiate them from tumors of mullerian origin. The term mesonephroma was avoided because it has previously been.used, admittedly incorrectly, to designate both clear cell adenocarcinomas and yolk sac tumors of the ovary. Since the initial report of these tumors, approximately 65 cases have been reported, approximately 60% of which have been encountered in the broad ligament (1,4,5,8- 13), with most of the remainder in the ovary (7,12,14); rare examples have also been encountered in the retroperitoneum (2,12) and paravaginal region (6). The recently proposed alternate designation for these tumors- "retiform wolffian adenoma" (12) - is, in our opinion, not entirely appropriate considering that not all of these tumors have a retiform pattern, and that a minority of them have been clinically malignant. Although the term "FA TWO" was initially used to refer only to tumors occurring in the broad ligament, in the following discussion, it is used to refer to tumors in the latter site and within the ovary. Clinica.l Features Patients typically present with nonspecific clinical manifestations such as abdominal pain (occasionally due to torsion of the mass) and swelling, or have asymptomatic masses discovered on physical examination or at operation. The patients have ranged from 15 to 79 years of age; the median and mean ages of the patients in the few series of these tumors have been between 40 and 50 years. Only two FATWOs have been associated with spread at the time of operation: one tumor, •connected" to the ovary, was stage Im (10) and another tumor of definite ovarian origin was stage ill (14); one of these patients was alive and free of disease 4 years after chemotherapy (10) and the other was lost to follow-up (14). In addition to these two cases, five other cases have been associated with postoperative recurrence, hematogenous metastases, or both (1,2,8,13, 14) (thus approximately 10% of the reported FA TWOs have been clinically malignant). In one malignant case, the patient had three recurrences at 2, 5, and 12 years postoperatively, but was alive at 17 years (2). In three other cases, the metastases appeared at postoperative intervals that exceeded 5 years: hepatic metastases at 6.5 years in one case (13), pulmonary metastases at 8 years in another (14), and peritoneal metastases at 6 years in a third case (1). The last case is the only reported case of a fatal FATWO , and the patient's terminal 80 course was complicated by paraneoplastic hypercalcemia. Pathological Features On gross examination the tumors have ranged from 1 to 25 em in djameter (median 6 em in the largest series) and are typically rounded masses with bosselated external surfaces. Their cut surface may be solid or solid and cystic. The solid tissue varies from gray-white to tan or yellow and is usually firm or rubbery. Hemorrhage and necrosis are rare. On histological examination the low-power appearance of these tumors varies from cystic, to solid and cystic, to solid, depending on the relative proportion of cysts, closely packed tubules and diffuse sheets of epithelial cells. Several architectural patterns usually coexist in the same specimen, but generally one predominates. When cysts predominate there is often a striking sieve-like appearance on low power. Many of the cysts are empty but others contain watery eosinophilic fluid that is mucin-negative. The cysts are usually lin~ by flattened cells but occasionally by hobnail cells. Some tumors have a focally prominent hyalinized stroma and fibrous bands may separate cellular foci into lobules. The tubules may be solid or hollow and may be essentially indistinguishable from those of a Sertoli cell tumor. Occasionally, the tubules are large and dilated and may simulate the glands of an endometrioid adenocarcinoma. The cells lining the tubules are mostly cuboidal with scant cytoplasm but some are columnar and a few contain abundant pale cytoplasm. When the tumor cells grow diffusely they typically have scanty cytoplasm and may be spindle-shaped, sometimes focally simulating a spindle cell tumor. A reticulum stain may be helpful in showing an epithelial pattern in the solid areas. In otherwise solid foci, small spaces that resemble the vacuoles seen in adenomatoid tumor may be seen. 1n typical FATWOs, the nuclei lack significant atypicality and mitotic figures are rare. In contrast, most, but not all of the malignant tumors have had worrisome histologic features, including a high mitotic rate, focal nuclear atypicality, or areas of undifferentiated carcinoma. The lesional cells of FATWOs are immunoreactive for cytokeratin, but typically negative for EMA, B72.3, and CEA (12). Electron microscopic examination ofFA TWOs has shown thick peritubular basal lamina, an absence or paucity of cilia, Golgi, secretory granules, and glycogen, favoring a wolffian rather than mullerian origin. Differential Diagnosis The histology of the FATWO is sufficiently different from other tumors that may occur in the broad ligament that their correct recognition in this site is rarely a problem. In this differenti.al, it is noteworthy that Daya et a1 (3) have recently described endometrioid carcinomas of the fallopian tube that had patterns mimicking those of the FATWO (3). In contrast to the latter, however, the endometrioid carcinomas were intratubal and involved the tubal mucosa, as well as containing foci of typical endometrioid carcinoma, abortive squamous elements, intraluminal mucin, and focal nuclear atypicality and mitotic activity that exceeded that seen in most FATWOs. Additionally, the carcinomas were immunoreactive for EMA and B72.3, findings absent in FATWOs (12). 81 In the ovary, FATWOs may be a more challenging diagnosis because they may simulate several other ovarian tumors and in the ovary the former diagnosis tends not to come readily to mind. The tubular pattern of ovarian FATWOs causes them to be misinterpreted most often as Sertoli or Sertoli-Leydig cell tumors. The other patterns in FATWOs , bowever, are incompatible with a diagnosis of SLCfs. The absence of cells resembling Leydig cells and the absence of hormonal manifestations in the wolffian tumors also facilitate the diagnosis. The diffuse areas of some ovarian FATWO s may suggest the diagnosis of granulosa cell on low-power examination, but the cells of the former lack the angular appearance and grooved nuclei of the granulosa cell tumor, and other patterns seen in FATWOs are incompatible with the latter diagnosis. Focal patterns within FATWOs may raise the possibility of an endometrioid carcinoma, but the latter contain luminal mucin, lack sieve-like patterns, and exhibit greater degrees of nuclear atypicality and mitotic activity than seen in FATWOs Small cysts lined by flattened and hobnail-like cells and small foci of cells with glycogen in some ovarian FATWO s have raised a question of a clear cell carcinoma. These tumors, however, typically contain abundant glycogen, luminal mucin, sheets of clear cells, papillary areas, typical hobnail cell, and greater degrees of nuclear atypicality and mitotic activity that seen in FA TWOs. REFERENCES I. Abbot RL, Barlogie B, Schmidt WA. Metastasizing malignant juxtaovarian tumor with terminal hypercalcemia: A case report. Cancer 48:860-865, 1981. 2. Brescia RJ, Cardosos de Almeida PC, Fuller AF, Dickersin GR, Robboy SJ. Female adnexal tumor of probable Wolffian origin with multiple recurrences over 16 years. Cancer 56:1456-1461 ' 1985. 3. Daya D, Young RH, Scully RE. Endometrioid carcinoma of the fallopian tube resembling an adnexal tumor of probable Wolffian origin. Int J Gynecol Pathol 11 :. 122-130, 1992 4. Demopoulos RI, Sitelman A, Flotte T, Bigelow B. Ultrastructural study of female adnexal tumor of probable Wolffian origin. Cancer 46:2273-2280, 1980. 5. Flanagan AM, Kane JL, Normal-Taylor JQ. Female adnexal tumour of probable Wolffian origin. Case report. Br 1 Obstet Gynaecol94:270-272, 1987 6. Hinchney WW, Silva EG, Guarda LA, eta! . Paravaginal Wolftian duct (mesonephros) adenocarcinoma: A light and electron microscopic study. Am 1 Clin Pathol 80:539-544, 1983. 7. Hughesdon PE. Ovarian tumors of Wolffian or allied nature: their p1ace in ovarian oncology. J Clin Pathol 35:526-535, 1982. 8. Kao GF, Norris HI. Juxtaovarian adnexal tumor - A clinical and pathological study of 19 cases. Lab Invest 38:350-351, 1978 9. Kariminejad MH, Scully RE. Female adnexal tumor of probable Wolfflan origin. A distinctive pathologic entity. Cancer 31:671-677, 1973. 10. Prasad CJ, Ray JA, Kessler S. Female adnexal tumor fo Wolffian origin. Arch Pathol Lab Med 116:189-191, 1992 II. Sivathondan Y, Salm R, Hughesdon PE, Faccini JM. Female adnexal tumour of probable Wolffian origin. J Clio Pathol 32:616-624, 1979 12. Tavassoli FA, Andrade R, Merino M. Retiform Wolffian adenoma. In: Progress in surgical pathology, Vol. XI. Fenoglio-Preisor CM, Wolfe M, Rilke F, eds. New York: Field and Wood Medical Publishers, Inc. 121-136, 1990. 13. Taxy JB, Battifora H. Female adnexal tumor of probable Wolffian origin. Evidence for a low grade malignancy. Cancer 37:2349-2354, 1976. 14. Young RH, Scully RE. Ovarian tumors of probable Wolffian origin. Am J Surg Pathol 7:125-135, 1983. R? CASE 23 (Acc#2640S) DIAGNOSIS: STEROID CELL TUMOR (NOS) OF OVARY DISCUSSION: The terms "lipid cell tumor• and "lipoid cell tumor• have been applied to a heterogeneous group of ovarian neoplasms composed entirely of cells resembling typical steroid-hormone secreting cells, i.e. lutein cells, Leydig cells, and adrenocortical cells. Since some of these tumors contain little or no lipid, and neoplasms of other types may contain large amounts, the term •steroid cell tumor• is appropriate (22,34). It reflects both the morphologic features of the neoplastic cells and their propensity to secrete steroid hormones. These rare tumors (0.1% of all ovari.an neoplasms) are derived from ovarian stromal cells or their luteinized derivatives, from Leydig cells of hilar or stromal origin, and possibly from adrenocortical rest cells. The last origin is considered unlikely, except perhaps in very rare cases, as adrenocortical rests are extremely rare within the ovary (27) and h<~;ve not been described within the postnatal ovary. On the basis of knowledge or lack of knowledge of their origin, steroid cell tumors are classified as stromal luteomas, Leydig cell tumors (hilus cell tumor and Leydig cell tumor, non-hilar type), and steroid cell tumor, not otherwise specified (NOS); their major clinical and pathological features are compared in the Table at the end of the discussion. TUmors composed of steroid cells arising on a background of spindle-shaped cells, such as luteinized thecomas and stromal Leydig cell tumors (35), although closely related to steroid cell tumors, are more appropriately grouped with the sex cord-stromal tumors. STROMAL LUTEOMA The stromal luteoma, which accounts for approximately 20% of steroid cell tumors, is characterized by a location within the ovarian stroma and an absence of Reinke crystals, distinctive inclusions of Leydig cells (8,21). These neoplasms are of necessity small because larger tumors of this type cannot be identified as being confined within the ovarian stroma and fall into the category of steroid cell tumor NOS. In view of its location , the stromal luteoma must be viewed as arising from luteinized stromal cells or their precursors, the spindle cells of the ovarian stroma. The presence of luteinized stromal cells in the same or contralateral ovary (stromal hyperthecosis) in 90% of cases is supportive of a stromal origin (8), as is the occurrence of a lesion intermediate between stromal hyperthecosis and the stroma luteoma, nodular hyperthecosis. The latter is characterized by multiple nests of stromal lutein cells that are large enough to be visible on gross examination, but do not form a single tumorous mass. It is probable that many steroid cell tumors NOS are stromal luteomas that cannot be diagnosed as such because the topographical relation of the tumor to the ovarian stroma is no longer apparent. Clinical Features. Eighty percent of stromal luteomas occur in postmenopausal women (range 28-74 yrs; mean 58.4) (8). The most common initial manifestation (60%) is abnormal vaginal bleeding related to estrogen production by the tumor. In contrast to patients with Leydig cell tumors and steroid tumors NOS, only 12% of those with stromal luteomas are virilized (8). Underlying stromal hyperthecosis may contribute to the clinical picture. All the reported tumors have been benign. Pathological Features. On gross examination, the tumors are almost always under 3 em (mean, 1.3 em), and with rare"exceptions, are unilateral. They are well circumscribed, solid, gray-white or yellow-brown; one-third have red or brown areas. Microscopic examination reveals an unencapsulated, rounded nodule composed of polyhedral cells arranged diffusely or in nests and cords. In 20% of the cases, foci of degeneration within aggregates of neoplastic cells result in the formation of spaces that mimic acini or vascular lumens. The stroma is typically sparse, consisting of delicate connective tissue supporting a prominent capillary network. In about 20% of cases, however, a more prominent and occasionally hyalinized fibrous stroma is present. The cytoplasm of the neoplastic cells is abundant and usually eosinophilic and slightly granular but occasionally it is pale and foamy. Lipochrome granules are commonly present. The nuclei are typically small and round and contain single prominent nucleoli; mitotic figures are rare. As noted above, stromal hyperthecosi.s is present in the stroma of one or both ovaries in 90% of the cases, and hilus cell hyperplasia is seen in 25% of the cases (8). LEYDIG CELL TIJMORS Because Leydig cells cannot be distinguished from lutein or adrenocortical cells unless they contain Reinke crystals, the Leydig cell nature of a steroid cell tumor can be demonstrated conclusively only by the finding of these inclusions on light microscopic or electron microscopic examination. Since only 35-40% of I.:eydig cell tumors of the testis contain crystals on light microscopic examination (12), it is probable that a number of steroid cell tumors NOS are crystal-negative Leydig cell tumors that can not be specifically identified as such. Almost all ovarian Leydig cell tumors arise in the hilus from hilar Leydig cells (hilus cells), which can be identified in over 80% of normal adult ovaries (24). Rare Leydig cell tumors that are located within the ovarian stroma are referred to as Leydig cell tumors, nonhilar type. Clinical Features. Hilus cell tumors, which account fc:>r approximately 15% of steroid cell tumors (17), like stromal luteomas usually occur in postmenopausal patients (average age, 58 years; range 32-82). They are only rarely palpable (5, 10,15,17,20). Androgenic manifestations are present in 83% of the cases ( 17) and in some patients have been present for many years prior to presentation; the androgenic changes are typically less abrupt in onset and milder than those associated with Sertoli Leydig cell tumors (33). The patients usually have a high serum level of testosterone. Virilizing changes regress but may not disappear following removal of the U)mor. Estrogenic changes may also be present and are attributable to secretion of estrogens by the tumor, peripheral conversion of tumor-derived androgens, associated stromal hyperthecosis, or a combination of these factors. Almost all the hilus cell tumors that have been reported have been benign; only one purported malignant case in the literature merits serious consideration (6), but in that case Reinke crystals were not convincing! y documented in the illustrations. 84 Pathological Features. Hilus cell tumors are typically reddish-brown to yellow but may be dark-brown to almost black. They are characteristically small (mean diameter, 2.4 em), circumscribed nodules centered in the ovarian hilus; they may extend for varying distances into the ovarian stroma (17). Rare tumors have been bilateral (1). Microscopic examination reveals an unencapsulated nodule composed of steroid cells typically growing diffusely but occasionally growing as nests or nodules intersected by fibrous stroma. The tumor cells typically contain abundant granular eosinophilic cytoplasm; occasional cells contain foamy cytoplasm suggesting the presence of lipid. Cytoplasmic lipochrome pigment, which is usually sparse, is present in most cases. Cellular clustering with abvascular pooling of cytoplasm and stromal hyalinization is present in half the cases. Degenerative changes similar to those seen in stromal luteomas may be present; sometimes the spaces contain cells with abundant spongy cytoplasm, and the stroma: between the spaces may be prominent and fibrous. An unusual feature in one-third of cases is fibrinoid necrosis of the vessel walls. The round or angular nuclei are often hyperchromatic and contain single small nucleoli. The nuclei may exhibit some variation in size and shape, but this is usually not marked; occasional multinucleated cells may be observed. Invagination of the cytoplasm into the nucleus may give the latter a hollow appearance. Rare mitotic figures are present in an occasional case. Elongated eosinophilic Reinke crystals of varying sizes are present in varying numbers but may require prolonged search for their identification. The have tinctorial properties that differ slightly from those of red blood cells, which can be confused with Reinke crystals when compressed and elongated within capillaries. Special stains such as iron hematoxylin and trichrome may make these inclusions more conspicuous. On electron microscopic examination the crystals are needle shaped structures when cut longitudinally or hexagonal when cut in cross section (2:3). lntracyto· plasmic spheres, probably crystal 'Precursors, are also tY'Jlically present, but are not specific for the diagnosis of hilus cell tumor. Stromal hyperthecosis, hilus cell hyperplasia, or both, are associated findings in occasional cases. A diagnosis of crystal-negative or probable hilus cell tumor is suggested if a crystal-free steroid tumor has a predominant location in the hilus and one or more of the following features: a juxtaposition to non-medullated nerve fibers like that of normal hilus cells, a background of hilus cell hyperplasia, cellular clustering with intervening acellular zones., and fibrinoid change in the vessel walls ( 17). Only four non·hilar Leydig cell tumors have been feported, ,and their features are similar to those of hilus cell tumors except for their location (19). An ovarian stromal derivation of these tumors is supported by the finding of stromal Leydig cells in rare otherwise typical cases of stromal hyperthecosis. In some cases, it may be impossible to determine if a Leydig cell tumor is a hilus cell tumor or a Leydig cell tumor, non-hilar type; in such cases a diagnosis of Leydig cell tumor NOS is appropriate. 85 STEROID CELL TUMOR NOS Clinical Features. Tumors in this category account for approximately 60% of steroid cell rumors (9,28). They occur at any age but the patients are typically younger (mean age 43 yrs) than those with other types of steroid cell tumor. In contrast to stromal luteomas and Leydig cell tumors, they may occur in children. They may cause heterosexual pseudoprecocity (4) and less commonly isosexual pseudoprecocity (3,9). Steroid cell tumors NOS are associated with androgenic changes, which may be of many years' duration, in 52% of the cases. Eight percent of the tumors are estrogenic and occasional examples are progestagenic. Four tumors have secreted cortisol and caused Cushing's syndrome (9,31), and three others have been associated with elevated cortisol levels in the absence of clinical manifestations of the syndrome. Rare tumors have been associated with hyperaldosteronism (1 4), hypercalcemia, erythrocy- tosis or ascites, the latter on a basis probably similar to that seen in association with ovarian fibromatous tumors. The remaining cases have been unassociated with endocrine or paraendocrine manifestations. Hormone studies performed in·patients with androgenic changes, Cushing's syndrome, or both, typically show elevated urinary levels of 17-ketosteroids and 17-hydroxycor ticosteroids as well as increased serum levels of testosterone and androstenedione. ln 20% of cases, extraovarian spread of tumor has been apparent at the time of operation; three of the four patients with Cushing's disease had extensive intra-abdominal metastatic tumor (31). In the two largest series, the proportion of tumors that were clinically malignant was 25% (28) and 43% (9); rare tumors recur as many as 19 years postoperatively. Patients with clinically malignant tumors were on average 16 years older than patients with benign tumors in one series (9); no malignant steroid cell tumors have been reported in the first two decades of life. Because of the high frequency of malignancy of steroid cell tumors NOS, careful staging should be performed. In a young patient with stage IA disease, unilateral oophorectomy is adequate, but follow-up study is essential and should include measurement of hormone levels, particularly those demonstrated to have been elevated before the removal of the primary tumor. In peri menopausal or postmenopausal patients, hysterectomy with bilateral salpingo-oophorectomy is the procedure of choice. In patients with high-stage disease, tumor debulking is advisable. Radiation therapy and chemotherapy have been generally disappointing but effective in occasional patients (9). Pathological Features. The tumors are typically solid, well circumscribed, occasionally lobulated, and have ranged from 1.2 to 45 em (mean 8.4 em) in diameter (9); only approximately 5% of them are bilateral. They are orange or yen'ow if large amounts of intracytoplasmic lipid are present, red to brown if the cells are lipid-poor, or dark brown to black if large quantities of intracytoplasmic lipochrome pigment are present. Necrosis, hemorrhage, and cystic degeneration are occasionally observed. On microscopic examination, the cells are typically arranged diffusely but occasionally they grow in nests, irregular clusters, thin cords and columns; a rich vascular network is usually evident. The stroma is inconspicuous 86 in most cases but in approximately 15% of the tumors a fibrous stroma which may be hyalinized is present. Rarely the stroma is edematous or myxoid with tumor cells being loosely dispersed within it. A minor fibromatous component, necrosis and hemorrhage may be seen. Exceptionally the stroma may exhibit calcification and even psammoma body formation. The polygonal to rounded tumor cells have distinct cell borders, centtal nuclei, and moderate to abundant amounts of cytoplasm that varies from eosinophilic. and granular Qipid-free or lipid-poor) to vacuolated and spongy (lipid-rich); lipid was present in 75% of the tumors stained for this material in one series (9). Rarely, cells with large fat droplets have a signet-ring appearance. Intracytoplasmic lipochrome pigment has been present in 40% of the tumors. In 60% of cases in the largest series (9), nuclear atypia was absent or slight and mitotic activity was low (1-2 MF/10HPFs). In the remaining cases, grade 1 to 3 nuclear atypia, usually associated with a parallel increase in mitotic activity (up to 15 MF/lOHPFs), was present. Ultrastructural examination in rare cases has demonstrated abundant smooth endoplasmic reticulum in the cytoplasm of the tumor cells (1'3). The best pathological correlates with a malignant behavior in one series (9) were: 2 or more mitotic figures per 10 HPF (92% malignant); necrosis (86% malignant); a diameter of 7 em of greater (78% malignant); hemorrhage (77% malignant); and grade 2 or 3 nuclear atypia (64% malignant). Occasional tumors that appear cytologically benign, however, may be clinically malignant. The metastatic tumors may appear similar to the primary, but may be more poorly differentiated in other cases. Differential Diagnosis of Steroid Cell Tumors Steroid cell tumors, especially those in the NOS category, may be confused with other neoplasms of diverse types on rare occasions, particularly extensively luteinized granulosa cell tumors and thecomas, lipid-rich Se.rtoli cell tumors, clear cell carcinomas (particularly those of the oxyphil type), hepatoid yolk sac tumors, hepatoid carcinomas, metastatic renal cell carcinomas, adrenocortical carcinomas and hepatocellular carcinomas, primary and metastatic melanomas, and struma ovarii. The focal presence of non luteinized cells in granulosa ceU tumors and thecomas, as well as the characteristic cytologic features and patterns of these neoplasms, and the finding of abundant reticulum in thecomas, are of help in the identification of these tumors. The distinction of a lipid-rich Sertoli cell tumor with a prominent diffuse pattern from a steroid cell tumor depends on identifying areas with a tubular pattern in the former (30). In contrast to steroid cell tumors, the clear cells of clear cell carcinomas and metastatic renal ceiJ carcinomas have glycogen-rich cytoplasm and eccentric nuclei. Also, the presence of other patterns (tubular, glandular, papillary) inconsistent with a steroid cell tumor, generally facilitates the differential diagnosis. Radiologic studies to rule out a renal cell carcinoma may also be helpful. Oxyphilic clear cell carcinomas (32), hepatoid yolk sac tumors (18), and hepatoid carcinomas (II) are all characterized by neoplastic cells with abundant eosinophilic cytoplasm. The first of these tumors generally exhibits epithelial patterns, may 87 contain glandular lumens, and is almost always accompanied by the more common patterns and cell types of clear cell carcinoma. The hepatoid tumors also have epithelial patterns and may contain glandular lumens; they are characterized by immunohistochemical staining for AFP. We are not aware of any cases of. hepatocellular carcinoma or adrenocortical carcinoma that have presented as an ovarian mass although such an event is conceivable. Primary and metastatic melanomas can simulate steroid cell tumors if amelanotic, and if they are pigmented, the pigment granules may be confused with the lipochrome granules of a steroid cell tumor. Melanomas generally have more malignant nuclear features than steroid cell tumors. Special staining, including immunohistochemical staining, may be helpful in difficult cases. The rare struma ovarii that takes the form of an oxyphil (Hurthle cell) adenoma may resemble a steroid cell tumor; an association with other teratomatous elements, the presence of colloid, and immunostaining for thyroglobulin are features that should enable one to distinguish these two tumors. The extensive formation of degenerative spaces in occasional steroid cell tumors may cause confusion with an adenocarcinoma and· more often a vascular tumor. Awareness of this phenomenon, which is often accompanied by the presence of lipid-laden cells, chronic inflammatory cells, or fibrous septa surrounding these spaces, or a combination of these features; as well as the finding of typical steroid cell tumor elsewhere in the specimen, should facilitate the diagnosis. Electron microscopic examination of most of the neoplasms that simulate steroid cell tumors should disclose strikingly different features. Finally, the presence of absence of endocrine manifestations and their nature may serve as important clinical clues to the diagnosis. A nonneoplastic lesion, the pregnancy luteoma (16,25), can also closely resemble a steroid cell tumor. Pregnancy luteomas are hyperplastic nodules of lutein cells that are dependent on the hCG stimulation of pregnane~. are discovered almost exclusively during the third trimester, and involute spontaneous! y after the termination of pregnancy. They can attain diameters of up to 30 em. They may also be associated with virilization of the mother, female infant, or both. Unlike steroid cell tumors, however, pregnancy luteomas are bilateral in about one-third of the cases and multiple in almost half of them. On microscopical examination, the cells have abundant eosinophilic cytoplasm with little or no cytoplasmic lipid, and the nuclei often show mitotic activity, with up to 7 MFs/lOHPFs (mean 2-3). In contrast, a steroid cell tumor with minimal cytologic that resembles a pregnancy luteoma usually contains only rare mitotic figures. It may be impossible to distinguish a lipid-poor or lipid-free steroid cell tumor NOS from a solitary pregnancy luteoma, but if the lesion is encountered during the third trimester it is usually presumed to be the latter unless clearly proven otherwise. Extra-ovarian Steroid Cell Tumors in the Female Genital Tract Exceptionally, steroid cell tumors originate in the broad ligament. Adrenocortical rests have been found in the broad ligament in 27% of hysterectomy specimens by one investigator (7), and could be the source of these rare tumors. Adrenocortical rests may also undergo 88 hyperplasia in the congenilal adrenogenilal syndrome simulating a small steroid cell tumor. Multiple hyperplastic nodules in the vicinity of the ovaries, presumably of adrenal rest origin, can develop in Nelson's syndrome, sometimes associated with virilization (2,29) and resemble small steroid cell tumors on microscopic examination. The clinical background and location of these lesions enable one to differentiate them from ovarian steroid cell tumors. CLINICAL AND PAmOLOGICAL FINDINGS OF STEROID CELL 1lJMOBS • STROMAL CRYSTAL+ CRYSTAL- STEROID LUTEOMA HILUS CELL HILUS CELL CELL TUMOR TUMOR TUMOR, NOS NO. OF CASES 25 12 9 63 AGE RANGE 28-74 32-75. 34-82 2-80 (MEAN) (58) (57) (61) (43) VIRILIZATION 12% 83% 33% 52% IHIRSUTISM ESTROGENIC 60% 0 44% 8% MANIFESTATIONS ANDROGENIC MANIFESTATIONS (DURATION) 1.5-5 y 2-20 y 1-24 y 0.5-30 y NO ENDOCRINE 20% 17% 23% 27% ABNORMALITY CUSHING'S SYNDROME 0 0 0 ~% DIAMETERCM 1.3 2.4 1.8 8.4 (MEAN) STROMAL 92% 42% 67% 23% HYPERTHECOSIS ENDOMETRIAL HYPERPLASIA OR CARCINOMA 88% 8% 33% 24% *FROM REFERENCE 17 89 REFERENCES 1. Baramski TA, Leddy AL, Woodruff JD. Bilateral hilus cell tumors of the ovary. Obstet Gynecol 1983;62: 128-131. 2. Baranetsky NG, Zipser RD, Goebelsmann U et al. Adrenocorticopin-de~ndent virilizing paraovarian tumors in Nelson's syndrome. J Clin Endocrinol Metab 1979;49:381-386. 3. Campbell PE, Danks DM. Pseudoprecocity in an infant due to a luteoma of the ovary. Arch Dis Child 1963;38:519-523. 4. Case Records of the Massachusetts General Hospital (Ca~ 22-I 982). New England J Med 1982;306: 1348-1355 5. Dunnihoo DR, Grieme DL, Woolf RB. Hilar cell tumors of the ovary. Report of 2 new cases and a review of the world literature. Obstet Gynecol 1966;27:703-713. 6. Echt CR, Hadd HE. Androgen excretion patterns in a patient with a metastatic hilus cell tumor of the ovary. Am J Obstet Gynecol 1968; 100: 1055-1061. 7. Falls JL. Accessory adrenal cortex in the broad ligament. Incidence and functional significance. Cancer 1955;8:143-150. 8. Hayes MC, Scully RE. Stromal luteoma of the ovary: A clinicopathological analysis of 25 cases. Int J Gynecol Patholl987;6:313-321. 9. Hayes MC, Scully RE. Ovarian steroid cell tumor (not otherwise specified): A clinicopathological analysis of63 cases. Am J Surg Pathol1987;11:835-845. )0. Ichinohasama R, Teshima S, Kishi K, et al. Leydig cell tumor of the ovary associated with endometrial carcinoma and containing 17beta-hydroxysteroid dehydrogenase. Int J Gynecol Pathol 1989;8:64-71. 11. Ishikura H, Scully RE. Hepatoid carcinoma of the ovary. A newly described tumor. Cancer 1987;60:2775-2784. 12. Kim I, Young RH, Scully RE. Leydig cell tumors of the testis. A clinicopathological ·analysis of 40 cases and review of the literature. Am J Surg Pathol 1985 ;9: 177-192. 13. Koss LG, Rothschild EO, FleisherM, Francis JE. Masculinizing tumor of the ovary, apparently with adrenocortical activity. Cancer 1969;23: 1245-1258. 14. Kulkarni JN, Mistry RC, Kamal MR, Chinoy R, Lotlikar RG. Autonomous aldosterone-secreting ovarian tumor. Gynecol Oncol1990;37:284-289. 15. Motlik K, Stejskalova A, Stekskal J, Kobilkova J, Starka L. Hilus cell tumors of the ovary. Cesk Patol 1988;24: 144-160. 16. Norris HJ, Taylor HB. Nodular theca-lutein h~rplasia of pregnancy (so-called "pregnancy luteoma"). A clinical and pathological study of 15 cases. Am J Clin Pathol 1966;47:557-566. 17. Paraskevas M, Scully RE. Hilus cell tumor of the ovary: A clinicopathological analysis of 12 .R~i~ke crystal-positive and nine crystal-negative cases. Int J Gynecol Pathol 1989,8.299-310. 18. Prat J, Bhan AK, Dickersin RG , Robboy SJ, Scully RE. Hepatoid yolk sac tumor of the ovary (endodermal sinus tumor with hepatoid differentiation). Cancer 1982;50:2355-2368. 19. Roth LM, Sternberg WH. Ovarian stromal tumors containing Leydig cells. II. Pure Leydig cell tumor, non-hilar type. Cancer 1973;32:952-960. 20. Salm R. 0 •1arian hilus-cell tumours: their varying presentations. J Pathol 1974;113:117-127. 21. Scully RE. Stromal luteoma of the ovary. Cancer 1964;17:769-778. 22. Scully RE. Tumors of the ovary and maldeveloped gonads: Atlas of tumor pathology, second series, Fascicle 16, Armed Forces Institute of Pathology, Washington, D.C., 1979, pp 215. 23. Schnoy N. Ultrastructure of a virilizing ovarian Leydig-cell tumor. Hilar cell tumor. Virchows Arch (Pathol Anat) 1982;397;17-27. 24. Sternberg WH. The morphology, androgenic function, hyperplasia and tumors of the human ovarian hilus cells. Am J Pathol 1949;25:493-521. 25. Sternberg WH, Barclay DL. Luteoma of pregnancy. Am J Obstet Gynecol 1966;95: 165-184. 90 26. Sternberg WH, Roth LM. Ovarian stromal tumors containing Leydig cells. I. Stromal-Leydig cell tumor and non-neoplastic transformation of ovarian stroma to Leydig cell. Cancer 1973; 12:940-951. 27. Symmonds DA, Driscoll SG. An adrenal cortical rest within the fetal ovary. Report of a case. Am J Clin Pathol 1973;60:562-564. 28. Taylor HB, Norris HJ. Lipid cell tumors of the ovary. Cancer 1967;20: 1953-1962. 29. Wild RA, Albert RD, Zaino RJ, Abrams CS. Virilizing paraovarian tumors: A consequence of Nelson's syndrome? Obstet Gynecol 1988;71: 1053-1056. 30. Young RH, Scully RE. Ovarian Sertoli cell tumors. A report of ten cases. Int J Gynecol Pathol 1984;2:349-363. 31. Young RH, Scully RE. Ovarian steroid cell tumqrs associated with Cushing's syndrome: a report of three cases. Int J Gynecol Patholl987;6:40-48. 32. Young RH, Scully RE. Oxyphilic clear cell carcinoma of the ovary. A report of nine cases. Ali! J Surg Pathol1987;11:661-667. 33. Young RH, Scully RE. Sex cord-stromal tumors, steroid cell tumo:rs and other ovarian tumors with endocrine, paraendocrine and paraneoplastic manifestations. I: Blaustein's Pathology of the Female Genital Tract. RJ Kurman (Ed.) Springer-Verlag, New York, 1987, pp. 607-658. 34. Young RH, Scully RE. Steroid cell tumors of the ovary: An update. Progress in reproductive and urinary tract pathology,· 1990;2: :49-68 35. Zhang J, Young RH, Arseneau J, Scully RE. Ovarian stromal tumors containing lutein or Leydig cells (luteinized thecomas and stromal Leydig cell tumors) - A clinicopathological analysis of fifty cases. lnt J Gynecol Pathol 1982; 1:275-285. 91 CASE 24 (Ace #27347) DIAGNOSIS: MULTILOCULAR PERITONEAL INCLUSION CYST DISCUSSION: PeritoneaJ inclusion cysts typically occur in the peritoneal cavity of women in the reproductive age group.l-10 Rarely they occur in males and similar lesions have been described in the pleural cavity.ll-13 Some are incidental findings at laparotomy in the form of single or multiple, small, thin-walled, translucent, unilocular cysts that may be attached or lie free in the peritoneal cavity. Occasionally they may involve the round ligament simulating an inguinal hemia. l4 The cysts have a smooth lining, contents that vary from yellow and watery to gelatinous, an uncomplicated histologic appearance of a single layer of typically flattened, benign-appearing .mesothelial. cells, and pose no diagnostic problems. While most of these unilocular mesothelial cysts are probably reactive in origin, some of those located in the mesocolon, mesentery of the small intestine, retroperitoneum, and splenic capsule may be developmentaJ.10 Multilocular cystic masses that may measure up to 20 em in diameter and which are lined by mesothelial cells are referred to as "multilocular peritoneal inclusion cysts" (MPICs), "benign cystic mesotheliomas", "inflammatory cysts of the peritoneum", or "postoperative peritoneal cysts" .1-10 MPICs are usually associated with clinical manifestations, most commonly lower abdominal pain, a palpable mass, or both. They are usually attached to pelvic organs and may simulate a cystic ovarian tumor on clinical examination, at laparotomy, 8 or even on pathological examination; 15 the upper abdominal cavity, the retroperitoneum, or hernia sacs may also be involved. lO Unlike the smaller unilocular cysts, the septa and walls of MPICs may contain considerable amounts of fibrous tissue. Their contents may resemble those of the unilocular cysts or be serosanguinous or bloody. On microscopic examination, MPICs are typically lined by a single layer of flat to cuboidal, occasionally hobnail-shaped mesothelial cells with generally bland nuclear features, although a degree of reactive atypia is not infrequent. The lining cells occasionally form small papillae and cribriform patterns or undergo squamous metaplasia. 9 • I 0 In some cases, mural proliferations of typical or atypical mesothelial cells arranged singly, as gland-like structures or nests, or in adenomatoid tumor-like patterns may be encountered, creating infiltrative patterns that should not be confused with a malignant tumor. 8-10 Occasional vacuolated meso.thelial cells in the stroma may simulate slgnet-ring cells.lO The septa typically cpnsist of a loose, fibrovascular connective tissue with a sparse inflammatory infiltrate. In some cases; marked acute and chronic inflammation, abundant fibrin, broad bands of granulation and fibrous tissue, and evidence of recent and remote hemorrhage may be seen in the cyst walls. A history of a prior abdominal operation, pelvic inflammatory diSea.se, endometriosis, or combinations thereof, was present in 84% of patients in one series,10 suggesting a role for inflammation in the pathogenesis of the cysts. 8-10,16-18 An infl'ammatory pathogenesis is also 92 supported by the occurrence of cases jn which the dividing line between florid adhesions association with inflammation and a MPIC may be difficult. With one exception,l3 there has been no association with asbestos exposure. Follow-up examinations have not disclosed a malignant behavior in cases thai'we consider MPICs, but in as many as one-half of the cases the lesions have recurred one or more times from months to many years postoperatively .tO It is likely, however, that at least some of these "recurrences" are the result of newly-formed postoperative adhesions. For these reasons (while accepting that low grade cystic mesotheliomas occur rarely, see below), we prefer the designation "multilocular peritoneal inclusion cyst" to "benign cystic mesothelioma" for such lesions, until there is convincing evidence for their neoplastic nature. Differential Diagnosis. Aside from the contentious problem of their distinction from "true" cystic mesotheliomas (see below), MPICs are confused most often with multilocular cystic lymphangiomas.! In contrast to MPICs, the latter typically occur in children, more frequently in boys, and are usually extrapelvic, being almost always localized to the mesentery of the small intestine, omentum, mesocolon, or retroperitoneum. Their contents may be chylous, and on histological examination lymphoid aggregates and smooth muscle, which are rare findings in MPICs, ar.e typically present within their walls. In problematic cases, immunohistochemical stains to distinguish between endothelial and mesothelial cells may be useful. Another lesion that merits consideration in the differential diagnosis of MPICs is the rare multicystic adenomatoid tumor. I9,20 In contrast to MPICs, the latter typically involve the myometrium, contain foci of typical adenomatoid tumor, and lack prominent numbers of inflammatory cells. A detailed discussion of other lesions in the differential diagnosis of MPICs has recently been presented elsewhere. l 0 93 REFERENCES I. Carpenter HA, Lancaster IR, Lee RA. Multilocular cysts of the peritoneum. Mayo Clin Proc 1982;57:634-638. 2. Schneider V, Partridge JR, Gutierrez, et al. Benign cystic mesothelioma involving the female genital tract: reP.Ort of four cases. Am J Obstet Gynecoll983;145:355-359. 3. Katsube Y, Mukai K, Stlverberg SG. Cystic mesothelioma of the peritoneum. A report of five cases and review of the literature. Cancer 1982;50: 1615-1622. 4. Dumke K, Schnoy N, Specht G, et al. Comparative light and electron microscopic studies of cystic and papillary tumors of the peritoneum. Virch Arch A 1983;399:25-39. 5. Mennemeyer R, Smith M. Multicystic, peritoneal mesothelioma. A report with electron microscopy of a case mimicking intra-abdominal cystic hygroma (lymphangioma). Cancer 1979;44:692-698. 6. Miles JM, Hart WR, McMahon IT. Cystic mesothelioma of the peritoneum. Report of a case with multiple recurrences and review of the literature. Cleve Clin Q 1986;53:109-11 4. 7. Moor JH Jr, Crum CP, Chandler JG, Feldman PS. Benign cystic mesothelioma. Cancer 1980;45 :2395-2399. 8. McFadden DE, Clement PB. Peritoneal inclusion cysts with mural mesothelial proliferation. A clinicopathological analysis of six cases. Am J Surg Pathol 1986;10:844-854. 9. Weiss SW, Tavassoli FA. Mulicystic mesothelioma: An analysis of pathologic findings and biologic behavior in 37 cases. Am J Surg Pathol1988;12:737-746. 10. Ross MJ, Welch WR, Scully RE. Multilocular peritoneal inclusion cysts (so-called cystic mesotheliomas). Cancer 1989;64: 1336-1346. II. Blumberg NA, Murrary JF. Multicystic peritoneal mesothelioma. SA Med 1 1981 ;59:85-86. 12. Sienkowski I , Russell AJ, Dilly SA, et al. Peritoneal cystic mesothelioma: an electron microscopic and immunohistochemical study of two male patients. J Clio Pathol 1986;39:440-445. 13. Kjellevold K, Nesland JM, Holm R, et al. Multicystic peritoneal mesothelioma. Path Res Pract 1986;181:767-771. 14. Harper GB Jr, Awbrey BJ, Thomas CG Jr, et al. Mesothelial cysts of the round ligament simulating inguinal hernia. Report of four cases and review of the literature. Am J Surg 1986; 151:515-517. 15. Jones EG, Donovan AJ. Adenomatoid tumor of the ovary versus mesothelial reaction. Am J Obstet Gynecol 1965;92:694-698. 16. Demopoulos RI, Kahn MA, Feiner HD. Epidemiology of cystic mesotheliomas. lnt J Gynecol Pathol 1986;5!379-381. 17. Gussman D, Thickman D, Wheeler JE. Postoperative peritoneal cysts. Obstet Gynecol 1986;68:53S-55S. 18. Lees RF, Feldman PS , Brenbridge NAG , et al. Inflammatory cysts of the pelvic peritoneum. Am J Roentgenol1978; 131 :633-636. 19. Iwasaki I, Yu TJ, Tamaru J, Asanuma K. A cystic adenomatoid tumor of the uterus simulating lymphangioma grossly. Acta Pathol Jpn 1985;35:989-993 20. Bisset DL, Morris JA , Fox H. Giant cystic adenomatoid tumor (mesothelioma) of the uterus. Histopathology 1988; 12:555-558. 94