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Home , Endometrioid tumor, Uterine fibroid

CALIFORNIA TUMOR TISSUE REGISTRY

104th SEMI-ANNUAL SEMINAR

ON

TUMORS OF THE AND

CASE HISTORIES

PRELECTOR:

Fattaneh A. Tavassoll, M.D. Chairperson, GYN and Breast Armed Forces Institute of Pathology Washington, D.C.

June 7, 1998 Westin South Coast Plaza Costa Mesa, California

CHAIRMAN:

Mark Janssen, M.D. Professor of Pathology Kaiser Pennanente Medical Center Anaheim, California CASE HISTORIES 104ru SEMI-ANNUAL SEMINAR

CASE #t- ACC. 2S232 A 48-year-old, gravida 3, P.ilra 3, female on oral contraceptives presented with and amenorrhea of three months duration. Initial treatment included Provera and oral contraceptives. Pelvic lev~aled a 7 x 5 em right ovarian and a possible small . Six months later, she returned with a large malodorous mass protruQing through the <;>fan enlarged uterus. The 550 gram uterine specimen was 13 x 13 x 6 em. The was 4 em thick. A 8 x 6 em polypoid, pedunculated mass protruded through the cervix. The cut surface of the mass was partially hemorrhagic, surrounded by light tan soft tissue. (Contributed by David Seligson, M.D.)

CASE #2- ACC. 24934 A 70-year-old female presented with of recent onset. A total abdominal and bilaterl!] salpingo-oophorectomx were performed. The 8 x 9 x 4 em uterus was symmetrically enlarged. The ·endometrial cavity was dilated by a 4.5 x 3.0 x4.0 em polypoid mass composed of loculated, somewhat mucoid tissue. Sections through the broad stalk revealed only superficial attachment to the myometrium, without obvious invasion. (Contributed by Paul Ortega, M.D.)

~ASE #3- ACC. 28293 An 80-year-old female presented with complaints of pelvic pain. A hysterectomy was performed. The uterus witl!out adnexa weighed 223 grams and measured 7.6 x 9.2 x 6.2 em. The serosal surface was fairly smooth tan. However, at the parametrial margins there were fleshy tan protrusions. The endometrial cavity was fairly symmetrical with a slightly shaggy, red-tan surface. The myometrium was up to 2.5 em thick. There was some accentuation of the trabecular architecture. (Contributed oyKenneth Frankel, M.D.)

CASE#4- ACC.1753l A 17Cyear-old, gravida, 1 para I female presented \vith abdominal swelling and pain. Physical examination revealed an enlarged uterus of approximately 8 weeks size, with bilateral ovarian masses. Chest x-ray showed small round lesions scattered throughout both lung fields. A test was positive in a high dilution. Afte( two courses ofmethotrexate, the uterus appeared to decrease in size, although the ovarian were still palpable. The uterine specimen measured IS x 1.2 x 7 em. In the right and left cornu were two irregular, !Hable, yellow rumor masses invading the myometrium but not penetrating the serosa. each measuring 2 x 2 x 2 em and blending with overlying . Throughout the myometrium were small yellow, fairly well-defined nodules. (Contributed by Milton Bassis, M.D.)

CASE #5- ACC. 23764 A 57-year-old Caucasian female presented \vith periumbilical and supra-pubic pain. Physical examination 1evealed a fixed uterus enlarged to four months gestation. The uterus with attached adnexa weighed 280 grams. The uterus measured 9;S x 5.0 x 4.0 em, but the cervical portion was much larger than the fundus and had a diameter of 6.0 Cot The mucosa of the portio vaginalis was somewhat granular and studded with millimeter-sized pale yellow papules. The external os was I .5 em broad.and had prominent red-tan tissue on the anterior lip. The lower portion 6fthe endometrial canal, as well as the cervical canal, was lined by soft, pale gray-tan gelatinous material up to 0.8 em thick. !his same type ofmaterial was pre.sent throughout the.wall of the cervix. (Contributed by Melvin Ariderson, MD.)

CASE 1«>- ACC. 28375 A 22-year-old Caucasian female presented with irregular uterine bleeding and an abnormal Pap smear. showed a fungating cervical mass. Patient's past medical history was unremarkable. She.had used BCP at age 16 for several months and was on Triphasil (combination BCP containing and ethinylestradiol) for nine months prior to her presentation. A hysterectomy was performed. The anterior and lateral cervical walls were replaced by a fungating papillary mass. (Contributed by Fattaneh Tavassoli, M.D.)

CASE #7-ACC. 28376 A 14-year-old female presented \vith weight loss and fever of unknown origin. On physical examination, the uferus was enlarged and fixed to surrounding tissues. At , a massive tumor involved the uterus and extended to the upper vagina and parametrium. (Contributed by Fananeh Tavassoli, M.D.) CASE IDSTORIES 1 04n1 SEJ\<11-ANNUAL SEMINAR

CASE 118- ACC. 28377 A 71-year-old female was found to have a uterine mass on routine physical examination. A hysterectomy and bilateral salpingo-oophorectomy were performed. The anterior fundus oontained a hemorrha&ic, panly necrotic, 7 x 8 em mass. The endometrial surface was intact and was not involved by tumor, but did have a small polyp (0. 7 em in maximum diameter). (Contributed by Fattaneh Tavassoli, M.D.)

CASE 119- ACC. 18101 A 42-year-old gravida 5, para 5, Caucasian female present.ed with an enlarging pelvic mass of several months' duration. Recent Pap smear was negative. Menses had been irregular for the last six months. Physical examination revealed an , 24-26 weeks in size, in the left adnexal area. T AH-BSO was performed. The 1400 gram left was 30 x 25 em. The external surface was smooth and gray with no excrescences. The cut surface showed a soft yellow to tan lobulated rumor mass with a few small foci ofhemorrhage and a few small cysts. (Contributed by Avrum Jacobson, M.D.)

CASE 1110- ACC. 22614 A 5-year-old female presented with a six month history of breast enlargement and development ofaxillary hair. She also had an abdominal mass which filled the abdomen. Preoperative plasma FSH was Jess than 1.0 ml U/ml (normal 0 to 6 ml U/ml), lureiniz.ing 2.6 ml U/ml (normal 0 to 6 ml U/ml). HCG was non-detectable. Total was 27 meg. 24-hour urine was oomposed ofEstrOne 7 mcg/24-hours, S meg/24-hours, and Estriol IS mcg/24-hours (normally trace amounts only in prepubertal females). Plasma Estriol was 1.1 mglml (normal less than 0.2 mglml). At laparotomy, a smooth, finn, weU-encapsulated, freely mobile rumor replaced the left ovary. The 14 x 12 x 10 em mass had a soft, variegated red-yellow, and finely cystic cut surface, marked by interlacing narrow fibrous bands. (Contributed by T. J. Cosgrove, MD.)

CASE Ill 1 - ACC. 28378 A 24-year-old Caucasian female presented with a pelvic mass. The right ovary was enlarged on physical examination. At laparotomy, a 17 x 14 x 8 em right ovary was removed. It weighed II 00 grams. The cut surface was yellowish, solid with focal cystic areas and a 4.0 em area ofnecrosis . There was no gross peritoneal or omental seeding. Three months earlier, the patient bad had a C-section; at that time, both ovaries and rubes appeared normal (Contributed by Fananeh Tavassoli, MD.)

CASE 1112-ACC. 22743 A 32-year-old Caucasian female presented with severe lower quadrant pain and accompanying backache. Physical examination revealed a cystic mass of the right ovary. An emergency TAH·BSO was performed. (Contributed by Horace Spear, M.D.)

CASE#I3- ACC. 28166 A 42-year-old, gravida I para I, female presented with a right ovarian mass. Right salpingo-oophorectomy was performed. The specimen consisted ofa 38 gram, moderately linn mass which measured 6.5 x 4.0 x 3.8 em. The external surface was bosselated and pink-white. The cut surface was solid pink-white with areas of light gray softening and focal cystic changes beneath the capsule. (Contributed by Arthur Koehler, M.D.)

CASE 1114- ACC. 28379 A 63-year-old female presented with a pelvic mass. A 7 x S x 2 em, partially cystic left ovarian mass was removed along with the contralateral ovary, uterus, omental segment, and para-aortic lymph nodes. (Contributed by Fattaneh Tavassoli, M.D.)

CASE 1115- ACC 10286 A 59-year-old Caucasian female presented with lower abdominal pain and a IS pound weight loss over a threo-month period. Pelvic exam revealed a large mass. Bilateral oophorectomy, pelvic exploration and multiple biopsies ofthe peritoneum were done. The right ovary was replaced by a 219 gram globoid mass. liS cut surface consisted of a latticework of slimy glistening gray-tan tissue exuding mucoid material. The left ovary measured 4 x 2 x 2.5 em, and had similar lacy-looking rumor present in its central ponioo. (Contributed by John Gilrane, M.D.)

2 CASE HISTORIES 104TU SEMlCANNUAL SEMINAR

CAS£ftl6- ACC. 25047 1). 72-year-old Caucasian female presented widt complaints ofindigestion, urinary rrequency, and swelling of the right lower extremity of a few days duration. A large mass was palpable, filling both lower abdominal quadrants. At laparotomyJ a cystic and solid mass was removed. The 9 em cystic mass had soft, red-brown, polypoid masses filling it, The outer surface was smooth to slighdy wrinkled. The wall averaged 0.2 to 0.4 em in thickness, with solid tan areas in the wall up to 3.0 em in diameter. The patient had undergone hysterectomy and removal ofri_ght and left fhll6pian tubes and right ovary twenty-six years previously for . (Contributed by Edward 1

CASE 1117- ACC. 24904 A 42-year-old Caucasian female presented with vague abdominal pain, hirsutism and irregular menstrual periods. and was found to have a 5 x 8 em cystic periumbilical mass. Hysterectomy with bilateral salpingo­ oophorectomy was performed. The specimen consisted of a 9 x 7 x 5 em multinodular, cystic mass with a firm white capsule. The center ofthe cyst contained hair and yellow-white, greasy material. A 5 x 4 x 3 em bright yellow, solid area was noted during sectioning. (Contributed by. Douglas Andorka, M.D.)

CASE #18- ACC. 17746 A 1-9-year-old, !,>ravida 0, para 0, Black fc.male presented with vaginal bleeding, a five month history of amenorrhea and three months of rapid abdominal enlargement. lVP showed a pelvic mass \vith . A pregnancy test was negative. At surgery, a large left ovarian mass and para-aortic nodes were noted, as well as a nodular fiver. The 2600 gram left was 29 x 17 x 12 em. The tumor had multilocular cystic spaces with intervening firm, rubbery, yellow areas. There were also areas filled with greasy, gritty, keratin debris and dark black iuiir, as well as one area with a cartilaginous consistency. (Contributed by C. P. Schwinn, M.D.)

CASE 1119 - ACC. ~1050 A 33-year-old Caucasian female presented with left-sided pelvic discomfort and pain. Physical examination revealed a large left a_dnexal mass which ~ended up to the umbilicus. A pregnancy test was negative. At lapar.atomy, the 1520 gram, 18 x 14 em left ovary was fim1, nodular and reddish-purple. The cut surface was yellow­ tan, spongy and mucoid with areas of degeneration and hemorrhage. (Contributed by John Swift, M.D.).

CASE #20- ACC. 28380 A 32-year-old female presented with a pelvic mass. An 8.0 x 5.3 x 4.4 em lobulated, circumscribed right ovarian tumor was removed at laparotomy. Cut surface ofthe tumor was granular and tan-yellow. (Contributed by Fauaneh Tavassoli, M.D.)

3 ,• . " • ' . l ' ~ .

June 7,1998 Westin South Coast Plaza Costa Mesa, California

Tumors of the Uterus and Ovaries

Fattaneh A. Tavassoli, M.D.

Armed Forces Institute of Pathology Washington, D.C. CALIFORNIA TUMOR TISSUE REGISTRY

104TH SEMI-ANNUAL SLIDE SEMINAR

GYNECOLOGIC PATHOLOGY

"Ovarian and Uterine Tumors"

Fattaneh A. Tavassoli, M.D. Chair, Gynecologic & Breast Pathology Armed Forces Institute ofPathology Washington, D.C.

Sunday, June 7, 1998 8:30a.m.-4:30p.m. Westin South Coast Plaza Costa Mesa, California TABLE OF CONTENTS

Case 1 page3 Case2 Adenosarcoma of the uterus page 11 Case3 Endometrial stromal sarcoma, low grade page 14 Case4 page 18 CaseS Mucinous (colloid) with signet ring cell page22 differentiation Case6 ViUoglandular adenocarcinoma of the cervix page28 Case? Inflammatory myofibroblastic tumor page32 CaseS Malignant giant cell tumor (leiomyosarcoma with osteoclastic page3 giant cells) Case9 Granulosa cell tumor, adult type page3S Case 10 Gonadal stromal tumor, c/w anaplastic granulosa cell tumor page3S Case 11 Small cell C¥Cinoma, hypercalcemic type page40 Case 12 Consistent with tumor, metastatic type page43 Case 13 of low malignant potential page45 Case 14 Serotransitional cell page 50 Case IS page 54 Case 16 Clear cell carcinoma of ovary with oxyphilic type differentiation pageS8 Case 17 Lipid cell tumor (Steroid cell tumor) page 61 Case 18 Yolk sac tumor (Endodermal sinus tumor) page64 Case 19 Polyembryoma with prominent hepatoid differentiation page64 Case20 Mixed germ cell - sex cord stromal tumor page68 Color Images page70 Image Legends Page 80

I 04"' Semi-Annual CTTR Seminar. Gynecologic Pathology 2 ... CASES1&8

History (Case #l -Ace. 28232) A 48-year-old, gravida 3, para 3, female on oral contraceptives presented with dysmenorrhea and amenorrhea of three months duration. Initial treatment included Provera and oral contraceptives. Pelvic ultrasound revealed a 7 x 5 em right and a possible small uterine fibroid. Six months later, she returned with a large malOdorous mass protruding ihrough the cervix ofan enlarged uterus. The 550-gram uterine specimen was-13 x 13 x 6 em. The myometrium was 4 em thick. An 8 -x 6 em, polypoid, pedunculated mass protruded through the cervix. The cut surface of the mass was partially hemorrhagic, surrounded by light tan soft tissue. (Contnouted by David Seligson, M .D.)

Diagnosis: Leiomvosarcoma

Note: Despite the history of progestin therapy, the significant diffuse atypia and the abundance of mitotic figures (cotoeeding I 0 per I 0 HPF) including many abnormal forms is the basis for designation of this tumor as .a leiomyosarcoma.

History (Case 118 - Ace. 28377) A 71-year-old female was found to have a uterine mass on routine physical examination. A hysterectomy and bilateral salpingo-oophorectomy were performed The anterior fundus contained a hemorrhagic, partly necrotic, 7 x 8 em mass. The endometrial surface was intact and was not involved by tumor, but did have a small polyp (0. 7 em in maximum diameter). (Contributed by Fattaneh Tavassol~ MD.)

Diagnosis: Malignant giant cell tumor (leiomyosarcoma with osteoclastic giant cells)

DISCUSSION

Leiomyosarcomas account for 45% of uterine sarcomas. They occur mostly in women over 40 years of age. are generally solitary, large lesions rarely smaller than 5 em. They may be intramural, subserosa!, ·or pedunculated into the endometrial cavity. The appearance of the cut surfuce is highly variable ranging from uniformly solid to highly variegated.

Classification of smooth muscle tumors into benign and malignant relies heavily, but not exclusively, on the 85$6$.Srnent ofmitotic activity in the tumor. To obtain a reliable mitotic count, lt is iinportant to adequately sample tbe tumor (I tissue section per every 1-2 em ofthe maximum tumor diameter). The number ofmitotic figures is expressed per 10 high power fields and is often obtained after scanning each slide and counting 50 HPF in the most active areas of the tumor and getting an average per 10 HPF. Variations in mitotic count due to delay in fixation, differences .in size ofthe -high power fields in different, microscopes, variable ratio of the.number of mitotic figures relative to the number ofcell .s in a given field are sources of proolems in reproducibility. These issues have raised questio)ls concerning the influence ofmitotic activity as a prognostic factor in smooth muscle tumors. A recent study highlights the importance of using features other than mitotic index to predict outcome in uterine smooth muscle tumors; coagulative tumor cell emerged as a crucial feature (Bell et al, Table 1). ·-

As a rule, a uterine smooth muscle tumor would qualifY as a leiomyosarcoma ifit displays I 0 or more mitotic figures per 10 HPF along with significant nuclear atypia. Aside from the abundant mitotic activity, leiomyosarcoma may manifest atypical mitotic figures, infiltrative margins, extrauterine extension, and areas ofnecrosis due to large size. The presence of coagulative tumor cell necrosis is helpful, but sometimes it is difficult to determine what is coagulative t~or cell necrosis. We have noted an increasing number of smooth muscle-tumors with areas of

104.,.8emi-Annual CTTR Seminar:

Furthermore, while mitotic activity is generally considered a cardinal feature ofleiomyosarcomas and an indication of aggressive behavior, mitotically active smooth muscle tumory occur in women less than 40 years ofage as a response to hormonal stimulation either during pregnancy or as a result of oral contraceptive steroid use, and even possibly due to elaboration of nongestational endogenous . The mitotic activity in these tumors exceeds 4/IOHPF and is often less than 10/JOHPF, but may exceed lOper 10 HPF. Rarely, such tumors have over 20 mitotic figures per 10 HPF. These are so rare that there is not enough information available concerning their behavior and . Atypia is absent or minimal, however. Tumors in this setting often, but not always, have areas ofedema, hemorrhage and necrosis with the mitotic activity most conspicuous around the degenerating foci. Therefore, the mitotic activity in these tumors is considered a reactive response to the hormonal stimulus or a reparative process around the foci ofdegeneration. Intra tumoral vascular extension is present in 15% ofthese tumors (Prayson and Hart, 1992). The designation of mitotically active smooth muscle tumor is appropriate for these lesions and follow­ up ofthe patient is recommended. It is important to obtain clinical information regarding use oforal contraceptives and pregnancy (current or recent) when evaluating mitotically active tumors from young women as it is well known that progestins increase mitotic activity in uterine smooth musele tumors. The term "apoplectic " or "hemorrhagic cellular leiomyoma" has been used for a group of occurring in women taking oral contraceptives or those who are pregnant. These wom.en often present with acute abdominal signs secondary to rupture of the tumor into the peritoneal cavity. The leiomyoma shows areas of hemorrhage often associated with cystic change. Microscopically, there are stellate areas of hemorrhage and up to 8-9 mitotic figures per 10 HPF, but there is no atypia and not even significantly increased cellularity. In addition, the vessels show intimal myxoid change and , medial hypertrophy, fibrinoid necrosis, and thrombosis.

A diagnosis ofleiomyosarcoma should be made with extreme caution in young women witb a clinical history of endogenous or exogenous progestin stimulation. The addition of progestins to tbe postmenopausal hormone replacement regimens is also having an impact on the morphology of tumors in older women substantially complicating the diagnostic ·process in some cases_

With increasing use ofTamoxifen in treatment of breast cancer as weU as for preventive purposes in women at increased risk for breast ·cancer, the eftect. ofthis hormone on uterine smooth muscle tumors will need evaluation. A rare case report has suggested that Tarnoxifen may stimulate growth ofleiomyornas (Kang eta!, 1996), but data on this issue is limited.

Smooth muscle'tumors may assume a variety ofmorphologic features and appear cellular, vascular, atypical, epithelioid or xanth.omatous.

Cellular Leiomyoma

Cellular leiomyomas are densely cellular lesions that are significantly more cellular than the adjacent myometrium. These tumors' are devoid of nuclear atypia, and coagulative tumor cell necrosis. Mitotic activity is limited and there are fewer than 5 mitotic figures per I 0 HPF. Grossly, they may appear yellow-tan and have a fleshy consistency simulating an endometrial stromal tumor. Microscopically, they may also mimic endometrial stromal tumors because of their compact cellularity. They lack the typical vascularity of.enaometrial stromal rumors, however. Hemorrhage and necrosis are evident in a minority of cases. Immunostains for desrnin show intense.positivity in cellular leiomyomas, whereas endometrial stromal tumors are basically negative. .- Enithelioid Smooth Muscle Tumors (Jeiomyoblastoma, clear cell leiomyoma)

Mixtures of epithelioid, clear cell, and plexiform pattern are not uncommon in smooth muscle tumors either as a focal or a. diffuse change. A transition to typical smooth muscle is evident in most instances, confirmlng smooth muscle origin ofthe pure lesio!'s. Features related to a favorable prognosis include the presence ofclear cells, an expansile tumor inargin, extensive hyalinization, and absence ofextensive necrosis. AI AFIP, the presence ofan epithelioid differentiation in smooth muscle tumors is considered comparable to the presence ofatypia. Therefore, the presence

104., Semi-Annual CTTR Seminar: Gynecologic Pathology 4 of5 mitotic figures per 10 HPF in an epithelioid smooth musde tumor is sufficient for a diagnosis ofleiomyosarcoma. Wbco 3 to 4 mitotic fignrt$ ~ 10 high po~ fields are enoountered in an epithelioid smooth muscle tumor, careful evaluation and additional sampling of the rumor is warranted to exclude the presence of areas with more abundant mitotic activity that would qualifY the tumor as a sarooma.

Epithelioid smooth muscle tumors show immunoreactivity with actin and desmin, but sometimes only focally; some also immunoreact with epithelial markers.

Inlnlvegous !e!omyomato~i~

Intravenous lejoroyomatosis IJVL) is a me uterine characterized by nodular masses ofhistologically benign smooth muscle (may be myxoid, cellular, edematous, etc.) growing within veins. The intravascular growth takes the form of visible worm-like projections that may extend variable distances into the uterine and hypogastric veins. Direct extension from the pelvic veins into the inferior vena cava and into the right atrium has occurred, and in some of these instances the outcome was fatal. There are two theories oforigin ofiVL; it may originate either from the Wllll of veins within the myometrium or reflect extensive vascular invasion ofa leiomyoma. When the vascular extension is limited to a microscopic field in an otherwise benign leiomyoma, the term leiomvoma wjth yamlar extension is preferred. The presence ofany vascular extension should be noted in the diagnosis since it implies a capability to metastasize to the lungs.

Mnoid Leiomyour

Rarely, uterine smooth muscle tumors appear grossly gelatinous and microscopically display abundant aceUular mucoid matrix. The myxoid change may be diffuse or patchy in distribution. The abundant myxoid matrix is rich 'in acid mucins as confirmed by Alcian blue or colloidal stains. Pretreatment with hyaluronidase does not remove the material that stains with colloidal iron. Hydropic changes may mimic myxoid alterations, but lack stainable mucoid material. When these tumors display infiltrating margins or vascular invasion, they display aggressive behavior generally in the form oflocal recurrences, despite a very limited number ofmitotic figures. Using the conventional approach to counting. the mitotic activity rarely exceeds 0-2/lOHPF. Therefore, this type of tumor is an e>

Recurrent or distant melliSUISCS bave developed within 6 months to 10 years after the di&g~~Qsis in almost all reponed cases. The recurrent lesions are generally morphologica!Jy similar to the primary tumor.

Our experience with myxoid leiomyosarcomas has not confirmed this invariable aggressive behavior. Only tumors with vascular infiltration have behaved aggressively.

Unu~unl Smooth Myscle Tumors

Smooth muscle tumor with osteoclastic giant cells and malign!!nt giant cell tumor.

Rarely, smooth muscle tumors show admixture of smooth muscle bundles with osteoclastic type giant cells. The giant cells may be distributed focally or diffusely in the tumor. Depending on the mitotic activity of the smooth muscle cells, the lesion is designated either as a leiomyoma or a leiomyo..,·coma with osteoclastic giant cells. The osteoclastic giant cells are negative for actin or d~in, but intensely positive for KP I and acid phosphatase confirming their histiocytoid nature.

Malignant giant cell tumors devoid of any smooth musde component rarely occur in the uterus (Lars-JGndblom and Seidal, 1981 ).· These are characteriud by an admixture ofosteoclastic giant cells, pleomorphic mono and multinucleated cells, and occasionaliibroblast-like spindle ceUs. The nuclei of the mooonueleated cells in the background are irregularly shaped and chromatin rich. Mitotic activity is very high and atypical mitotic figures are

104• Scmi-Anllual CTTR Seminar; Gynecologic Pathology 5 easily identifiable. Phagocytic activity by both cell populations may occur. At the ultrastructuralleve~ the giant cells show abundant intracytoplasmic lipid droplets and mitochondria. The surrounding mononucleated tumor cells also .may contain phagosomes, lipid droplets and lysosomal structures. These tumors are identical to malignant giant cell tumor of soft parts (MGCT) which is considered to be a variant ofmalignant fibrous histiocytoma. This lesion is highly aggressive and the patient reponed by Lars-Kindblom and Seidal died within IS days after presentation; she had pulmonary metastases at the time of presentation.

In the uterus, osteoclastic giant cells often immediately surrounded by monoilucleated cells similar to those ofGCT are most often seen in smooth muscle tumors. The proportion ofthese areas relative to the smooth muscle component is highly variable. Association ofosteoclast-lik e giant cells with leiomyosarcomas has been noted in 8.7% of deep-seated nonvisceralleiomyosarcomas (Mentzel et al, 1994). Whether the MGCTs ofihe uterus are pure lesions or reflect overgrowth ofthis comp<)neni in a smooth muscle tumor is difficult to establish but favored at sites where smooth muscle tumors are common also due to the fact that careful assessment of these tumors often shows at least focal aggregates of smooth muscle cells that stain positively for actin and desmin.

Xantbomytous smooth musde tumors

Even more infrequently, a prominent popUlation of large cells with abundant intracytoplasmic lipid vacuoles are found admixed with typical smooth muscle bundles; these tumors are designated as xanthomatous leiomyosarcomas or leiomyoroas depending on the mitotic activity ofthe typical smooih muscle component and nuclear features of the xanthomatous component.

Plexiform Tumorlet

Generally, an incidental microscopic finding, it often presents as a: solitary n9dule composed of a plexiform nest of cells. Several multifocal examples have also been reported. So far, both the solitary and the multifocallesions have behaved in a benign fashion. Nonetheless, follow-up ofthe multifocallesions is prudent because ofthe limited experience with them. Immunohistochemical and ultrastructural analysis support smooth muscle differentiation in these tumors.

(mmunohistochemistry And SpedaJ Studies

Oflittle assistance in very primitive or poorly differentiated mesenchymal tumors, immunohistochemistry is very helpful in differentiating a variety of unusual and usual smooth muscle tumors from endometrial stromal tumors. It is particularly llelpful in distinguishing a cellular leiomyoma from a stromal nodule. Smooth muscle tumors are diffusely positive with actin and desmin, wbile endometrial stromal tumors fail to react with desmin, but may display often focal and minimal positivity with actin. llnmunohistochemistry has been particularly helpful in establishing the myoid nature of a variety of unusual uterine mesenchymal tumors (Devaney & Tavassoli).

Recent studies have shown·a lack ofgamma-smooth muscle isoactin gene expression in 100% of 10 leiomyosarcomas, two of which were uterine; twelve leiomyomas, however, did express the gene (Trzyna eta~ 1997). Cytogenetic studies have noted del( I J){q22) in some leiomyosarcomas suggesting that genomic alterations in this region .may be specific for .malignant smooth muscle tumors (Laxman et al, 1993}. Cytogenetic instability has been noted in a metastatic uterine leiomyosarcoma, whereas a leiomyoma studi¢ by the same investigators demonstrated cytogenetic stability. Furthermore, the leiomyosarcoma was hyperdiploid, whereas the leiomyoma was hypodiploid (Fletcher et at). .- Clinical Behavior and Trutment

Leiomyosarcomas are aggressive tumors with a tendency to recur both locally and at distant sites. Median interval to recurrence is about 2 years, Most metastases are in the lungs and abdomen. Qveral~ less than S% -

104"' Semi·Annual CTTR Seminar: Gynecologic Pathology 6 oophorectomy is the main treatment;" adjunctive therapy in the form ofeither radiotherapy or chemotherapy seems to be mainly palliative effect with limited impact on the outcome (Gadducci et al, 1996).

The use ofleuproUde acetate (GoRH-a), a gonadotropin-releasing hormone analog can reduce the uterine tumor volume; this is used mainly for leiomyoniaS. The impact ofleuprolide treatment ofmorphology ofsmooth muscle tumors is controversial. Some investigators have reported reduced cellularity, but no significant change in mitotic activity (Upadhyaya, eta!), fibrosis or edema as a result ofleuprolide treatment. The reduction in cellularity has been attributed to the degree ofhyperestrogenism induced and it reverts·soon after cessation of GoRH-a therapy. The endometrium becomes thinned with inactive glands, reduced vascularity and atrophic stroma. In contrast, Colgan et al observed increased cellularity· in uterine myomas following treatment with GoRH-a. The reduction in tumor size was at.tnouted to cellular atrophy and ischemic injucy. Necrosis also occurs following leuprolide treatment. Sreenan et al (1996) compared 107 uterine leiomyomas treated with Leuprolide acetate with 126 controls and concluded that LA-treated tumors do not significantly differ from the untreated lesions in their cellularity, atypia, mitotic activity, coagulative necrosis, myxoid changes, hydropic cltat)ges, calcification or hemorrhage.

TABLEt

Low to medium magnification assessment oftumor: Ditfuse, significant cellular atypia? Coagulative tumor cell necrosis?

Both features absent

Leiomyoma "Leiomyoma with increased mitoses" ifMI > or= 5

Ml>or=10

Leiomyosarcoma Failure: 7/14 I At)'picalleiomyoma Smooth muscle tumor with low risk of of low malignant poten~al, recu·rrence Limited experience Failure: 1/46 Failure: 1/4

J 04~ Semi-Annual CTTR Seminar: Gynecologic Pathology 7 TABLE2

Simplified histologic criteriJI exclusive of tu mor cell necrosis

Mit. FigsJHPF Cytologic Atypia Cellularity Diagnosis

0-4 Hyper- CellularLM

0-4 ++(diffuse) Variable Atypicai LM

5-15 Normo- Mitotically Active LM

~ 10 ++ Hyper Leiomyosarcoma

Minimal Hyper- UMP

TABLE3

Types of uterine smooth muscle tumor

Uncertain Maljgnant Potential aJMP) Malignam

Leiomyoma (LM) Intravenous Leiomyomatosis Leiomyosarcoma

VascularLM Smooth Musele tumor ofUMP (rarely used now) MyxoidLM

Cellular LM

AtypicaiLM

Epithelioid LM

Mitotic8lly Active LM

104• Semi-Annual CTIR Seminar: G}ncoologic Pathology 8 ...

REFERENCES

I. BeD SW, Kempson RL, Hendrickson Mlt. Problematic Uterine smooth muscle . A clinicopathologic studyof213 cases. AmJSurgPatho/ 1995. 2. Buscema J, et ~L Epithelioid Leiomyosarcoma ofthe uterus. Cancer 57:1192-1196, 1986. 3. Chen KTK, Vergon JM. Carcinomesenchymoma ofthe ut~s. Am J C./in Patho/75:746-748, 1981. 4. Clement PB, et al. Intravenous leiomy0matosis of the uterus: A clinicopathologic analysis of 16 cases with unusual histologic features. Am J Surg Patho/12:932-945, 1988. 5. Clement PB, Scully RE. Uterine tumors resembling ovarian sex-cord tumors. A clinicopatholqgic analysis of fourteen cases. 66:51.2-525, 1976. 6, CJenien1 PB, Young RH. Diffuse leiomyomatosis ofthe uterus: A report offour cases. lnt J Gynecol Palhol 6;j22-328, 1987. 7. Clement PB. Intravenous leiomyomatosis. Pathol AllllU 23(2):I 53-183, 1988. 8. Glement PB. Pathology of the uterine corpus. Hum Patho/22:176-791, 1991. 9. Colgan TJ, Pendergast S, LeBlanc M. The of uterine Jeiomyomas following treatm.ent with gonadotropin-releasing hormone analogues. Hum Pathol 24:1073-1077, 1993. 10. Devaney .K, Tavassoli FA. Immunohistochemistry as a diagnostic aid in the interpretation of unusual mesenchymal tumors of the uterus. Arch Pathol Lab Med 4:225-231, 1991. 11. Evans·HL, et al. Smooth muscle.neoplasms of the uterus other than ordinary leiomyoma. A study of 46 cases, with emphasis on diagnostic criteria and prognostic factors. Cancer 62:2239-2247, 1988. 12. Feclmer RE. Atypicalleiomyomas and synthetic progestin·therapy. Am J Clin Patho/49:697-703, 1968. 13. Fekete PS, Vellios F, Pl!tterson BD. Uterine tumor resembling an ovarian ·sex-cord tumor: Report of a~ of an endometrial stromal tumor with foam cells and ultrastructural evidence ofepithelial differentiation. Int J · Gyneco/ Patho/4:318-387, 1985. · 14. Fletcher JA, et al. Chromosome aberrations in.uterine sinooth muscle tumors: potential diagnostic relevance of cytogenetic instability. Cam;er Res 50:4092-4097, 1990. 15. Franquemont DW, FriersonHF, Mills SE. An immunohistochemical study ofnormal endometrial stroma and endometrial stromal neoplasms. Evidence of smooth muscle differentiation .. Am J Surg Patho/15:861-870, 19,91. 16. Friedman AJ, Barbieri RL, 13enacerrafBR, et·al A randomized. double-blind trial ofgonadotropin releasing­ hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri. Fertil Steri/49:404-409, 1988. 17. Gadducci A, Landoni F, Sartori E, et al .. Uterineleiomyosarcoma: Analysis of treatment failures and survival. Gynecologic 62:25-32, 1996. 18. Graem N, HelwegCLarsen K. Mitotic activity and delay in fixation of'tumour tissue. Acta PaJJwl Microbial Scand(A) 87:375-378, 1979. 1·9. · ~wasaki l, Yu TJ, Takahashi A, et al. Uterine tumor resembling ovarian sex-cord tumor with osteoid metaplasia. Acta PatlwlJpn 36:1391-1395, 1986. 20. I

10~• Semi-Annual CTI'R Seminar: Gynecologic Pathology 9 28. McCiuggage WG, Shah V, Walsh MY, Toner PG. Uterine tumor resembling ovarian sex-cord tumor: evidence for smooth muscle differentiation. Histopa!hology 23 :83-85, 1993. 29. Mentzel T, Calonje E. Fletcher CDM. Leiomyosarcoma with prominent osteoclastic-like giant cells. Analysis ofeight cases closely mimicking the so-called giant cell variant of malignant fibrous histiocytoma. Am J Surg Patho/18:258-265, 1994. 30. Moll M, Hom T. An unusual uterine tumor resembling sex-cord-tumor of the ovary with papillomatous features. Acta Obstet Gyneco/ Scand1J:S50-554, 1992. 31 . Myles JL, Han WR. Apoplectic leiomyomas ofthe uterus. A clinicopathologic study of live distinctive hemorrhagic leiomyomas associated with oral contraceptive usage. Am J Surg Patho/9:798-805, 1985. 32. Nogales FF, et al. Myxoid leiomyosarcoma ofthe ovary: Hum Palho/22: 1268-1273, 1991. 33. Norris RJ, Hilliard GD, Itey NS. Hemorrhagic cellular leiomyomas ("Apoplectic leiomyoma") of the uterus associated with pregnancy and oral contraceptive. /111 J 0)111ecol Pa!ho/7:212-224, 1988. 34. Norris HJ, Pannley T. Mesenchymal tumors ofthe uterus. V. Intravenous leiomyomatosis. A clinical and pathologic study offourteen cases. Cancer 36:2164-2178, 1975. 35. Norris ID, Taylor HB. Mesenchymal tumors ofthe uterus I: a clinical and pathological study of53 endometrial stromal tumors. Cancer 19:755·766, 1966. 36. O'Connor DM, Norris HJ. Mitotically active Jeiomyomas of the uterus. Hum Patho/212:223·227, 1990. 37. Pellilo D. Proliferative stromatosis ofthe uterus with pulmonary metastases. Remission following treatment with a long-acting SYDthetic progestin: a case report. Obstet Gyneco/31 :33-9, 1968. 38. Perrone T, Dehner LP. Prognost:ically favorable "mitotically active" ~muscle tumors ofthe uterus. A clinicopathologic study of 10 cases. Am J Smg Palho/12:1-8, 1988. 39. Peters WM, Wells M, Bryce FC. Mullerian clear cell carcinofibroma ofthe uterine corpus. Hlsropathology 8:1 069-1078, 1984. . 40. Pounder DJ, Lyer PV. Uterine leiomyosarcoma with myxoid stroma. Arch Pathol Lab Med 109:762-764, · 198S. 41. Pryson RA, Han WR. Mitotically active leiomyomas ofthe uterus. Am J Clin Patho/91: 14-20, 1992. 42. Rlz.eq MN, Van de Rijn M, Hendrickson MR. Rouse RV. A comparative immunohistochemical study ofuterine smooth muscle neoplasms with emphasis on the epithelioid variant. Hum Patho/25:61 1..(511, 1994. 43. Sahin AA, Silva EG, Landon G, Ordonez NG, Gershenson OM. Endometrial tissue in myometrial vessels not associated with . l11t J Gynecol Pa!hol 8: 139-146, 1989. 44. Srecoan JJ, Prsyson RA, Bisconi CV, et aL Histopathologic findings in 1071eiomyomas treated with Leuporlide acetate compared with 126 controls- Am J Surg Pa!ho/20:421-432, 1996. 45. Tang C, Toker C, Ances IG. Stromomyoma ofthe uterus. Ca11cer 43 :308-316, 1979. 46. Tiltrnan AJ. The effect of progestins on the mitotic activity of uterine fibromyomas. /111 J Gyuec Pa!ho/4:89- 96, 1985. 47. Trzya W, McHugh M, McCue P, McHugh KM. Molecular determination ofthe malignant potential ofsmooth muscle neoplaSms. Cancer 80:211-217, 1997. 48. Upadhyaya NB, et aJ. Histopathological changes in leiomyomata treated with leuprolide acetate. Fertility and Sterility 54:811-814, 1990. 49. Zaloudek CJ, Norris HJ. Mesenchymal tumors ofthe uterus: In :Fenoglio CM, WolffM (eds.). Promss in Sunzjca! Patholotrv, Vol. ffi, Masson, NY, Chap. I, p. I.

104" Semi·Annual CTTR Seminar: Gynecologic Pathology 10 CASE2

History (Case N2 - Ace. 14934) A 70-ycar~ld female presented with vaginal bleeding of recent onset. A total abdominal hysterectomy and bilateral salpingo~ophorectomy were perfonned. The 8 x 9 x 4 em uterus was symmetrically enlarged. The endometrial cavity was dilated by a 4.5 x 3.0 x 4.0 em polypoid mass composed ofloculated, somewhat mucoid tissue. Sections through the broad stalk revealed only superficial attachment to the myometrium, without obvious invasion. (Contributed by Paul Ortega, M.D.)

Diagnosis: Adenosarcoma of the uterus

DISCUSSION

Approximately 250 cases of uterine adenosarcoma have been reponed. Some ofthese tumors have been referred to as adeoofibroma (cystic or papillary) in the literature particularly prior to the 'description ofthe adenosarcomas in 1974 (Clement and Scully). Patients generally range in age between 50-70 years, the median in the largest series (Clement and Scully, 1990) was 58 years. Almost a third ofthe tumors occur in women less than 50 years ofage, however, and at least 10 adenosarcomas have been reported in young women in the second decade of life. Occasional cases have been reponed in women with Stein-Leventhal syndrome, ovarian or exogenous estrogen therapy. Two recent reports have noted the development of adenosarcomas in women on tarnoxifen'thetapy (Clement eUI 1996; Bocklage et al 1992),

Oinical Features

The most common presentation is abnonnal vaginal bleeding, usually accompanied by a pelvic mass and associated by lower abdominal or pelvic pain. The uterus is enlarged in most ofthe women. Endometrial adenosarcoma typically forms a sessile, polypoid mass that fills the endometrial cavity. In half ofthe cases, the lesion protrudes through the external os presenting as a large polyp. A massi'-e polyp at any age and recurrent polyps should be assessed carefully to exclude the possibility of adenosarcoma Approximately I 00/o of adenosarcomas are endocervical in origin. Typically stage I at presentation, the presence ofextrauterine tumor is a reflection ofeither multicentricity or metaslatic tumor. Metastases occur most often in association with rumors that have sarcomatous overgrowth and/or myometrial invasion.

Pathologic Features

Typically polypoid, surface erosion or ulceration, hemortbage and necrosis oe<:ur in approximately one quarter of cases. The cut surface ofthe tumor bas a spongy appearance with small cysts filled with watety or mucoid secretion. ln most cas<:s there is no evidence of myometrial invasion on gross examination, but in about one sixth of the cases arass suggestive of myometrial invasion are apparent at the base of the lesion.

Microscopically, the surface of the tumor is characterized by broad papil.lae covered by benign appearing that resembles glands of proliferative or hyperplastic endometrium. Within the substance ofthe polyp, small and sometimes dilated glands are dispersed randomly within a variably appearing stroma composed ofeither fibroblasts or endometrial stromal cells. The glands are generally lined by proliferative type endometrial epithelium. Epithelial asypia as manifest by nuclear enlargement, byperchromasia and nucleolar enlargement may be seen in one third of cases). The atypical cells are often stratified with intraluminal tufting. However these changes are always focal. Metaplastic mucinous or squamous epithelium often lines a portion ofthe epithelium. The mesem:.hymal component of the neoplasm is a sarcoma despite its often-benign appc;arance. Allematiog between bypo and bypercellular areas, it is at least focally hypercellular around the glandular epithelium, forming a characteristic cuff ofstromal condensation. All grades of cytologic atypia may be seen. Even though up to 40 mitotic ligures per 10 HPF has been

104~ Semi·Annual CTTR Seminar: Gynecologic Pathology II reponed, the mitotic activity tends to be low and often confined to the subepitheijal or periglandular stromal condensation. At AFIP, we require a minimum of 4 mitotic figures per 10 I:IPF in the stromal component particularly ifthe perigJandular SU'omal condensation is not ell developed. Heterologous elements including cartilage, striated muscle and adipose tissue have been reponed in approximately one quarter ofcases . The cartilage may be of the fetal type similar to what occurs in embryonal rhabdomyosarcoma of be vagina and cervix. In young women, distinction of adenosarcoma from an embryonal rhabdomyosarcoma can be very difficult. Smooth muscle is rarely present in the stroma. Occasionally, adenosarcomas contain sex cord-like elements similar to those described in endometrial stromall1lmors and uterine rumors resembUng ovarian sex cord rumors. Adenosarcomas may also demonstrate sarcomatous overgrowth. The sarcomatous overgrowth may be oftlle homologous or beterolog0us type. The homologous sarcomas display more atypia and mitotic activity and may occupy at least 25% oftlle tumor volume. In a series ofadenosarcomas witll sarco.matous overgrowth reponed from tlle Group (GOG), 60% of the cases had rhabdomyosarcoma as the pure heterologous element (Kalru et ai. 1991). Depending on the consultation practice, 100/o to 55% ofadenosarcomas my have sarcomatous overgrowth. Myometrial and lymphatic vessel invasion is more common in adenosarcomas with sarcomatous overgrowth. A case of adenosarcoma with a stroma composed exclusively ofangiosarcoma has been described (Lack et a!. 1991 ).

Differential Diagnosis

Adenosarcomas should be distingui.~ from adenofibroma, benign endometrial polyps, adenomyomas and other tumors that are either typically bipbasic (carcinosarcomas) or occasionally manifest a bipbasic appearance (endometrial SU'Omal sarcoma with endometrial glands). Adenofibromas and polyps lack the periglandular stroma condensation typical ofadenosarcomas . The stroma is less cellular, fibrotic or edematous in adenofibromas and polyps. The low mitotic aetivity, reduced cellularity and absence ofcytologic atypia differentiate adenofibrom,a from adenosarcoma. Adenomyomas display predominantly a smooth muscle stromal component. lack periglandular stromal Cll.ffing. as well as the atypia and mitotic activity ofadenosarcomas. Glandular atypical hyperplasia and squamous metaplasia are also noted in the atypical adenomyomas. Endometrial stromal sarcomas have a uniformly bypercellular stroma along with an infiltrative and often intravascular tumor in the myometrium. Carcinosarcomas and mixed mesodermal tumors are composed of malignant epithelial as well as stromal components. Adenosarcoma, in contrast, contains benign epithelium while the stroma is malignant.

Bwvior and Treatment

Twenty-five percent ofadenosarcomas recur and/or metastasiu. MetastaSes and recurrences are most commonly abdominopelvie or vaginal, altbough they can develop outside the pelvis in a small proportion of patients. Hematogenous spread has been noted in less than 5% ofcases. Recurrences often develop within 5 years ofthe diagnosis in one tllird ofthe patierus; rarely 11lmors recur I0 or more years after hysterectomy. Long tenn follow-up ofthe patients is, therefore, prudent. The composition oft .he recurrern tumor has been pure sarcoma in 700/o ofthe cases, adenosarcoma in 300/o and a carcinosarcoma in one case (Clement and Scully, 1990). The recurrent tumor rarely contains heterologous elements not apparent in the inltiallesion. Features associated with an increased risk of recurrence include the presence ofmyometrial invasion with or without lymphatic space involvement and sarcomatous overgrowth. In the absence ofmyome trial invasion, 12.7% oftumors recur in comparison with 46% of thoso with myometrial invasion (Clement & Scully, 1990). The tumors demonstrating sarcomatous overgrowth are more aggressive, with a greater rate of progression. When sarcomatous overgrowth is present, 70% develop recurrent disease, 40% manifest hematogenous spread, and 600/o die from th~ tumor (Clement and Scully, 1989). Recurrences may take the form of a pure sarcoma, an adenosarcoma or even a heterol9gous malignant mixed mesodermal11Jmor. Overall approximately 100/o of patients die of tumor. The mean interval from diagnosis to death is 7 years. Similar tumors may occur in the cervix, ovary and adnexal region. •

Treatment is total hysterectomy and bilateral salpingo-oophoreetomy. Staging ofthe rumor has been recommended by GOG to include peritoneal washings. Tumors invading greater than halfway through the myometrium and those with sarcomatous overgrowth have a high likelihood of recurrence, and consequently, postoperative pelvic radiation or chemotherapy may be tried. but the value ofsuch adjuvant therapy has not been established. Recurrences have been successfully treattd with local excision in 50% ofcases .

104., Semi·Annual CTTR Seminar: Gyneoologje PelholoJJY 12 REFERENCES

I. Bocklage T, Lee KR, !lel.inson JL. Uterine Mullerian adenosarcoma following in a woman on wnoxifen therapy. Gynecol Onco/44(1) 104-9, Jan 1992. 2, Clement PB, Scully RE. Mullerian adenosarcomas of the uterus. A clinicopathologic analysis of I OO.cases with a review of the literature. Hum Patho/21:363-381, 1990. 3. Clement PB, Scully RE .. Mullerian adenosarComas of the uterus with sex cord-like elements. A cliiiicopathologic aoalysis ofeight cases. Am J Clin Pathoi 91 :664-672,.1989. 4. Clement PB. Mullerian adenosarcoma of the uterus with sarcomatous overgrowth. A clinicopathological analysis of10 cases. 1/.mJ Surg Patho/13:28-38, 1989. 5, <;:lementl'!l, Scully RE. Extrauterine mesodermal (Mullerian) adenosarcoma, a clinicopathologic study offive cases. Am J Surg Pathdl 69:276-283, 1978. 6r Czernobilsky B, Hoblweg-Majert P, Dallenbach-Hellweg G. Uterine adenosarcoma: ·A clinicopathologic study of 11 eases with a reevaluation of histologic criteria: Arch Gyneco/ 233( 4):281-94, 19.83. 7. Dietze 0, Hopfei-Kreiner I, ScharfO, Ortner A. Heterologous Mullerian adenosarcoma ofthe uterus-a rare tumor. Light- and electron-microscopic findings, biological behavior (author's trans!). Arch Gyneco/231(1);15- 85, 1981. 8. Fehmian C, Jones T, Kress Y, Abadi M. Adenosarcoma of the uterus with extensive smooth muscle differentiation: ultrastructural study and review ofthe literature. Ultrastruct Patho/21(1):73-9, Jan-Feb 1997. 9. Hallak M, Peipert IF, Heller PB, Sedlacek TV, Schauer OM Mullerian adenosarcoma ofthe uterus with sarcomatous overgrowth. J Surg Oncoi.Sl (1):68-70, Sep 1992. 10. Hariri J. Mullerian adenosarcoma ofthe endometrium: review ofthe literature and report oftwo cases. 1111 J Gynecol Patho/2(2):182-91, 1983. U. JonesMW, Lefkowitz M. Adenosarcoma of the uterine cervix: a clinicopathological study of 12 cases. In/ J Gyneco/ Palho/14(3):223-9, Jull~S . 12. Juarez Azpilrueta A, Villarreal Petal C, Cacho Mendez E, Chen FJ, Motta Martinez E. Heterologous adenosarcoma of the Mullerian ducts in adplescence. P.resentation ofclinical case and review ofthe literature. Glnecol Obstet Mex 63:398-400, Sep 1995. 13. Kaku 1:, Silverberg SO, Major FJ, Miller A, Fetter B, !lrady MF. Ad~osarcoma ofthe uterus: A Gynecologic Oncology Group clinicopathologic study of31 cases. 1111 J Gynecol Patho/11(2):75-88, 1992. 14. Lack EE, Bitterman P, Sundeen IT. Mullerian adenosarcoma of the uterus with pure angiosarcoma: case repon. HumPathol22(12):1289-91, Dec'l99L 15. Zaloudek CJ, Norris HJ. Adenofibroma and adenosarcoma ofthe uterus. A clinicopathological study of 35 cases. Cancer 48:354-366, 19.81. 16. Zaloudek CJ, Norris HI. Mesenchymal tumors ofthe uterus. ln Blaustein's Pathology ofthe Female Genital Imt. 3"' ed. 'Kurman RJ (ed.) New York, Heidelberg, 1987, 373-408. 17. Zanotti F, Mussida M, Merlo F, Milesi M, Aletti L. High-grade sarcoma with areas of Mullerian adenosarcoma of the uterus. A1111 Ostet Gi11ecol Med Perinat 112(1):29-35, Jan-Feb 1991. 18. Zichella L, Perrone G, De Falco V, PelleR, Eleuteri Serpieri D. Heterologous mesodermal adenosarcoma of the endocervix. Description of a clinical case. Mi11en>a Ginecol 46{9):51 I -4, Sep 1994.

I 046 Semi-Annual CTTR Seminar: Gyncpologic Pathology 13 CASE3 llistory {Ca

Diagnosis: Endometrial stromal sarcoma, low grade

DISCUSSION

Accounting for I 0 to I 5% of uterine sarcomas, endometrial stromal tumors are composed of neoplastic cells that resemble the proliferative phase endometrial stromal cells. Endometrial stromal tumors are subdivided into two major categories based on the presence or absence ofan infiltrative margin ofgrowth. The clinically benign endometrial stromal tumor, designated as a stromal nodule, is a circumscribed lesion that displays a pushing growth pattern. The sarcomas, in contraSt, have infiltrative margins and have been further subdivided into low grade (LGESS) and high grade (HGESS) based mainly on the number ofmitotic figures per 10 HPF. lo our current practice, however, we rarely use tbe designation ofhigh-grade endometrial stromal sarcoma. This is due to the fact that non-smooth muscle sarcomas with significant mitotic activity often also display atypia and no longer resemble endometrial stromal cells. ln most cases, a designation of "high-grade undifferentiated " is more appropriate; many of these rumors may not be of endometrial stromal origin.

Clinical Features

Endometrial stromal tumors most often OCQ.lr in peri- and post-menopausal women whose median age ranges from 42 to 58 years. A majority of the women (75%) are younger than 50 years ofage at presentation; occasional cases have been reported in children (Chuaqui et al 1994). Women with high-grade tumors in one report (Norris and Taylor) were significantly older those with LGESSs, with median ages of6l and 39 years respectively. Specific risk factors are not known, but rare association with prolonged estrogenic stimulation, tamoxifen therapy and history of pelvic irradiation has been noted (Kempson and Hendrickson, 1988).

Aboonnal vaginal bleeding is the most frequent symptom; it is usually more severe than in patients with leiomyomas­ Some patients present with pelvic or abdominal pain, while occasional patients are asymptomatic. An enlarged uterus with an irregular contour is noted on physical examination. Occasionally, tumor protrudes through the external os. Most tumors involve the endometrium, but rarely LGESS present.s as recurrent cervical "polyps." Rarely metastases present prior to detection of the primary lesion. Presentation may be with hemaruria when there is involvement oftho (Dgani et al, 1989), as a primary ovarian tumor due to metastases to one or both ovaries (Young and Scully, 1990), or with pulmonary nodules appearing before detection ofthe uterine primary (Abrams, et aJ 1989).

Extrauterine extension is present in up to a tbi.rd ofthe women with LGESS at the time ofhystere<:tomy. The extension may ap~ as worm-like plugs oftumor within the vessels of the broad ligament and adnexa_ ·Rarely removed for assessment, the retroperitoneal lymph nodes have been negative on histological ewnioation.

104* Semi-Annual CTIR Seminar: Gynecologic Pathology 14 .., Gross Appearance

Presenting ·either as an endometrial (40%) or an intramural lesions (60"~). the endometrial stromal nodule presents as aweD-circumscribed, non-encapsulated, solitary, rounded mass located. Some are coilfi.ned to the endometrium (7%) and may appear as a polypoid mass. Approximately 20% protrude into the endometrial cavity.

The.median tumor diameter was 4.0 em (range 0.8 to 15 em) in the only series of such cases reported (Tavassoli and Norris).

Frequently protruding into the endometrial cavity, LGESSs often present as a solitary and predominantly intramural mass. Extensive permeation of the myometrium is common, with extension to the serosa in approximately half ofthe cases. The cut surface appears yellow to tan and the tumor has a softer consistency compared to leiomyomas. Cystic and myxoid degeneration as well as necrosis and hemorrhage are seen occasionally.

The higb"grade endometrial sarcomas more commonly resemble MMMTs, characterized by one or more fungating, polypoid, fleshy, gray to yellow endometrial masses, often with prominent hemorrhage and necrosis. Myometrial invasion is common but Jacks the diffuse permeative pattern typical ofLGESS.

Both 10\v and high-grade endometrial stromal sarcomas may develop in the endocervix. In this location, they are either polyp

Microscopic Features

The distinction between ESN and ESS requires assessment ofthe tumor margin. ESN has a pushing, circumscribed growth lllll!gin, while LGESS infiltrates the myometrium in often well-rounded aggregates that may show an angulated edge or extend into lymphatic channelS. Mitotic .activity cannot be used to separate the nodules from sarcomas, because some ESNs may have mitotic activity that exceeds I 0 per 10 HPF, while many LGESS hardly contain any mitotic figures and rarely would they have more than 3-4 mitotic figures per 10 HPF. Therefore, distinction·of a LGESS from ESN is not possible on curettage specimen.

Both.ESN and LGESS are densely cellular tumors composed ofuniform, oval1o spindle-shaped cells of endometrial stromal-type; significant atypia and pleomorphism are absent. A network ofdelicate small arterioles resembling the spiral arterioles ofthe late secretory endometrium is typi~ly present. · Stainable intracytoplasmic lipid is present focally in almost half of the cases, and cells with foamy cytoplasm (tumor cells, foamy histiocytes, or both) are prominent in some cases. Focal de:cldual change is evident in some tumors; this may reflect an endogenous or , exogenous progestational effect. Both lesions are characterized by a very low mitotic rate. Over 90% ofthe ESNs in the series reported by Tavassoli and Norris had 3 or fewer MFs/1 OHPFs and almost half the tumors had no discernible mitotic activity. Three·cases, however, had over 10 mitotic figures per HPF. Likewise, LGESSs usually have 3 or fewer MF/!OHPFs; higher mitotic rates can be encountered occasionally.

Perivascular liyaliniution is a common finding and may be prominent enough to obscure the basic pattern oftbe tumor; the term angiosclerotic stromal tumor bas been used for these. A Stellate pattem ofhyalinization occurs in some cases. Reticulin stains usually reveal a.dense network offibrils surrounding individual cells or small groups of cells. Necrosis is typically absent or inconspicuous.

It is not unusual to find focal smooth muscle differentiation or cells with differentiation that is ambiguous between stromal and smooth muscle cells in endometrial stromal tumors. When the smooth muscle component is prominently evident, we use the tenn combined smooth muscle stromal tumor. Some have used the-designation of st(omomyoma. Rarely, foci ofosteoid or trabecular bone may occur. Benign endometrioid glands have been described in both ESN and LGESS; this feature is of no clinical consequence. Rare cases ofLGESS with prominent benign endometrioid glands have been descn'bed and designated as interpreted extrauterine LGESSs with prominent glanqular differentiation.

High-grade ESSs are composed of spindle to polygonal cells with marked degrees of nuclear pleomorphism and

104• Semi-Annual CTTR Seminar: Gynecologic Pathology IS admixed multinucleated giant cells. Mitotic rates exceed 10/IOHPFs, and are often beyond 20 or 30 MF/ lOHPFs. Atypical mitotic figures are also commonly identified. The distinctive vascular pattern of the low-grade tumors is typically absent. In contrast to LGESSs, there is usually destructive invasion of the myometrium with frequent areas of necrosis. The vascular invasion lacks the permeative pattern seen in LGESSs.

The cells of the high-grade tumors do not resemble endometrial stromal cells. It has been suggested that some of these may be monophasic variants of MMMTs with exclusive overgrowth of the sarcomatous component (Evans, 1982). Indeed, additional histologic sampling ofan apparently pure high-grade endometrial sarcoma may reveal rare foci ofcarcinoma that were missed on initial sampling, warrantiiJ8 a final diagnosis ofMMMT. A recurrentLGESS followi1J8 pelvic irradiation displayed a high-grade morphology, possibly refiecting dedifferentiation (Smith et at, 1980; Cbumas et at, 1990). lmmunohistocbemital Features and Other Special Techniques

The neoplastic cells of both stromal nodules and LGESSs are immunoreactive for vimentin and actin. Desmin­ positivity has been noted in some studies, but in my experience endometrial stromal tumors have been consistently negative for desmin with the exception ofone case that had focal positivity. Both ofthese tumors also display positivity for both estrogen and receptors (ER and PR). High-grade stromal sarcoma, however, are negative for ER and PR.

ESNs and LGESSs are typically diploid and with a low S-phase fraction; the high-grade endometrial sarcomas are typically aneuploid.

Differential Diagnosis

Cellular smooth muscle tumors are the major lesions that should be distinguished from endometrial stromal tumors. The endometrial location and lack ofimmunostaining for desmin help make tllis distinction.

LGESSs containing endometrioid glands should be distinguished from adenosarcomas. This distinction is important because as stage I tumors, LGESSs have a higher recurrence rate (36%) compared to adenosarcomas (24%). Also, LGESS are probably more responsive to radiation and progestin therapy. The efficacy ofsuch therapy in the management ofadenosarcomas remains unknown. In contl"ast to the loealiud dism'bution ofglands within LGESSs, those of adenosarcomas are scattered more diffusely throughout the tumor, and are typically surrounded by cellular condensations of the sarcomatous stroma. Furthermore. adenosarcomas lack the vascular and myometrial permeation typical ofLGESSs.

Behavior and Treatment

As noted earlier, categorization of endometrial stromal tumors into ESNs, LGESSs, and high-grade endometrial sarcomas is important because of prognostic and therapeutic implications. The benign ESNs are adequately treated by hysterectomy. Even stromal nodules with up to I 5 mitotic figures per I 0 high power fields have had a benign course with close to two decades offollow-up . In a young women whose curettage specimen is interpreted as endometrial stromal rumor, laparoscopic assessment ofthe lesion and imaging to confirm a cin:umscribed margin may help avoid or delay hysterectomy, but careful follow-up ofall such women is absolutely essential.

LGESSs are characterized by an indolent growth and late recurrences. Up to half ofthese women devel~ pelvic or abdominal recurrences. The interval to recurrence has ranged from 3 months to 23 years; the median interval to recurrence is between 3 to 5 years. For higher stage tumors, the interval is only a few months rarely exceeding a year. Multiple recurrences following hysterectomy have been reported. Pulmonary metastases occur in I O% ofstage I tumors and manifest in about I 0 yean after the initial diagnosis; when cystic, these have been misinterpreted as cystic hamartomas. Blood borne metastases and metastaseS to other sites are rare.

I 04"' Semi-Annual CTTR Seminar: Gynecologic Palhology 16 In most cases, both recurrent and meUistatic ESS may re.nain localized for long periods and are amenable to suc:cessful treatment by resection, radiation therapy, progestin therapy, or combinations thereof Approximately 90"/o to 100% of patients survive 10 years. Tumor-related deaths may occur as late as 30 years after the initial diagnosis.

The surgical stage is the best predictor ofrecurrence (and survival) for LGESSs. Of patient.s wit.h stage I disease, 36% developed recurrent disease compared to 76% ofpatients wit.h stage Ill-IV disease. Stage I patients had a 92% survival rate compared to 66% for higher stage cases (stages ill-IV). In ot.her studies that have utilized progestagen therapy, 100% survival rates have been achieved even for stage mpatients (Piver et al, 1984). Tumor size, mitotic rate and nuclear atypia are not useful predictors of recurrence in patient.S with stage 1 tumors.

Optimal initial management of patients with LGESSs requires total abdominal bysterectomy including bilateral salpingo-oophorectomy along wit.h wide parametrial excision. Conservation ofthe adnexa is not advised, because of the presence ofmicroscopic adnexal extensions oftumor and the possible stimulatory eflb:ts ofestrogen from the retained ovary (Berchuk et al, 1990). The tumor should be analyzed for hormone receptors and patients with Stage 1· receptor positive tumors could benefit from progestin therapy. In case ofa receptor negative stage I tumor, postoperative radiation may be justifiable. Overall; however, pelvic irradiation does not· appear to signifocantly decrease the relapse rate for stage 1tumors (Chang et aJ. 1990). Postoperative hormonal therapy, radiation therapy, or both may be used for patients with higher stage tumors after excision of the tumor to the extent technically feasible.

Tbe high-grade endometrial sarcomas are aggressive tumors, with death from tumor dissemination within three years after hysterectomy in most cases. A more favorable prognosis may ensue when the tumor is limited to the endometrium. The frequency of pelvic recurrence may be diminished by preoperative or postoperative radiation.

REFERENCES

1. Bishara M, Scapa E. Stromal uterine sarcoma arising from intestinal endometriosis after abdominal h}"terectomy and salpingo-oophorectomy. Harejuah 133(9):353-5, 415; 2 Nov 1997 2. Chl18'lui R, Etchart M, Hamed F, Barrena N. Extracorporeal uterine endometrial stromal type sarcoma. Rev Chi/ Obslel Gineco/59(4):284-8, 1994. 3. De Nictolis M, Curatola A, Tomnwoni S, Magiera G. High-grade endometrial stromal sareoma: Clinicopathologic and immunohistochemical study ofa case. Pathologica 86(2):217·21, Apr 1994. 4. Fukunaga M, Miyazawa Y, Ushigome S. Endometrial low-grade stromal sarcoma with ovarian sex cord-like differentiation: report of two cases with an immunohistochemical and flow cytometric study. Pathollm 47(6):412-5, Jun 1997. 5. Hennig Y, Caselitz J, Bartnitzke S, Bullerdiek J. A third case ofa low-grade endometrial stromal sarcoma with at (7; 17)(p 14 approximately 21 ;q 11 .2 approximately 21). Qmcer Ge11et Cytogene/98(1):84-6, Oct 1997. 6. Hrynchak M, Horsman D, Salskl C, Berean K, Benedet JL. Complex karyotypic alterations in an endometrial stromal sarcoma. Qmcer Genet Cytogenet71(1):45-9, Oct 1994. 7. ltoh T, Mochizuki M, Kumazald S, Ishihara T, Fukayama M Cystic pulmonary metestases ofendometrial stromal sarcoma ofthe uterus, mimicking lymphangiomyomatosis: A case report with immunohistochemistry of HMB45. Pathcl lnt 47(10):725-9, Oct 1997. 8. Kronzon 1., Goodkin GM, Culliford A, Scholes N, Boctor F, Freedberg RS, Tunick PA. Right atrial and right ventricular obstruction by recurrent stromomyoma. JAm Soc Ecltocardiogr7(5):528-33, Sep·Oct 1994. 9. Nordal RR, Thoresen SO. Uterine sarcomas in Norway 1956-1992:incidence, survival and mortality. Eur J Cancer 33(6):907-11, May 1997.

104• Sani-Annual CTIR Seminar. Gynecologic Pathology 17 ...

CASE4

History (Case 114- Att. 17531) A 17-year-old, gravida I, para I, female presented with abdominal swelling and pain. Physical examination revealed an enlarged uterus ofapproximately 8 weeks size, with bilateral ovarian masses. Chest x-ray showed small round lesions scattered tbroughou~ both lung fields. A pregnancy test was positive in a high dilution. After two courses ofmethotrexate, the uterus appeared to decrease in size, although the ovarian cysts were still palpable. The uterine specimen measured 15 x 12 x 7 em. In the right and left cornu were two irregular, fi:iable, yellow tumor masses invading the myometrium but not penetrating the serosa, each measuring 2 x 2 x 2 em and blending with overlying endometrium. Throughout the myometrium were small yellow, fairly well-defined nodules. (Contnouted by Milton Bassis, M.D.)

Diagnosis: Choriocarcinoma

Note: The extensive fibrinoid change replacing tumor cells is a result of chemotherapy.

Follow-up: On the third postoperative day, patient developed a hard and ~stended abdomen and· a fast pulse. Her hematocrit was 11 . She was·transfused and taken to the operating room where laparotomy disclosed bleeding from vaginal cuff. Patient did well for 4 days but was found dead. Suspected cause ofdeath was pulmonary embolus.

DISCUSSION

About 50% ofall occur subsequent to molar (complete hydatidifo.rm moles), but only about 3% of complete moles are followed by choriocarcinoma (R1ngertz 1970). Approximate1y, a quarter of choriocarcinomas follow normal pregnancies. Rarely, a gestational choriocarcinoma develops during a seemingly normal pregnancy within a non-molar (Brewer and Mazur 1981). Gestational choriocarcinomas become clinically apparent within several months after the pregnancy.

Abnoonal uterine bleeding is often the presenting sign. Because ofthe capability oftrophoblasts to invade vascular structures, hemorrhage is an important feature ofchori()carcinoma whether it occurs in the uterus or when it metastasizes to the lungs or the brain. The lungs are the most frequent site ofmetastatic disease being involved in 90% ofcases when dissel)'lination occurs. Brain and liver metastases also·occur.

Pathologic Features

Grossly,.tfie tumor is often well circumscribed and hemorrhagic in appearance. Histologically, solid or plexiform cords and clusters display a biphasic proliferation ofcyto· and syncytiotrophoblasts admixed with extensive hemorrhage and necrosis. Intermediate trophoblasts are also admixed with the other trophobl~sts. Atypia and mitotic activity may be mw:ked. Vascular invasion is often prominent. Placental villi are absent. Early or incipient choriocarcinoma is rarely diagnosed in a background ofchorionic villi, however. Since there is usually de.ep invasion ofthe myometrium and its vessels associated with necrosis, the curettings often contain fragments ofmyometrium destroyed by the invading trophoblast. It has been suggested~ that choriocarcinomas with predominance of syncytiotrophoblasts may have a better prognosis (DeligdiSh). High-grade has been suggested by the formation oftumor islands that display massive proliferation ofintermediate•type trophoblast, perpendicular invasion ofthe myometrium, and cytological atypia (Nishikawaet all98S).

Differential Diagnosis

Chonocarcinoma should be distinguished from placental site trophoblastic tumor (PSTI), poorly differentiated carcinoma with trophoblastic differentiation, and residual trophoblasts or invasive mole following evacuation ofa

I04'' Semi-Annual CTTR Seminar: Gynecologic Pathology 18 molar pregnancy. Distinction from PSTT is facilitated by the fact that it is a monophasic proliferation of predominantly intermediate trophoblasts in contrast to the bipbasic pattern ofchoriocarcinoma. Few syncytiOtrophoblasts may be present, but they are not abundant. Therefore, serum beta-HCG titers are low in PSTT, but elevated in choriocarcinoma. lmmunostains for HCG and HPL are helpful and would favor PSTT when there is predominance ofHPL positive cells. Furtl>ennore, I'STT lacks the hemorrhagic aspect ofchoriocarcinoma. Also, placental site trophoblastic tumor invades the myometrium by splitting musele fibers in contrast to diffuse destruction. With limited sampling, distinction from with trophoblastic differentiation can be difficult on the basis of morphology alone. The trophoblastic cells in the carcinoma are also immunoreactive for HCG. Extensive sampling often shows areas of recognizable adenocarcinoma that is the ultimate feature of greatest diagnostic value. AU tropbobla!ts are cytokeratin positive rendering immunoslains for cytokeratin worthless in discriminating between the twO lesions. The absence ofchorionic villi and the extensive tumor necrosis with bemotrllage enable one to distinguish choriocarcinoma from an iniiUive mole. fo.ialignant chorial invasion must also be distingu.ished from a benign invasion (exaggerated placental site reaction) which can be best recognized by the advance ofindividual trophoblastic cells along preformed clefts without injury to adjacent muscle cells. In uterine curettings, choriocarcinoma can be definitely diagnosed only when large sheets of cytologically atypical trophoblasts invading the endomyometrium are present, and placental villi aie absent.

Plaeental ~ite nodule

This well circumscribed accumulation ofintermediate tropbobla!t may be found in endometrial curettings or in the superficial myometrium, usually as a remnant and sometimes many years after intrauterine gestation. It is charaaeristically hyaliniud, and appean degenerated. There is no or very little enitotic activity \{oung et al 1990). The immunohistochemical reactions for PLAP (positive in 100% ofthe cases), cytokeratin (96%), EMA (84'Yo). HPL (78%) and B-HCG (42%) (Huettner and Gersell1994; Sbitabata and Rudgers 1994) may be used to differentiate the nodules from carcinoma or sarcoma. The distinction from placental site trophoblast tumor is possible by the nndular shape, absence of myometrial invasion, rare ifany mitotic figures, and hyalinization of the placental site nodule.

Metanatic cho rio cJ~ rcinoma

The frequency ofspread ofchoriocarcinoma of the uterus to the ovary has varied from one series to another. In an autopsy study of44 patients, Ober e1 at found no examples ofovarian metastasis; however, in other series the frequency has ranged from 6 to 22%. Although a choriocarcinoma that develops in a prepubertal girl is obviously of germ cell origin. the occurrence ofa similar tumor in a woman of child-bearing age that is not clearly metastatic from a uterine or tubal choriocarcinoma requires thorough sampling in an attempt to demonstrate the presence of teratomatous or other germ cell elements; thereby establishing the germ cell origin ofthe tumor. The way to distinguish gestational from non-gestational choriocarcinoma is to perform DNA analysis. Gestational choriocarcinoma h'as contribution from both maternal and paternal DNA; nongestational choriocarcinoma has the same DNA as the patient (Fisher et al, 1992). Post hydatidiform mole choriocarcinomas have an androgenetic origin If such elements are not found, it may be difficult to differentiate between a primary choriocarcinoma ofthe ovary either gestational or germ cell origin and a metastatic tumor from a choriocarcinoma of the uterus that has regressed without special studies. Invasive hydaiiHiform mole bas alsa been documented to spread to the ovary and at least twO placental site trophoblastic rumors have spread through the uterine wall to involve an ovary.

Management

Detailed protocols are now available for management of patients with a variety of trophoblastic disease. Of significant value is the possibility of monitoring disease and response to therapy with assessment ofthe serum levels ofbeta-HCG in those lesions where it is elevated (complete mole and choriocarcinoma).

Choriocarcinoma responds very well to chemotherapy (methotrexate) and patients with choriocarcinoma can often be cured with proper management.

104.. Sen1i-Annual CTTR Seminar: G)nccologjc Pathology 19 ...

TABLE4

WHO Classification of Gestational Trophoblastic Disease

Hydatidiform Mole a. complete b. partial

Invasive hydatidiform mole Choriocarcinoma Placental site trophoblastic tumor Miscellaneous trophoblastic lesions a. exaggerated placental site b. placental site nodule OJ;" plaque

Unclassified trophoblastic lesions

TABLES

Types of Trophoblast

1. Cytotrophoblast: The precursor cell to the other trophoblastic cells, it is a polyhedral cell with distinct borders, clear cytoplasm, and central vesicular nucleus; it is found at the periphery ofvilli, beneath syncytiotrophoblast. Mitotic activityis seen. !nearly gestation, it proliferates at one pole ofthe developing villous.

2. Intermediate trophoblast: A polyhedral to spindle shaped cell, it is larger than cytotrophoblast, has an eosinophilic cytoplasm, a single central nucleus and prominent nucleolus. Binucleated and rimltinucleared forms occur particularly at the implllntation site. The intennediate trophoblast is found within ilbrili, endomyometrium, or iJi the wall and lumens ofspiral anerioles. Mitotic'activity is seen.

3. Syncytiotrophoblast: This terminally differentiated cell is mitotically inactive but functional. It is multinucleated and a syncytium with arnpbophilic to purple cytoplasm and multiple, small hyperchromatic nuclei. Multiple lacunae may be present in the cytoplasm imparting a lacy appearance to the cells. This cell covers all chorionic structures where it is located superficial to the cytotrophoblasts in the villi and peripheral to them interfacing with the maternal blood where they line maternal vascular spaces. During early gestation, these cells are strongly immunoreactive for HCG, but weakly so for HPL. Later in pregnancy, this pattern of immunoreactivity reverses.

104"' Semi-Annual CfTR Seminar: Gynecologic Pathology 20 TABLE6

Immunohistochemical Features of T rophoblastic Cells

Cytokeratin BCG HPL

Cytotrophoblast +++ ' -

Intermediate Trophoblast +++ + +++

Syncytiotrophoblast +++ +++ +

REFERENCES

I. Brewer JJ, Mazur MT. Gestational choriocarcinoma. Tts origin in the placenta during seemingly normal pregnancy. Am J Surg Patho/5:261, 1981. 2. Fisher RA, Newlands ES, Jeffreys AJ, et al. Gestational and nongestational trophoblastic tumors distinguished by DNA analysis. Cancer 69:839-845, 1992. 3. Hopkins M, Nunez C, Murphy Jr., Wentz B. Malignantplacental site trophoblastic tumor. Obstet Gynecol 66:955, 1985. 4. Heutner PC, GerseU DJ. Placental site nodule: A clinicopathologic study of38 cases. 1111 J Gynecol Pathol 13:191-198, 1994. 5. Kurman RJ, ScuUy RE, Norris HJ. Trophoblastic pseudotumor ofthe uterus. An exaggerated form o( "syncytial engometritis" simulating a malignant tumor. C(]Jzcer 56:403-410, 1976. 6. Lage JM, Bagg A, Berchem GJ. Gestational trophoblastic . Cu"ent Opinion In Obstet Gyneco/8;79- 82, 1996. 7. Nishikawa Y, Kaseki S, Tomoda Y et a!. Histopathologic classification of uterine choriocarcinoma. Cancer (Philad) 55:1044, t985. 8. Ringertz N. Hydatidiform mole, invasive mole and choriocarcinoma in Sweden1958-l965. Acta Ohstet Gyneco/U3:420, 1970. 9. Scully RE, Young RR. Trophoblastic pseudotumor. A reappraisaL Am J Surg Patho/1981; 5:75.Szulman AE, Buchsbaum I:U. (eds.) 1987. Gestational trophoblastic djsww .• Springer, Berlin Hiedelberg, New York. 10. Shitabata PI<. Rutgers JL. Tbe placental site nodule: An immunohistocheoriical study. Hum Patlzo/25 :1295, 1994. II. Young RH, Kurman RJ, Scully RE. Placental site nodule and plaques in a clinicopathologic analysis of20 cases. AmJSurgPafho/14:1001, 1990.

1046 Semi-Annual CITR Seminar: Gyncoologic.Pathology 21 CASES

History (Case #5-Ace. 23764) A 57-year-old Caucasian female presented with periumbilical and supra-pubic pain. Physical examination revealed a fixed uterus enlarged to four months gestation. The uterus with attached adnexa weighed 280 grams. The uterus measured 9.5 x 5.0 x 4,0 em, but the cervical portion was much larger than the fundus and bad a iliameter of 6.0 em. The mucosa of the portio vllginalis was somewhat granular and studded with millimeter-sized pale yellow papules. The external os·was 1.5 em wide and had promineni red-tan tissue on the anterior lip. The [ower portion of the endometrial canal, as wel1. as the cervical canal, was lined by soft, pale gray-tan gelatinous material up to 0.8 em thick. This same type of material waspresent throughout the wall of the cervix. (Contributed by Melvin Anderson, MD.)

Diagnosis: Mucinous (colloid) Adenocarcinoma with signet ring cell differentiation

DISCUSSION

A useful classification ofendocervical which is based mainly on the cell type ofthe tumor is shown in Table 7.

TABLE7

CLASSIFICATION OF. ENDOCERVICAL CARCINOMAS f Mucinous a. endocervical type i. typical ii. minimal deviation ( malignum) b. Gftype II. Endometrioid a. typical b. villoglandular III. Serous JV. Clear Cell V. Adenosquamous cell carcinoma a. typical b. 'glassy cell VI. Adenoid cystic VIT. Adenocarcinoma with neuroendocrine differentiation VIII. Mixed carcinoma IX. Mesonephric

There has been a.growing interest in endocervical adenocarcinomas because of its apparent increased frequency over the past couple of decades in part due to the decrease in the frequeocy ofsquamous carcinomas. Also, an increased frequency in young women and ·the possible role of oral contraceptives in this increase has attracted attention. One study ofwomen under 50 years ofage with adenocarcinoma found a history ofBCl' use in 82% ofcases rising to 92% in those women with adenocarcinoma in situ. A controversial viewpoint presented by Dallenbach-Hellweg (1984) is that microglandular hyperplasia is a precursor lesions ofendocervical adenocarcinoma. Considering the well-known relationship between hYf>erplasia and carcinoma in other sites, this suggestion may not be totally .without

104ih Semi-AMual CTTR Seminar: Gynecologic Pathology 22 mctiL Alypical endocervical glandular hyperplasia and adeoocarcinoma in situ are believed to be morphologic precursors ofthis lesion. Currently, the interest is in relating these tumors to human virus. A majority of tumors contain HPV-DNA, usually type 18. A disproponionately small percentage ofin situ adenocarcinomas contain detectable HPV 18 compared to the invasive lesions; it has been suggested that HPV 18 may induce a more rapid malignant transformation than do some of the other HPV types. Squamous intraepithelial neoplasia has been reponed in close ofhalf(43%) ofthe patients. An increased incidence of primary ovarian carcinomas has also been reported.

Endocervical adenocarcinomas account for 3% to 25% ofmalignant cervical lesions according to various reports. The clinical profile ofwomen with adenocarcinoma is somewhat different from those with squamous carcinoma. The pslients are usually older with a mean age between 48 to 56, better off socio-ecooomicatly, and lad< association with some ofthe venereal diseases previously noted among women with squamous carcinoma. Vaginal bleeding and profuse discharge are the two main symptoms.

Pathologic Features

Grossly, a high proponion (40-50"/o) are exophytic. Approximately IS% are not grossly apparent, and the remaining are endophytic or barrel shaped.

Microscopic classification bas been highly variable in different reports. The WHO basically divides these rumors into the endocervical and eodometrioid types. At AFIP, the eodometrioid variant is seen with highest frequency, but in general practice, the eodocefVical type accounts for up to 60"/o ofthe cases.

The typical endocervical variant is characterized by tbe proliferation ofcells with abundant intracytoplasmic mucin lining well to poorly formed glands. Abundant intraluminal mucin is present in many. Some ofthe rumors contain goblet cells and morphologically resemble GI adenocarcinomas; these should be distinguished from metastatic GI . Signet ring cells are sometimes present in those associated with abundant colloid production as seen in the seminar case. We have seen increased nuclear atypia in some recurrent cases following radiation therapy. About 5% to 15% ofendocervical mucinous carcinomas are composed ofvery well differentiated glands and are classified as "minimal deviation adenocarcinoma." Many patients are less than 40 years of age. Some ofthese lesions have been associated with the Peutz-Jeghers syndrome and simultaneous mucinous ovarian tumors. This is a highly differentiated carcinoma with a poor prognois and early nodal metastases. Because ofits deoeptively bland cytology, it is difficult to distinguish from normal eodocefVical glands. It is the deep location ofthe glands, often irregular architecture, and a desmoplastic stromal response that indicate the correct diagnosis. Positive intmunoreaction for CEA is helpful.

The eodometrloid variant constitutes 20"/o to 30"/o ofendocervical adenocarcinomas in the general pathology practice. These show glands or papillae lined by columnar pseudostratified endometrial-type cells. Squamous metaplasia may be present in this type. The papiUary villoglandular adenocarcinoma is generally of endometrioid type (see discussion for case 9). Rarely, a "minimal deviation endometrlold" carcinoma also occurs with less than 20 such cases reponed_ Women in the reponed studies have been 34 to 48 years ofage. In conlrast to the minimal deviation mucinous carcinomas, the eodometrioid variant bas a relatively good prognosis.

Both adenoid cystic and adenoid basal carcinomas occur in !he cervix. The former is often large and aggressive, while the latter is frequently an incidental fi.nding and has a very indolent course. Adenoid cystic carcinomas occur in older and almost always postmenopausal women \\ith a median age ofabout 65 years. It may be eitber C«Ophytic or endophytic in its growth. Composed of basaloid cells with scant cytoplasm and hyperchromatic nuclei, it may form cribriform arrangement, solid nests, cords, or tubules. The spaces formed by the tumor may be empty or contain mucinous and basement membrane-like material. The tumor cells show immunoreactivity for both cytokeratins and actin suggesting myoepithelial differentiation although myoepithelial cells are not a known component ofthe normal cervix_ Lymphatic invasion is common. Cervical intraepitbelial neoplasia is evident in 60% of the cases. An associated adenocarcinoma is present in 16%. These are believed to arise from n:serve cells. The adenoid basal cell carcinoma has an infiltrative proliferation ofclusters and cords of basaloid cells with focal squamous differentiation in some clusters. Small acini lined by a single layer ofcuboid to columnar cells are also admixed. The proliferating cells

104° Semi-Annual CTTR Seminar: Gynecologic Pathology 23 maybe surrounded by a desmoplastic stromal reaction. Occasionally, the lesion appears to emanate from the basal portion oflhe overlying cpilhetium.

The glassy cell carcinoma is a rare variant ofadenosquamous carcinoma wilh a poor prognosis. It is composed of large cells with abundant eosinophilic to amphophilic cytoplasm. disllnct cell borders, large nuclei and one or more prominent nucleoli. The cytoplasm has a ground glass appearance and a dislloct membrane. Actual gland formation is evident in some eases.

Mesonephric adenocarcinomas are extremely rare tumors. The handful ofreported cases have occurred in women ranging in. age from mid thirties to late sixties. These arise from and are almost invariably seen in association with residual mesonephric remnants. They are generally deeply located in the lateral wall of the cervix. These may show gland formation or papillary processes. Some show a distinct transition from normal to atypical mesonephric remnants around lhe areas of overt carcinoma. The cells are often cuboidal in shape and do not contain intracytoplasmic mucin or glycogen. Many ofthe reported eases have described patients who died from lhe tumor.

Adenocarcinoma metastatic to tbe endoui'Vix

The cervix most frequently shows involvement by endometrial carcinomas either by contiguous spread along the surface epithelium or by stroma invasion. The differentiation of primary adenocarcinoma oftbe endometrium from an endocervical can be very difficult when an endometrioid pattern is encountered. Primary mucinous carcinomas account for Jess lhan S% of endometrial carcinomas and rarely cause a problem. Endometrioid carcinomas of endoeervix have 8 more fibrous stroma whereas an endometrial type stroma is more common around lhose of endometrial origin. The presence ofadjacent endocesvieal glandular atypia or in situ carcinoma would lilvor an endocesvieal origin. Expression ofCEA is more common in endocervical adenocarcinomas. Nonelheless, it is sometimes practically impossible to make a distinction. The location is lhe hysterectomy specimen is often helpful. Some lesions, however, appear to originate at the junction in the lower uterine segment with subsequent extension into both directions. Metastallc ovarian carcinoma is lhe next most common genital tract tumor, while metastatic tubal carcinoma is very rare. Extragenital tumors lhat metastasize to the cervix include breast, colorectal and gastric carcinoma.

Special Studies

Approximately 25% of endocervical adenocarcinomas expressER or PR, but this feature does not appear to have any prognostic significance (Fujiwara et al, 1997). Ploidy levels correlate with prognosis in stages I and n disease. Tumors that have triploidy or greater DNA content are associated with a worse prognosis. Elaboration of CA 125 has been associated with a worse prognosis in a small number ofcases studied. Regardless of its prognostic value, CA125 may be useful in monitoring progression of the disease and response to lherapy.

P.rog~>ostic Fe.atures

Survival of the patients depends on the interaction of various factors such as stage, histologic type, and size ofthe tumor. Tumor stage is a most important feature for prognostic purposes. Most tumors are in stages I or ll at the time ofdiagnosis . The five-year survival depends on the stage ranging fi·om 60 to 91% for stage I and 11 to 60% for stage ll disease. For stages ill and IV, the S-year survival is dismal and only 0 to 10"/o in past reports; with adjuvant combination chemolherapy, a 39% 5-year survival has been reported for some stage ill carcinomas. The frequency of lymph node metastases is directly relat.ed to lhe tumor stage, and inversely to survival.

Among histologic subtypes, glassy cell carcinoma, adenoid cystic and neuroendocrine carcinomas are associated with a more aggressive course. The papillary and endometrioid types are associated wilh a better prognosis. The impact oftumor grade is not well established. Depth ofinvasion has significance. Approximately 90% of patients whose tumors are less than S mm are cured. If the tumor is 3cm in diameter, however, half ofthe patients have metastases. There is a significant dift'erence in survival for stage lb (76%) and stage lib (49%) at 5 years. Tumors with Jess than 2 mm invasion almost never have nodal metastases, wbereas 57% of those wilh invasion in excess of I em have nodal metastases. Recurrences may develop, however, even with 3 mm ofi nvasion. The co~pt ofmicroinvasion has not

104"' Semi-Annual CTTR Seminar: G)necologie Pathology 24 been well established for endocervical adenocarcinomas. This is due to the faa that ideotification and measurement of what constitutes early invasion is extremely dillicuh. Vascular/lymphatic invasion portends a more aggressive behavior regardless ofthe nodal Sl8tus. Mucin leakage.into the stroma is also associated with elevated incidence of nodal metastases.

Treatment for invasive adenocarcinomas depends on the stage at presentation. Generally, radical hysterectomy and pelvic lymphadenectomy for early stage disease. An alternative approach is to use radiation therapy as the initial treatment followed by simple hysterectomy.

REFERENCES

Adenorareinoma I. Albores-Saavedra J, Rodriquez..Martinez HA, Larraza·Hernaodez 0. Carcinoid tumors ofthe cervix. Pathcl Amnt 14:273, 1979. 2. Boon MEet al. Adenocarcinoma in situ ofthe cervix: An underdiagnosed lesion. Cancer 48:768-73, 1981. 3. Burghardt E: Early histological diagnosis ofcervical cancer. Philadelphia, WB Saunders, 1973, pp. 335-362. 4. Chan JKC, Tsui WMS, Tung SY, Ching RCT. Endocrine cell hyperplasia ofthe uterine cervix. Am J Clin Patho/9:825, 1989. S. Clement PB, Scully RE. Carcinoma ofthe cervix. Histologic types. Seminars Oncol9:251-64, 1982. 6. Fujiwara, H. Tortolero-Luna G, Mitchell MF, Koulos JP, Wright TC Jr. Adenocarcinoma of the cervix. Expression and clinical significance ofestrogen and progesterone receptors. Ca11cer 79:505-12, 1997. 7. Gallup DG, Abell MR. Invasive adenocarcinoma ofthe uterine cervix. Obstet Gyneccl 49:596-603, 197,7. 8. Hun WG et al. Adenocarcinoma ofthe cervix: Histopathologic and clinical features. Am J Obstet Gynecol· 129:304-15, 1977. 9. Inoue T, Yatnaguchi K, Suzuki H, et al. Production ofimmunoreaetive-polypeptide honnones in cervical carcinoma. Cancer 53:1509, 1984. 10. Kaminski PF, Norris IU. Coexistence ofovarian neoplasms and endocervical adenocarcinoma. Obslet Gynecol 64:553-56, 1984. I L Lojek MA, Fer MF, Kasselberg AG, et at Cushing's srndrome with small cell carcinoma ofthe uterine cervix. AmJMed69:140, 1980. 12. Maier RC, Norris HJ. Coelcistenec of cervical intraepithelial neoplasia with primary adenocarcinoma ofthe endocervix. Obstet Gynecol 56:361 -64, 1980. 13. Matsuyatna M, Inoue T, Ariyoshi Y, et al. Argyrophil cell carcinoma of the uterine cervix with ectopic production of ACTH, b-MSH, serotonin, histamine, and amylase. Cancer 44: 1813, 1979. 14. Mayer EO et al. Adenocarcinoma ofthe uterine cervix: Incidence and the role ofradiation therapy. Radiology 121:725-29, !'976. 1S , Miller BE, Flax SO, Atheart K, Photopulos G. The presentation of adenocarcinoma of the uterine cervix. Cancer 12:128 1-5, 1993. 16. Mullins JD, Hilliard GO. Cervical carcinoid ("argyrophil ecU" carcinoma) asmated with an endocervical adenoearoinoma: A light and ultrastructural study. Callcer47:78S, 1981. 17. Norris HJ, McCauley KM Unusual forms of adenocarcinoma of the cervix: An update. Pathcl AIIIIU 28:pL 1:733-95, 1993. 18. Ostor A, RomeR, Quinn M. Microinvasive adenocarcinoma of 1he cervix: a clinicopathologic study of 77 women. Obstet Gyneccl 89:88-93, 1997. 19. Reagan JW, Ng ABP. The cellular manifestations of uterine . In The Uterus, Norris HJ, Henig AT, Abell MR, eds. Williatns and Wilkins Co., Baltimore, pp. 320-47, 1973. 20. Rutledge FN et al. Adenocarcinonta of the uterine cervix. Am J Obstet Gyneaol 122:236-45, 1975. 21. Savargaonkar TR, Hale RJ, Pope R, Fox H Buckley CH. Enteric differentiation in cervical adenocarcinomas and its prognostic significance. Histopathology 23:275-7, 1993. 22. Schwartz SM, Weiss NS. Increased incidence ofadenocarcinoma ofthe cervix in young women in the . Am J Epidennil 124:1045-1047, 1986. 23. Scully RE, Aguirre P, DeLellis RA. Atgyrophilia, serotonin, and peptide hormones in the female genital trsct and its tumors. ImJGynecc/Patho/3:51, 1984.

104,. Scmi-Annuol CTTR Seminar: Gynecologic Pathoh>&Y 25 24. Stassatt J, Crum CP, Yonlan EL, et al. Argyrophilic carcinoma of the cervix: A report of a case wilh coexisting cervical intraepithelial neoplasia. GJmecol Ot~eo/13 :247, 1982. 25. Tase T, Okagaki T, Clark BA, Manias DA, Ostrow RS, Twiggs LB, Faras AJ. Human papillomavirus 1ypes and locali%ation in adenocarcinoma and adenosquamous carcinoma of the uterine cervix: a study by in situ DNA hybridization. Cancer Res 48:993-98, 1988. 26. Tasker JT, Collins JA. Adenocarcinoma of the uterine cervix. Am J Obstet Gyneco/118:344·48, 1974. 27. Tateishi R, Wada A, Hayakawa K, et al. Argyrophil cell carci.noma () oflhe cervix. Light and electron microscopic observations of5 cases. Virchows Arch Pathol Anat A 366:257, 1975. 28. WcinerS, WtzenbergMJ. Treatmentofprimaryadenocarcinomaoftbecervix. Cancer35:1514-16,1975. 29. W'ubur DC. Bonfiglio TA, Stoler MH. Continuity ofhuman papillomavirus (HPV) type between neoplastic precursors and invasive cervical carcinoma. An in siru hybridization study. Am J Surg Patho/12:182-86, 1988. 30. Wilczynski SP, Walker J, Liao SY, Berger S, Berman M. Adenocarcinoma of the cervix associated witb human papillomavirus. Cancer 62: 1331·36, 1988. 31. Yamasaki M, Tateishi R, Hongo J, et al. Argyrophil small cell carcinomas of the uterine cervix. lmJ G;mecol Pathol3: 146, 1984. 32. Yeh l·T, LiVolsi VA, Noumotr JS. Endocervical carolnoma. Path Res Praf.'l 187:129-144, 1~1.

Adenoma Maligm•m (Minimal Deyiation Adenocarcinnmal 1. Gilks CB, Young RH, Aquirre P, DeLellis RA, Scully RE. Adenoma malignum (minimal deviation adenocarcinoma) oftbe uterine cervix. A clinicopalhological and immunohistochemical analysis of 26 cases. Am J Surg Pa1ho/13:717-29, 1989. 2. Jones MA, Young RH, Scully R.E. Dilfuse laminar endocervical glandular hyperplasia. A benign lesion often confused -..ith adenoma malignum (minimal deviation adenocarcinoma). Am J Surg Patho/15:1123·29, .1991. 3. McGowan L, Young RH, Scully RE. Peutz-Jeghers syndrome with "adenoma Malignum" of the cervix. Gynecol Oncol10:125-33, 1980. 4. McKelvey JL, Goodlin RR. Adenoma malignum ofthe cervix: A cancer of deceptively iMocent histological pattern. Cancer 16:549-557, 1963. 5. Silverberg SG, Hurt WG. Minimal deviation adenocarcinoma (''adenoma malignum") ofthe cervi><: A reappraisal. Am J Obstet Gyneco/121:971-15, 1975. 6. Szyfelbcin WM, Young RH, Scully RE. Adenoma malignum oflhe cervix - cytologic findings. Acta Cytol 28:691-98, 1984. 7. Young RH, Scully RE. Mucinous ovarian rumors associated wilh mucinous adenocarcinomas oftbe cervix A clinicopathological analysis of 16 cases. /111 J GytleCOI Pathol1:99·111, 19&8.

Minimal-Deviation Endometrioid Adenocarcinoma I. Kaminsky PF, Norris HJ, Minimal deviation carcinoma (adenoma malignum) of the cervix. /m J Gynecol Pathol2:141:'!52, 1983. 2. Rahilly MA, Williams ARW, AI-Nafussi A. Minimal deviation endometrioid adenocarcinoma ofcervix: a clinicopatbological and immunohistochemical study oftwo cases. Histopathology 20:35 1-354, 1992. 3. Young RH, Scully RE. Minimal-deviation endometrioid adenocarcinoma oftbe uterine cervix. A report offive cases ofa distinctive neoplasm that may be misinte>])reted as benign. Am J Surg Patflol17:660-5, 1993.

Villoelandular Paoillary Adenoarcinoma I. Jones MW, Silvergerg SG, Kurman RJ. WeD-differentiated villo-glandular adenocarcinoma of lhe uterine cervix: A clinicopathological study of24 cases. lnt J Gynecol Pathol12:1 ·1, 1993. 2. Young RH, Scully RE. Villoglaodular papiUary adenocarcinoma oftbe uterine cervix. A clinicopat_hologic analysis of 13 cases. Cancer 63: 1773-9, 1989. 3. Stamatakos M. 'ravassoli FA. Papillary villoglandular adenocarcinoma ofth.e cervix. Pathology Case Reviews 2:38-42, 1997.

Ad ~nnid Cvstic Carcinoma I. Albores-Saavedra J, Manivel C, Mora A, Vuitch F, Milcbgrub S. Gould E. The solid variant ofadenoid cystic carcinoma oftbe cervix lm J Gynecol Patho/11 :2-10, 1992. 2. Ferry JA, Scully RE. and adenoid basal carcinoma ofuterine cervix: a study of29

104'" Semi-Annual CTTR Scntincr: Gynecologic Pathology 26 cases. Am J Surg Patho/12: 134· 44, 1988. 3, Miles PA, Norris HJ. Adenoid cy>1ic carcinoma of the cervix: an analysis of 12 cases. Ob.rtet Gyneco/38 ;1 03 · 10, 1971. 4. Morimura Y. Honda T, Hoshi K, Yamada J; Nemoto K, Sato A. A case of uterine cervical adenoid Cystic carcinoma: Immunohistochemical study for basement membrane material. Obstet GJo11eCCI8S:903-05, 1995. S. Musa AG, Hughes RR, Coleman SA. Adenoid cystic carcinoma ofthe cervix: a repon of 17 cases. Gyneool Onco/22:161·13, 1985. 6. Thackray AC, Lucas RB. Adenoid cystic carcinoma. In: Tumor of the major salivary glands. Armed Forces Institute ofPathology, Washington, DC. 1974, pp. 91-99.

Mqonephric Adenosarcinoma I. Buntine DW. Adenocarcinoma of the uterine cervix of probable wolffian duct origin. Pathology 11 :713-18, 1979. 2. Gupta OP, Guirguis MN, Diejomaoh F. MeSQnephric adenocarcinoma ofcervix: a case repon. lnl J Gynaecol Obstet 26:137-40, 1988. 3. McGee CT, Cromer DW, Greene RR. Mewnepfuic carcinoma ofthe cervix-ith focal endocrine cell differentiation. lnt J Gynecol Patho/12:264-9, 1993.

104• Scmi-AnnWII CTTR Saninar: Gyn<:colowc Pathology 27 CASE6

Hi5tory (Case 1M-Ace. 28375) A 22-year-old Caucasian female presented with irregular uterine bleeding and an abnorrnal l'ap smear. Pelvic examination showed a fungating cervical mass. Patient's past medical history was unremarkable. She bad used BCP at age 16 for several months and was on Tripbasil (combination BCP containing levonorgestrel and ethinylestradiol) for nine months prior to her presentation. A hysterectomy was performed. The anterior and lateral cervical walls were replaced by a fungating papillary mass. (Contributed by Fattaneh Tavassoti, M-D.)

Diagnosis: Villoglandular Adenocarcinoma of the Cervix

Pathologic Findings: Biopsy of the tumor showed numo;rous branching papillary projecrions composed of thin fibrovascular cores covered by a single layer o(columnar epithelial cells. The biopsy was interpreted as a well­ differentiated papillary adenocarcinoma and a radical hysterectomy was performed. Gross examination of the hysterectomy specimen showed an exophytic, fungating mass measuring 4.5 x 3.0 x 3.0 em in the endocervix and occupying the anterior and right lateral portions ofthe cervix.

The biopsy and the hysterectomy specimen showed identical histology. The cervix was replaced by an arborizing papillary lesion. The papillae were supponed by a fibrovasc:ular core and covered by stratified columnar epithelial cells. Most ofthe epithelial cells bad an endometrioid appearance with a IDI1dly eosinophilic cytoplasm, but a Iew. cells had intracytoplasmic mucin, which was confirmed by mucicarmine stain. The nuclei ofthe epithelial cells were oval with indistinct nucleoli. Mild cytologic atypia was present throughout with some variation in nuclear size and shape, Mitotic figures were present in the epithelial cells with about three to four mitotic figures per I 0 high power fields. Neutrophils were sparsely distributed within the papillary stalks, gland lumens, and in the cervical stromal surrounding the tumor. No epithelial tufts or psammoma bodies were identified. The papillary stroma displayed variable fibroblastic proliferation around small vessels.

The tumor was basically exophytic with only superficial invasion ofthe cervical stroma. A few foci of early stromal invasion characterized by small groups ofcells and individual cells extending from the surface and invading into the papillary stroma were identified. The invasive cells generally displayed a more rounded contour and a more eosinophilic cytoplasm. Vascular and lymphatic space invasion were not identified. The endometrium was in late secretory phase and displayed no involvement by the cervical carcinoma. lmmunohistocbernical stains were performed on paraffin embedded tissue. The tumor cells stained positive for cytokeratins AEI/ AE3, CAM 5.2, polyclonal carcino-embryonic antigen (CEA) and progesterone receptor. The tumor stained negative for estrogen receptors and for HPV 6,11,16,18,3 1,33, and 35 (in situ hybridization).

Bilateral external iliac and obturator lymph nodes were removed at the time ofsurgery and showed no evidence of metastatic tumor. The patient is free ofdisease 12 months after surgery.

DISCUSSION

While assumption of a papillary growth pattern by cervical adenocarcinoma has been well recognized for a long time, villoglandular papillary adenocarcinoma ofthe cervix was first described as a distinct entity in 1989 (Young and Scully). About45 cases ofvilloglandular papillary adenocarcinoma of the cervix have been reported in the literature. After the description of the first 13 cases by Young and Scully, twenty-four cases were reported by Jones eta!, four by Costa et al, three by Hopson et al, and a single case in a pregnant patient was reponed by Huneau et al.

The etiology ofVP A ofthe cervix has not been well established. An association between oral contraceptive use and

104• Semi-Annual CTTR Scminor: (jyn«o logi~ Pathology 28 VPA was suggested by Jones et at The authors noted that at least IS of the 24 (63%) patients in the study bad taken oral contraceptives prior to diagnosis as compared to 28% in a control group of patients with other histologic types of cerncal adenocarcinoma One might argue that. the frequency oforal contraceptive use in that group is due to the relatively young age of tbe patients with VP A An association between oral contraceptive use (particularly greater than 12 years) and the development of usual cervical adenocarcinomas has also been suggested in the literature, but this association has not been universally accepted.

An association between VPA and infection with the human papilloma virus (HPV) bas not been deseribed. A possible role could be s~ated, however, since foci of in situ (CIS) were identified in II ofthe previously reported cases as well as in the present case. Invasive squamous cell carcinoma bas also been identified in one case. In addition, foci ofadenocarcinoma in situ were reported in 12 ofthe previous cases. lmmunoperoxidase staining for HPV was not performed in any ofthe previous reports. lmmunoperoxidase stains for HPV 6,11,16,18,31,33, and 35 were negative in the case pubtished here.

Clinical Features

The most common presenting symptom is abnormal vaginal bleeding, which was noted in this case and documented in 9 of the 45 previous cases. Three of these 9 women also complained of post-coital bleeding. Abnormal cytologic findings were noted in 13 of the 45 women. Three women were asymptomatic and were found to have an abnormal cervix on routine pelvic examination.

Vdloglandular (papillaty) adenocarcinomas occur in a )'OW1ger age group than cervical adenocarcinomas in general. The age range ofthe reported patients with VPA is 22 to 61 years. with an average of35. In comparison, the average age for adenocarcinoma ofthe cervix ranges between 47 to 58 years.

On physical examination, almost all reported women with VPAhave grossly visible exophytic lesions protruding out ofthe endocervical canal; the tumors ranged from O.S em to 8 em. Microscopically, VPA is composed of multiple elongated papillary processes with delicate to relatively prominent fibrovascular cores. Varying amounts ofacute and chronic inflammatory cells are present within the papillary cores and in the cervical stroma along the periphery of the tumor. The overlying epithelium shows only mild to moderate cytologic atypia, and increased mitotic activity may be present. The epithelial cells vary from predominaJltly mucinous (endocervical or intestinal) to mainly nonmucinous columnar cells.

Differential Diagnosis

The diagnosis ofVPA can be difficult on small biopsy.specimens. TI1e differential diagnosis ofVPA includes mainly typical papillary endocervical adenocarcinoma and serous papillary carcinoma. Typical endocervical adenocarcinomas can show a minor villoglandular component but generally display more cytologic atypia. The diagnosis ofVPA should only be made when the villoglandular pattern is the exclusive or almost exclusive pattern (3). Villoglandular papillary adenocarcinoma differs from serous papillary carcinoma by the lack ofmarked nuclear atypia, epithelial rufting. and detached epithelial fragments.

There are a few infrequently encountered benign lesions that may demonstrate a papillary pattern and should be included in the differential diagnosis of VP A The presence ofcytologic atypia, albeit mild, distinguishes VP A from these benign lesions. It must be emphasized, however. that the finding ofan extensive papillary pattern on a cervical biopsy must always be interpreted cautiously with a strong suspicion for malignancy. Chronic cervicitis !!lay show papillary projections similar to VP A. A few cases ofMullerian papilloma, a rare lesion with an arcllitecture closely resembling VP A that most commonly occurs in the vagina of children, have been reported in the cervix. Rare cases ofadenofibroma have been encountered in the cervix. The papillae in VPA are typically thinner than the broad fronds and bulbous configuration ofthose in an adenofibroma. Two cases ofvillous adenoma ofthe uterine cervix have been reported). However, in both ofthese eases, invasive adenocarcinoma was found elsewhere in the same cervix_

104°' Semi-Annual CTTR Seminar: Gynecologic Pathology 29 Behavior and Treatment

ViUoglandular papillary adenocarcinoma has an extremely good prognosis compared to other variants ofcervical adenocarcinoma. Invasion, when present, does not generally e>

Treatment ofVPA has varied from radical hysterectomy (26 patients) to simple hysterectomy (9 women) and even a cone biopsy in 6 patients. Four ofthe patients who were treated by simple hysterectomy received subsequent radiation therapy. All of the 45 previously reported women were surviving without recurrence at the time reponed with follow-up periods ranging from 8 months to 14 yeaFS. This includes six patients who had only a cone biopsy. In tho case ofVPA in a pregnant patient reported by Hurteau et al, the tumor was noted at 20 weeks gestational age, and tbe patient was followed until 32 weeks gestational age when she underwent a Cesarean section and radical hysterectomy. Pelvic and periaortic lymphadenectomies were performed one week later. The patient was a~ve and well I 4 months later. In contrast, adenocarcinoma ofthe cervix has an overall five-year survival rate ofaround 500/o with a five-year survival rate of 60-83% for stage I disease.

The good statistical outcomes and the young age of the patienu with VP A have led some to advocate con~ve therapy when feasible. Considering the excellent prognosis of these rumors, which may be due to the limited depth of in-ion in most cases, radiation and chemotherapy are probably of ~mited value. However, the number ofreported cases is still relatively small, and the current standard oftreatment is to regard these lesions as a carcinoma. Furthermore, the large size of many ofthese lesions, as also noted in our case, often neoessitates more e>

REFERENCES

I. Abell MR, Gosling JRG. Gland cell carcinoma (adenocarcinoma) ofthe uterine cervix. Am J Obst

104" Scmi·Aonual CTTR Seminllf: Gyru:cologic Pathology 30 12 Hurteau JA, Rodriguez GC, Kay HH, Bentley RC, Clark-Pearson D. Villoglandular adenocarcinoma of the cervix: A ease report. Ohstet Gyneco/85:906-8, 1995. 13. Ireland D, Hardiman P, Monaghan JM. AdenO<:arcinoma ofthe uterine cervix: A study of73 cases. Obstet Gynecc/65:82-85, 1985. 14. Jones MW, Silverberg SO. CeNical adenocarcinoma in young women. Possible relationship to microglandular hyperplasia and use oforal contraceptives. Obstet Gyneco/13:984·989, 1989. 15. Jones MR, Silverberg SO, Kurman RJ. Well-differentiated viUoglandular adenO<:arcinoma ofthe uterine cervix: A cllnicopathological study of24 cases. !111 J Gynecol Patho/12:1-1, 1993. 16. Leminen A, Paavonen J, Forss M, Wahlstrom T, Vesterinen E. AdenO<:arcinoma of the uterine cervix. Cancer 65:53-59, 1990. 17. Michael H, Sutton G, Hull MT, Roth LM. Villous adenoma ofthe uterinec:esvix associated with invasive adenocarcinoma: A histologic, ultrastructural, and immunohistochemical study. lnt J Gytt PaJito/5:163-169, 1986. 18. Rombaut RP, Charles D, Murphy A. Adenocarcinoma of the cervix: A clinicopathologic study of47 cases. Cancer 19: 891-900, 1966. 19. Stamatakos M, Tavassoll FA. Villoglandular'papillary adenO<:arcinoma of the cervix. Case report ofthe literature. Pathology Case Reviews 2:38-42, 1997. 20. Ulbright TM, Alexander R W, Kraus FT. Intramural papilloma of the vagina: Evidence ofMullerian histiogenesis. Cancer 48:2260-2266, 1981. 21. Ursin G, Peters RK, Henderson BE. d' Angliang G, Monroe KR. Pike MC. Oral contraceptive use and adenocarcinoma ofthe cervix. lAT~Cet 344:1390-1394, 1994. 22. Valente PT, Hanjani P. Endocervical neoplasia in long-term users oforal contraceptives: Clinical and paihologic observations. Obstet Gyencoi61:695-704, 1985. 23. Young RH, ScullyRE. Villoglandular papillary adenocarcinoma ofthe uterine cervix: A clinicopathologic analysisofl3cases. Cancer63:1773-1779,1989. 24. Young RH, Scully RE. Invasive adenocarcinomlt and related tumors of the uterine cervix. Seminars in Diagnostic Pathology 7:205-227, 1990.

104• Semi-Annual CTTR Seminllr: G}nocologie Pathol<>&\' 31 CASE7

llistory (Case tt7 - Ace. 28376) A 14-year-old female presented with weight loss and fever of unknown origin. On physical examination, the uterus was enlarged and fixed to surrounding tissues. AI laparotomy, a massive tumor involved the uterus and extended to the upper vagina and parametrium. (Contributed by Fattaneh Tavassoli, M.D.)

Diagnosis: Inflammatory myofibroblastic tumor

DISCUSSION

A vast majority ofmesenchymal lesions ofthe uterus are smooth muscle or endometrial stromal in nature. Rarely, however, a variety ofother benign and malignant mesenchymal tumors occur in the uterus. Inflammatory myofibroblastic tUmor (IMT) is·a distinctive pseudosarcomatous appearing lesion that occurs in the soft tissue and viscera of children and young adults. Some cases have beeQ multif

IMF occurs in both sexes. Patients have ranged in age from 3 months to 86 years. The mean and median age of the patients in one ofthe largest series of extrapulmonary IMT (Coffin et aJ. !9.95) was 9.7 and 9 years respectively. Patients most commonly present with a mass associated with fever, pain, weight loss, malaise, and nonspecific Gl and abdominal symptoms. Sometimes the mass is detected during physical examination or imaging ·studies for · unexplained fever or weight loss. More than a third ofthe patients have , generally ofnonno- or hypochromic, microcytic type.

The tumors may be massive. Tanging in size from I em to over 20 em; the median size is around 6.0 em. Multiple nodules are present in 15% ofcases . The nodules may be contiguous inclose proximity-ofeach other. The mass is white to tan on cut surface with a fleshy or myxoid consistency. Foci of hemorrhage, necrosis, and calcification occur in a minority ofcases . Central scarring is e.vident in some cases.

Microscopically, three patterns have been described; these may be present simultaneously and in variable proportions in any given tumor:

1. The first pattern is that of loosely arranged, stellate to plump spindle cells in an edematous to myxoid background. An irregular network ofdelicate tilood vessels produces a granulation tissue· like ap~ce that resembles nodular fascutis. Some of the stromal cells may have abundant eosinophilic cytoplasm and vesicular nuclei reminiscent of rhabdomyoblasts; cross striations are not evident, however. Mitotic figures may be abundant, but there are no abnormal figures. An inflammatory infiltrate composed of polymorphs, lymphocytes, neutrophils and eosinophils permeates the lesion. 2. In the second pattern, a more compact proliferation of spindle cells is evident forming solid, confluent areas or distributed in a patchy fa.Shion within a densely collagenous background. Either a fascicular or storiform pattern may be evident simulating fibromatosis, a myogenic, or fibrohistiocytic neoplasm. The inflammatory infiltrate

104"' Semi-Annual CTTR Seminar: Gynecologic Pathology 32 consists ofaggregates of plasma cells and lymphoid follicles. The proliferating cells may protrude into vessels or form ~ cuff around them. 3. The least proliferative pauern shows extensive densely collagenous zones that resemble a desmoid or scar with entrapped isolated plasma cells and lymphocytes. Punctate calcifications and metaplastic bone formation may be encountered.

Rartly recwrences develop a more undifferentiated or histiocytoid appearance with locally aggressive behavior (Cofftn, 1995).

Immunohistochemical Features and other Special Studies

About 90% ofthe cases show immunoreaction for actin (muscle specific or smooth muscle actin). Almost 100% are positive for vimentin. About 70% show positivity for desmin. Interestingly, a third have a positive reaction with cytokeratin and about 25% have KPI positive cells.

IMT is not aneuploid and does not have a clonal expansion ofeither T orB lymphocytes (Broughan, et aJ 1993). A translocation involving chromosomes 2 and 9 bas been reported (Treissman et a!, 1994).

Recent cytogenetic sfudies have demonstrated clonal chromosomal abnormalities lending support to a neoplastic proliferation.

Behavior and Treatment

About I 5% to 20% of patients develop recurrences or die ofthe disease. The few patients who have died ofthe · disease have had extensive disease with contiguous growth into adjacent structures, but no evidence ofdistant metastases even at autopsy. Recurrence and aggressive behavior appears to be related to site, proximity to vital structures, andmultiuodularity, all ofwhich compromise complete excision of the tumor. Significantly, several tumors that were only biopsied subsequently regressed and recurrences are successfully managed by local excision (Coffin et aJ 1995).

A vast majority of patients are treated by excision only, while some have had only biopsy and others have also received chemotherapy. The multinodular lesions and those with contiguous growth in the retroperitoneum, omentum or mesentery are more difficult to excise completely and are associated with recurrences in 25% ofcases . The constitutional symptoms and laboratory abnormalities regress within a few days after resection of the lesion. Chemotherapy or radiation therapy do not appear to have a role in management of IMT (Day et al 1986; Tang et a!, 1990; Coffin et al, 1995).

Consideration ofthis entity in the difterential diagnosis ofspindle cell tumors that simulate a malignant process particularly in children and adolescents is important to avoid over treatment and a malignant diagnosis.

The pathogenesis and etiology ofthis lesion remain unknown.

REFERENCES

1. Azumi N, Rubin MA, Boyle L, Harunann OP. Oesmin, mqsclc-speeific actin, and alpha-smooth muscle actin expression in nonmuscular sarcomas and sarcoma-like lesions. Mod Parho/7:4A, 1994. - 2. Babadori ]1.1, Liebow AA. Plasma ceO granulomas ofthe lung. Cancer 31:191-208, 1973. 3. Broughau TA, Fischer WL, Tuthill RJ. Vascular invasion by hepatic inflammatory pseudotumor: a clittical study. Cancer 11:2934-40, 1993. 4. Chan YF, White J, Brash H. Metach.ronous pulmonary and cerebral inflammatory pseudotumor in a child. Pediatr Parhol14:805-15, 1994. 5. Coffin CM, Watterson J, Priest JR. Dehner LP. Extrapulmonary inflammatory myofibroblastic tumor Onllammatory pseudotumor). A clinicopatbologic and itnmunobistocbemieal study of S4 cases. Am J Srng 104• Semi-Annual CTIR Seminar: G)·necologic Pathology 33 Patho/19:859-872, 1995. 6. Day DL, Sane S, Dehner LP. lnflammatOl)' pseudotumor ofthe mesentery and small intestine. Pediatr Radio/ 210-5, 1986. 7. Gilks CB, Taylor GP, Clement PB. Inflammatory pseudotumor ofthe uterus. /111 J Gyrrecol Patho16:215-286, 1987. 8. Hollwood K, Fletcher COM. Soft tissue sarcomas that mimic benign lesions. Semi11 Dlagrr Pathol 12:87-97, 1995. 9. l

I 04'" Semi-Annual CTTR Seminar. Gynecologic Pathology 34 CASES9& 10

History (Case 119- Au 18101) A 42-year-old gravida 5, para 5, Caucasian female presented with an enlarging pelvic mass of several months' duration. Recent Pap smear was negative. Menses bad been irregular for the last six months. Physical examination revealed an abdominal mass, 24-26 weeks in size, in tho left adnexal area. T AH-BSO was performed. The 1400 gram left ovary was 30 x 25 em. The external surface was smooth and gray with no excrescences. The cut surfat:e showed a soft yellow to tan lobulated tumor mass with a few small foci of hemorrhage and a few small cysts. (Contributed by AvrumJacobson, M.D.)

Diagnosis: Granulosa cell tumor, adult type

History (Case 1110-Ace. 22614) A 5-year-old female presented with a six-month history of breast enlargement and development ofaxiUary hair. She also had an abdominal mass that filled the abdomen. Preoperative plasma FSH was less than 1.0 ml U/ml (nonnal 0 to 6 ml U/ml), luteinizing hormone 2.6 mJ U/ml (normal 0 to 6 ml U/ml). HCG was non-detectable. Total estrogen was 27 meg. 24-hour urine was composed ofEstrone 7 mcg/24-hours, Estradiol S mcg/24-bours, and Estriol IS mcg/24-hours (norrnaUy trace amounts only in prepubenal females). Plasma Estriol was 1.1 mg/ml (nonnalless than 0.2 mglml). At laparotomy, a smooth, finn, weU-encapsulated, freely mobile tumor replaced the left ovary. The 14 x 12 x 10 em mass bad a soft, variegated red-yellow, and finely cystic cut surface, mark:ed by · interlacing narrow fibrous bands. (Contnl>uted by T. J. Cosgrove, MD.)

Diagnosis: Gonadal stromal tumor, c/w anaplastic granulosa cell tumor

Note for Case 10: Composed ofa compact proliferation of atypical spindle cells that have abundant cytoplasm and some very arypical nuclei and easily identifiable mitotic figures, this tumor lacked morphologic features ofany epithelial or . Immunohistochemical evaluation showed no elaboration ofgerm cell markers or classic epithelial reactions. The cells did show intense reaction with inhibin confirming a gonadal stromal type lesion. Furthermore, among gonadal stromal rumors, the type ofatypia evident in this tumor is most often, though still rarely, seen in granulosa tumors.

DlSCUSSION ·

Accounting for 1.5% ofall ovarian tumors, granulosa cell tumors occur in a wide age range; cases have been reponed in newborn infants as well as postmenopausal women. About 5% occur prior to puberty, while almost 60"/o occur after . Predominantly associated with evidence of hyperestrinism, a rare unilocular thin-walled cystic variant is often androgenic when functional (Norris and Taylor, 1969;Nakashima et aJ, 1984). Tumors that occur prior to puberty differ morphologically from the usual granulosa ceU tumors encountered in adults (adull granulosa cell tumor) and often display a distinctive morphology designated as juvenile granulosa ceU tumors.

ADULT GRANULOSA CELL TUMOR

CliniCJtl Features

The neoplastic granulosa cell is capable of producing orstoring a variety ofsteroid hormones and may produce either estrinizing or virilizing effects. The hormonal activities ofthese tumors may produce clinical symptoms in up to thr~uaners of the patients. A majority have clinical manifestations related to estrogenic type hormones, but androgenic activity has also been weU documented. The nature of the symptoms and the clinical presentation varies depending on the patient's age and reproductive status. In prepubertal girls, granulosa rumors frequently induce

10410 Scmi·AMual CTIR Seminar: Gynecologic Pathology 35 isosexual precotiQus puberty - accounting for I0% ofcases of precocious puberty. In women of reproductive age, the tumor may be associated with a variety of menstrual disorders related to hyperestrinism including , oligomenorrhea and even prolonged amenorrhea. In post-menopausal women, irregular uterine bleeding due to various types ofendometrial hyperplasia is the most common manifestation of hyperestrinism. Other women present with abdominal swelling or pain; acute abdomen due to rupture and hemoperitoneum occurs in up to 100/o ofthe cases. The tumor is usually palpable on pelvic or abdominal examination, but in about !0% ofthe patients the tumor is clinically occult (Fathalla, 1967).

Pat.hologic Features

Granulosa cell tumors are generally unilateral; less than S% are bilateral. Commonly encapsulated. they have a smooth or lobulated surface and show tremendous variation in size. Approximately 50% are over 10 ern, and only 10'/o areS em or smaller; the average size is around 12 em (Norris and Taylor, !968;Fox et al, l97S;Stenwig et al 1979). Cross-section ofthe tumor shows a yellow to white solid neoplasm in a majority of eases. A high proportion have fotal cystic areas, and a small percentage are totally cystic. Hemorrhage is seen in larger tumors; necrosis is focal and uncommon.

Microscopically, there is proliferation ofgranulosa cells with or without a stromal component offibroblasts, tMc.a cells or lutein cells. The cells are small, round to spindle-shaped with small amount of cytoplasm. Their nuclei are ovoid or spindle shaped with a longitudinal groove and occasional small nucleolus. Mitotic activity is generally limited and rarely exceeds I or 2 per I0 HPF. When luteinized, the cells develop abundant pink or vacuolated cytoplasm and the nuclei become round and loose their characteristic groove. In about 2% ofcases, multinucleated or mononucleated cells with bizarre nuclei are found focally; the presence ofthese cells does not have any adverse effect on the prognosis. The cells grow in a variety of patterns; two or more patterns commonly coexist in the same tumor. The best known pattern is the microfollicular pattern characterized by the presence of Cali-Exner bodies. The follicular content varied from an eosinophilic secretion with nuclear debris to basophilic mucinous secretion. A macrofollicular pattern characterized by large spaces lined by layers ofgranulosa cells is much less common. Insular, trabecular and diffuse patterns are relatively common; the trabecular pattern is not infrequently mistaken for a carcinoid tumor. In the insular and trabecular patterns there are islands and broad anastomosing bands ofgranulosa cells. The moire silk pattern shows thin winding cords with more diffuse arnngement compared to the trabecular variant. The typical diffuse pattern forms sheets ofcells ofround, oval or s6ghtly spindle shaped ceUs assuming a ''sarcomatoid" appearance.

A variable amount of thecomatous o•· fibromatous component surrounds the granulosa cells; these cells are rarely the dominant cell population comprising 40% to 60% ofthe tumor.

Differential Diagnosis

Moderately differentiated endometrioid carcinomas may display abundant rosette-like arrangement of nuclei mimicking Call-Exner bodies. The readily identifiable mitotic figures in this setting are an important clue to their carcinomatous nature; granulosa tumors with abundant Call-Exner bodies rarely display more than 1 or 2 mitotic figures per 10 HPF. Undifferentiated carcinomas and poorly differentiated adenocarcinomas are often confused with the sarcomatoid variant ofgranulosa cell tumors. MMy of these have already extended beyond the ovary and may be bilateral at presentation. Granulosa cell tumors are almost always unilateral and Stage l The absence of nuclear grooves is an important feature that helps distinguish all varieties ofcarcinoma from gran.ulosa tumors. Thorough samp6ng is helpful in identifYing mullerian type glands of mullerian type in carcinomas with a diffuse gro~h pattern.

Some endometrioid carcinomas grow in discrete nests and lack significant atypia or mitotic activity. These may be confused with the insular pattern ofa granulosa cell tumor. The presence ofsquamous metaplasia in endometrioid tumors is a helpful feature.

As mentioned earlier, the insular and trabecular patterns ofgranulosa tumor are oot infrequently mistaken for a carcinoid tumor and vice versa. Caroinoid tumors uniform round nuclei that lack the nuclear grooves typical of granulosa cells, however. Furthermore, special stains (Churukian-Schenk) or immunostains for chromogranin will i046 Semi-Annual CTTR Semiruu: Gynecclogic Pathology 36 demonstrate neuroendocrine granules in the carcinoid tumors establishing the diagnosis. Funhennore, primary carcinoid tumors ofthe ovary are usually associated with other teratomatous elements, while the merastatic ones are generally multinodular and bilateral.

The diffuse pattern ofgranulosa cell tumors may be confused with a thecoma particularly when there is luteinization. A reticulum stain is often helpful since granulosa cells typically grow in sheets or aggregates bound by reticulin fibers, while and fibrothecomas contain an abundance ofintercellular fibrils. The almost exclusive spindle cell nature ofthe cells in fibrothecomas is also unusual for a granulosa cell tumor.

Another frequently problematic lesion is the aggressive small cell carcinoma, which occurs in children and young women and is often associated with paraneoplastic hypercalcemia. Morphologically, it is easily confused with a granulosa cell tumor. Dissemination beyond the ovary is evident in 20"/o ofthese small cell carcinomas at presentation. a feature that is most unusual for a granulosa tumor. The presence ofnecrosis on gross and microscopic evaluation associated with significant cytologic atypia, lack ofnuclear grooves, and abundant mitotic activity in the carcinomas are additional features that can help. Presence of mucinous epithelium in I 0"/o ofcases and clusters oflarger cells in almost all small cell carcinomas provide further support. Finally, immunostains for inhibin are positive in granulosa tumors, but completely negative in the carcinomas.

JUVENILE GRANULOSA CELL TUMOR

Oinia~l Futures

Encountered predominantly during the first two decades of life in the female gonad and during infancy in the male · gonad, the juvenile granulosa cell tumor (JGT) has distinctive microscopic features that differ from those of the well­ known forms of granulosa cell tumor encountered in oldet patients. In prepubertal girls, approximately eighty percent of these rumors are associated with isosexual pseudoprecocity. Association ofjuvenile granulosa cell tumors with Oilier's disease (Tamini and Bolen. 1984) and Maffucci's syndrome (Velasco-Oses eta!, 1988; Vassal et al, 1988). JGT presents almost always in stage I; less than 5% are bilatetal.

Pathologic Features

The macroscopic appearance is not distinctive and is similar in its spectrum appearances to the adult granulosa cell tumor. Microscopically, JGT is characterized by a nodular or diffilse cellular growth punctuated by follicles of varying sizes and shapes. The follicles, though large, rarely anain the size ofthose encounteted in the macrofollicular fonn ofadult granulosa cell tumor. The cell population is predominantly composed ofgranulosa cells, but theca cells are also present, generally dispersed in an edematous stroma. The granulosa cells have.hyperchromatic nuclei and there is abundant mitotic activity. The cells lack nuclear grooves. Extensive luteinization is common in the theca cells but also the granulosa cells. Cytomegaly with macronuclei, multinueleation. and bizarre multilobulated nuclei are occasionally obSetVed. Lesset degrees ofatypia are evident in approximately 15% ofcases. Despite the abundant mitotic activity and occasional presence of atypical nuclei, only about 5% of these rumors behave aggressively.

Differential Diagnosis

While a variety oftumors may occasionally have a remote resemblance to JGT, it is only the small cell carcinoma that poses significant diagnostic problem. The presence offoUicle-like structures in small cell carcinoma along with the young age at which it occurs are responsible for confusing it with a JGT. The differences may be rather subtle with more eccentric nuclei in small cell carcinomas. JGT shows a positive immunoreaction with inhibin, whereas small cell carcinoma is negative.

Oinical Behavior and Treatment

All granulosa tumors bave a polentiAI for aggressive behavior. There is no single histologic feature, however, that would separate the benign lesions from the malignant ones. An older study had suggested that the sarcomatoid

104• Semi-Annual CTTR Seminar: Gynecologic Pathology 37 pattern is associated with a more aggressive behavior, but more recent studies do not support any panicular association between the pattem ofgrowth and clinical behavior of the tumor.

The most important prognostic factor is th~ stage ofthe tumor and the pre=ce ofexuaovarian spread. In a recent study, 17% ofth ose with stage I died oftheir lesion compared to 75% ofthose with stages D to IV. Approximately 17% of patients with stage l disease eventually die oft he disease compared to 75% of those with stages n to IV. Almost 90'Ai ofgran ulosa tumors are stage l, however, and it is the prediction of behavior ofthis group ofne oplasms that is most difficu!L Factors related to a relatively poor prognosis include age over 40 years at the time ofdiagnosis, solid and large tumor, bilaterality, numerous mitotic figures, and atypia. Ther~ is, however, disagreement on~ significance of some of these factors.

When preservation of reproductive functions is a major concern, unilateral salpingo-oophorectomy is justifiable wben there is no extension beyond the ovary and the opposite ovacy appears uninvolved. Hysterectomy and bilateral salpingo-oophorectomy are the treaunent ofchoice o~se. Recurrences may develop as late as 3 decades after the initial diagnosis. Therefore, long-term follow-up is required. Surgical resection, radiation, or a combination thereof has been used in managing recurrences that generally develop in the pelvic peritoneum.

The 1-year survival varies from 60".4 to over 90'.4. With longer periods of follow-up, a prognessive decline in survival bas been documerned. The overall prognosis for juvenile granulosa tumor is good with a 1.5% mortality associated with stage lai tumors; but it is poor in stageD tumOrs (Young et al, 1984).

TABLES Classification of Sex Cord-Stromal Tumors A GRANULOSA-STROMAL CELL TUMORS l. Granulosa cell rumor a. adult type b. juvenile type 2. Tumors in the thecoma- group (a) thecoma I. typical 2. luteinized {b) fibroma-fibrosarcoma I. fibroma 2. cellular fibroma 3. fibrosarcoma (e) sclerosing stromal tumor ( d} unclassified B. SERTOLI-LEYDIO CELL TUMORS (ANDROBLASTOMAS) 1. Well differentiated 2. Ofintermediate differentiation 3. Poorly differentiated 4. With heterologous elements 5. Retiform C. GYNANDROBLASTOMA D. SE.X CORD TUMOR WJTH ANNULAR TUBULES E. UNCLASSIFIED

38 REFERENCES

1. Biscoui CV, Hart WR. Juvenile granulosa cell tumors of the ovary. Arch Patlrol lAb Med 113;40-46, 1989. 2. Bjorkholm E, Pettersson F. Granulosa-cell and theca-cell tumors. The clinical picture and long-term outcome for the Radiumhemmet series. Acta Obstel Gynecol Scand 59:361-365, 1980. 3. Bjorkholm E. Silfersward C. Prognostic factors in 8Ja11Uiosa cell tumors. Gytrecol Onco/11 :261-274, 1981. 4. FathaUa MF. The occurrence ofgranulosa and theca tumors in clinically normal ovaries. J Obstet Gynaec Brit Cmwlth 74:279-282, 1967. 5. Fox H. Agrawal K. Langley FA. A clinicopathologic study of92 cases ofgranulosa cell tumor of the ovary with special reference to the factors influencing prognosis. Cancer 35:231-241, 1975. 6. Henderson ON. Granulosa and theca cell tumors of the ovary. Am J Obstet Gynecol 43: 184-2 10, 1942. 7. Hodgson JE, Dockerty MB, Mussey RD. Granulosa cell tumor of the ovary: A clinical pathologic review of sixty-two cases. Sutg Gyt~ecol Obstet81:631-42, 1945. 8. Lack EE, Perez-Atayde AR. Munhy ASK. Golstein DP, Crigler JF, Vawter GF. Granulosa theca cell tumors in premenarchal girls. A clinical and pathologic study often cases. Cancer 48:1846-1854, 1981. 9. Lawrence D, Young RH, Scully RE. Juvenile granulosa cell tumor ofthe infantile testis. A report of 14 cases. Am J Surg Patho/9:81-96, 1985. 10. Nakashima N, Young RH, Scully RE. Androgenic granulosa cell tumors ofthe ovary. A clinicopathologic analysis of 17 cases and review ofthe literature. Arch PathollAb Med 108:786-791, 1984. II. Norris HJ, Taylor HB. Prognosis ofgranulosa-theca tumors of the ovary. Cancer 21 :255-263, 1968. 12. Roth LM, Nicholas TR, Ehrlich CE. Juvenile granulosa cell tumor. A clinicopathologic study ofthree cases with ultrastructural observations. Cancer 44:2194-2205, 1979. . 13. Sjostedt S, Whalen T. Prognosis ofgranulosa cell tumors. Acta Obstet Gynecol SCQ/rd 40(suppl 6):3-26, 1961. 14. Stenwig IT, Hazekarnp JT, Beecham JB. Granulosa cell tumors ofthe ovary. A clinicopathological study of 118 cases with long tenn follow-up. Gynecol Onco/1: 136-152, 1979. IS. Tarnini JK, Bolen J. Enchondrornatosis (Oilier's disease) and ovarian juvenile granulosa cell tumor. Cancer 53:1605-1608, 1984. 16. Vassal G, Flarnant F, Cailaud JM, Demeocq F, Nihoui-Fekete C, Lemerle J. Juvenile granulosa cell tumor of the ovary in children; A clinical study of I 5 cases. J Clin Onco/6;990-995, 1988. 17. Young RH. Dickersin GR. Scully RE. Juvenile granulosa cell tumor ofthe ovary. A clinicopathologic analysis of 125 cases. Am J Surg Pat/w/8;515-596, !984. 18. Young RH, Hickersin GR, Scully RE. Juvenile granulosa cell tumor. A clinicopathological analysis of 125 cases. Am J Surg Patho/ 8:515-596, 1984. 19. Young RH, Oliva E, Scully RE. Luteinized adult granulosa cell tumors of the ovary: A report of four cases. 1111 J Gynecol Pathol 13 :302-10, 1994. 20. Young RH, Oliva E. Scully RE. Luteinized adult granulosa cell tumors ofthe ovary: A report of four cases. lm JGynecol PO!ho/13:302-310, 1994. 21. Young RH, Scully RE. Ovarian sex cord-stromal tumors. Recent advances and current status. Clin Obstet Gyneco/11 :93-134, 1984. 22. Za!Gudek C, Norris JH. Granulosa tumors of the ovary in children. A clinical pathologic study of32 cases. Am J Surg Patho/6:503-51 2, 1982.

104• ~i-Annual CTTR Semin!V: Gynecologic Pathology 39 CASE 11

Hi$!Ory (Case Nil-Ace. 28378) A 24-ycar-old Caucasian female presented with a pernc mass. The right ovary was enlarged on physical examination. At laparotomy, a 17 x 14 x 8 em right ovary was removed. It weighed II 00 grams. The cut surface was yel.lowish, solid with foeal cystic areas and a 4.0 em area of necrosis. There was no gross peritoneal or omental seeding. Three months earlier, tlte patient had had a C-section; at that time, both ovaries and tubes appeared normal. (Contributed by Fattaneb Tavassoli, M.D.)

Diagnosis: Small cell carcinoma, hypercalcemic type

Microscopl< Features: A diJfuse compact proliferation ofcells was dominant in the lesion. In addition, focal areas displayed nests or cords oftumor cells. A small number ofirregularly shaped or rounded follicl~like spaces were dispersed throughout the lesion; these spaces were either empty or contained an eosinophilic secretory material. The predominant proliferating cells were small and rounded with scanty cytoplasm. Round to oval nuclei with minimal variation in size displayed moderate hyperchromasia, Mitotic figures were readily apparent. Small aggregates of cel.ls with more abundant pale to lightly eosinophilic cytoplasm were present in some tissue section.

The tumor cells were immunoreac1ive with CAM5.2 and chromogranin, but failed to react with inhibin.

DlSCUSSlON

First described in 1982, small cell carcinoma is a rare and distinctive type of undifferentiated carcinoma that is ollen associated with byperealcernia. A tumor that occun mainly in younger women, the patients range in age from 9 to 45, with an average of around 25 yean. Familial clustering ofsmall cell carcinoma has been observed in several repons. In one repon it occurred in three sisters. More than half of the tumors have already spread beyond the ovary at the time of presentation.

The tumors are generally large (often exceeding 10 em) at presentation. Cut surface is solid with cystic areas; rarely, it is predominantly cystic.

Generally composed of compact proliferation ofsmaU cells with scant cytoplasm, occasional cases are composed of large cells with abundant cytoplasm. In almost half of the cases, a second population of cell with more abundant eosinophilic cytoplasm is present in small islands throughout the tumor. Far less frequently (in about 10'/o of eases) mucinous ccl.ls are present in small clusters. Mitotic figures are abundant. Follicl~like structures filled with eosinophilic secretory material are present in SO'/o ofthe tumors. The tumor cells may also arrange in cords, trabeculae, and small islands. The minimal stroma evK!ent in some cases may appear edematous or myxoid.

The undifferentiated appearing tumor cells are positive for epithelial markers and vimentin; immunostains for chromogranin have been reponed as positive in only a smaU number ofeases. By flow cytometric evaluation, these tumors are almost always diploid. At the ultrnstrueturallevel, the tumor cells characteristieally show abundant rough endoplasmic reticulum, but generally no dense core granules.

Differential Diagnosis

The two most imponant lesions in the differential diagnosis are juvenile granulosa tumor and small cell carcinoma of the pulmonary type. The morphologic appearance of the tumor with the follicle-like spaces and the young age of most patients result in misinterpretation ofa good proponion ofthese tumors as juvenile granulosa tumor. The

104"' Semi-Annual CTTltSeminar: Gyncxoiogi~ Pathology 40 distinction is now facilitated by the use of immunostain for inhibin, which is positive in granulosa tumors, but negath•e in small cell carcinomas. The next lesion in the differential is smaU cell carcinoma ofthe pulmonary type. Small cell carcinomas ofth e pulmonary type are not associated with hypercalcemia, occur mainly in peri· and postmenopausal women; they are bilateral in close to half of the cases.

Microscopically, they are composed ofislands and trabeculae ofround to spindle shaped small cells with scant cytoplasm. The nuclei are hyperchromatic with rare nucleoli and a stippled chromatin. Argyrophilic granules and l:hromogranin positivity is obsetVed in a small number ofcases. Most rumors are aneuploid, but some are diploid.

A more remote possible source ofconfusion is with lymphomas. The epithelial growth pauem of smal.l cell carcinomas and the immunostaining characteristic can easily differentiate it from a lymphoma.

Behavior and Treatment

Small cell carcinoma of the hypercalcemic type is a very aggressive rumor with a poor prognosis. A majority of patients die within two years after the diagnosis. Tumor that occur in women older than 30 years of age, lack hypercalcemia, are less than I 0 em. and do not contain the islands oflarger cells are associated with a more favorable outcome. Even in stage IA. only about a third of the women are disease free with follow-up ranging from 1 to 13 years (average of 5.7 years). Adjuvant chemotherapy and radiation therapy have been. disappointing, though occasionally result in improved survival. Rare survival beyond 5 years has been observed among patients with higher stage tumors after intensive chemotherapy.

TABLE9

Small Cell Carcinomas of the Ovary

Small cell ca, BCf SmaU eU ca, YT Juvenile Granulosa Tumor Hypercalcemia 60% absent absent

Age (yr) 1~2 (mean 23) 28-85 (mean 59) 80"/o prepubertal Bilateral 1% 45% 2% Follicle-like spaces Common Rare Common Large cells 40"/o Rare 15% Nuclear chromatin Clumped Evenly dispersed Clumped Nucleoli Single, wtiform Inconspicuous Single, small Mucinous Epithelium 10% 10% Rare lnhibin Negative Negative Positive EMA Occasionally + Occasionally+ Negative R.ERonEM Abundant Some Some Dense Core Granules Absent Present Absent DNA content Diploid Aneuploid in 65% Aneuploid in 40%

Abbreviations: HCf • hypercalcemic type; PT 5 pulmonary type

104., Semi-Annual CTTR Seminar: G)nccologic Palhology 41 REFERENCES

I. A&uirre P. Thor AD, Scully RS. Ovarian small cell carcinoma. Histogenetic considerations based on immunohistochemical and other findings. AmJCii11 Patho/92:140-149, 1989. 2. Dickerson OR, Kline JW, Scully RE. Small cell carcinoma ofth e ovary with hypercalcemia: a report ofeleven cases. Cancer 49:188-197, 1982. 3. Eichhorn JH, Bell DA, Young RH, et a!. DNA content and proliferative acti,ity in ovarian small cell carcinomas ofthe hypercalcemic type. Implications for diagnosis, prognosis, and histogenesis. Am J Cli11 Potho/98:579-586, 1992. 4. Eic:hbom JH, Young RH. Scully RE. Non-pulmonary small cell carcinomas ofextragenital origin metastatic to the ovary. A report ofseven cases. Cancer 71 :177-186, 1993. 5. Eichhorn JH, 'Young RH, Scully RE. Primary ovarian small cell carcinoma of pulmonary type. A clinlcopathologic, immunohistologic, and Oow cytometric analysis of II cases. Am J Surg Patho/16:926-938, 1992. 6. Forster C, Ostertag H, Schmitt J, Roessner A Small cell carcinoma of the ovary, hypercalcemic type. A case report with immunohistochemical, ultrastructural and cytophotometric analysis and review of the literature. Gen Diagn Patho/142:365-310, 1997. (Cases in mother and daughter). 7. Fukunaga M, Endo Y, Nomura K., Ushigone S. Small cell carcinoma ofthe ovary: a case report oflarge cells variant. Patho/Jn/41:250-255, 1997. 8. Jensen ML, ~ KL. Jacobsen M Ovarian small cell carcinoma. A case report with histologic, immunohistochemical and ultrastructural findings. APMTS. Suppl23:126-131, 1991. 9. Longy M, Toulouse C. Mage P, et al. Familial cluster ofovarian small cell carcinoma: a new Mendelian entity. J Med Gene/33:333-335, 1996. I 0. Matias-Guiu X. Prat J, Young RH, eta!. Human parathyroid honnone-related protein in ovarian small cell carcinoma. Cancer73:1878-1881, 1994. II . McMalton JT, Hart WR. Ultrastructural analysis of small cell carcinomas ofthe ovary. Am J Clln Pothol 90:523-529, 1988. 12. Rishi M, Howard LN, Bratthauer GL, Tavassoli FA Utility of monoclonal antibody against human inhibin as a marker for sex cord-stromal tumors ofthe ovary. Am J Surg Patllo/21: 583-589, 1997. 13. Scully RE. Small cell carcinoma ofhypercalcemic type. ln/J Gynecol Palho/12: 148-152, 1993. 14. Young RH, Oliva E. Scully RE. Small cell carcinoma of the ovary, hypercalcemic type. A clinicopathological analysis of 150 cases. Am J Surg Patho/18:1102-11 16, 1994.

104'" Scmi-Annunl CTTRSeminar: 0)11etologic Pathology 42 CASE 12

History (Case #12-Ace. 22743) A 32-year-<>ld Caucasian female presented with severe lower quadrant pain and accompanying backache. Pby$ical eYamination revealed a cystic mass ofthe right ovary. An emugency T AH-BSO was performed. (Contributed by Horace Spear, M.D.)

Diagnosis: Consistent with Carcinoid tumor, metastatic tyne

Note: While the morphologic features are typical ofcarcinoi d tumors, the tumor cells were negative for neuroendocrine granules with Grimelius stain and chromogranin immunostain. The bilaterality, involvement of endometrium, myometrium and a lymph node along with the absence of any teratomatous elements funber suppon a metastatic carcinoid. Neuroendocrine granules ~ doaJmented at the extra strucrurallevel.

DISCUSSION

Clinical Features

Primary carcinoid tumors are the second most common type ofmonodermalteratoma ofthe ovary. Predominantly a tumor of postmenopausal women, carcinoid tumor also occurs during the reproductive years. Patients typically present with a pelvic mass. Less than a third ofthe patients with primary ovarian carcinoid tumor have the carcinoid syndrome which disappears after removal ofthe tumor. The carcinoid syndrome occurs more often in women over SO years of age that have tumors over 7 em in diameter.

Pathologic Features

Primary carcinoid tumors are unilateral, but a cystic , Brenner tumor, or mucinous tumor has been reported in the contralateral breast in I 5% ofthe cases. A majority of primary carcinoid tumors arise in a teratoma. The carcinoid component appears as a solid nodule with predominantly solid yellow-tan cut surface. The carcinoid tissue is typically finn, tan to yellow, predominantly solid, and variably fibrous in texture. Cysts filled with clear fluid arc occasionally present; rarely the tumor is predominnntly cystic. Approximately 75% ofthe tumors are mixed 'vith other teratomatous elements. It may also be mixed with struma forming struma! carcinoid.

Microscopically, form either insular and trabecular patterns. Pure carcinoid tumors, strumal carcinoids and mucinous carcinoids. The insular pattern is characterized by discrete cellular masses and nests separated by a scant to abundant fibromatous stroma resembting midgut carcinoids. The peripheral cells ofthe islands contain coarse reddish-brown granules. Small acini lined by columnar cells witb copious cytoplasm and filled by an eosinopbillc secretory material are dispersed between the cellular islands. The tumor cells have round uniform nuclei containing coarse chromatin; mitotic figures are rare.

Long, parallel ribbons of cells separated by a scant to abundant fibro matous stroma characterize the trabecular panem that resembles foregut and hindgut carcinoids (44). The rumor cells are columnar with oblong nuclei and moderate amounts ofeosinophilic cytoplasm that typically contains argyropbillc granules. The nuclei contain finely dispersed chromatin; mitotic figures arc sparse. An insular pattern is observed as a minor feature in abou1 20"/o ofme cases.

Struma! carcinoids show an intimate admixture of both struma and carcinoid; either component may predominate. The carcinoid component may exhibit either the trabecular, insular, or both patterns. The thyroid component may appear as normal thyroid tissue or a follicular adenoma. Neuroendocrine granules are demonstrable in the cells fomling carcinoid trabeculae and thyroid follicles with ~ostain for chromogranin or Cburukian-Schenk stain. On ultrastructural examination, neuroendoain~type granules are present within the trabecular cells and are admixed with the thyroid epithelium lining the follicles in transitional zones.

104°' Semi-Annual CTTR Seminar; Gynecologic Potl>ology 43 Mucinous carcinoid$ (goblet cell carcinoids) resemble those ofappendiceal origin. They usually e«ur in pure form, but may be associated with a mature teratoma or epidermoid cyst. They consist ofsmall nests or gland composed of varying numbers ofgoblet cells and argyrophil cells, some ofwhich may also be argentaffinic; their nuclei are unifom1, small, and round to oval. Small pools of mucin may lie within cystically dilated glands or within the stroma. More poorly differentiated cells, often of signet-ring rype, may invade the stroma, singly or in small nests. Irregular dense core granules have been identified on ultrastructural examination in some cases. Rare ovarian carcinoids include those of spindle cell type resembling their pulmonary counterparts and those with nonspecific, sometimes poorly differentiated pauems.

DifT~reo tial Diagnosis

In the absence ofteratomatous elemenu;, primary carcinoids may be difficult to distinguish from metastatic carci.noids. Evidence favoring or establishing the diagnosis of metastatic disease includes the presence ofa definite or probable carcinoid in the small bowel or elsewhere, extraovarian metastases, bilateral involvement, intraovarian growth as multiple nodules, and persistence of the carcinoid syndrome after removal of the ovarian tumor. Most ofthe above features may be equally useful in differentiating a mucinous wcinoid with a prominent signet-ring component from a metastatic signet-ring carcinoma.

Despite tbcir distinctive microscopic characteristics, ovarian carcinoids can be confused with several other primary ovarian tumors, especially the granulosa cell tumor, the Senoli-Leydig cell tumor (SLCT), and the Brenner tumor. In contrast to the acini ofa carcinoid, the Call-Exner bodies ofthe granulosa cell tumor have irregular margins and contain watery eosinophilic material and occasional shrunken nuclei. The granulosa cells surrounding a Call-~er body lack the copious cytoplasm that separates the nuclei from the lumen ofa carcinoid acinus and typically have· pale, grooved nuclei that are haphazardly oriented in relation to another and the lumen. The cords of Sertoli cells in SLCTs of intermediate differentiation tend to be shorter, less uniform, and more sparsely distributed than the elongated trabeculae ofa trabecular carcinoid; in addition, several other distinctive patterns ofSLCT may be present to facilitate the diagnosis. The epithelial cells ofBrenner tumors, in contrast to those of carcinoid tumors, have a distinct urothelial appearance with grooved nuclei. Additionally, the acini within the Brenner nests are often lined by mucinous cells unlike those of a carcinoid acinus.

Struma! carcinoid has been most frequently misdiagnosed as thyroid carcinoma arising in struma. The latter exhibits the typical patterns ofa papillary or foUicular thyroid carcinoma, and Jacks the trabecular pauem and argyrophil and argentaffin granules of the struma! carcinoid.

REFERENCES

I. Alenghat E, Okagaki T, Talerman A. Primary mucinous carcinoid tumor of the ovary. Cancer 58:777-783, 1986. 2. Czemobils~')' B, Segal RE, Bell DA. Primary mucinous carcinoid tumor ofthe ovary. A case report IntJ · Gynecol Paiho/8:151-162, 1989. 3. Robboy SI, Norris HJ, Scully RE. Insular carcinoid primary in the ovary. A clinicopathologic analysis of48 cases. Cancer 36:404-418, 1975. 4. Robboy SJ, Scully RE, Norris JH. Carcinoid metastatic to the ovary: a clinicopathologic analysis o£35 eases. Cancer 33:798-81I , 1974. 5. Roblloy SH, Scully RE. Struma! carcinoid of the ovary. An analysis of SO cases of a distinctive tumor composed of thyroid tissue and carcinoid. (;'ancer 46:2019-2034, 1980. - 6. Stagno PA, Petras RE, Hart WR. Struma! wcinoid ofthe ovruy. An immunohistologic and ultrastructural study. Arch Pathol LabMed II 1:440-446, 1987. 7. Snyder RR, Tavassoli FA. Ovarian struma! carcinoid: immunohistochemical, ultrastructural, and clinicopathologic observations. !ttl J Gynec Pathol 5: 187-20 I, 1986. 8. Talennan A. Carcinoid tumors ofthe ovary. J Cancer Res Ch'n Oncc/101:125-135, 1984. 9. Wolpert HR. fuller AF. Bell DA. Primary mucinous carcinoid tumor of the ovary. A case report. Int J Gynecol Patho/8: 157-162, 1989.

104'' Semi-Annual CTTR Semi114r: Oyncc:ologio Pathology 44 ., CASE 13

History (Case #13- Ace. 28166) A 42-year-old, gravida I para I, female presented 'With a right ovarian mass. Right salpingo-<>ophorectomy was performed. The specimen consisted ofa ·38 gram, moderately firm mass that measured 6.5 x 4:0 x 3.8 em. The external surface was bosselated and pink-white. The cut surface was solid pink-white with areas oflight gray softening and focal cystic changes beneath the capsule. (Contributed by Arthur Koehler, M.D.)

Diagnosis: Endometrioid tumor of low malignant potential

DISCUSSION

Tumors oflow malignant potential (LMP), alternately referred to as bordedine tumors, of the ovary show a more florid epithelial proliferation compared to that seen in benign twnors ofthe same cclJ type but an absence ofdestructive invasion of the stroma. Despite this lack ofinvasiveness -within the ovary, these tumors can implant on peritoneal surfaces and the implants may invade the underlying tissue; rarely, they spread via lymphatics and, exceptionally, through blood vessels. The diagnosis, however, is based on morphologic features ofthe primary ovarian tumor regardless ofthe presence or absence of tumor spread beyond the ovary.

The distinction ofLMP twnors from frank carcinomas is ~me of the commonest problems in ovarian1Umor pathology'. . Borderline tumors are also designated carcinomas oflow malignant potentiaf but the term borderline tumor is preferable because it avoids having "carcinoma" in the diagnosiS and is less·likely to lead to overly aggressive therapy.

Endometrioid tumors oflow malignant potential are uncommon. Patients range in age from 26 to 79 years. The tumors present as solitary, unilateral, predornlnantly solid masses that range from 2 to 40 em in size. Microscopically, two types have been identified. One has a prominent fibrous component being basicaUy an adenofibroma. The second and far less common variant is basicaUy epithelial in composition with minimal fibrous stromal component. The epithelium in both variants resembles either the endometrium in atypical hyperplasia with low rnltotic activity or low-grade carcinomas. There is no destructive infiltrative gro)Yth. Almost 25% ofthe tumors are associated with pelvic endometriosis, and I 0% are associated with endometrial adenocarcinoma

Because of the rarity of borderline endometrioid adenofibromas, as well as those with rnlcroinvasion. and the clinically benign behavior ofthe relatively few-reponed cases in these categories, recognition offeatures that may predict a malignant behavior requires additional experience with these tumors. For the present, ·the gynecologist should be aware of the apparently eKcellent prognosis ·associated with aU t11ese neoplasms.

When an intracystie papillary villoglandular tumor is Uned by atypical endom~rioid epithelium we designate it b<;>rderline with epithelial atypia but ifthe epitheUum.is malignant, we diagnose bordedine with intraepithelial carcinoma.

Micro~copic Features

Benign Endometrioid Tumors

Endometrioid are rare. They are lined by stratified, typicaUy non-ciliated, non-mucin-containing epithelium; underlying endometrial-type stroma, pseudoxanthoma cclls containing hemofuscin, hemosiderin, or both, and the distinctive stroma- containing small spindle-shaped fibroblasts that often develops in the wall of an endometriotic cyst are absent. Extensive sampling ofa cyst ofthis type, however, may reveal foci where these stromal findings are present, establishing the diagnosis ofan endometriotic cyst.

104" Semi-Annual CTTR Seminar: Gynecologic Pathology 45 The endometrioid adenofibroma is cbaracten 7.ed typically by glands lined .by stratified non-mucin containing epithelium "ithin a predominant fibromatou·s stromal component Occasionally, the epithelium is simple columnar, cuboidal or flat, creating a problem in differentiationJrom a serous adenofibroma.

Squamous differentiation in the form ofmorules, which may exhibit central necrosis, may be present ~thin variable numbers ofthe glanM The morules occasionally excite a myxoid fibroblastic response in the adjacent stromal component, which should not in itselfbe regarded as evidence ofborderline malignancy. Very rare intracystic polypoid and papillary tumors containing bland-appearing endometrioid epithelium also belong in the benign endometrioid category.

Serous Tumor Of Low Malignant Potential

The mo;i corrunon of the category of tumors oflow malignant potential, serous low malignant potential tumors (SLMP) account for from one-quarter to ooo-third of malignant serous tumors. They are most common in the fuurth and fifth decades. Approximately 70"/o are confined to the ovary (Stage I); the remaining tumors have spread ~bin the pelvis (Stage D) or upper abdomen (Stage III). On<>-third of the tumors are·bilateraJ. Rather than discussing the characteristic gross and microscopic features ofSBT, wbich are weD discussed in many standard texts, we will focus on specific diagnostic problems and recent data.

Pseudoinvasion

SLMPs often exhibit a cotiJplex glandular and papillary proliferation. The glands often invaginate into the stroma and, particularly when sectioned tangentially, it may appear as ifinvasion has occurred. This pseudoinvasion differs, however, from·the destructive stromal invasion ofa carcinoma. The stroma in areas ofpseudoinvasion is identical in its ap~ee to the stroma elsewhere and the glands are orderly arranged. In a carcinoma there is typically a desmoplastic stroma and the di;tribution ofthe neoplastic glands in the.stroma is more disorderly. On rare occasions, SLMP shows auto-implants and may have the desmoplastic stroma usually seen in extraovariail implants.

Micronapillary Serous Carcinoma 0\:IPSQ

Recently, a variant ofwell differentiated ovarian carcinoma that does not display destructive ihfiltrative growth (carcinoma in situ), but manifests aggressive behavior has been descnbed and designated MPSC. Its microscopic features include highly complex·micropapillae, high nuclear-to-cytoplasmic ratio and numerous mitotic figures. Most MPSC contain areas ofSBT, indicating that the former probably.arose from the latter. Ofa series of26 ofthese tumors 17 were noninvasive and nine contained areas ofinvasion ranging from minimal to extensive. Eight o£ the 26 tumors were stage I, and none of those patients developed recurrence. In contrast, half of the 16 women ~b stage II disease or higher either died of carcinoma or were alive ~h disease. In these eight patients the ovarian tumors were associated ~ invasive peritoneal implants, which per se carry a poor prognosis. In Stage I tumors, however, there is no objective evidence that the micropapillary, solid, and cnbriform patterns equal frankly invasive carcinoma in terms ofprogno sis.

In our experience, MPSC should be designated as a carcinoma not othe~se qualified' only areas offrank invasion are identified; otherwise, they should be designated as SLMP or serous intraepithelial neop1asia, low grade or high grade depending on the cytologic features. Extensive sampling is indicated.

SL~IPs with Microinvasion

Otherwise typical SLMPs may contain foci ofmicroinvasion. In the first series of 18 cases ofthese tumors reported from AFIP described, 12 were Stage I and 6 were Stage n or m. Only one patient died ofdisease, and she had Stage ill rumor. All the other .patients were alive and well ~thou! evidence ofdisease from 2;5 to 5,5 years after presentation. In a subsequent series, composed of2l cases, foUow-up was available for 17 patients. Sixteen ofthem were alive and well ";thout evidence ofdisease from I to II (average S.2) years after presentation. One patient developed recurrent SLMP ~th microinvasion in the contnilateral ovary almost 3 years after diagnosis and was.wel.16 months later. These tumors do not di!fer grossly from typical SLMPs. Microscopically, they show foci (under 3 mm in greatest dimension) ofsingkcells, nests and small clusters ofcells , which often have abundant eosinophilic cytoplasm, in the stroma. They are unassociated 104"' Semi-AMual CTtR Seminar: Gynecologic Pathology 46 "'ith a sigl1ificant stromal -ction. Oecasionally, foci oflympbatic invasion may be present. Ths finding does not appear to have altcted the prognosis to date. The results in these twO studies indicate that SLMPs with miaoinvasion have a prognosis similar to that ofSLMPs without this feature and consezvation ofthe contralateral ovar; and uterus may be accepcable therapy in young women, so as to preserve fertility. Microinvasion is easily overlooked and may not be rare as suggested by a review of36 consecutive SLMPs in which it was found in 4 cases after careful search.

Tbe distribution of the basement membrane components laminin and type IV collagenase has been investigated in a series of serous tumors of the ovary, including SLMPs with microinvasion. Benign serous cystadenomas and SBTs with microinvasion showed a continuous basement membrane; in contraSt, invasive carcinomas had frequent disruptions and extensive areas lacking basement memb1811e. Early invasion in borderline tumors was characterized by oomplece abseooe of laninin and type IV collagen around clusters ofmiaoinvasive cells. 1yPe IV coiJagena.se_ an enzyme that initiates the cMgradation of type IV coHagen, could not be demonstr.tted in cystadenomas, whereas in invasive carcinomas the reaclivity for 1ype IV collagenase was moderate to intense. Type IV coUagenase immunoreactivity was also found in SLMPs in 1 noninvasive cells with abundant eosinophilic cytoplasm, as ·well as in the foci ofmicroinvasion .

SLPMs with Peritoneal Implants

Peritoneal implants are found in 30 per cent of SLMPs. Implants are seen with greater frequency in patients with tumors that have an exophytic component compared to those which do not. Peritoneal implants may vary greatly in their histologic appearance. They most often appear similar to the primary ovarian tumor showing slight to moderate cytologic atypia, no or only a modest stromal reaction and no destructive invasion. In some cases, however, the implants appear more atypical or Jess atypical than the primary tumor. In the first instance there may be severe cytologic arypia and invasion of the involved tissues producing a picture similar to that ofinfillnl!ing serous carcinoma. In the second instanoe the foci ofserous epithelium are benign or minimally atypical and are indistinguishable from what is designated endosalpingiosis in patients who do not have an ovarian serous tumor. When a patient has a SBT it is possible that many foci of"endosalpingiosis" represent mature implants (endosalpingiosis, however, usually lacks papillae and cell stratification). A frequent finding in maturing implants is numerous psammoma bodies; as the implants mature they appear to undergo obsolescence and are replaced by psammoma bodies.

The peritoneal implants ofSLMPs have been classified into non-invasive and invasive categories with the fonner being funher subdivided into epithelial and desmoplastic subtypes. In some non-invasive implants, papillary proliferations of atypical cells are present on the surf.u:e orthe peritoneum or in smoothly comoured subperitoneal iovagioations or invaginatioos becween lobules ofomental fat. The cytologic atypia in these cases usually approximates thai in the parent ovatian twnor and there is little or no sigl1ificant stromal reaction to tbe tumor. In contrast, the desmoplastic subtype of non-invasive implant is characterized by a predominant stromal reaction to the tumor that is layered upon serosal surfaces. The stromal reaction exceeds quantitatively the epithelial component of tl1C implant. In these foci single cells, small glands, and papillae fonned and lined by atypical serous cells as well as psammo11)8 bodies are entrapped by proliferating fibroblastic tissue that is often infiltrated by acute and chronic inflammatory cells. Necrosis with surface fibrin deposition and hemorrhage are often present. Invasive intplants are characterized by an irregular infiltration of normal tissues, such as the omentum. They resemble histologically a low-grade serous adenocarcinoma; marked cytologic atypia may be present.

Some studies ofSLMPs associated with peritoneal implants have shown thai separation ofthe implants into invasive and non-invasive categories has imponant prognostic implications. In one report, 56 patients were studied (Kennedy and Hart, 1996). When followed for four years or more, or until death, 94 percent of patients with non-invasive implants had no progression ofdisease, in contrast to only 17 percent of those with invasive implants. Severe nuclear atypicality and mitotic activity in the implants were independently correlated with a poor prognosis. In another study, which included _19 Stage IJ. ill tumors, the only four patients who died of tumor had invasive aneuploid unplants (Kllman et a1 , 1986). Although correlation between DNA ploidy ofthe primary ovarian tumor and survival was not statistically significant, three ofthe four patients who died oftumor had aneuploid ovarian tumors. On the basis of these results we do not consider chemotherapy indicated for non-invasive implants ofSLMPs but, on the other hand, think it appropriate for patients with invasive implants. It should be noted that other studies have failed to show a diJference in prognosis between patients with invasive and nco-invasive implants, but they may have included lesions that others would consider desmoplastic non-invasive implants, in the invasive implant category.

104" Sen>i-Annual CTTR Seminar: GynocolOI,'iC Pali>Oiogy 47 Another study also has empbasized the relatively favorable prognosis of patients with extra-ovarian spread ofSLMPs. Disease-free survival rates for 82 patients were 95% at five yellrS and 91% at ten years. lt should be noted that almost all these patients received adjuvant therapy. It is also noteworthy that. five patients in that series died ofacute myelogenous leukemia as a of tl1e adjuvant therapy they received. A conservative approach to the management of borderline tumors in general is currently preferred; in some cases even cystectomy may be appropriate.

SLMPs in Lymph Nodes

Benign epithelial inclusions are present in pelvic and periaortic lymph nodes in up to 14 percent of women; it is therefore not swprising that occasionally proliferative changes, including borderline tumors, occur in this epithelium. When this happens in a patient with a SBT ofthe ovary, lhe relationship of the borderline neoplasia in the lymph nodes and ovaries is problematic. Sometimes tl1e borderline neoplasia in the nodes is a focal finding in a case in which there are numerous foci of benign.inclusions and it is logical to interpret the lymph node proliferation in these cases as simultaneous neoplasia. On the other band, in some cases there is involvement of vasculat sinuses at the periphery of the node suggesting spread to the node. In addition, in some. of these cases foci oflymphatic invasion are seen in the primary ovarian tumor. Whether the lymph node involvement in these caseS is synchronous neoplasia or true metastatic disease, this finding should not, in the opinion ofsome investigators influence the treatment ofthese cases. ·

Manllgemerlt of SLMP

Standard surgery consists of bilateral salpingo-oophorectomy and omentectomy along with peritoneal washings. Conservative sutgery- ofunilateral salpingo-oophorectomy and omentectomy along with peritoneal washings· is an alternative for stage la tumors in young women who have not completed their fiunily. The efficacy ofadjuvant chemotherapy remains to be shown; it has been suggested for patientS who have infiltrative implants.

REFERENCES

Endometrioid tumors of low malignant potential I. Bell DA, Scully RE. Atypical and borderline endometrioid adenofibromas of the ovary. A report of 27cases. Am J Surg Pa!ho/9:205·214, \985. 2. Fukunaga M, Nomura K, Ishikawa E, Ushigome S. Ovarian atypical endometriosis: Its close association with malignant epithelial tumours. Histopathology 30:249-255, 1997. 3. Norris HJ. Proliferative endometrioid tumors and endometrioid tumors oflow malignant potential of the ovary. JntJGyneco/Patltol 12:134-140, 1993. 4. Roth LM, Cz.emobilsky B, Langley FA Ovarian endometrioid adenofibromas and cystadenofibromatous rumors: benign, proliferating and malignant. Cancer48:1838-1845, 1981. 5. SnY.der RR; Norris HJ, Tavassoli FA Endometrioid proliferative and low malignant potential tumors ofthe ovary. A clinicopathologic study of46 cases. Am J Surg Parlto/9:66!-611, !989.

Serous tumors of low malignant potential I. Bell D,A, Scully Re. Ovarian serous borderline tumors with stromal microinvasion: A reported of21 c;tseS. Hum Patho/21 :391-403, 1990. 2. Bell DA, Rutgers JL, Scully RE. Ovarian epithelial tumors of borderline ma!iSrulncy. Progress in reproductive and uriney tract pathology (Damjanov L Cohen AH, Mills SE, Young RH, Eds) Vol. l. p.J-29, Field and Wood, Inc., Philadelphia, 1989. 3. Bell DA, WeinstockMA, Scuiiy RE. Peritoneal implants ofserous borderline tumors: Histologic featureS and prognosis. Cancer 62:2212-2222, 1988. 4. Biscotti ChV, Hart WR. Peritoneal serous micropapillomatosis oflow malignant potential (serous borderline rumors ofthe peritoneum). A clinicopathologic study of 17 cases. AmJ SurgPathol16:461-415, 1992. 5. BostwickDG, Tazelaar HD, Ballon SC, Hendrickson MR. Kempson RL. Ovarian epithelial tumors of borderline malignancy. A clinical and pathologic study of 109 cases. Canar 58:2052-2065, 1986. 6. Burks RT, Sherman ME, Kurman RJ. Micropapilliuy serous carcinoma of the OVary. A distinctive low-grade carcinoma related to serous borderline tumors. Am J Swg Patho/20: 1319-1330, 1996. 104'' Semi-Annual CTTR Seminar: G).necologic Pathology 48 7. Campo E, Merino MJ, Tavassoli FA, Charonis AS, Stetler-Stevenson WG, Liotta L.O.. Ewluarion ofbasement memtnne compooems and the 72 kDa type IV collagenase in serous tumors ofthe 0\'31}'. AmJ Surg Patho/16:500. 507, 1992. 8. De Nictotis M. Garbisa S, Lucarini G et al. KiloDalton type IV Collagenase, type IV Collagen, and Ki67 antigen in serous rumors of the ovary: A clinicopathologic, inununohistochemical and serological study. Jnt J Gynecc/J>at!Jol 15:102-109, 1996. 9. De Nictolis M. Montironi R, Tommasoni S, Carinelli S, Ojeda B, Madas-Guiu X. Prat J. Serous borderline tumors of the ovary: A ctinicopathologic, inununohistochemical and quantitative study of 44 cases. Cancer 70: I 52-160, 1992. 1o. Ehrmann RL, Feder-scbneider JM. Knapp RC. Distinguishing lymph node metastases from benign glandular inclusions in low II. Eichhorn m, Bell OA, Young RH, Scully RE. Ovarian serous borderline tuinOrS ofsolid, micropapillary and cn'briform typeS: A studyof42 cases. Modem Pathoii0:99A, 1197. 12. Ger$henson OM, Silva E.G. Serous ovarian tumors oflow malignant potential with peritoneal implants. Cancer 65:578-585, 1990. 13. Histological Typing of Ovarian TUmours. Geneva: World Health Organization, pp. 17-18. 1973. 14, Kaem J, Trope CG, Abeler VM. A retrospective stUdy of370 borderline tumors ofthe ovary treated at the Norwegian Radium Hospital from 1970 to 1982. A review ofcli .nicopathologic features and treatment modalities. Cm~r71 : 1810-1820, 1993. IS. Karp LA, Czemobilsky B. Glandular inclusions in pelvic and abdominal para-aortic lymph nodes. A study ofautopsy and augical material in males and females. AmJ Clin Patho/52:212-218, 1969. 16. Katzenstein AA, Mazur MT, M~ TE, Kao M-S. Proliferative serous tuinOrS ofthe ovary. Histologic fcatw"es and progoosis. Am J Surg Patho/2:339-355, 1978. 17. Kennedy AW, Han WR. Ovarian papillary serous tumors oflow malignant potential (serous borderline tumots). A long term follow-up study, including patients with microinvasion, lymph node metaStaSis and transformation to invasive serous carcinoma Cancer 78:278-286, 1996. 18. Kllinan L. Rom~ RM, Fonune OW. Low malignant potential tumors oftbe ovary; A study of76 cases. Obslet Gyrwco/68:338-344, 1986. 19. Lim-Tan SK, Caji~ HE, Scully RE. Ovarian cystectomy for serous borderline tumors: A follow-up study of35 cases. Obstel GyrN!cc/12: 775-781, 1988. 20. McCaughey WTE, Kirk ME, Lester W, Oardick t Peritoneal epithelial lesions associated with protiferative serous tumors ofovary . Histopathology 8:195-208, 1984. 21. Mic:had H. ROib LM. Invasive and non-invasive implams in ovarian serous tuinOrS oflow malignant potential. Cancer. 47:1240-1247, 1986. 22. Russell P. The pathological assessment ofovarian neoplasms. ll: The protiferating "epithelial" tumours. Pathology 11:251-282, 1979. 23. Serov SF, Scully RE, Sobin LH. Jmemational Histological Classification ofTumours, n• 9. 24. Tavassoli FA. 'Serous tumor oflow malignant potential with early stromal invasion (serous LMP with microinvasion): Modem Pathology I :407-413, 1988. 25. Trope C, Kaern J. Prognosis and management of borderline tumours ofthe ovary. CtnTenl OpiniOIIS Obstet Gyrrecol 8:12-16, 1996.

104" Stmo·Annual CTTR Seminar: Gynccologie Pnthology 49 .. CASEl4

Jlistory (Case 1114- Ace. 2S3i9) A 63-year-old female presented with a pelvic mass. A 7 x 5 x 2 em, partially cystic left ovarian mass was removed ~ong with the contralateral ovary, uterus, omental segment, and para-aortic lymph nodes. (Contributed by Fattaneh Tavassoli, M.D.)

Diagnosis: Serotraositional Cell Carcinoma

DISCUSSION

It has recently been recognized that a subset of surface-epithelial carcinomas histologically resemble transitional cell carcinoma (TCC) ofthe urinary bladder, but are not associated with a recognizable benign Brenner tumor as are malignant Brenner tumors. Such neoplasms have been classified as transitional cell carcinoma (TCC) ofthe ovary.

Microscopically, TCCs are characterized by blunt pap)llaeextending into spaces that are largely free ofnecrotic debris. The papillae are lined by multiple (often over 15 to 20 layers) layers of polygonal cells that show substantial cytologic atypia. In solid areas, the tumor infiltrates the stroma as irregular nests of similar cells. TCCs often coexist with more typical forms of ovarian carcinoma in the ovarian neoplasm, most frequently a serous carcinoma. Ovarian TCCs may metastasize as either pure TCC or as TCC mixed with other cell types with either predominating. The . seminar case ·had focal areas of admixture with a serous type differentiation that is represented in your slide.

It has been noted that TCCs are more frequently high stage at presentation and have a worse prognosis than malignant Brenner tumors. It has also been suggested in a series ofarticles from investigators at the M.D. Anderson Hospit~ that patients with TCC and peritoneal spread oftumor have a much better response rate and longer. survival interval after treatment ·with platinum containing chemotherapy than patients with other histologic subtypes ofhigh grade, high stage ovarian carcinomas. These investigators have noted that patients with primary ovarian TCC whose metastatic tumor is composed purely or predominantly ofTCC have a better prognosis than those whose metastatic tumor is of another histologic subtype or in which TCC is only a minor element.

The distinction between these tumors and undifferentiated carcinoma is difficult, and to some extent; subjective. Features that may aid in separating the two tumor types are that TCCs 1,1sually contain cystic areas with papillae resembling papillary·TCC ofthe bladder, and the tumor cells infiltrate the stroma as nests, whereas unditl:'erentiated carcinomas are usually solid proliferations oflarge sheets ofcells. Cytologically, the cells ofTCCs tend to be leis pleomorphic and anaplastic appearing than those of undifferentiated carcinoma.

Primary TCC ofthe ovary must also oe distinguished from the very me cases of ovarian metastases from TCC of the urinary tract. Jn.our experience, this distinction is a very difficult one. Features that favor metastatic TCC include deep invasion by the urinary tract TCC, metastasis to other sites at the time ofovarian involvement, bilaterality or multinodularity ofthe .ovarian tumors, or lymphatic or bloed vessel invasion or both in either the ovarian or urinary tract tumor. Features that favor independent primary tumors are,a long interval between the detection of the ovarian and urinary tract tumors, dissimilarity in their histological features, an absence of invasion or only superficial invasion ofthe urinary tract tumor, the absence of metastasis to other sites, coexisting benign Brenner tumor and an absence ofextraurinary tract tumor for three years or more after treatment of the ovarian tumor. lmmunoreaction with CK 20 would favor a urinary tract TCC, but focal CK 20 Positivity is rarely evident in ovarian transitional cell tumors also.

Pathologic Findings

Macroscopically, the tumor is often multiloculated on cut surface. The variably sized cysts are filled with blood­ tinsed serous fluid. Papillary and knobby excrescences are evident lining the cyst walls.

104" Semi-Annual CTTR Seminar: Gynecologic Patltology 50 ~1jcroscopically, the lesion displays solid and papillary growth. The papillae and solid areas were composed of proliferation ofspindled atypical transitional cells resembling grade 2-3 (out of4 ) transitional ceU carcinomas ofthe urinary bladder. Some nuclei have longitudinal grooves. ln the seminar case, numerous spaces were present among the solid neoplastic areas; some of these contained a granular secretory material. These SJ:eas resembled the filigree pattern of serous carcinoma.

Discussion

Urothelial epithelium has been long recognized in ovarian neoplasms such as benign, proliferative, and malignant Brenner tumor as well as in non-neoplastic WalthSJ:d nests in the adnexal region. Urothelial differentiation also occun in a variable extent in 9 to 12% ofovarian CSJ:Cinomas and there are carcinomas that are composed purely of transitional cells. Transitional cell carcinomas differ from malignant BreMer tumors by the lack ofa benign Brenner component. So defined, transitional cell carcinomas appear to be more aggressive than malignant Brenner tumors. The similarity of the epithelium in these lesions to the normal and neoplastic epithelium of the urinary bladder is mainly at the level ofmorphologic appearance. There are functional differences between the lesions that display transitional cell morphology in the ovary and those that occur in the urinary tract. At the ultrastructural level, a well­ developed nuclear groove is apparent. The cells have distinct cell borders, complex interdigitating projections and well developed desmosomes. ln contrast to urinary tract transitional cell tumors, expression ofcytokeratin 20 is rare and very focal, if present 81 all, in ovarian transitional ceU lesions. They do express cytokeralin 7, however, as do other epithelial tumors ofthe ovary. We have observed apparent derivation ofBrenner tumors from both the surface epithelium and the rete ovarii. Brenner tumors occur most frequently in women between ages of 40 to 60. The proliferative and malignant Brenner tumors account for less than 5% ofthe cases even in consultation practice. Transitional cell carcinomas are rare with a majority encountered among women between 50 and 70 years ofage. ·It accounts for fSJ: less than 1% ofthe surface epithelial derived carcinomas.

Brenner tumor variants

The lyj>ital Brenner tumor is a fibroepithelial tumor composed of multiple nests of benign transitional cell epithelium within a prominent ovarian type stroma. The epithelial cells are rounded to polyhedral with "coffee-bean" shaped nuclei. Small cysts lined by mucinous epithelium are found in the center ofsome epithelial nests. SqUSJ:Oous metaplasia may be present. The stromal cells sometimes appear luteinized. Brenner tumors are generally incidental findings and rarely exceed 2 em in maximum diameter. About 100/o are bilateral.

First described by Roth and Sternberg in 1971, proliferative Brenner tumors present as a solid and cystic mass that shows significant epithelial proliferation of the urothelial cells within a background stroma identical to that found in benign Brenner rumors. In contrast to the generally small size of benign Brenner tumors, proliferating BreMer tumors tend to be large, with a median diameter of 16 em in one series (Miles and Norris), and 20 em in another (Roth et a!). Patients generally present with an abdominal mass, enlarging abdomen, or abdominal pain. The women range in age from 30 to 87 years; the average age has been reported as SO, 66, and 70 years in various studies. Cysts often develop within these tumors and the epithelium forms papillary processes composed of urothelial epithelium and areas ofsquamous metapluia. focal, mild arypia may be seen, but the proliferating cells are generally quite unifonn and lack charaCieriStics of highly malignant cells. The appearances are similar to a low grade (Grade 1-2) papillary transitional cell carcinoma ofthe urinary bladder. The papillary tumor may be partially or totally inverted. Mucinous epithelium lines some of the cysts. Typical benign Brenner tumor is always present in the adjacent area. . -

Some proliferative Brenner tumors display nuclear atypia and mitotic activity resembling grade 3 transitional cell carcinoma of the urinary bladder or squamous carcinoma in situ; the designation of Bremter h1mor oflow malignant poteutial hu been used for these tumors. The clinical features and gross appearances are similar to those of protiferative Brenner tumor.

None of the well-documented proliferative Brenner tumors have either recurred or metastasized. Tumors designa1ed as borderline or oflow malignant potential have also had an exceUent prognosis. Whether or not there is any

104• Semi· Annual CTTR Seminar; Gynecologic Polhology 51 difference in the biologic behavior justifYing separation of these unusual variants will require study of a large number ofcases with long-term follow-up.

Malignant Brenner tumor displays small cysts or solid nests lined by cells that appear cytologically malignant and show stromal invasion. Intimate association with one of the benign patterns ofBrenner tumor is required. These tumors are often large with an average size of 15 em. Typically, they show both cystic and solid area.s.

Transitional Cell Carcinoma

Transitional cell carcinomas present in advanced stages (Jll-IV) more frequently (69-100"/o) than mali!,>nant Brenner tumors (11- 19%). Furthermore, a higher proportion of patients with malignant Brenner tumor are free at last contact (69%) compared to women with·transitional cell carcinoma (24%).

These differences persist even when tumors are compared within the same stage. About 43% of patients with stage IA transitional cell carcinoma are alive and well at last COQtact compared to 88% ofwomen with stage lA malignant Brenner tumor. Since a majority ofeither tumor typ;e is grade 2 or 3, histologic grade does not appear to be responsible for the differences in behavior. It is possible that TCC could have arisen from a Brenner tumor and overgrown resulting in complete obliteration ofthe benign precursor areas. This probably does occur in some instances, but at least some transitional carcinomas are independent de novo lesions. Aside from the fact that TCC is more aggressive than MBT stage for stage, distinct areas of calcification are present in a majority ofMBT and common in benign Brenner tumors, but absent in ovarian TCC. The development of transitional cell differentiation among ovarian tumors may be explained by the proxintity ofthe gonadal ridge to the mes<>nephros in the early coelom and the common mesothelial covering of the two. The gonadal ridge arises at the ventral border of the mesonephros and is covered by mesothelium that is continuous over the mesonephros. The mesonephros differentiates to form the mesonephric ducts, the ends of which become incorporated in a portion of the urogenital sinus that fs destined to be the bladder. Continuous with both the genital ridge and mesonephros, the coelontic mesothelium retains the potential to form similar-appearing neoplasms in each location.

Of great importance is recent data suggesting that some ovarian tumors with a pure or predominant transitional cell component display a better response to chemotherapy and show improved ~'lm50%) is a favorable prognostic factor. Gershenson eta! compared response to cisplatin based chemotherapy in 62 patients with transitional cell carcinoma with matched serous car~inonia patients. The surgical complete response rate for women with transitional cell carcinoma was. 37% compared to 11% for those with serous carcinoma. The survival time was 52.3 months for those \vith transitional cell carcinoma compared to 22.0 months for women v.1th serous carcinoma. They concluded that transitional cell carcinoma is significantly more chemosensitive resulting in better survival compared to the more common serous carcinomas.

Classification ofepithelial neoplasms of the ovary includes those with a transitional cell type. The distinction between MBT and TCC may have therapeutic and prognostic implications and some women with extra-ovarian spread ofTCC appear to benefit from adjunctive therapy. .- REFERENCES

1. Austin RM, Norris HJ. Malignant Brenner. tumor and transitional cell carcinoma: a comparison. lnt J Gynecol Patho/6:29, 1987. 2. Einhorn N, Nielsson B, SjovaU K. Factors influencing survival in ca~cinoma ofthe ovary. Study from a well- defined Swedish population. Cancer 55:2019, 1985. · 3. Gershenson OM, Silva EG, Mitchell MF, Atkinson EN, Wharton JT. Transitional cell carcinoma ofthe ovary: A matched control study of advanced-stage patients treated with cisplatin-based chemotherapy. Am J Obstet

104" Semi-Annu~l CTTR Seminar: Gynecologic Pathology 52 GytltJ:()/168: 1178-1187, 1993. 4. Halgrimsson J, Scully RE. Borderline and malignant Brenner tumours ofthe ovary. A repol1 of I 5 cases. Acta PorhMicrabio/Scand[A]80(Supp. 233):56-66, 1972. 5. Kataoka A, Nishida T, Imaishi K, et al. Malignant Brenner tumor of the ovary: two cases of unusual histologic features of relapsed tumors. J Obsrcr Gyneco/ 21: 249-256, 1995. 6. Klemi PJ, Nevafainen TJ. Ultrastructure of the benign and borderline Brenner tumors. A era Parh oi Mlcrobiol Scand (A) 85:826-838, 1977. 7. Link CJ, KohnE, Reed E. The relationship between borderline ovarian tumors and epithelial ovarian carcinomas: Epidemiologic, pathologic, and molecular aspects. Gynecol Onco/60:341-354, 1995. 8. Miles PA, NorrisHJ. Proliferative and malignant Brenner tumors of the ovmy. Cancer 30:174, 1972. 9. Postoloff AV, SonoLSJ. Secondmy changes in Brenner tumor with special reference to calcification. Obstet G>•ltJ:()/8:704-709, 1956. 10. Robey SS, Silva EG, Gersbenson DM, et al. Transitional cell carcinoma in high grade, high stage ovarian carcinoma: an indicator offavorable response to chemotherapy. Cancer 63:839, 1989. II. Roth LM, Czemobilsky B. Ovarian Brenner tumors. II. Malignant . Cancer 56:592, 1985. 12. Roth LM, Dallenbach-Hellweg 0 , Czemobilsky B. Ovarian Brenner tumors. I. Metaplastic, prolifera ting, and low malignant potential. Cancer 56: 1582, 1985. 13. Roth LM, Gersell DJ, Ulbright TM. Ovarian Brenner tumors and transitional cell carcinoma: Recent developments. 1111 J G)h1ecol Patlta/12: 128-133, 1993 . .14 . Santini D, Gelli MC, Mazzoleni G, Ricci M, et al. Brenner tumor ofthe ovary: A correlative hi5tologic, bistochemical, immunohiStochemical, and ultrastructural investigation. Hum Padw/20:781-795, 1989. 15. Scldenrijk CA, Wtllig AP, Baak 1P A, Kuhne! R, et al. Malignant Brenner tumor. A histologic, morphometrical, immunohistochemical, and ultrastructural study. Cancer 58:754-760, 1986. . 16. Shay MD, Janovski NA. Malignant Brenner tumor associated with endometrial carcinoma. Obstct Gynecof · 22:246-252, 1963. 17. SUva EG, Robey-Cafferty SS, Smith TL, Gershenson DM Ovarian carcinomas with transitional cell carcinoma pattern. AmJC/inPatho/ 93:451, 1990.

104"' Scmi-Annuol CTTRScminar: G}ncoologic Pathology 53 CASE 15

History (Case 1115-Ace 10286) A 59-year-old Caucasian female presented with lower abdominal pain and a 15 pound weight loss over a three-month period. Pelvic exam reveaJed a large mass. Bilateral oophorectomy, pelvic exploration and multiple biopsies ofthe peritoneum were done. The right ovary was replaced by a 219 gram globoid mass. Its cut surface consisted ofa latticework ofslimy glistening gray-tan tissue exuding mucoid material. The left ovary measured 4 x 2 x 2.5 em, and had similar lacy-looking tumor present in its central ponion. (Contributed by John Gilrane, M.D.)

Diagno_sis: Krukenberg tumor

DISCUSSION

Metastatic tumors to the ovary are responsible for signi6cant diagnostic problems in the assessment of ovarian neoplasms. The ovaries arc involved in 29 to 37% of women succumbing to malignant disease; in 60'/o of the patients with ovarian metastases, there is no obvious lesion on gross inspection ofthe ovary. In the adult women,.the most common sources ofmetastatic carcinoma to the ovary include the gastrointestinal tract and breast The incidence is variable depending on the origin ofthe primary tumor. Ovarian metastases occur in 50% ofwomen with gastric carcinoma, 44% of those dying of breast carcinoma, 30% of women with colonic cancer, and !6% of those with malignant . Ov8rian involvement is noted in 1% to 40% ofwomen with cervical carcinoma, and 0 to 60.% of those with endometrial carcinoma. It is therefore, imponant to distinguish primary lind metastatic ovarian carcinoma.

How tumors spread to the ovary

There are multiple pathways by .which tumors spread to the ovary. These include:

1. Direct spread: Direct extension from a tubal, endometrial and colonic carcinoma is facilitated by presence of adhesions.

2. Surface Implantation: lmplantation.oceurs from widespread carcinoma in the peritoneum and through the fallopian tube from endometrial carcinoma.

3. Lymphatic spread: Because ofthe rich lymphatic network in the pelvis, this is a common mechanism of spread to the ovary. Breast and even gastric carcinoma may spread to the ovary in this manner. The lumbar lymphatics connect the lymphatic channels ofthe upper GI tract and those ofthe ovary.

4. Hematogenous Spread: This is a common mode oftumor spread to the ovary.

Characteristics of Metastatic Carcinomas

A high proportion (60'/o) of th~ tumors are bilateraL They may persist as diffuse enlargement oft he ovaries, as multiple discrete solid nodules, as partly cystic, or even entirely cystic lesions. Areas of hemorrhage and·necrosis are common. Features supponing metastatic involvement include abundant necrosis, multifocality and vascular invasion.

Krukenberg Tumor

The classic Krukenberg tumor is usually a bilateral tumor characterized by the presence ofmucin -filled signet ring cells, typically lying v.ithin a cellular stroma derived fromthe ovarian stroma. The sourceofKrukenberg rumors in from 70 to 100% of reponed cases is a gastric carcinoma, usually arising in the pylorus. Carcinomas of the large

1 04'' Semi-Annual CTTR Semin'!J': Gynecologic Pothology 54 intestine, appendix and breast are the next most common primary sites; the gallbladder, biliary tract, pancreas, cervix, and urinary bladder are rare sources ofthese tumors. Sapbir demonstrated in an autopsy study that signet ring cell carcinomas ofvarious organs are more often associated with ovarian metastasis than carcinomas ofother histologic types by a ratio ofabout 4 to I. More recent studies have supported his observation. Gastric signet ring cell carcinomas metasusiz.e to the ovary in 41% ofthe cases whereas intestinal-type carcinomas ofthe stomach do so in only 17%. Signet ring cell carcinoma ofthe colon also metastasizes to the ovaries more frequently than does the usual colonic adenocarcinoma.

The frequency of the Krukenberg tumor varies with that ofgast ric carcinoma in the population analyzed ranging from 39% of ovarian metastases at the radium reminett to very large proportion in countries such as Japan, witl1 a high prevalence of gastric carcinoma and a low prevalence of primary ovarian carcinoma. Tlie average age of patients with Krukenberg tumors is about 45 years. From one-quarter to almost half ofthe patients have been under 40 years, and only slightly more than !0% ofthem have been over 60 years. This age distribution is related in part to the disproportionate frequency ofgastric signet ring cell carcinomas in young women as weU as the greater vascularity of the ovary in young women. In one study I 0% of wo~en 35 years or younger with this tumor had ovarian metastases at presentation.

Almost 90"/o of patients with Krukenberg rumors have symptoms related to ovarian involvement, the most conunon of.whicb are abdominal pain and swelling; occasionally, there is abnonmal uterine bleeding and rarely overt signs of excess hormone production such as virilization. The remainder of the patients have gastrOintestinal or miscellaneous symptoms, or are asymptomatic. A history of prior carcinoma ofthe stomach or, rarely, another organ can be obtained in 20 to 30% ofthe cases. The interval between the diagnosis ofa gastric carcinoma and the subsequent discovery ofovarian involvement is usually six months or less, but periods as long as 12 years have been reported. In most cases, the diagnosis ofthe gastric carcinoma is made preoperatively, during the operation for the ovarian metastasis, or within a few months thereafter. Often, tbe primary tumor is too small to be detected at operation, and radiographic examination ofthe upper gastrointestinal tract may also fail to reveal evidence ofa tumor even after the diagnosis ofKrukenberg rumor has been established. Rarely, the gastric carcinoma may not be detected until five or more years after discovery ofthe ovarian metastatic tumor.

Most tumors with the microscopic features ofthe Krukenberg tumor are metastatic, but very rare examples may be primary. lt is well known that mammary and gastric carcinomas may remain silent for many years. ln some cases of Krukenberg tumor, the primary gastric carcinoma may not become apparent until ovu five years after the ovarian tumor had been removed. Thus, clinical dormancy of the primary tumor probably accounts for some of the cases of Krukenberg tumor with long survival As poorly differentiated primary mucinous carcinoids ofthe ovary may have extensive foci of signet ring ceU proliferation. it is possibly that some ofthe "primary Krukenberg" tumors in the literature reflect mucinous carcinoid tumors.

Gross Futures

Krukenberg tumors typically cause diffuse ovarian enlargement or may form rounded, firm, white masses that may be bosselated and may attain a large size. The cut sumces are usually yellow or white but areas of purple, red, or brown discoloration and extensive hemorrhage are also encountered. The consistency is characteristically firm but fleshy, gelatinous, or spongy areas are common. l'

Microscopic examination of a Krukenberg tumor reveals mucin-laden, signet-ring ceUs strewn individually and in smaU clusters within a cellular ovarian stroma; oc.casionally the stroma has a storiform pattern. Frequent variations from the classical appearance include small glands, a prominent tubular architecture, mucin-poor tumor cells in trabec:ular and large masses, abundant coUagen formation. marked stromal edema, and cell-free pools ofmucin in the stroma. Occuionally, small or large cysts lined by minimally atypical appearing mucinous epithelium forms a conspicuous component ofthe tumor, with more characteristic areas lying between the cysts. The cytoplasm ofthe signet ring cells is occasionally granular and eosinophiijc rather than pale and vacuolated; the cytoplasm sometimes 11as a bull's-eye appearance, containing a large vacuole with a central eosinophilic body. As with metastases in

104., Scmi-AMt~l CTTR Seminar. Gynecologic PatlJOioro• ss general, blood vessels and lymphatic invasion is common. Lutein cells are occasionally present in the stroma, particularly if the patient is pregnant.

Clinical course of the disease

Almost all the patients die within a year of the diagnosis·ofovarian metastasis, with an average duration ofseven months from diagnosis to death, but a rare patient has survived, apparently free oftum .or, for as long as six years after gastrectomy and bilateral oophorectomy. Such a result, even though exceptional, justifies removal of both the stomach and the ovarian metastases for possible cure in cases in which the tumor appears limited to those organs. It is also prudent for the surgeon to remove the ovaries routinely in menopausal and postmenopausal women having a gastric resection for carcinoma to prevent the later complication ofovarian metastasis and avoid another operation.

Differential Diagnosis

The Krukenberg tumor may resemble a fibroma or any other type of solid ovarian tumor on gross examination. Its appearance may also occasionally be deceptive on frozen section or low-power examination but should be readily diagnosable on high-power microscopic examination, especially with the aid of mucin stains. A frequent misdiagnosis is a Serioli-Leydig cell tumor, particularly when a prominent tubular component and a luteinization of the stroma are encountered in a Krukenberg rumor; signet ring cells, however, are not a feature of Sertoli-Leydig cell tumors except for occas.ional tumors of heterologous type. The sclerosing stromal tumor may contain cells resembling ·signet cells as well as a proliferating fibroblastic component, but such cells contain lipid rather than mucin. The rare signet ring stromal tumor also may enter the difterential but the signet ring cells in that tumor also fail to react with mucin stains. In clear cell carcinomas, the clear cells contain glycogen; mucin, when present, is typically luminal and extrace,tlular. In rare cases portions ofthe tumor contain aggregates ofsignet ring cells but the presence of other characteristic · features of this tumor permit its identification: Mucinous carcinoid tumors that contain large numbers of signet ring cells are distinguished from Krukenberg tumors by their additional component of carcinoi~ the presence ofwhich can b.i confirmed by argyrophil staining. These tumors are discussed further in the section on metastatic carcinoid tumor. Finally, the rare non-neoplastic lesio11, mucinocarminophilic histiocytosis, which is caused by injection ofsubstances containing polyvinylpyrrolidioe is characterized by signet ring-like cells and may involve numerous tissues and organs including the ovaries. Although these cells are stained by mucicarmine, they are PAS-negative.

.REFERENCES

L Barens JJ. Krukenberg tumors ofthe ovary. Am J Surg 81 :484, 1951. 2. Berezowski K, Stastny JF, Komstein MJ. Cytokeratins 7 and 20 and carcinoembryonic antigen in ovarian·and colonic carcinoma. Mod Pathol9:426-429, 1996. 3. Fowler LJ, Maygarden SJ, Novotny DB. Human alveolar macrophage-56 and carcinoembryonic antigen monoclonal antibodies in the differential diagnosis between primary ovarian and metastatic gastrointestinal carcinomas. 11um Pathof25:666-670, 1994. 4. Fox H. Metastatic tumors of the ovary. In: Haines and Taylor. Obstetrical and Gynecological Pathology. New York. Churchill Livingston 1987; 714. 5. Holtz F, Hart WR. Krukenberg tumors of the ovary. A clinicopathologic analysis of27 cases. Cancer 50:2.418, 1982. 6. 1'ray59n RA, Hart WR and Petras RE. : A clinicopathologic study of 19 eases with emphasis on site oforigin and nature of associated ovarian tumors. AmJ Surg Pa!ho/ 18(6):591-603, 1994. 7. RonnettBM, Shmookler BM, Diener-West M, SugarbakerPH, Kunnan RJ. InununohJstochemic£evidence supporting tlie appendiceal origin ofpseudomyxoma peritonei in women. Tnt J Gynecof Pathof 16:1-9, 1997. 8. Spadoni LR, Lindberg MC, Mottet NK et al. Virilization coexiSting with Krukenberg tumor during pregnancy. AmJObstetGyneco/92;981, 1965. 9. Wang NP, SeeS, Zarbo RJ, Bacchi CE, Gown AM. Coordinate expression ofc)'tokeratins 7 and 20 defines unique subsets ofcarcinomas. App/lmmunohistochem 3:99-107, 1995. 10. Young RH, Scully RE. Metastatic tumors of the ovary . .In: Kurman RJ, et. Blaustein's Pathology~ female genital tract. New York: Springer Verlag, 1987. p. 742.

104'" Semi-Annual CT.TR Scmiliar: Gynecologic Pathology 56 11. Young RH, Gilks CB, Scully RE. Mucinous tumors ofthe appendix associated v.ith mucinous tumors of the ovaty and pseudomyxoma peritonei. A clinicopathological analysis of22 cases supporting an origin in the appendix. Am J Surg Pathol I 5:41 S-429, 199 1. 12. Young RH, Han WR. Metastases fro m carcinomas ofthe pancreas simulating primaty mucinous tumors of the ovary: A l'eport ofseven cases. Am J Surg Pathol\3:148-156, 1989. 13. Young RH, Scully RE. Metastatic tumors in the ovaty: A problem-oriented approach and review oft he recent literanare. Sem Diag Pathol 8:250-276, 1991.

104• Semi-Annual CTTR.SemiJJar: Gynecologic Pathology 57 CASE 16

History (Case #16- Ace. 25047) A 72-year-old Caucasian temale presented with complaints ofindigestion, urinary frequency, and swelling of the right lower extremity of a few days duration. A large mass was palpable, filling both lower abdominal quadrants. At laparotomy, a cystic and solid mass was removed. The 9 em cystic mass had soft, red-brown, polypoid masses 61ling it. The outer surface was smooth to slightly wrinkled. The wall averaged 0.2 to 0.4 em in thickness, with solid tan areas in the wall up to 3.0 em in diameter. The patient had undergone hysterectomy and removal ofright and left fallopian tubes and right ovary twenty-six years previously for endometriosis. (Contributed by Edward Klatt; M.D.)

Diagnosis: Clear cell carcinoma of ovarv with oxyphilic type differentiation

Note: The oxyphilic differentiation wa..~ focal.

Histologic Findings: The tumor displays a papillary, tubulocystic and solid growth pattern. The papillae are lined by cells with vacuolated, granular or homogeneous eosinophilic cytoplasm. Arohitecturally, the eosinophilic cells line many papi1Jae. Deflllite glandular difterentiation is present in some areas, and dilated tubules are focally present. Scattered throughout the tttmor are markedly pleomorphic cells with large hyperchromatic nuclei. Stromal vascularity is not prominertt. Glassy eosinophilic basement membran.e-like material surrounds many of the tumor cell neSts and glands. This·is especially well seen in PAS-stained sections that also focally show a moderate amount of intracytoplasmic glycogen deposits. Mucicarmine stain shows only a rare intraluminal mucin deposit. lrtmmnostains are strongly positive for AEI-3, EMA ana CD! S (Leu-Ml) and are negative for SlOO, vimeotin and inhibin.

DISCUSSION

Scully proposed the name "clear cell carcinoma" for the group of neoplasms originally described and designated as mesonephronia by" Schiller. More than half ofthe patients in Scully's study had pelvic endometriosis, and many of the carcinomas developed from the lining ofendometriotic cysts leading to the conclusion that clear ceU carcinoma is related to endometriosis. It is now accepted that clear cell carcinoma develops from the surface epithelium of.the ovary·and in a minority ofcases (15%) from endometriosis. It accounts for 6-7% of ovarian carcinomas. Clear cell carcinomas ofthe female genital.tract (and urethra) have numerous distinctive architectural and cellular patterns. The most common architectural patterns are solid, glandular, tubular or tutiulocystic and papillary. Less common are the trabecular (Senoliform), adenofibromatous and parvilocular patterns. About 800/o of tumors have a mixture of patterns. The neoplastic cells classically have abundant clear or vacuolated cytllplasm that contains glycogen. Clear cells are usually most abundant in the solid and glandular patterns, but are found to some extent in practically all clear cell carcin.omas. In the tubular and tubulocystic patterns, flat, cuboidal and so-called hobnail cells are especially prominent. These features are well known. Less well known are tumors in which the cells have abundant eosinophilic cytoplasm. We found these eosinophilic cells to be present in greater numbers. than clear cells in 43% of a series of29 ovarian clear cell carcinomas. Young and Scully proposed the term "oxyphilic clear cell carcinoma" for tumors in which these cells are especially prominent.

Oxyphilic clear cell carcinomas have the same general clinical features (age, clinical presentation, etc.) and gross appearance as clear cell carcinomas in general. The importance ofrecognizing this histologic variant' is its7distinction from other primary and metastatic ovarian tumors with an abundance of-eosinophilic cells. The differential diagnosis includes the following primary tumors: steroid (lipid) cell tumors, oxyphilic variant ofendometrioid carcinoma, luteinized sex cord-stromal tumors, yolk sac tumors and the extremely rare hepatoid carcinoma. The most common metastatic tumors that must be considered in the differential diagnosis are melanoma and . Parenthetically, it is-also worthwhile knowing that the more typical clear cell carcinoma may be mimicked by-ovarian metastases from the uncommon primary clear cell carcinoma ofthe small and large intestines.

I 04., Semi-Annual CTTR Seminar: Gyn«ologic Pathology 58 Cells with large pleomorphic nuclei are very common in all clear cell carcinomas. Also the presence of homogeneous glAssy eosinophilic basement membrane-like material around glands or within papillae always suggests a diagnosis of clear cell carcinoma. Other patterns and cell types of clear cell carcinoma should be searched for to confirm the diagnosis. Oxyphilic endometrioid carcinomas usually have more diagnostic areas with branching complex glands or squamous differentiation. Renal cell carcinomas rarely metastasize to the: ovary. They are characteristically hemorrhagic tumors with a rich vascular network.

In some particularly difficult cases especially when considering a lipid ceU tumor or melanoma, immunostains may be helpful in the differential diagnosis. Cytokeratins AEIIAE3, CD 15 (~u·M 1) and EMA are typically strongly positive in clear cell carcinomas, while steroid cell tumors have been reported to be uniformly negative for CDIS, positive for EMA in only a small minority of cases (0 to 8%) and generally have only focal cytokeratin positivity. Melanoma is oegative for the various epithelial markers but positive for HMB4S and/or S 100. Furthermore, lipid cell rumors show intense and diffuse positivity with inhibin. Clear ceU carcinomas may also show focal positivity with inhibin.

Clear cell tumor oflow malignant potential account for S to 8 percent of clear cell neoplasms, but the accuracy of these figures is questionable because of a lack of a wiiform definition of these tumors' Approximately 28 cases of clear cell tumors ofLMP have been reported in the literaiure; the 19 cases described in detail had the pattern of adenofibromas with atypical, proliferating epithelium ofclear cell type (CCLMP). The peak frequency of these tumors has been in the 7"' decade.

CCLMPs are solid or solid with small cysts, resulting in their designation by Schiller as "parvilOQIIar cystomas". Most reponed cases have been confined to the ovaries; bilateral ovarian involvement was present in only one case. Microscopic examination reveals widely spaced or crowded glands, small cysts or smoothly contoured solid nestS of epithelial cells embedded in a fibromatous stroma without evidence ofdeStrUctive stromal invasion. The epithelial cells show the cytologic features of low-grade malignancy (grade I of3). In such tumors. the glands are lined by one to three layers of hobnail or polygonal cells with clear or occasionally eosinophilic cytoplasm and slightly pleomorphic nuclei containing irregularly clumped chromatin and prominent nucleoli. The cells within the solid nests are also slightly atypical and contain abundant clear cytoplasm. Papillae have been absent in all of the well described cases. Most of the tumors also contain areas ofbenign-appearing clear cell adenofibroma. These features are similar to those described by Roth and coworkers; however, Russell includes rumors with higher grade epithelial proliferation in the absence ofstromal invasion in the borderline category. Because clear cell adenofibromatous foci are often associated with invasive clear cell carcinoma, the former diagnosis should not be rendered unless the specimen has been exten.sively sampled.

Endometriosis was presem in the ipsilateral ovary or elsewhere in the pelvis in 2S percent ofthe cases in one series; this increased frequency ofendometriosis is similar to that observed in association with clear cell carcinomas of the ovary.

With only a small number ofCCLMP rumors described, the prognosis appears excellent, with no deaths from tumor having been reponed thus far. However, one patient, with a clear cell adenofibroma of borderline malignancy and foci of rnicroinvasive carcinoma that ruptured intraoperatively and was incompletely removed, developed a pelvic mass that had the histologic appearance ofa CCLMPT 3.3 years later. The therapy of most patients has been total abdominal hysterectomy and bilateral salpingo-oophorectomy. but more conservative therapy may be considered in a young woman with unilateral involvement.

REFERENCES

1. Bell DA. Scully RE. Benign and borderline clear cell adenofibromas of the ovary. Cancer 56:2922·2931, 1985. 2. Goff BA. DeLa Gusta RS, Muntz HG. Fleischhacker 0, Ek, M, Rice LW, Nikrui N, Tamimi HK, Cain M, Geer BE, Fuller AF, Jr. Clear cell carcinoma of the ovary: A distinct histologic type with poor prognosis and resistance to platinum-based chemotherapy in stage m disease. G;yT.ecclogic Oncology 60:412-417, 1996. 3. Kennedy AW, Bisconi CV. Hart WR and Webster KD. Ovarian clear cell adenocarcinoma. 0}71ecol Oncol 32:342-349, 1989.

104•Semi-Ammnl CTTR Scmin3f: Gyoccologic Plllhology 59 . ... .4. Klemi Pl, Meurman L, Gronroos M, Talerman A. Clear cell (mesonephroid) tumors of the ovary with characteristics resembling endodermal sinus tumor. lui J Gyuecol Patholl :95-100, 1982. 5. Norris, HJ, Rabinowitz M. Ovarian -adenocarcinoma of mesonephric type. Cancer 28:1074-1081, 1971. 6. Pitman l\1B, Young RH, Clement PB, Dickersin GR; Scully RE. Endometrioid carcinoma of the ovary and endometrium, oxyphilic cell type: A report ofnine cases. Jnt JGynecol Patho/ 13:290-301 , 1994. 7. YoungRH, Scully RE. Oxyphilic clear cell carcinoma of the ovary: A report of nine cases. Am J Surg Pathol 11:661-667, 1987. 8. Young RH, Hart WR. Metastatic intestinal carcinomas simulating p(imary ovarian clear cell carcinoma and secretory endometrioid carcinoma: A clinicopathologic and immunohistochemical study offive cases. Am J Surg Pathol (in press) 9. Young RH and Hart WR. Renal cell carcinoma metastatic to the ovary: A report ofthree cases emphasizing possible confusion with ovarian clear cell adenocarcinoma. 1111 J Gynecol Patho/11 :96-104, 1992. I0 . Young RH, Scully RE. Oxyphilic clear cell carcinoma ofthe ovary. A report ofnine cases. Am J Surg Pathol 11 :661-667, 1987. II . Zirker TA, Silva EG, Morris M and Ordonez NG. Immunohistochemical differeritia_tion ofclear-cel l carcinoma ofthe female genital tract and endodermal sinus tumor with the use ofalpha-fetoprotein and Leu-MI. Am J Clln Patho/91:511-5 14, 1989.

104°' Scmi-AnniJill CTTR Seminar: Gynecologic Pathology 60 CASEJ7

History (Case II I 7- Ace. 24904) A 42-year-old Caucasian female presented with vague abdo.minal pain, hirsutism and irregular menstrual periods, and was found to have a S x 8 em cystic periumbilical mass. Hysterectomy with bilateral salpingo­ oophorectomy was performed. The specimen consisted of a 9 x 7 x 5 em multinodular, cystic mass with a firm white capsule. The center of the cyst comained hair and yellow-white, greasy material. AS x 4 x 3 em bright yellow, solid area was noted during sectioning. (Contributed by Douglas Andorka. MD.)

Diagnosis: Lipid cell tumor

DISCUSSION

Lipid cell tumors account for less than 0.1% of all ovarian neoplasms. Opinions vary, however, regarding the use of this term as a specific or generic designation. At AFIP, this term is used as a specific designation for a clinicaliy and histologically similar group divided into Leydig (hilar) cell tumors, adrenal cortical-like tumors, and stromal luteomas. The term steroid cell tumor has been the latest designation proposed for this group of tumors; this has been justified on the basis ofresemblance ofthe tumor cells to typical steroid hormone-producing cells. Considering the steroid­ producing capabilicy ofother gonadal stromal tumors and the lack ofsteroid production by some of the "steroid cell tumors," this designation is not optimal.

Oinical Presentation

Most patients with lipid cell tumors are adults with only a few tumors reported in prepubertal children. Androgenic activity and virilization are recognized as the major functional manifestation oflipid cell tumors occurring in 75 to 90% of cases. In the adult female, the majority of the patients present with progressive virilization over a 5- to 10- yearperiod. The main virilizing symptoms are hirsutism, amenorrhea, deepening ofthe voice, and clitoral enlargement. The variety of hor.mones that are produced by this tumor include testosterone, androstenedione, dihydrotestosterone, 17-hydroxyprogesterone, progesterone, cortisol, and less frequently estrogenic hormones. Evidence of estrogenic activity is actually present in close to 25% of the patients. While production of may be responsible for some ofthese, it is also possible that the estrogens result from periphenil aromatization of androstenedione in adipose tissue. Features of Cushing's syndrome lu)ve been reported in about 5 to I 0% of patients, but well-documented cases are few. Diabetic glucose tolerance test, , and also occur. A palpable tumor mass is a rare presenting complaint. Iil prepubertal girls, virilization occasionally associated with precocious puberty may develop. Removal ofthe tumor results in rapid regression of the hormonal effects, although some sti!ll)lata ofthe androgenic effects (i.e., hirsutism) usually persist.

(:;ross Features

These tumors are almost all unilateral, lobulated, sofi, and smooth ·with sharply defined margin. The color varies and may be yellow, orange, tan, or brown. Areas ofhemorrhage and necrosis may be present. The size varies extensively but is uS.Ually around 5 to 7 em. ·

Microscopic Features

Lipid cell tumors are well circumscribed with an expansile growth margin; an .infiltrating .margin is rarely observed. The tumor is generally composed oftwo ceJJ types that are present in varying proportions , but soine are composed purely o(one or the other cell type. One celll)'pe (Leydig or hilar) is cuboidal or polyhedral with a round eccentric nucleus and a granular eosinophilic C}1oplasmwhich may contain lipochrome or Reinke crystals (the latter is required by some for designating. a cell as hilar or Leydig in tYPe). The·other cell lJPe resembles cortical cells. It is often

104'' Semi-Annual CTTR Seminar: Gynecologic Pathology 61 .., larger than the hilar cells and has a rounded contour and abundant· foamy or clear cytoplasm. The nuclei in these cells arc generally smaller and bave a more dense chromatin than those of the hilar cell. These cells do not contain lipochrome pigment. Considerable amounts of intracytoplasmic lipid may be found in either cell type, but many of the hilar or Leydig eell variants are totally devoid ofstainable fut. Lipid cell tumors generally have a rich vascular network. Areas of fibrosis and hyalinization may be found but are not very common. There is no correlation between the cell type and the associated functional manifestation.

Differential Diagnosis

Steroid cell tumors may be confused with other neoplasms particularly highly luteinized granulosa cell tumors and thecomas, clear cell carcinomas compose entirety of either clear cells or cells with abundant eosinophilic Cytoplasm, metastatic renal cell carcinomas and rarely, lipid-rich Sertoli. cell tumors. The rare granulosa cell tumor or thecoma tbat is markedly lute.inized can be distinguished from a steroid cell tumor by the focal presence of non-luteinized granulosa cells in the fonner and the finding of abundant intercellular reticulum in the latter. Clear cell carcinomas that are composed exclusively ofclear cells bave glycogen-rich Cytoplasm and typically eccentric nuclei in contrast to the charaCteristic lipid-filled cytoplasm and central nuclei'ofsteroid cell tumors containing clear cells. Clear cell carcinomas composed largely ofcells with dense, eosinophilic Cytoplasm tend to exhibit epithelial arrangements of their cells and almost always contain foci ofmore typical clear cell carcinoma. A very rare steroid cell rumor, however, may be difficult to distinguish from a clear cell carcinoma or a metastatic renal cell carcinoma, just as some adrenal cortical carcinomas may be difficult to distinguish from renal cell carcinomas. The distinction ofa 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.

Pregnancy luteomas, which are hyperplastic nodules composed of lutein cells that develop during pregnancy, may· form large masses that resemble steroid cell tumors grossly and microscopically. Like the latter they may also be virilizing. Unlike steroid cell tumors, however, approximately one-third of pregnancy luteomas are bilateral and approximately one-half are multiple. Microscopic examination reveals masses ofcells with abundant eosinophilic cytoplasm containing little or no lipid; mitotic figures may be numerous, sometimes up to two or three per 10 HPF. In conttast, a steroid cell tumor with minimal Cytologic atypia thai resembles a pregnancy usually contains only rare mitotic figures. Although it may ·be impossible to distinguish a lipid-poor o.r lipid-free steroid cell tumor from a solitary pregnancy luteoma, a·lesion encountered during the third trimester ofpregmiocy is presumed to be·the latter unle~ clear -cut evidence indicates otherwise.

Behavior and Therapy

These tumors are generally benign, but about 10 to 15% ofthem are associated with an aggressive behavior. Extension to conti1,>\Jous pelvic· structures at the time ofinitial operatiol) is an ominous sign. A majority ofmalignant tumors have been 8 em or larger in diameter. They may exhibit Cytologic pleomorphism and increased'mitotic aCtivity or, rarely an infiltrating margin. Aggressive bcha\1or is rare in tumors ofthe hilar cell type with identifiable Reinke crystals. Aside from these features, no consistent correlation ofmorphologic findings and behavior bas been established. Unilateral oophorectomy is generally curative except for the rare malignant tumors. A standard approach to management ofmalignant lipid cell tumors has not been established.

REFERENCES

I. Anderson MC. Hllar cell tumour ofthe ovary. J Clin Po tho/ '}.5: 106, 1972. 2. Boivin Y, Richart RM Hilus cell tumors of the ovary. A review \vith a report of3 new cases. Cancer 28:231, 1965. 3. .Bonaventura LM, Judd H; Roth LM, Cleary RE. Androgen, estrogen, and progestagen production by a lipid cell tumor of the ovary. Am J Obstet Gyneco/131 :403, 1978. 4. Chetkowski, RJ, Judd HL, Jagger PL, Nieberg RK, Cbange J, Autonomous cortisol·secretjon by a lipoid cell tumor ofthe ovary . .lAMA 245:2628, 1985.

104"' Semi-Annual CTTR Seminar: Gynecologic Pathology 62 ' 5. Dunnihoo DR, Grieme DL, WoolfRB. Hilar cell tumors ofthe ovary: a repon of2 new cases and a review of the world literature. Obslet Gyneco/21:103, I 966. 6. Hayes MC, Scully RE. Ovarian Steroid cell tumors, not otherwise specified (lipid cell tumors): A clinicopathological analysis of63 cases. Am J Surg Palho/11 :83 5-845, 1987. 7. Hayes MC, Scully RE. Stromal luteoma ofthe ovary: A clinicopathological analysis of25 cases. fnl J Gyneco/ Patho/6:313-321 , 1978. 8. Imperato-McGinley J, Peterson RE, Dawood MY, Zulllo M, Kramer E, Saxena BB, Arthur A, Huang T. Steroid hormone secretion from virilizinglipoi

104'' Semi-Annual CTTR Seminar: Gynecologic Pathology 63 CASE 18 & 19

History (Case 111 8 - Ace. 17746) A 19-year-old, gravida 0, para 0, Black fe male presented with vaginal bleeding, a five month history of amenorrhea and three months of rapid abdominal enlargement. IVP showed a pelvic mass with hydronephrosis. A pregnancy test was negative. At surgery, a large left ovarian mass and para-aonic nodes were noted, as well as a nodular liver. The 2600 gram left ovarian tumor was 29 x 17 x 12 em. The tumor had multilocular cystic spaces with intervening fum, rubbery, yellow areas. There Wtte also areas filled with greasy, gritty, keratin debris and dark black hair, as well as one area with a cartilaginous consistency. (Contn"buted by C. P. Schwinn, M.D.)

Diagnosis: Yolk sac tumor (endodermal sinus tumor)

History (Case 1119- Ace. 21050) A 33-year-old Caucasian female presented with left-sided pelvic discomfort and pain. Physical examination revealed a large left which extended up to the umbilicus. A pregnancy test was negative. At laparotomy, the 1520 gram, 18 x 14 em left ovary was fum, nodular and reddish-purple. The cut surface was yellow­ tan, spongy and mucoid with areas of degeneration and hemorrhage. (Contributed by John Swift, M.D.)

Diagnosis: Polyembryoma with prominent hepatoid differentiation

DISCUSSION

Clinical Features

Yolk sac tumors (YSTs) account for 1% ofall ovarian , but approximately 20% ofmalignant primitive germ ceU tumors. They are the second most common ovarian malignant germ ceU rumor, almost as common as in females under the age of20 years. Patieots range in age from 14 months to 45 years with a median age of 19 years. It is rare over the age of40 years. Approximately balfofthe patients repon sudden onset of symptoms ofabout a week's duration. Three quarters of the patients experience abdominal pain. A large abdominal or pelvic mass is readily detected on physical examination. Elevation ofserum level ofalpha -fetoprotein preoperatively is an impOrtant clin.ical feature of this tumor; assessment ofits level is useful in monitoring the effects oftherapy and detecting recurrent disease.

Gross Features

A rapidly growing and highly malignant tumor, YST is associated with extraovarian spread to the peritoneum, retroperitoneal lymph nodes, or both, in approximately one-third oft he patients at presentation. Yolk sac rumors present as a large (median diameter of 1S em), well-delineated, unilateral mass. Bilaterality is seen only in association with disseminated disease. Tbe surface is ruptured in 25% ofthe tumors. Cut surface is predominantly solid admixed with cystic areas; foci ofhemorrhage and necrosis are common within the friable yellow-gray solid areas. A honeycomb appearance indicates the presence of a polyvesicular vitelline component.

Microscopic

A wide range of patterns is often present in variable proponioos in all YSTs. Domination ofone pattern to the exclusion of others is rare. The reticular pattern is the most common characterized by a loose meshwork ofspaces and channels tined by attenuated or cuboidal cells with scant clear cytoplasm; the cytoplasm contAins mainly glycogen and sometimes lipid. The nuclei are irregular and hyperchromatic with prominent nucleoli Mitotic figures are numerous. Variably sized, eosinophilic, PAS-positive, diastase resistant, hyaline bodies are common in this pattern.

I 04'' Semi-AnnlUll CTTR Semirulr: Gynecologic Pathology 64 The classic festoon pauem is chancteriud by columns and cords of primitive germ cells. A layer ofcolumnar germ cells tine simple elongated or rounded papiUae with a delicate vascular core that protrude into spaces surrounded by a mantle of auenuated to hobnail primitive appearing cells (Schiller-Duval bodies); these structures are thought to recapitulate the endodennal sinuses of the yolk sac. A solid growth pattern dominates in some lesions. Hyaline bodies are found in most YST, but also only in a wide variety of tumors (AI Naffusi et al, 1993). Hyaline bodies are common in this pattern.

Among the more rare patterns that may occasionally predominate or occur in pure fonn is the polyvesicular-vitelline pattern. This pattern is characteriud by the presence ofcysts sometimes with eccentric constrictions lined by low columnar cells that become attenuated in parts of the lining. The cylts are distributed in a dense fibroblastic stroma. The cysts with eccentric constrictions simulate the division of the primary yolk sac vesicle into a large component corresponding to the vestigial yolk sac ofthe embryo and a smaller component, which is the forerunner ofthe primitive gut A lesion that closely resembles polyvesicular vitelline pattern is the polyembryoma. Polyembryoma is an exceedingly rare primitive germ cell tumor characteriud by proliferation ofembryoid bodies composed of ectodermal and endodermal vesicles and resembling the normal early embryos. The embryoid bodies are widely separated by a loose myxoid stroma composed ofcells with stellate nuclei. In the seminar case, there are also numerous glands lined by mucinous epithelial cells and clusters ofhepatoid cells, some with bile pigment. This loose stroma is in sharp contrast to the relatively dense stroma ofthe polyvesicular vitelline YST. Furthermore, the ectodermal plate of the embryoid bodies has an appearance ofsomewhat stratified columnar cells in contrast to the more cuboidal cells ofthe polyvesicular vitelline pattern. The presence of trophoblastic cells and/or teratomatous elements in the polyembryoma can funher assist in separating these two lesions.

One of the rarest fonns is the solid pattern composed of nests and sheaths oflarge cells "'ith abundant eosinophilic cytoplasm vaguely resembling hepatoblasts separated by thin fibrous bands (Prat et al, J982) . While the hepatoid · variant is rare, hepatoid ce11 clusters are present in 15% ofyolk sac tumors. Occasional YSTs are composed ofor contain glands lined by a nonspecific or vacuolated cells, and in rare tumors, a predominant glandular pattern resembling that of typical or secretory endometrioid carcinoma is seen; tumors ofthis type have been designated "endometrioid-like" YSTs (Clement et al 1987). Enteric-type glands occur in as many as 50% ofYSTs but are rarely numerous; rarely intestinal type glands predominate in the tumor ((Cohen et al, 1987). These glands are lined by bland mucinous columnar cells, goblet cells, and rarely, Paneth cells... Parietal'' differentiation is characterized by small extracellular accumulations of basement-membrane material, typically within reticular foci (Ulbrigln et a1, 1986). Nonspecific patterns that may occur in YSTsinclude solid, papillary and adeno6bromatous. Cells with large intncellular vacuoles that displace the nucleus simulating liposarcoma are seen focally in some YSTs. lmmunobistocbemical Features and Othu Studies lmmunohistochemical6ndings are useful in confirming a diagnosis ofYST, panicularly in case of unusual ntmors or those with nonspecific histologic patterns. Many ofthe cells in the hepatoid variant contain hyaline globules that are positive for AFP and alpha-1-antitrypisin (AAT). The cytoplasm ofthe tumor cells well as the luminal contents ofthe glands and cysts in tumors with polyvesicular-vitelline and endometrioid-like patterns as well as almost all other variants show at least focal immunoreacriviry with AFP and AAT.

At the ultrastructural level, the cells ofthe solid (bepatoid) EST contain numerous intracytoplasmic osmiophilic bodies ofvarious sizes and densities corresponding to the AFP and alpha- I,antitrypsin. Intracellular and extracellular canaliculi are common.

DifT~rentiAI DiAgnosis

Historically and currently, clear cell carcinoma remains the tumor most commonly confused with YST (l

Behavior and Treatment

Yolk sac tumor is characterized by an extremely rapid growth with evidence or spread to the peritoneum, retropentoneum, ·and IYn!ph nodes in alm.ost on.e thin! ofthe patient. In the precbemotherapeutic era, 84% of the patients with. stage Ia tumor died despite surgical extirpation and adjuvant radiation therapy. Combination chemotherapy has resulted in survival rates exceeding 80% in patients with stage I tumors, and over 50% io patients with higher ·stage tumors (Gershenson et al, 1983).

REFERENCES

1. Al-Nafussi AI, Hughes DE, Williams ARW. Hyaline globules in ovarian tumors. Histopathology 23 : 56~-{), 1993. 2. Clement PB, Young RH; Scully RE. Endometrioid-like yolk sac tumor of the ovary. A clinicopathological analysis of eight cases. Am J Surg Pat hoi I I :767-78, 1987. 3. Climine ARW,.Heath LP. Malignant degeneration of benign cystic ofthe ovary. Review ofthe literature and report of a chondrosarcoma and carcinoid tumor. Cancer 22:824-32, 1968. 4. Cohen MB, Friend DS, Molnar JJ, Taleman A. Go.nadal endodermal sinus (Yolk sac) tumor with pure intestinal differentiation: A new histologic type. Path ResPracl 182:609-16, 1987. 5. Genadry R, Parmley T, WoofruffJD. Secondary malignancies in benign cystic teratomas. Gynecol Oncol 8:246-5 1, 1979. 6. Gershenson DM; Del Junco G, Herson J, et al. ~ndodermal sinus tumor of the ovary: The M.D. Anderson experience. Obstet Gyneco/61: 194-202, I 983. 7. Huntington RW, Bullock WK. Yolk sac tumors ofthe ovary. Cancer 25 :1357-{)7, 1970. 8. Ishikura H, Sculfy RE. Hepatoid carcinoma ofthe ovary. A newly described tumor. Cancer 60:2775-84, 1987. 9. Klemi PJ, Metirman L, Gronroos M, Talerman A. Clear cell (mesonephroid) tumors of the ovary with characteristics resembling endodermal sinus tumor. 1111 J Gynec'ol Patho/1 :95-100, 198.2. 10. KuJ'l)'lan RJ, Norris JH. Endodermal sinus tumor ofthe ovary. A clinical and pathologic analysis of71 cases. Cancer38:2404-19, 1976. I I. Kurman R J, Norris HJ. of the ovary. A clinicopathologic entity distinct from endodermal sinus tumor reserilbling embryonal carcinoma of the adult testis. Cancer 38:2420-33, 1976. 12. Langley .FA, Gaven ADT, Anderson MC, et al. Yolk sac and allied tumours of the ovary. Histopathol 5:389- 401, 1981. ' 13. Nagales FF Jr, Matilla A, Nogales-Ortiz F, et al. Yolk sac tumors with pure and mixed polyvesicular vitelline patterns. Hum Patho/9:553-66, I 978. 14. Pantoja E, Noy MA. Axtmayer RW, et al. I. Ovarian dermoids and their complications. Comprehensive historical review. Obstet Gyneco/·Surg 30:1-20, 1975. 15. Prat J, Bhan AK, Dickersin GR, Robby SJ, Scully RE. Hepatoid yolk sac tumor ofthe ovary (endodermal sinus tumor with hepatoid diffe~entiation). A light microscopic, ultrastructural and immunohistochemical study of seven cases. Cancer 50:2355-{)8, 1982. 16. Prat J, Matias-Guiu X, Scully RE. Hepatic yolk sac differentiation in ao ovarian polyembryoma. Surg Pathol 2:147-50, 1989.

104°' Semi -Annu~l CTTR Seminar: Gynecologic Pad>ology 66 .17. Rutgers JL. Scully RE. Functioning ovarian tumors with peripheral steroid cell proliferation: A report ()f twenty-four cases. Int J Gynecol Pathol 5:319-37, 1986. 18. Schiller W. ''Mesonephroma" of ovary. Am./ Cancer 20:1405-1411 , 1967. 19. Simard L-C. Polyembryonic embryoma of the ovary of parthenogenetic origin. Cancer 10:215-223, 1957. 20. .Takeda A, Ishizuka T, Goto T, et at. Polyembryoma of ovary producing alpha-fetoprotein and HCG: immunoperoxidase and electron microscopic study. Cancer 14:1878-89, 19&2. 21. Teilum G. The concept of endodermal sinus (yolk sac) tumor. Scand J Jmmunol &(Suppl 8}:75-&4, 1978. 22. Ulbright TM, Roth LM, Brodhecker CA. Yolk sac differentiation in germ cell tumors. A morphologic study of 50 cases with emphasis on h~patic, enteric, and parietal yolk sac features. Am JSurg Patho/lO:lSl-64, 1986. 23. Young RH, Gersell DJ, Clement ·PB, Scully RE. metastatic to the ovary: A report of three cases discovered during life with discussion ofthe differential diagnosis ofhepatoid tumors·ofthe ovary. Human Patho/23:514-80, 1992. 24. Zirl

10'1°' Semi-Annual CTrR Seminar. Gynecologic Palhology 67 .· .. CASE20

History (Case #20- Ace. 28380) A 32-year-old female presented with a pelvic mass. A 7.0 x 5.3 x 4.4 em lobulated, circumscribed right ovarian tumor was removed at laparotomy. Cut surface of the tumor was granular and tan-yellow. (Contributed by Fattaneh Tavassoli, M.D.)

Diagnosis: Mixed germ cell-sex cord stromal tumor

Additional History and Follow-up: Thirty-three months earlier, patient had presented with persistent pelvic paitl showed massive pelvic adhesions believed to secondary to a healed pelvic inflamrnatoiy process. No biopsies were taken. After excision of the ovarian mass, no further therapy was given. Five years later, a large pelvic mass was n.oted just above· the uterine fundus extending to the left adnexa. Sonography and CAT scan delineated the mass. At laparotomy, a 7 em mass adherent to the uterine serosa and anterior abdominal wall with multiple peritoneal implants was removed along with hysterectomy, left salpingo-oophorectomy, omentectomy and lymphadenectomy. This was followed by chemotherapy (bleomycin, CispJatin, and etoposide) v.;th excellent response. Ten months later, the patient was free of tumor.

Microscopic Features: The primary and metastatic tumors were morphologically identical. Small cells with scanty cytoplasm and oval grooved nuclei were admixed and larger cells (germ cells) with abundant clear cytoplasm containing PAS positive material, central round nuclei and small nucleoli. A single layer ofthe small cells generaqy surrou~ded the cell nests that were separated from each other by bands ofeosinophilic hyaline material. Up to 5 mitotic figures per I OHPF were present among the germ cells. There was no evidence of calcifications or necrosis. An epithelial element or a retiform tubular pattern was not present. The residual right ovarian tissue contained normal siructu{es. The subsequently removed left ovary was unremarkab.le. The tumor differed morphologically from gonadoblastoma by the absence of calcifications and its occurrence in a normal ovary.

The patient had a normal 46XX karyo[We in contrast to those with gonadoblastoma who often have ·mixed gonadal dysgenesis with persistent Mullerian duct structures, chromosomal mosaicism with a Y chromosome component, and gonads.that resemble a differentiated testis or streaks that may show partial differentiation toward either testis or ovary.

DISCUSSION

Gonadal neoplasms contaihing a combination of two or more cell lines are relatively uncommon. Among those that occur, mixtures of epithelial and mesenchymal cells are relatively common. Combinations ofgonadal stroma and germ cells are quite rare. Gonadoblastoma is the best knowaofthe combined germ eells-sex cord stromal tumors and it occurs in intersex individuals (Cabanne 1971; Scully 1970). Another variant of this combination occurs in normal females and has l5een described by Talerman (Talerman tumor); these notably lack the nested pattern and the prominent collagen bands. '

Both gonadoblastoma and Talerman tumor are basically benign. Approximately half ofgonadoblastomas are overgro\YII by a matignantgenm cell tumor, however, making early prophylactic removal ofthe gonads advisable in all patients. The malignanr tumor is usually a dysgemtinoma, but yolk sac rumor, immature teratoma, embryonal ' carcinoma and choriocarcinoma occur in 8o/o of cases (Welch and Robboy, 1981).

The present case is unique in displaying an aggressive behavior despite absence ofany superimposed malignant germ cell tumor.

I 04'' Semi-Anllual CTTR Seminar: Gynecologic Pathology 68 REFERENCES

1. Cabannef. Gonadoblastoma et tumeurs de l'ebauche gonadique. Ann Anat Pa1hol (Paris) 16:387-392, 1971. 2. Gershenson DM, Del Junco G, Copeland IJ, et al. Mixed germ cell tumors of the ovary. Obstef Gynecol 64:200-6, 1984. 3. Kurman RJ, Norris HJ. Malignant mixed germ cell tumors of the ovary. A clinical and pathologic analysis of30 cases. Obstet Gyneco/48:579-89, 1976. 4. Lacson AG, Gillis DA, Sbawwa A. Mali!,'IIant mixed germ cell-sex cord-stromal tumors ofthe ovary associated with isosexual precocious puberty. Cancer 61 :2122-33, 1988. 5. Scully RE. Gonadoblastoma, A review of74 cases. Cancer 25 :1340-56, 1970. 6. Scully RE. Gonadoblastoma: a gonadal tumor related to the (seminoma) and capable of sex­ hormone production. Cancer 6:455-63, 1953. 7. Talerman A, van der Harten JJ. A inixed germ ce!J-sex cord stro.mal tumor ofthe ovacy associated with isosexual precocious puberty in a nonnal girl. cancer 40:889-94, 1977. 8. Talelll)an A. A mixed germ cell-sex cord stromal tumor ofthe ovary in a normal female infant. Obstetrics and Gynecology40:413-78,1912. 9. Talerman A. The pathology ofgonadal neoplasms composed ofgerm cells and sex cordstromal derivatives. Path Res Prac/110:24-38, 1980. 10. Tale.rman A. A distinctive gonadal neoplasm related to gonadoblastoma. Cancer 30:1219-24, 1972. I I. Tavassoli FA. A combined germ cell-gonadal stromal-epithelial tumor ofthe ovary. Am J Surg Patho/7;73-84, 1983. 12. Tokuoka S, Yoichiro A. Hayashi Y, Yokoyama T, Ishii T. A mixed germ cell-sex cord-stromal tumor ofthe ovary with retiform tubular structure: a case report. Jnt J Gynecol Patho/4:161-10, 1985. 13. Welch WR, Robboy SJ. Abnormal sexual development: a classification with emphasis on pathology and neoplastic conditions. In: Pediatric Andrology , Kogan SJ and Hafez ESE, editors. 1981, Martinus Nijhoff Publisber:s; Boston; pp:71-85. 14. Young RH, Welch WR, Dickersin GR, Scully RE. Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 \vith Peutz-Jeghers syndrome and 4 with adenoma malignum of.the cervix. Cancer 50: 1384- 402, 19&2.

104'" Semi-Annual CTTR Seminar: G)'necologic Pathology 69

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Case 1. Leiomyosarcoma. (a) At low magnification, the tumor shows a compact proliferation ofspindle cells without any evidence o( an epithelial component. (b) A fascicular growth pattern and palisading ofbundles of spindle cells is suggested. There. is an admixture ofcells with cigar-shaped nuclei and others with ovoid and atypical nuclei. The cells show significant nuclear atypia; mitotic figures are readily apparent. (c) Patchy areas of hemorrhagic necrosis are scattered throughout the tumor.

Case z. Adenosa~oma. (a, b) Broad polypoid fronds are covered by benign epithelial cells. The major bulk of the polypoid structures are ·composed ofa compact proliferation of ovoid to spindle cells inost closely·resembling endometrial stromal cells. The low magnification appearance is reminiscent of phyllodes tumor ofthe breast. (c) Deeper within the lesion, periglandular cuffing is characteristic ofthis tumor.

Case 3. Low grade endometrial stroma sarcoma.· (a,b) Irregularly shaped aggregates ofa densely ceUular tumor. proliferate through the myometrium and protrude into vessels (b). (c) Higher magnification shows a delicate vascular suppon.· The proliferating tumor cells resemble the proliferative endometrial stromal cells. Mitotic figures are rare. (d) Immunostain for actin sbows absence ofimmunoreactivity in tlie'tumor cells and intense positivity in the myometrial smooth muscle. Immunostains for desmin were similar.

Case·4. Choriocarcinoma. (a) Syncytio· and cytotrophoblasts form biphasic aggregates invading the myometrium and (b) vascular channels: (c) Fibrinoid necrosis is superimposed on the proliferating tumor cells, a reflection of.the therapy induced changes. ·

Case 5. Mucinous (colloid) adenocarcinoma Oftbe cervix. (a) The cervical stroma is infiltrated by distended gl!lllds containing abundant muc

Case 6. Villoglandular adenocarcinoma of the cervix. (a) Long papillary projections branch out from the surface ofthe cervical epithelium. (b) The papillae have abundant stromal suppon. (c) The papillae are lined by columnar cells lacking significant atypia; only occasional mitotic figu_res are evident.

Case 7. Inflammatory myofibroblastic tumor of the uterus. (a) The tumor is composed ofa diffuse and loose proliferation of spipdle cells infiltrating the myometrium; foci ofcalcification are evident. (b) Higher magnification shows bland spindle cells with a paucity ofcytoplasm and rather small and sometimes pyknotic nuclei admixed with plasma cells; small number oflymphocytes and even fewer eosinophils were evident in other fields.

Case 8. Sarcom.a (leiomyosarcoma) with osteoclastic giant cells. (a) A hemorrhagic tumor irregularly invades the myometrium. (b) A large number of multinucleated giant cells containing numerous bland round nuclei are dispersed among atypical mononucleated cells that contain irregularly. shaped nuclei and display frequent mitotic figures. The giant cells have a more eosinophilic and granular cytoplasm compared to the background mononucleated cells. (c) Immunostain for KP I shows intense staining and confirm the histiocytic nature ofthe multinucleated giant cells, while the mononuclear tumor cells fail to react.

Case 9. Granulosa cell tumor, adult type. (a) A diffuse and relatively compact proliferation of tumor cells shows mainly a cord-like or trabecular arrangement ofthe cells. (b) The nuclei are relatively uniform and some have longitudinal.grooves. The cells have smaU amount ofgranular eosinophilic/amphophilic cytoplasm.

Case 10. Gonadal stromal tumor, consistent witb anaplastic granulosa tumor. (a) A solid proliferation of tumor ceiJs alternate with edematous stroma. (b) Higher magnification shows atypical nuclei and mitotic figures. (c) Some cells had irregular nuclear grooves. (d) Immunostain for inhibin shows positive reaction in the tumor cells.

104"' Semi-Annual CITR Seminar: Gynecologic Pathology 80 Case 11. Small ~ell carcinoma. (a,b) Low power magnification shows an irregularly clustered proliferation of cells with scattered ovoid follicle-like spaces filled with eosinophilic secretory material. (c) Higher magnification shows atypical cells with cell defined margins and mitotic figures. (d) lnununostains for cytokeratin shows patchy areas of intense immunoreactivity.

Case 12. Carcinoid tumor. (a) The tumor is composed ofa highly unifonn population ofcells fonnin.g irregular islands in a fibrous stroma. Some oftbe islands have central spaces where the cells seem to have lhllen off. (b) The tumor cells have round unifonn nuclei and a small amount of amphophilic cytoplasm. The cells in the periphery of the islands fom1 a more distinct layer.

Case 13. Endometrioid tumor of low malignant potentw. (a) At low power, islands ofendometrioid glands without or without squamous metaplasia are found dispersed in a dense fibromatous stroma. (b,c) The endometrioid glands are back to back or distended with extensive squamous metaplasia. (d) The appearance ofthe epithelial elements is like hyperplastic endometrium.

Case 14. Serotransitional cell carcinoma. (a) A papillary pattern is evident overlying solid areas ofepithelial growth. (b,c) At higher magnification, the solid areas display a clear and spindle cell population reminiscent of squamous epithelium. Atypia is focally evident. . (d) Scattered through the solid areas, are spaces containing small amounts of secretory material; these areas resemble serous tumor.

Case 15. Krukenberg Tumor (Metastatic signet-ring cell carcinoma). (a) At low power, there is simply some irregularity in th.e distribution of the spindle cells; areas ofcellularity alternate with edematous areas. (b) The cellular areas show aggregates ofsignet ring cells. (c) Even the edematous areas contained numerous signet ring cells; immunostain for cytokeratin unmasks the abundance of the carcinoma cells permeating the ovarian stroma.

Case 16. Oear cell carcinoma. (a,b,c). The tumor is characterized by a combination of tubulocystie and papillary growth pattern; solid areas constitute a minor component. (d) The tumor cells have vacuolated, granular or eosinophilic cytoplasm with irregular nuclei.

Case 17. Lipid (steroid) cell tumor. (a) A solid proliferation ofcells with abundant vacuolated cytoplasm. (b) The nuclei are unifonn and lack atypia or mitotic activity; a rich vascular network is characteristic ofthis tumor. (c) Some areas are composed ofcells with a more granular eosinophilic cytoplasm.

Case 18. Yolk sac tumor. (a) The tumor displays a honeycomb appearance with cysts lined by a single layer of Oat cells or naked nuclei (the reticular pattern) and a loose myxoid loose reticulum. (b,c) Some of the cystic spaces in a denser fibrous stroma show constrictions reminiscent ofthe polyvesicular vitelline pattern.

Case 19. Polyemhryoma with prominent bepatoid dill'e.rentiation. (a) A loose myxoid reticulum supports small glands and embryoid bodies . . (b) At higher magnification, the embryoid bodies are composed of ectodermal and endoderrnal vesicles and are surrounded by a loose myxoid reticulum. (c) Clusters ofhepatoid cells are dispersed in the loose reticular stroma. (d) Some cells even have bile pigment.

Case 20. Combined g~nn cell- Jex rord stromal tumor. (a) Rounded nests ofcells are surrounded by thick basement membranes. Rounded hyaline bodies composed of basement membrane are found within the nests. (b) At higber·magnification, the islands are composed predominantly ofcells with ovoid nuclei. Scattered among these cells are large cells with round nuclei and prominent nucleoli- germ cells. (c) lmmunostain for inhibin shows. a positive reaction in the sex cord stromal cells while the germ cells fail to react with inhibin.

I 04• Semi-Annual CTTR Seminar: Gyoooologic Pathology 81