Teaching Monograph

The Pathology of the Female Reproductive Tract

John M. Craig, MD

Boston Hospital for Women Harvard Medical School Boston, Massachusetts Copyright 0 1979, Universities Associated for Research and Education in Pathology, Inc. All rights reserved The American Journal of Pathology Official publication of The American Association of Pathologists

Published by The American Association of Pathologists, 9650 Rockville Pike, Bethesda, Maryland The Patholo of the Female Reproductive Tract

Vulva 385(1 391(7) Endometnum 400 16) Myoumeium 408(24 Fallpian Tubes 411(274) Ovay 415I31) The Patholo of Pregnancy 429(45) Malf ains of the 430(46) Circulating Disorders of the Plcenta *32(48) Infecims of the Plaxcet 43:3 49) Placental Pathology Associated With Maternal Disease 434 50) Tumors of the Placenta 4:35(51) Foreword to Teaching Monographs

This teaching monograph is being published by The American Journal of Pathol- ogy for Universities Associated for Research and Education in Pathology as a service to medical students and their teachers of pathology. This venture repre- sents a joint effort to make such teaching material available to a wide audience. Separately bound copies of this Teaching Monograph can be purchased from Universities Associated for Research and Education in Pathology, Inc., 9650 Rockville Pike, Bethesda, MD 20014. The charge is $2.25 per copy for orders of up to ten and $1.25 per copy for orders of ten or more (prepaid).

The Editorial Board

John R. Carter, MD, Case Western Reserve University School of Medicine Francis E. Cuppage, MD, University of Kansas Medical Center Joe W. Grisham, MD, The University of North Carolina School of Medicine Robert B. Jennings, MD, Duke University Medical School Werner H. Kirsten, MD, The University of Chicago Vincent R. Marchesi, MD, Yale University School of Medicine Goetz W. Richter, MD, The University of Rochester School of Medicine Dante G. Scarpelli, MD, Northwestern University Medical School Robert E. Stowell, MD, University of California, Davis Benjamin F. Trump, MD, University of Maryland Series Editor: Dante G. Scarpelli, MD The Pathology of the Female Reproductive Tract John M. Craig, MD

Vulva The vulva, covered by epidermis, is subject to most of the infections and reactive processes of the remaining coverings of the body. In addition, however, because of its reactivitv to the local levels of estrogen and because of the special adnexal structures and arrangements, the exposure to venereally acquired pathogens and to vaginal and urethral discharges, it has its own unique pathology. It is at the extremes of life that estrogen lack can play an etiologic role in vulvar pathology. In voung children, the nonestrogenicall.v stimulated thin epithelium is susceptible to attack bv gonococci, giving rise to acute vulvovaginitis, an acute edematous lesion with a marked polvmorphonu- clear reaction. This mav be quickly relieved by the application of estro- gen. In very old women, the lack of estrogens causes atrophv not only of the epidermis but also the adnexal gland structures and subcutaneous fat, so that a generalized atrophy occurs: a condition labeled "'kraurosis.'" This process, with the attendant atvpical epidermal and dermal reactions that accompanv it in varving degrees, have been labeled more recentlv "vulvar dvstrophv." The markedlv thinned vulvar skin may be the site of infection or ulceration. The skin reacting to the infection may become acanthotic and hvperkeratotic; in the latter instance, gross white patches can be identified clinicallv (so-called ). Other histologic forms of dvs- trophv include scaling of lichenification, sclerosis and hvalinization of the papillary dermis, and flattening of the rete pegs. The reactive state in the dvstrophic vulva is not static: a hypertrophic area with thickening and elongation of the rete pegs and hyperkeratosis with varving degrees of inflammation of the dermis may be seen in the same patient as areas of atrophv. Such variations are induced by irritating discharges, chronic infection, and trauma induced by scratching. Aside from the nonspecific infections mentioned above, the common specific infections of the vulva are venereal and mvcotic. The ulcer of syphilis, with its firm, elevated, painless, round edge and central ulcer- ation, shows on microscopic examination a marked papillary hvperplasia of the epithelium with an intense plasma cell infiltration in the dermis accompanied by a marked increase in capillarv net to form a gran- ulomatous lesion. The femoral and inguinal lymph nodes will be enlarged if the infection is more than 2 to 3 weeks in duration. The second venerally acquired disease that gives rise to lesions of the vulva is herpes genitalis. This causes shallow, painful, ervthematous ulcer- 0002-9440/79/0208-0381$01.00 385(1) 0 1979 UAREP 386(2) CRAIG American Journal of Pathology ation, occasionally with small peripheral vesicles. The inflammation is intense, with lymphocytes and mononuclear cells in the dermis. The distinguishing feature is the presence of intranuclear inclusions in bal- looned nuclei of the squamous epithelium, often as syncitial giant cells in the vesicles at the borders of the lesions. The third common, although nonvenereal, specific infection is monilial. This is primarily seen in diabetic patients, in whom a combination of high tissue and urine glucose levels give rise to a favorable fungal culture media. The vulva is erythematous, with elevated white patches which can be partially scraped away. The Candida organisms grow on but may invade the superficial layers of the desquamating epidermis. The under- lying dermis shows a nonspecific lymphocytic and monocytic response. Of the infections of the adnexal structures, acute infection of Bartho- lin's gland lying just at the lateral border of the vulva and vagina leads commonly to duct obstruction and subsequent dilatation and infection of the squamous-cell-lined ducts. The thinned epithelium of the duct may be eroded and replaced by a subacute inflammatory reaction. There is usually little or no involvement of the mucus-secreting glandular ele- ments. Of the benign tumorous growths in the vulvar area, there are two which are relatively common and special to this area. The first of these is a venereally acquired epithelial overgrowth of viral etiology, ie, condyloma acuminata. Similar lesions occur in the vagina and cervix and under the foreskin in the male. These warty papillary growths are often multicentric and, in rare cases, cover much of the vulvar and perianal skin. They consist of acanthotic epidermal overgrowths, with a regular maturational progression from the basal layers to the surface. The cells contain little glycogen. They may keratinize just before desquamation, but hyper- keratosis is not common. The papillae of the dermis are narrowed and contain few inflammatory cells. The margins of the lesions are sharply demarcated, and there is little "field change" in the adjacent epidermis. No inclusion bodies are present, although perinuclear halos can be found. Mitoses are limited to the basal layer. These lesions occasionally may be confused with squamous papillomata. The second benign tumor of the vulvar area, rarely seen elsewhere in the skin, is an adenoma of the apocrine gland, ie, the hidradenoma. These form small circumscribed masses in the labia. Microscopically, they are usually well-circumscribed by a pseudocapsule and are composed of very thin papillary fronds covered by a single layer of cuboidal cells. The tumors are slowly growing and do not contain mitoses. The vulva, like the cervix, appears to undergo malignant degeneration Vd. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 387(3) February 1979 over a long time; premalignant changes may be fairly widespread before invasion occurs. Such degeneration is chieflv seen in older women and may accompany the vulvar dystrophies mentioned previously. The lesions progress through hyperkeratotic acanthotic changes in the epidermis with varying degrees of dysplasia to carcinoma in situ. The dysplasias are characterized by the presence of immature cells, at first confined to the lower third of the epidermis but, with more severe lesions, atvpical basal cells having large hyperchromatic nuclei and reduced cytoplasm extend up to one half of the thickness of the epidermis, and finally the entire thickness of the epithelium is replaced by dysplastic atypical basal cells with verv scant cytoplasm and very granular hyperplastic nuclei. The latter stage can then be labeled "intra epithelial carcinoma" or "carci- noma-in-situ." Such lesions may be limited in extent or may rarelv extend widely over the vulva. Because of the hyperkeratotic surface layer, they will appear as white patches grosslv, hence the term "leukoplakia," but the same hyperkeratosis may be present without malignant alterations so that the term should be used only descriptively. Because of the non- tumorous growth characteristics, the determination of the extent of the lesion is often dependent on multiple biopsy specimens. Invasive squamous carcinoma forms one end of a continuous spectrum with those of earlv dysplasias. It has the varied histologic equivalents of squamous carcinoma of the skin, but again the vulva has unique charac- teristics. Here squamous carcinoma is distinguished by its rapid spread to adjacent lymph nodes and by its poor prognosis. The latter is influenced by the size of the lesion, by the grade of histologic differentiation, by the depth of the invasion of the local lesion (Levels I through IV), and most stronglv bv the clinical stage (Stage I, less than 2.0 cm in diameter and confined to the vulva; Stage II, confined to the vulva and over 2.0 cm in diameter; Stage III, suspicious involvement of the groin nodes; Stage IV, grosslv positive groin nodes or other metastases). Stages I and II have 90% 5-year survivals, and Stage III has less than 25%, with an overall survival for all stages of a little more than 50%. The poor survival is related to diagnostic delay largely due to patient factors. Death occurs from local spread, infection, and hemorrhage. Paget's disease of the vulva, a disorder of older women, appears as an erythematous blush on a roughened epidermis. The disorder may involve the entire vulva and extend to the perianal area and proximal vagina. The microscopic picture is similar to that of Paget's disease of the nipple, with large adenocarcinoma cells with abundant pale cytoplasm Iving among and bordering the basal cells of the epidermis. They have round or indented nuclei with a mucus-containing vacuole bordering the nucleus. 388(4) CRAIG American Journal of Pathology The cells follow the dermal epithelium into the dermal appendages. In some cases, the basement membrane may be ruptured, with spread of the tumor to the dermis and subcutaneous tissue. Rarely, small discrete adenocarcinomas of the sweat glands can be identified as the origin of the cells in the epidermis, but because of the diffuse nature of the infiltration, a primary source is often not identified, so that some observers take the view that the basal layer of the epidermis undergoes a diffuse malignant change. Very rarely, metastases to local lymph nodes are found. A few cases have been recorded in which metastases from breast carcinoma have been suspected as a source of the peculiar distribution of the cells. In the usual case, if the borders of the tumor can be defined so as to permit complete removal of the lesion, the prognosis is excellent. of the vulva is third in frequency of vulvar malignancies. Its behavior and prognosis are similar to other trunk . Of the benign lesions of the vagina, unique to the region, only adenosis deserves mention. This has been brought into prominence because of the marked increase in incidence of the lesion (approximately 35-fold) in patients with intrauterine fetal exposure to the synthetic estogenic com- pound diethylstibestrol in the first trimester of pregnancy (Figure 1). In this process, there is in fetal life an extension of the columnar epithelium of the endocervix from its normal position on the cerival os, down the

Figure 1-Adenosis of the vagina In a patient exposed in utero to diethylstilbestrol. Two mucus-secreting glands lie beneath a thickened slightly disordered squamous epithe- lium. (X85) Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 389(5) February 1979

' V 5P'5tss~~~~i4 %h qpqi^

F 2-Aenocarcinoma of the vagina in a patient exposed in utero to diethyistil- bestrol. Irregular, enlarged cells with hyperchromatic nucle line gland spaces. (X 143) sides of the vagina. This downgrowth gives rise in voung women to areas of abnormal appearance and inflammation on the walls of the vagina and causes the formation of an extra fold of reduntant vaginal mucosa above the anterior fornix of the cervix, partially obscuring the portio of the cervix. Microscopicallv such lesions consist of islands and confluent areas of thickened, occasionallv hyperkeratotic, vaginal mucosa with numerous glandular elements, similar to those in the endocervix, which replace the squamous epithelium or lie below an intact squamous epithelial layer. Such areas are susceptible to erosion and inflammation. The glands ap pear to be gradually replaced by squamous epithelium or by metaplastic transformation (squamous metaplasia) into squamous epithelium. In a rare case there mav be a dysplastic change in the squamous epithelium, but these have rarely progressed to identifiable malignancy. The gland elements of the lesion in a significant number of exposed patients undergo malignant change to a papillary adenocarcinoma. The tumor cells have a distinctive epithelium with the nucleus often at the tip of an elongate clear cytoplasmic stalk (hob-nail cells) and for this reason have been considered to have an origin similar to the primitive m-ullerian epithelium (Figure 2). is usuallv the first symptom in the pubertal, adolescent, and young adult host (average age, 17 years). The tumors metastasize to local lvmph nodes and lung. 390(6) CRAIG American Journal of Pathology Since its association with intrauterine diethylstilbestrol exposure, ap- proximately 250 cases of clear cell carcinoma of the cervix and vagina have been gathered by the registry for this disorder. Only two thirds of the patients had such a history of exposure; therefore, such a history is not necessary for the development of the lesion. The most common malignant tumor of the vagina is invasive squamous carcinoma. This may develop after a fairly long period of dysplastic unrest in the epidermal layer or of carcinoma in situ. The tumor will present as an altered area of squamous epithelium, as an area of abnormal keratin formation, or as an eroded, ulcerated area. The tumor cells have the same variations in degree of differentiation as do those of the skin and cervix. Because of the anatomic relations of the vulva to the bladder and rectum, with a thin connective tissue plane between the vagina and the other organs, spread beyond the vagina occurs early in the course of the natural history of the tumor. For surgical cure, exenteration or at least vagi- nectomy is required. The other tumor of importance, but of low frequency, is a malignant melanoma of the vagina. This tumor appears to arise on the anterior vaginal wall in the mucosa at the basal cell layer as it does in the skin. The large pale cells with prominent nuclei and the melanin granules invade upward through the epithelial layer to the vaginal surface, laterally under the mucosa, and deep into the submucosa. The tumors are of interest because of their origin in a mucous membrane away from the actinic stimulation, although, of course, it is to be remembered that the outer two thirds of the vaginal mucosa is formed by an ingrowth from the skin, so that melanoblasts might be expected to be present embryologically. The tumor spreads to local inguinal and pelvic lymph nodes. Because of their late discovery, often after a bleeding episode, their prognosis is poor. Some have first been identified by vaginal smear. A majority of the malignant tumors of the vagina are metastatic. They have three main origins: the most common by far is from an adenocarci- noma of the , where the spread is by venous channels from the .' These metastases are submucosal but may erode the overlying mucosa. The second most common metastatic carcinoma in the vagina is a squamous carcinoma which may spread superficially along the mucosal surface, replacing the normal epithelium, from carcinoma of the cervix or of the vulva. Finally, direct spread through the lymphatics, from an invasive carcinoma of the cervix, may produce a nodule in the vaginal submucosa, with subsequent erosion into the mucosa. Although not strictly metastatic, further malignant degeneration of an incompletely excised dysplasia of the cervix may give rise to squamous carcinoma of the Vd. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 391(7) February 1979 vagina. The third malignant tumor commonly metastatic to the vagina, especiallv to the suburethral area on the anterior vaginal wall, is meta- static from the uterus, traveling bv venous channels to form a bluish hemorrhagic nodule just behind the urethral orifice. Cervix The cervix on its convexly rounded vaginal surface is covered with squamous nonkeratinizing epithelium which is hormonallv dependent on estrogenic compounds for its growth and maturation. The latter includes a gradual condensation and pyknosis of the nucleus and an increase in the amount of cytoplasm along with increased glycogen stores within the cyttoplasm. In the absence of estrogen, as in the prepubertal girl or the postmenopausal woman, the squamous cells fail to replenish themselves at a normal rate and remain small with scant cytoplasm, without glveogen, and with small vesicular nuclei with a dust-like chromatin pattern. Pro- gesterone also acts on the squamous cells, but its effect is less profound and it appears to block the full development of the estrogen effect, so that the cells are of intermediate size with an incomplete development of the pvknotic change in the most superficial cells. The portio epithelium may respond to mechanical or infective agents by proliferation, giving rise to an increased thickness of the squamous cell laver (prickle cell hyper- plasia), by the production of keratohyaline granules and keratin at the vaginal surface (the cervical squamous epithelium does not ordinarily produce keratin), by the downgrowth of immature squamous epithelium into the submucosa to form elongate rete pegs (usually no rete pegs are present) (pseudoepitheliomatous hyperplasia), or bv the production of a slightlv immature squamous cell which does not contain glvcogen and in which the nucleus does not undergo complete pyknosis (parakeratosis). The endocervical epithelium, a mucus-secreting element with cilia, lines the cervical canal and the contiguous tunnel-like glands up to the level of the inner cervical os, where it gives way to the endometrial tissue. The junction of the squamous and endocervical glandular epithelium shows a great variability in its position within the cervix during life. In the newborn, the columnar epithelium may extend a short distance out onto the portio, as it may also during pregnancy, only to retreat a considerable distance into the endocervical canal during menopause. The endocervical epithelium is also morphologically responsive to estrogen and pro- gesterone. The endocervical cells are replaced verv slowlv so that in the absence of estrogen, the atrophic changes are not as marked as on the portio, but the cells do get smaller in diameter. These endocervical cells are responsive to progesterone in a more dramatic wav: on stimulation 392(8) CRAIG American Journal of Pathology they become actively secretory with much taller columnar cytoplasm containing supranuclear vacuoles and excrete an abundant thick mucoid secretion into the gland lumens. Such a maximum response is seen physio- logically in midpregnancy or pharmacologically after progesterone ther- apy for several weeks. The endocervical cells respond to noxious stimuli, infection being the most common one, by undergoing squamous meta- plasia (Figure 3) (a change of the maturing mucinous cells into squamous cells) or by a proliferation of certain indifferent cells in the basal layer to form squamous cells (reserve cell hyperplasia). Aside from the disturbances of the cervix related to migration of the squamocolumnar junction and to repair of erosions, the cervix is subject to inflammatory processes with or without loss of the superficial epithelium; such lesions can be seen post partum but are more often venereally acquired. The most common which have any degree of histologic specific- ity are the viral infections of herpes and cytomegalic inclusion disease, both of which give rise to an intense infiltration of lymphocytes and plasma cells and proliferation and swelling of the endothelial cells. They can be identified by the specific inclusions in epithelial cells (Figure 4); in the case of herpes, multinucleate giant cells are found among the epithe- lial cells. In patients with syphilis one could expect a fairly specific histologic appearance with marked infiltration with plasma cells and

Figure 3-Squamous metaplasia of cervix, near the squamocolumnar junction with thickening of the epithelium and conversion of the columnar to squamous type cells. (x1 14) Vol. 94, No.2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 393(9) February 1979

~00

bodies. (XS37) marked downgrowth of newly formed rete pegs of the squamous epithe- lium; the endothelial cells again are prominent. The exact diagnosis would require demonstration of the treponema by metal impregnation techniques. The overwhelming proportion of clinically inflamed have no etiologically identifiable findings but consist of some disturbance to the surface epithelium, infiltrations of acute inflammatory cells in the glands, and a chronic inflammatory reaction of the cervical stroma, pre- dominantly lymphocytes and plasma cells. In the course of repeated infections, the openings of the cervical glandular tunnels may become blocked; then the lumen becomes dilated and filled with mucus (nabo- thian cyst). Benign cervical polyps, common lesions of the cervix, are always ac- companied by some degree of inflammation. They arise within the cer- vical os and elongate to extend onto the portio. They are usually covered by a columnar epithelium, with dilated endocervical glands in their centers; the stroma contains a mixed acute and chronic inflammatory response. Because of their exposed position, they are subject to trauma which may cause bleeding. They rarely undergo malignant change, al- though squamous metaplasia is not uncommon. Smooth muscle tumors of the cervix, although they may be polypoid and symptomatic, usually are silent and lie deep within the cervical 394(10) CRAIG American Journal of Pathology stroma. If large enough, they can encroach other nearby viscera and thus cause symptoms or can obstruct the birth passage. They consist of smooth muscle fibers arranged in intertwining bundles, separated from the sur- rounding stroma by a pseudocapsule. They respond to the hormonal situation in a similar manner to the muscle cells of the uterine fundus. The most important pathologic entities of the cervix are those pre- malignant and malignant lesions of the portio epithelium which progress to invasive squamous carcinoma. The majority of such lesions, while spreading both up into the endocervical canal and outward onto the cervical portio, are found within 1.0 cm of the squamocolumnar junction. Grossly, the lesions appear as granular erythematous patches, often more opaque than the normal epithelium. In a small percentage of cases, no lesion can be detected by the naked eye. Because all dysplastic lesions have more or less immature cells on or near the surface and because such cells do not contain glycogen, when the cervix is stained with iodine solution (Lugol's) (Schiller test), the affected areas remain white; the glycogen in the remaining normal cervical squamous epithelium stains brown. This lack of staining is not specific for dysplasia because the lesions previously mentioned, eg, squamous metaplasia, hyperkeratosis, erosion, parakeratosis, or extension of the mucous columnar cells out onto the portio, would also fail to stain brown. This failure of the cervical portio to stain for glycogen offers the clinician an opportunity to select the most likely lesions for diagnostic biopsy, as does the colposcope, which identi- fies abnormal vascular patterns in the submucosa. Cervical dysplasia begins in the epithelium by an abnormal prolifera- tion and persistence of basal cells. These cells have enlarged nuclear cytoplasmic ratios, with abnormal variation in size and granularity of the nucleoplasm. The cells are often smaller than normal but are compressed laterally by the increased number of cells. Mitotic figures are found in cells lying well above the basement membrane and, in the most severe case (carcinoma in situ), may extend to the surface of the epithelium. In the dysplasias, the maturation of the cells is delayed, immature cells appearing nearer and nearer the surface, and, in carcinoma in situ, cells having the cytologic appearance of basal cells lie on the luminal surface so that the basilar and most superificial cells are identical in appearance (Figure 5). In lesser degrees of the process, the border zone of mitoses, immature cells with increased nuclear cytoplasm ratios and maturing cells with shrunken pyknotic nuclei may occur at various sequential levels in the stratified squamous epithelial layers above the basement membrane so that a gradation of the severity of the dysplasia into minimal, moderate, and severe (Figure 6) can be assigned. It is an implicit supposition that a Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 395(11) February 1979

45- '- ,Tm WD 4w 41P % %7,4tm*,. VW Alb- 46 ob ** 1% 0 W a go * 40 I a 41V A .410b.; .1 0 g4ft, , W-A qk

eI3-s w A *p4..* * o 6^

Fgure 5-Portio of the cervix with moderate dysplasia. Mitoses extend one half the distance from the base to the surface; the upper epithelium shows fair differentiation. (X214) high proportion of such d.splastic lesions will progress to carcinoma in situ (Figure 7) and, later, to invasive squamous carcinoma. The interval before the advent of invasion is inversely proportional to the severity of the dysplastic process, provided there is no corrective intervention.

Fei 6-Portio of cervix with severe dysplasia. Mitoses extend to the upper third of the epithelial layer and maturation is delayed. (x280) 396(12) CRAIG American Journal of Pathology

Figure 7-Portio of the cervix with carcinoma in situ. Mitoses and dysplastic basal cells are present from the basal layer to the surface. (X214)

Such lesions spread along an intact basement membrane of the surface epithelium to involve the portio and the endocervical canal, as well as to replace the glandular epithelial cells in the gland crypts. Carcinoma in situ has almost never been found to metastasize, so that local excision by cervical conization or simple hysterectomy is adequate therapy (Stage 0). When the basement membrane is breached, the lesion acquires invasive potential (Figure 8). In the earliest stages, the downgrowths are attached to the superficial or glandular replacing tissues and are accompanied by considerable inflammation in the surrounding connective tissue (early stromal invasion); here, too, spread to nearby lymph nodes is unusual. If invasive tongues of cancer tissue separate from the superficial epithelial layer but are found less than 4 mm from the surface, the diagnosis is microinvasive carcinoma, here the cure rate is 96% or better with simple hysterectomy (Figure 9). When the invasion goes deeper, the cure rate drops off rapidly, and radical hysterectomy or radiation is required for an acceptable cure rate of 75 to 80% (Stage I). Invasive carcinoma in the cervix presents as a deeply cratered ulcer (endophytic), an ulcerated mass, or, occasionally, a polypoid lesion (exo- phytic). As it invades, it increases the size and the firmness of the cervix. Microscopically, the squamous cells may vary from small closely packed hyperchromatic linear cells with scant cytoplasm to large, often multi- nucleate, keratinized forms with focal differentiation to complete pearl Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 397(13) February 1979 formation. These cell masses growv dow-nward in anastomosing cords into the cervical stroma surrounded bv much inflammation. In the more dedifferentiated tumors. the cells may spread in small clumps throughout the cervix.

4kZ 'A .

lb

Figure 8A and B-Cervix with carcinoma in situ and early stromal invasion. The tip of the invasive column of cells has lost its basement membrane and is surrounded by lympho- cytes. (A, x33; B, x447) 398(14) CRAIG American Journal _e561|_:_I*i. of Pathology ....~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..~~~g.....

Figure 9-Cervix with microinvasive squamous carcinoma, with less than 4 mm from the surface to the most distant invasive point. (xl1)

When the tumor is confined on physical examination to the cervix, it is given a Stage I classification. If the cancer clinically involves the vagina or but not the lower third of the vagina or the pelvic side wall, it is labeled Stage II and the survival figures drop to 50 to 60% at 5 years. In Stage III, with extension to the pelvic side wall or the lower third of the vagina, a 30% survival is to be expected at 5 years. With extension beyond this, survivals at 5 years are in the 10% range (Stage IV). After extension of the tumor to the parametrium, the more distant spread is by lymphatics to the parametrial, hypogastric, iliac, and aortic lymph nodes, in that order. The degree of differentiation of the tumor is a minor factor in the determination of the prognosis but is overwhelmed by the importance of the clinical stage which is based on the degree of spread of the tumor. Death in treated carcinoma of the cervix is most frequently secondary to uremia from ureteral obstruction by compression from pelvic tumor growth. In neglected cases, death may result from hemorrhage or infec- tion. Since the cervical epithelium, like the vaginal, is continually desqua- mating normally, the superficial cells are an accurate reflection of the cells lining the surfaces of the cervix. When this epithelium becomes dysplas- tic, the desquamating surface reflects, in part, the maturation failure in the deeper layers of the epithelium; however, in cases of carcinoma in situ Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 399(15) February 1979 or invasive carcinoma, since the abnormal cells are present on the surface, they too are desquamated and can be identified in cervical or vaginal smears. Although the exact etiology of cancer of the cervix is unknown, we do know a number of factors associated with its development. These suggest that it is a venereallv transmitted disease, since any historv of intercourse, especially an early age at first intercourse and a multiplicity of partners, is associated with a higher incidence. The role of herpes virus II (genital herpes) in the etiology of squamous carcinoma of the cervix has not been determined, although it is certain that a high proportion of patients with carcinoma have herpes antibodies and that isolation of the virus from the cervix can be accomplished in a higher percentage of cases than in con- trols. Carcinoma arising from the endocervical glands is a disease of slightlyr older women and constitutes approximately 10% of all cervical carcino- mas. It may form small papillarv masses but, far more frequentlv, it is an endophytic lesion and invades deeply into the cervix. The more common lesion is made up of irregularly arranged glands often having a scalloped outline. The cells are polvgonal with an enlarged clear cytoplasm and large centrally placed nuclei. The "clear cell carcinoma" found in young women exposed in utero to diethvlstilbestrol is usuallv more papillarv with "hob-nail" cells having their nuclei at the luminal extremity of the cell. No preneoplastic lesions have been identified nor is carcinoma in situ often diagnosed, and, because their origin is deep in the cervical stroma by the time of discoverv, the tumor is more advanced than its squamous counterpart. Since both squamous and glandular elements arise embryologicallv from a primitive mullerian epithelium, it is hardlv surprising that tumors containing mixtures of squamous and secreting cells are found. Only two related malignant tumors of the cervical stroma of significant frequency are to be noted. These occur at the extremities of life, ie, in the newborn and in the postmenopausal woman. In the newborn, the tumor is composed of primitive embrvonal muscle elements, ie, a rhabdomvosar- coma. It grows verv rapidly and forms translucent polvpoid masses (sar- coma botrvoides) which fill the vagina. The tumor masses are covered by cervical epithelium; the elongate striated rhabdomyoblasts form a con- densed "cambium" laver beneath the epithelium, with more loosely arranged cells deeper in the polvpoid masses. Local invasion and pul- monarv metastases are early events; even with chemotherapy, the progno- sis remains dismal. In the elderly, mixed mesodermal sarcomas arise in the cervix with a 400(16) CRAIG American Journal of Pathology possible mixture of cell types including glandular, smooth and striate muscle, cartilage bone, and undifferentiated stromal cells. These tumors spread rapidly and give a poor prognosis. Endometrium Since the aberrations of the menstrual cycle play a key role in the pathology of the endometrium, it is essential to understand the function of estrogen and progesterone in the cyclic alterations of the endometrium. Estrogens act on the endometrial cells to bring about proliferation, maintenance of internal cellular structure, and preparation of the cell (binding sites) for the action of progesterone. In the premenarchal girl or in the postmenopausal woman with low estrogen levels, the endometrial glands are small and sparce and are made up of small cells having a scant cytoplasm and a bland, evenly staining nucleoplasm; the stromal cells are much reduced in size and are closely packed, with no identifiable cytoplasmic borders and small, evenly stain- ing nuclei. On administration of estrogen, both the endometrial glands and stroma respond by increases in cell size and nuclear size, by the appearance of nucleoli, and by the presence of mitotic activity. All this results in an increase in the number of glands, in stromal cells, and in the width of the endometrium. The gland cells become pseudostratified and the glands become coiled. This growth continues as long as the estrogen level is maintained or increased, but at any level of estrogenic stimulus, a maximum response will be reached; at this point, the endometrium begins to undergo necrosis focally, usually near the surface. This necrosis is usually not accompanied by significant leukocytic response but may leave holes filled with blood or debris in the endometrium. If increasing doses of estrogen are given, the endometrium responds by further proliferation so that eventually a greatly thickened endometrium results with the usual proportion of glands and stroma; possibly because of the greater propen- sity for stromal than glandular breakdown, the glands may become cys- tically dilatated with some infolding of the walls. The same pattern may ensue in the postmenopausal woman who no longer ovulates but, due to local conversion of steroid precursors of estrogens to active compounds or to conversion of similar compounds by peripheral tissues, may have an effective estrogen level and will have a similar tissue response lasting over a long period. Progesterone also acts on the endometrial cells to change their morphol- ogy but only maximally after pretreatment with estrogen; this estrogen priming is known to increase the binding sites for progesterone in the cell. Progesterone has four main roles: to induce and maintain secretion in the Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 401(17) February 1979 gland cells, to induce edema in the endometrial stroma, to cause a decidual reaction within the stromal cells, and to inhibit mitotic activity in the gland cells. The sequences of glandular secretion follow a predictable pattem for the first 8 days of exposure in a primed endometrium. Secre- tion vacuoles are first noted below the nucleus, then are seen above as well as below the nucleus, and then tend to disappear in the subnuclear area. Luminal products of secretion can be recognized as early as the fourth dav after the initiation of therapy. After the eighth dav, the continued active secretion of the glands depends on both estrogen and progesterone influ- ences. If an excess of progesterone is given (as in the cyclic combined birth control pills), the luminal secretion products decrease and the glands become "secretorilv exhausted" after a short burst of secretory activitv with small amounts of opaque supranuclear cytoplasm and inactive shrunken nuclei. If large amounts of estrogen and progesterone are given together, as naturally occurs during earlv pregnancy, then secretion will be maintained actively for 30 to 50 days. The stromal cells on pro- gesterone administration show a further enlargement of the nuclei and particularly of the cytoplasm. At first the cvtoplasm is not well-defined by light microscopy, but ultrastructurallv there is much intercellular edema, which reaches a maximum approximately 6 days after the primed endo- metrium is exposed to progesterone. After this time, the cvtoplasmic swelling encroaches the intracellular stromal spaces and eventuallv, be- ginning about the spiral arterioles, the cells become closely packed with sharply identifiable cell borders. If progesterone is continued for a long time, as with exogenous administration or a second and third trimester pregnancy, the entire superficial half of the endometrium is converted to decidua. The stromal nuclei remain large and the cells lav down much reticulum, but foci of stromal necrosis still may develop. It seems probable that the decidual reaction is a one-time response and that repeated cycles involving the same group of cells are not possible. This appears to be related to the mitotic inhibitory effect of progesterone on the endometrial gland cells. This one-time response is less certain in stromal cells, for mitoses are seen through the earlv phases of secretion in the gland cells; thev take up tritiated thymidine wvell on into pregnancy, although mitoses are rarely recognized. Like estrogen, protesterone is unable to maintain an intact decidua without focal stromal breakdown at high levels. When a preponderance of progesterone is present over long periods, mitotic inhi- bition is such that the endometrium becomes very thin since stromal breakdown continues. After long continued exposure to progesterone, the stromal cells main- tain their decidual change, but the glandular cells become progressively 402(18) CRAIG American Journal of Pathology atrophic and diminished in number, without visible secretory activity and with small dark inactive nuclei. At the end of the normal endometrial cycle of 28 days, the endome- trium breaks Up, with disintegration of the stroma and the glands; marked polymorphonuclear infiltration and hemorrhage ensue. Gradually, mono- nuclear cells replace the polymorphonuclear cells, and the secretorily exhausted glandular cells are replaced by cells with vesicular nuclei and scant cytoplasm. From Day 5 to 14 the endometrial tissue response is dominated by the developing estrogen-secreting follicle of the , with a resulting intense proliferative response in both glands and stroma. In the glands, the nuclei enlarge and become vesicular; many mitoses are pres- ent. The gland cells elongate and become compressed from side to side and pseudostratified. The glands coil and elongate. The stromal nuclei enlarge and also develop mitoses. After ovulation on the 14th day, the luteinized granulosa cells of the ruptured corpus luteum secrete pro- gesterone, which becomes the dominant hormone. Thus, by the 16th day, the first secretion appears as basal vacuolation, although mitoses will continue in the glands for 2 more days. The first evidence of progesterone response in the stromal cells is seen by the 19th day, when increasing edema of the stroma is evident; this increases steadily until the 22nd day, when it is at a maximum. The glandular secretion becomes more promi- nent from the 16th to the 19th day first by subnuclear, then supranuclear, found in postmenopausal women anyway) so that they become enlarged exhaustion occurs at the 24th day. Decidualization of the stroma begins on the 23rd day, about the spiral arterioles at a mid level in the endometrium, and spreads to the surface by the 24th day; it continues to increase, but by the 25th day, the arrival of a mononuclear infiltrate heralds the onset of menstrual breakdown. Poly- morphonuclear cells appear on Day 26, and by Day 28 of the ideal cycle, disintegration of the endometrial layer is obvious. If pregnancy alters the endometrial cycle, it is first apparent by the 23rd or 24th day and is recognized by a marked increase in stromal edema and prolongation and intensity of the glandular secretion, which often be- comes inspissated within the gland lumen; by a delay of the decidual response; and by the absence of the usual inflammatory response begin- ning on Day 25. The most common physiologic disturbance which provokes endometrial abnormality is the failure of ovulation, whether this be in the menarchal girl, in mid-reproductive life, or, most commonly, in the menopausal woman. In each of these cases the result is the same. Because of a continued estrogen stimulus (which may be at a lower level than in the Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 403(19) February 1979 usual ovulatorv cvcle), the absence of ovulation, and, hence, any' pro- gesterone secretion, the endometrium remains in the proliferative phase (Figure 10). It will build up until it exceeds the capacity of the estrogen level to sustain it or until the estrogen level fails again; then stromal breakdown will occur with clinical vaginal bleeding of an irregular nature or of an increased frequencv. The same stimulus and response is seen in anovulatorv women given exogenous estrogen. Pure acute inflammation of the lining of the uterus is rarely recognized except in conjunction with the pregnant state (postabortal, intrapartum, or postpartum). is usually subacute in the nonpregnant state, with a predominance of mononuclear cells, scattered polvmorpho- nuclear cells, and plasma cells; the latter are limited to the more superfi- cial lavers of the endometrium. Such inflammation initiates a partial decidual response bv itself and causes local breakdown in the endome- trium with the accumulation of hemosiderin; the usual precisely timed cyclic changes are distorted bevond recognition. It seems probable that the endometrium, if not reinfected, is able to return to a normal state when usual cvcling occurs and that persistent chronic endometritis is usuallv accompanied by a chronic inflammation of the adnexae (tubes and ). In the normal postpartum and postabortal states, partially because of

Fgw l0-Endornetrium with anovulatory stromal breakdown. Masses of necrotic stroma and intact glands with a proiferatv pattem lie beneath a pale mildly atypical surface epthlWium. (x113) 404(20) CRAIG American Journal of Pathology the ovulatory delay that accompanies these, chronic inflammation con- sisting of lymphocytes and mononuclear cells may persist for as long as 6 weeks. These conditions mav be distinguished by the absence of plasma cells, which should be a component of other, presumably infectious, inflammatory states. Intrauterine contraceptive devices cause minor changes in the endome- trium when their residence is not complicated by a more generalized infection. In an uncomplicated state, they will cause a focal erosion of the superficial endometrial cells, a slight chronic inflammatory response (without plasma cells), and a partial focal decidual reaction immediately subjacent to the device. Only one benign tumor arises from the endometrium with any fre- quencv, ie, the ; these may be sessile, on a broad base, or have a well-demarcated stalk. The endometrial glands Iying in their substance do not undergo the usual menstrual cyclic changes (most are found in postmenopausal women anyway) so that they become enlarged and cystic and have irregular gland outlines. The stroma in the center of the polyp is more collagenous than normal, and there are usually one or more arterioles occupying the center. Endometrial polyps are milked downward by the contractions of the uterus, often into or through the endocervical canal, where the tip will become ulcerated and congested, giving rise to vaginal bleeding. Although long continued estrogen administration without the maturing influence of progesterone usually results in a more or less orderly cystic hyperplasia of the endometrium with nearly equivalent growth of glands and stroma in a small percentage of cases, especially after very long estrogen exposure (10 to 15 years) and particularly in older women, there develops a disorderly growth with a predominance of glandular elements. Such adenomatous hyperplasia can occur focally (as can adenocarcinoma) even in the presence of otherwise atrophic endometrium, but they are most often seen in conjunction with the more common cystic hyperplasia. Such adenomatous growths consists of proliferative glands with marked pseudostratification of the gland cells; mitoses may or may not be present, and the nuclei tend to be large with very vesicular dark chromatin patterns, and, less often, with atypias of size, shape, and staining qualities of the cytoplasm. The glands will often have irregular polypoid outlines and will be irregular and closely packed, with a decreased amount of stroma between them. Atypical hyperplasias have very large eosinophilic staining cells. Because of the focal nature of the origin of adenomatous hyperplasia, the result is a polypoid gross appearance to the endometrium. Experience has shown that there is a complete spectrum in the intensity Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 405(21) February 1979 and degree of atypia of adenomatous hyperplasias and adenocarcinoma of the endometrium. Because of the continuity of the changes from benign hyperplasia to early cancer, disagreement of histologic diagnosis even by ackno-ledged experts may vary in as many of :30%' of cases. In carcinoma of the endometrium, the glandular element forms fields of back-to-back glands wvithout intervening stroma; the gland cells usually are enlarged with large vesicular nuclei and prominent nucleoli (Figure 11). Mitoses usually are present but are often not common in the lower grades of tumor. In the more undifferentiated cases. the tumor cells form confluent sheets of cells wvith marked v-ariation in size and shape of both nucleus and cytoplasm and loss of glandular structure. In a fair proportion (25% ) of cases. there mav be a metaplasia of the glandular surface cells to a squamous form in varying degree (although rarely wvith complete kerati- nization). These tumors have been labeled "adenoacanthomas." but since such changes appear to have no discernible influence on the treatment choice or prognosis. the term could be abandoned: the grade of such a tumor with s(luamous metaplasia is best determined by the accompanying glanduilar structures. In rare instances, malignant mitotically active squamous and adenocarcinomatous elements may be intimately mixed: both elements are usually undifferentiated. These are labeled "adeno- squamous carcinomas." Occasionally. endometrial carcinomas take a pap-

*- _zw4*- _ w2 Figure 11-Adenocarcinoma of the endometrium, Grade I, with hyperplastic back-to-back glands having much pseudostratification of nuclei. (X113) 406(22) CRAIG American Journal of Pathology illary form (with psammoma bodies) or the cells have a clear empty cytoplasm containing much glycogen and fat, so-called clear cell carci- noma. The early spread of adenocarcinoma of the endometrium is by invasion of the underlying and the adjacent cervix. In the former area, the tumor enters the blood vessels and spread to the lungs may be an early event. In the latter case, lymphatic invasion occurs secondarily with spread to the regional lymph nodes. Extension along the tubal lumens to form implants on ovaries and peritoneum may also be an early event. Spread to the submucosa of the upper vagina either by venous or lym- phatic channels is a relatively common location of metastases or early recurrence. The grading of such tumors by the criteria of the International Federation of Gynecologists and Obstetricians (FIGO) is as follows: Grade I, differentiated tumors; Grade II, partially differentiated and partially undifferentiated tumors (Figure 12), and Grade III, predominantly undif- ferentiated tumors (Figure 13). The tumors are also staged into four groups (FIGO): Stage I, confined to the endometrium; Stage II, invasion of the myometrium or cervix; Stage III, confined to the uterus or true pelvis; and Stage IV, involvement of the mucosa of the bladder of rectum and/or spread beyond the true pelvis. Unlike squamous carcinoma of the cervix, the correlation of histologic grade and prognosis is close in adenocarcinoma of the endometrium. In

sk

Figure 12-Adenocarcinoma of the endometrium, Grade II. Some well-formed glands are intermixed with sheets of nongland forming proliferating tissue. (X113) Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 407(23) February 1979

Fge 13-Adenocarcinoma of the endometrium, Grade 1II, wfth sheets of nongland forming epitheial cells. (x537)

properly treated cases, Grade I has a better than 88% 5-vear survival, Grade II has a 5-year survival of approximately 60%; and Grade III has a 5-vear survival of approximately 30%. Stage is also important prognos- ticall. Stage I gives a better than 80% 5-year survival; Stage 11, 50%; Stage III, 30%; and Stage IV, less than 10%. In endometrial carcinoma, even in Stage 1, confined to the endometrium, a Grade III lesion carries a poor prognosis. Fortunatelv, most carcinomas are of the lower grades. Approximately 30% of disseminated adenocarcinomas of the endome- trium will respond therapeutically to large doses of progestational agents. These are chiefly among the lower histologic grades of tumor, but histol- ogy is not an effective guide to the identification of those which are hormonally dependent. Sarcomas of the endometrium can be divided into two major groups; both are disorders of wvomen past menopause. The first of these is a monocellular type, the endometrial stromal sarcoma, which, following its name, is made up of sheets of stromal cells without accompanying gland structures. The cells are larger than normal, with more variation in both nuclei and cytoplasm (Figure 14). They can be showrn to lay down a marked increase in reticulum in comparison to normal cells. As in adeno- carcinoma, spread is to the underlving mvometrium and blood vessel invasion is the usual method of distant spread. The second form of sarcoma, the mixed mesodermal sarcoma, may 408(24) CRAIG American Journal of Pathology

D' t S

Figure 14-Stromal sarcoma of the endometrium with sheets of large moderately atypical malignant stromal cells without any accompanying glands. (X447) contain malignant glandular and stromal elements with an appearance of derivatives of the normal elements of the endometrium or they may contain any of the elements which are found in tumors of the gen- itourinary ridge (embrvomas of kidney) such as striate muscle, cartilage, fibrous tissue, bone, undifferentiated fibrous tissue elements, primitive vascular tissue, and glandular cells (Figure 15). Such tumors usually form polypoid masses in the endometrial cavity, invade the myometrium, and spread to the lung by the blood vessels. Prognosis is poor in both forms: 5- year survivals of approximately 50% can be expected. Myometrium The body of the uterus, derived from the fusion of two miullerian ducts, may have abnormalities of form resulting from failures of the fusion process, so that in the extreme case two laterally placed single horned uteri, each with its own cervical canal, are possible. More usually, the external form of the uteruis is nearly normal, but the internal division of the organ is incompletely abolished; in the least affected case, a remnant of a septum remains at the fundal area, incompletely dividing the endo- metrial cavity into two halves, each with a . Such malforma- tions are of particular significance in cases of midtrimester abortions when the implantation site is on the septum and is incapable of supplying vascular support to the developing embrvo. Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 409(25) February 1979 Infections of the myometrium are alwavs secondarv to those of the endometrium or peritoneum and have no independent significance. The benign proliferative lesions associated with the myometrium are those of and leiomyomas. The first of these arises from a downgrowth of endometrial glands and stroma into the mvometrium, extending occasionally through two thirds of the wall but never appearing to penetrate it completely. These collections of organized endometrial elements may appear isolated from the surface, vet serial sections will show connections to the mucosal elements. If florid enough, such down- growths mav give rise to a thickening of the muscle wall and an increase in uterine weight. The endometrium has the same inactive noncvcling histo- logic characteristics as the basilar endometrium; as that tissue, however, it will respond to high prolonged progestational drug administration and convert to decidua. In senile states, the glands may undergo atrophy preferentiallv to the stroma so that small fields of endometrial stroma may remain in the depths of the myometrium. Rarely, these latter surviving stromal elements will secondarilv proliferate and form polvpoid masses within enlarged deep myometrial vascular spaces (endolvmphatic stromal myosis). These endometrial elements may combine with neoplastic smooth muscle elements to form a localized benign overgrowth, so-called ade-

04.

- Fgu 15-Mixed mesodermal sarcoma wfth lose sarcomatous stroma, a few pnmitive gland ele.mnts, and a portkon of cartilage (arrow). (X85) 410(26) CRAIG American Journal of Pathology nomyoma, which is set off from the remainder of the myometrium by a pseudocapsule and a distinct muscle pattern. Adenomyosis is often cited by gynecologists as a cause of and/or menorrhagia. The mechanisms of these relationships are not ap- parent, and many women have extensive adenomyosis without a complaint. The most common tumor of the uterus, ie, the leiomyoma or fibroid, is found with increasing fre(uency from the mid 20s onward to menopause; it occurs in any region of the uterus although is most common in the fundus and presents in the subserous, intramural, or submucous zones of the fundus as well as the cervix. In the first and last instance it may distort the outline of the uterus or its endometrial cavity. It is composed of smooth muscle cells and fibroblasts and displays great variation in growth rate. It is separated from the rest of the uterine muscle by a pseudocapsule and the distinct growth pattern which does not blend with the rest of the myometrium. The cells of the tumor respond in pregnancy, as do normal myometrial cells, by hypertrophy and thus may outgrow the blood supply, which causes infarction and acute degeneration (a cause of pain in preg- nancy). Focal ischemic necrosis occurs in nonpregnant women and gives rise to fibrous replacement, calcification, and cyst formation. Polyploidv among the smooth muscle cells undergoing degenerative changes has often been misinterpreted as malignant degeneration. Leiomyomata may cause abnormal vaginal bleeding if they are located immediately beneath the submucosa, because of inhibition of contraction of the endometrial spiral arteries at menstruation. When large, they impinge on and cause displacement of the uterine cavity and adjacent organs, ie, colon and bladder. Other connective tissue elements of the uterine wall can also give rise to tumors, but these are uncommon. Of the malignant tumors which arise in the muscular wall of the uterus, the is the most common and most characteristic, yet in comparison to the high prevalence of benign leiomyomas, it is decidedly uncommon; the ratio of benign to malignant tumors is on the order of 1: 800. The incidence of these malignant tumors may have no relation to the benign variety since more than one authority denies the origin of the leiomyosarcoma from a benign leiomyomata which has undergone malig- nant degeneration. As with other sarcomas, it is a tumor of premenopausal or postmenopausal women. It often causes a diffuse enlargement of the uterus, and the margins of the tumor are indistinct. The tumor is highly cellular with primitive embryonal smooth muscle cells making up the majority of the tumor. The presence of mitoses is a prerequisite for the diagnosis, but there is dispute as to the number of mitoses per 10 high- Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 411(27) February 1979 power fields necessary to establish the diagnosis. Imprecise as the criteria are, a value of 10 or more mitoses per 10 high-power fields is a useful number provided one has thin, well-fixed, and well-stained sections of tissue (Figure 16). The cell cytoplasm is scant and the tumor has an ill- defined microscopic border where it invades the surrounding mvome- trium. The degree of anaplasia is not marked, and one may be misled bv the presence of bizarre polymorphous hvperchromatic nuclei occupying enlarged degenerate muscle cells. Such cells are found in degenerate myomas, and the cells here are without mitoses. Leiomvosarcomas of the uterine wall invade adjacent structures directly and metastasize to the lungs via the bloodstream. The prognosis of for a 5-vear survival is between 40 and 50%, but those invading nearby structures at the time of operative removal will have a worse prognosis. Fallopian Tubes The origin of the fallopian tubes as a thickening of the mesothelial surface of the peritoneum, which sinks beneath the surface and acquires a lumen, and the later fusion of these tubal structures in the midline to form the bodv of the uterus, cervix, and upper vagina indicate the range of congenital malformation. These include hydatid cysts (a cvstic portion of tube isolated at the proximal portion of the tubal mass) (Figure 17),

a ,-ft - 7: -ft I Ar.-Illl-qbeqb-6. "I*-* 4L. AL-,f '%

44b. I % 4h~'

FWe 16-Leiomyosarcoma of th uterine wall. Mitose number more than 15 per 10 high-power fields. A normal endometrial gland (left) is surrounded by tumor invading the endometrium. (X286) 412(28)A A4P, %- CHAIG. American Journal of Pathology

.: ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~. :

nf

Figure 17-Tubal mesentery with a cystic Walthard rest (upper left), mesonephric duct remnants (center), and portion of a hydatid of Morgagni (right). (X33) atresia, absence of the tubal lumen, and accessory tubal ostia. Absence o)f the tube is accompanied by absence of the ovary on the same side, but neither the tube nor the ovary is usually affected by the absence of the ipsolateral kidney. Primary infection of the tube is the source of the most frequent patho logic condition giving rise to symptoms as well as functional problems. Infection in the tube or in the uterine wall is secondary to infection elsewhere and comes to the tube along lympathics from the cervix, via the endometrium through the tubal lumen, and across the peritoneum from other intra-abdominal infections, particularly from the appendix. The first two are the most common and follow postpartum and post- abortal infection of the endometrium and cervix or are secondary to goniococcal infection. In first infections with acute , the tubes are swollen, beefy red, and edematous; in acute gonococcal infections, there may be filmy adhesions binding the tube to the ovary or to the pelvic walls. Microscop- ically, there is diffuse inflammation of the walls with considerable fibrin on the surface. The tubal folia are greatly swollen with polymorphonuclear cells and plasma cells in their substance and a predominance of polymor- phonuclear cells in the lumen. Properly treated with effective antibiotics, the majority of acute gonococcal tubal infections will heal without se- quelae or impairment of fertility. If, however, because of the minor nature Vd. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 413(29) February 1979 of the svmptoms or if neglected, irreparable damage to the tubes will take place with adherence of one folia to another and the formation of dense adhesions about the tube. The epithelium of the tube proliferates in response to infections and forms many isolated gland elements. These tend to move away from the central lumen, so that the entire wall may be permeated by organized gland-like spaces. This results in a general thick- ening of the tubal wall which mav acquire a nodular appearance in the tubal isthmus (salpingitis isthmica nodosa). It is also probable that a similar lesion may arise congenitally with no evidence of a postinfective origin in the ampulla or fimbria. Constant reinfection of the endometrium from a chronically infected tube as well as spread to the ovary after ovulation to form a tubo-ovarian abscess are common clinical events. The end stage is a greatly dilated tube, enlarged at the fimbrial end but closed at both ends. The tubal epithelium is thinned and flattened, but beneath it small closed acinar spaces extend out into the muscularis (follicular salpingitis). Dense adhesions bind the tube to the ovary, broad ligament, and peritoneum. In acute and chronic salpingitis, cultures are often sterile unless strict anaerobic conditions or special care is taken with direct inoculation and incubation on gonococcal media. Because of blockage due to intemal adhesions, the passage of sperm, ova, and blastocysts is delayed or obstructed and is one of the common causes of sterility, particularly secondarv . Tuberculous salpingitis, once a not uncommon cause of sterilitv, is now a raritv in the United States. Except in cases of widelv disseminated tuberculosis of pulmonary origin, in which tubal involvement itself is not important, tuberculous salpingitis is more commonly seen in patients in infertility clinics, in patients in whom the tuberculous lesion in the chest is inactive, or as a secondary process to bovine or intestinal tuberculosis. Then the tube is irregularly enlarged and flask-shaped, with fewer adhe- sions but with irregularly spaced caseous nodules in the serosa or sub- mucosa. As with nonspecific salpingitis, a re-infection of the endometrium from the tube is common, and the diagnosis is often first suspected on identification of the typical tuberculous granuloma in endometrial curett- ings. A high proportion of tubal ectopic pregnancies are secondarv to the chronic destructive effects of infection on the fimbrial and mucosal tubal structures. The blastocvst, delaved in its passage through the tube, im- plants on the mucosa of the fimbria or ampulla, and the chorionic villi of the placenta grow into, erode, and cause enlargement of the tubal vessels. As the tube is distended by the growing blastocyst cavity and embryo, the wall is weakened and rupture with hemorrhage into the peritoneum takes 414(30) CRAIG American Journal of Pathology place. Hemorrhage within the tube also is common with passage of the blood distally from the fimbria to the peritoneal cavity. The endometrium undergoes the usual decidual changes, but because abortion of tubal pregnancy is the usual event, by the time hemorrhage or tubal rupture has occurred, the endometrium has already reverted to the nonpregnant state; therefore, an endometrial biopsy may not reflect the presence of a recently failed pregnancy in the tube. Adenocarcinoma of the fallopian tube, an uncommon tumor of mid life, arises focally from small groups of anaplastic cells; several carcinomas in situ have been reported. The growth is usually papillary and forms cauli- flower-like excrescences within the tube and perforation of the wall on the surface of the tube (Figure 18). These tumors secrete in many instances a watery mucoid material which may cause distension of the tube or a watery (hydrops tubae profluens). In some cases the diagnosis has been established by the appearance of cancer cells in the vaginal fluid. Microscopically, the tumor is most often fairly well-differen- tiated with well-formed papillary arrangements with pseudostratified epi- thelium overlying a thin connective tissue stalk; the tumor cells may not be distinguishable from serous papillary tumors which arise in the ovary or the pelvic peritoneum. Extension from the fimbria or invasion through the tubal wall involves the peritoneum. More rarely, metastases to lymph nodes via the round ligament to the inguinal nodes or via the ovarian vein

4 ,^< f g+w llhw * # X c

Figure 18-Papillary carcinoma of the tube. (X70) Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 415(31) February 1979 lymphatics to the para-aortic groups occur. Survival figures are not very good; approximately 40% of patients remain alive after 5 years; this is probably because of the easy access of tumor cells to the peritoneum at an early stage in the disease. Metastases of malignant tumors to the tubal lumen or serosa are much more common than are tumors of primary tubal origin. The ovary and endometrium are the source of the majority of such tumors. Ovary Congenital malformations of the ovary include absence of the ovary, "gonadal dvsgenesis" or streak ovaries, and combinations of ovarian and testicular tissue. Absence of the ovary is usually accompanied bv absence of the tube on that side. Gonadal dysgenesis is found in the patient carrving an abnormal genotype, with 45 chromosomes and an XO sex chromatin complement. Such ovaries mav. before birth or at birth, contain a few primordial follicles and ova, but these soon disappear, leaving onlv ovarian stroma. These ovaries are narrow and elongate, hence the name "'streak ovaries." The ovo-testis, a mixture of cortical ovarian tissue and medullarv testicular tissue with a capsule, are usually found in XX karvo- types although mosaics with XX and XY as well as XO components have been described. The ovarian portion of the organ has the usual elements of a normal ovarv with the normal formation of corpora lutea, although reproduction is not possible. The testicular portion of such an organ is more rudimentarv, with Sertoli cells and a few primordial cells in the tubules; although the interstitial cells mav be prominent, only a small percentage of tubules contain spermatozoa. As the ovary goes through the menstrual cycle patterns, with the gradual formation of follicles and their subsidence, either after ovulation and formation of a corpus luteum or without ovulation, aberrant cyst formation in these physiologic structures is not uncommon. These cysts are of several kinds, related to the time of origin: a) follicular cyst, which is cyst formation in an atretic follicle; b) corpus luteum cvst, most often found in the first trimester of pregnancv; unless rupture or twisting occurs, these will subside spontaneouslv; c) theca lutein cyst, in which the granulosa layer is usually lost or inconspicuous, but beneath a thin con- nective tissue layer are lutein cells in large numbers from the theca intema, which arise from excess prolonged stimulation with chorionic gonadotropin from normal pregnancv, hydatidiform moles, or exogenous administration of chorionic gonadotrophin; and d) endometriotic cyst, which arises from , ie, the presence of normally cycling endometrial tissue in areas outside the uterine cavity, which mav arise by 416(32) CRAIG American Journal of Pathology implantation of endometrial tissue from the uterine cavity, by retrograde passage up the fallopian tubes at menstruation, by iatrogenic implanta- tion of surgery, or by metaplasia of peritoneal pelvic epithelium. It is most common in or on the ovaries, the tubes, or the pelvic peritoneum. The umbilicus, vagina, cervix, intestine, and lung have all been reported to be affected. In the depths of the ovary, where the blood and desquamating elements cannot escape, an organizing blood-filled cavity is formed with much hemosiderin and varying remnants of endometrial tissue with both stroma and glands in the wall. The endometrial tissue responds to both estrogen and progesterone normally so that in pregnancy, decidua re- places it and some degree of regression of the endometrial tissue takes place, as it does in the uterus during gestation. Other than the formation of cysts, endometriosis, as a result of the organization of shed blood at menstruation, causes the formation of adhesions of the ovary to the tube or uterus or of the posterior aspect of the uterus to the colon or posterior surface of the cul-de-sac. In the bowel, growth of endometriosis into the muscle layer from the serosa may cause an obstructive narrowing of the bowel lumen. Some physicians, concerned with the relief of sterility, believe that pelvic endometriosis is a cause of that disorder, but no rational etiology has related the two. A significant percentage of normally fertile women with no pelvic symptoms related to endometriosis are found to have endometriosis of some degree on total hysterectomy and oophorectomy for nonrelated complaints. Infection of the ovary is overwhelmingly secondary to infection in the tubes or the appendix. In the majority of cases, this is a peri- with chronic inflammatory cells, lymphocytes, and mononuclear and plasma cells mixed with fibrin on the surface and in the immediate subsurface cortical layers. In the more acute cases, a recently ruptured follicle (a good culture media) or, less often, a cystic atretic follicle will become infected to form an ovarian abscess. Then the inflammation will be more acute, with mixtures of polymorphonuclear and chronic inflam- matory cells in the wall of the abscess and diffusely through the ovarian stroma. Early rupture of an ovarian abscess can lead to a catastrophic generalized peritonitis. In the chronic state, dense adhesions form about the ovary and tubal structures. The classification of tumors of the ovary, as set by the World Health Organization has almost reached consensus. This is the classification used here (but simplified). Numerically, the largest general group of tumors of the ovary are those that arise from the "germinal" epithelium (specialized mesothelium cov- ering the ovary), and the most frequent members of this large group Vol. 94, No.2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 417(33) February 1979 (approximately 25% of all ovarian tumors) are those with the primarv epithelial element, a columnar but not mucus-secreting cell; such serous tumors originate from the proliferation of the surface mesothelium (to form surface papillae) or from invaginations of the surface epithelium, which occurs in the course of the continued reconstruction of the ovarv during reproductive life. In the simplest form, this epithelium in the cortex forms small inactive isolated gland elements Iying in the cortical stroma. These glands may proliferate in a controlled fashion, with induc- tion of a stromal proliferation to form an adenofibroma. With fluid accu- mulation, small cystic structures may thus form a cystadenofibroma. When the epithelial growth rate increases at a rate greater than the stromal response, papillae begin to form a papillary serous cvst- adenofibroma (Figure 19). From this point in complexity, growth rates, and dedifferentiation, there is a continuous spectrum to highlv undiffer- entiated malignant tumors of the ovary, with ultimate broad sheets of undifferentiated cells without polarity and perhaps onlv occasional gland or papillary formation and which have marked pseudostratification of the nuclei. Histologic grading of serous tumors is as follows: benign, border- line malignant (Figure 20) (with moderate papillarv proliferation, pseudo- stratification, little atypia, and no stromal invasion), and malignant (with marked pseudostratification, atvpia, and stromal invasion) (Figure 21). In the malignant group, three grades are present according to the degree of

Fgw 19-Papillary serous cystadenofibroma of the ovary. (x70) 418(34)A 4 951M A IL CRAIG- . .- American Journal of Pathology

Figure 20-Papillary serous of the ovary of borderline malignancy. (x1 13) dedifferentiation. The staging of ovarian carcinoma is the same for all histologic varieties: Stage Ia is limited to one ovary; Stage Tb, involvement of both ovaries; Stage Ic, presence of malignant ascites; Stage Ila, exten- sion to the uterus and tubes; Stage Ilb, extension to other pelvic tissues; Stage ITI, widespread abnormal metastases; and Stage IV, metastases outside the peritoneal cavity. Survival is correlated with stage, grade, and histologic type, with sur- vival of over 90% of patients with serous borderline tumors to less than 20% of patients with Grade III and similar survivals for all Stage I patients but less than 5% for patients with Stage IV disease. Spread, as indicated by the staging, is first to the opposite ovary and peritoneum, but in Grade III tumors spread to the aortic lymph nodes is a frequent early event. Eventually, papillary serous tumors coat the peritoneal surfaces, including the intestines, liver, and omentum. Mucinous epithelial tumors also arise from the germinal epithelium; metaplasia of this epithelium to serous, mucinous, endometrial, or a nonkeratinizing squamous (Walthard rests, Brenner tumor, urethelial) epithelium can be seen occasionally in the same ovary. Mucinous tumors of the ovary also have benign and borderline varieties. The mucinous cysts are lined by a closely packed, tall, columnar epithelium with a large supranuclear mucus-containing vacuole. Because of the nature of the secretion, large multiloculated cysts are common, and these tumors form Vol. 94, No.2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 419(35) February 1979 some of the largest of those arising in the ovary. Their metastatic spread is similar to the serous tumors; survivals at 5 years for all grades and stages are twice those of serous tumors. Their incidence is approximately one third that of the serous varieties (Figure 22). The third epithelial tumor of the ovary is the , whose benign counterpart we have discussed in the section on endometri- osis of the ovary. These tumors do not alwavs have the pronounced cystic structure of the first two members of the group, although they may contain small and inconspicuous cysts. Microscopically, the tumor closelv resembles carcinoma of the endometrium with small sheets of closely packed back-to-back glandular structures without intervening stroma. Often the cells will have a clear cytoplasm and a centrally placed nucleus (Figure 23). Mixtures of endometrial and papillary serous tumors are common (30% of all endometrioid tumors). In many of them, benign endometriosis can be recognized in the same ovary. The prognosis in Stage I and Stage II, even of the lower histologicallv graded tumors, is worse (approximately 50% 5-year survival for all grades and stages) than for those of serous and mucinous carcinomas, probably because of the high incidence of surface involvement of the ovarv in this type of tumor. Not infrequently, histologically similar tumors are found in the ovary and the uterine cavitv, and the point of origin (ovarv or uterus?) mav not be

t _% 4 I.b -

Fe 21-Papillary srous cystadenocarcinoma of ovary, Grade I, with clear-cut stromal invashn, aMough cystologically the cells are not pleomorphic. (X113) 420(36) CRAIG American Journal of Pathology

~~~~~~~~~~~~~~~~~~~At A i .: 22Munuj. Fiur cytdn.acnm of ovary, Gr ...... sad...... I. &(X';14i ..)

Figure 22-Mucinous cystadenocarcinoma of ovary, Grade 11. (X143) determined. A variant of the endometrioid carcinoma of the ovary is clear cell carcinoma, in which the ballooned cell bodies are free of cytoplasmic staining but contain large amounts of glycogen or fat; the cells are arranged in sheets or small clumps, and their nuclei are often hyper- chromatic and placed at the luminal border of the cell (peg cell). Their prognosis is less satisfactory than for the endometrioid tumors, with approximately 40% 5-year survivals. The last important tumor derived from the coelomic epithelium is the Brenner tumor. It is composed of widely infiltrating clumps of non- keratinizing transitional squamous (uro-epithelium) epithelium, the cells of which have a specific nuclear characteristic, ie, a linear fold or groove in the nuclear membrane, penetrating deeply into the nuclear envelope (Figure 24). These cells are identical to the constituent cells frequently found clumped on the serosal surface of the fallopian tube (Walthard rests). Such epithelial penetrations into the ovarian stroma elicit a marked stromal reaction, so that the bulk of the tumor consists of stroma. In approximately 25% of such tumors, a mucus-producing glandular element accompanies or is metaplastic from the specific cell. These tumors are overwhelmingly found incidently in ovaries removed for other causes before a clinically detectable tumor is noted. They are usually slow growing, and malignant variants are uncommon. The excessive stromal response induced by the tumor may result in increased estrogen produc- tion in the postmenopausal ovary. Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 421(37) February 1979 The tumors derived from the sex cords and/or stromal elements of the ovary (or other testicular counterparts, Sertoli and Leydig cells) provide a high proportion of the functional (steroid-secreting) tumors of the ovarv but only a minoritv of the malignant tumors. Tumors of the ovarian stroma are the most common of this group and include fibromas and . The former is a neoplastic proliferation of stromal elements which produce abundant reticulum and collagen. Thev are rounded, solid in cross section, and opaquely white. Thecomas by contrast are softer and can be bright vellow on cross section. They show the rounded cvtoplasmic outlines of the cells arranged in small clumps with an eosinophilic cytoplasm and positive staining for fat and steroid elements, which are characteristic of luteinization and steroid production. The latter tumors are much less common than the fibromas; the presence of minute fat droplets in the fibrous cells of a fibroma is not sufficient evidence to establish a diagnosis of . Thecomas may cause pre- cocious pubertv, abnormal menstruation, or postmenopausal due to their estrogen-secreting ability (or the precursors of estogen). Malignancv among fibromas and thecomas is uncommon, al- though fibromas mav cause abdominal ascites (Meig's syndrome); the mechanisms for this are unclear. Granulosa cell tumors which originate in the cells derived from the "germinal" epithelium and sex cord are seen in the premenarchal girl and in active reproductive life. They present as bosselated masses with cysts of

Fiure 23-Endometrioid (cear cell) carcinoma of the ovary. (X143) 422(38) CRAIG American Journal of Pathology

$~~~~~~~~~~~4

.x.u...X ..i ;...-.v.S~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.

Figure 24-Brenner tumor of the ovary with nests of uroepithelial squamoid cells and mucus-secreting glands (far right). Inset-The typical linear crease in the uroepi- thelial cells. (x 13; inset, X854) varying size. The constituent cells are identical to those seen in the unluteinized granulosa layer of the developing follicle with sharply stain- ing rounded cell borders, scant faintly staining cytoplasm, and a centrally placed nucleus with little pleomorphism. The cells are arranged in sheets punctuated with occasional small spaces containing an eosinophilic mass, the so-called Call-Exner bodies, which are also found in normal follicular structures. The tumor cells less commonly are arranged with an approach to primitive gland formation (folliculoid) as ribbons of parallel elongate cells (cylindroid) or as sheets of cells with slightly greater nuclear varia- tion, less well-defined cytoplasmic boundaries, and less closely packed cells (sarcomatoid pattern). Granulosa cell tumors, as they penetrate the normal ovarian stroma, may elicit luteinization in these latter cells. In children, the proportions of granulosa and theca cells may be nearly equal in such tumors, although the existence of granulosa-thecal cell tumors is denied by a number of authorities. The estrogen production of the gran- ulosa cell tumor presumably comes from the luteinized stroma cells, since many pure granulosa cell tumors show no evidence of estrogen produc- tion. As estrogen producers, they may give rise to precocious puberty, , and endometrial hyperplasia. The malignant poten- tial of such tumors is subject to wide variation from series to series, with from 60% to over 90% 5-year survivals. It seems most probable that the Vol. 94, No. 2 PATHOLOGY- .- .- %1- OF#% FEMALE9- f A. I- REPRDUCTIr%-r%M' IN'9 IVES -v 'P%A0'RACl 423(39)l-'lEIf # s'k February 1979 latter figure is correct and that many poorly differentiated tumors have been mislabeled as malignant granulosa tumors to account for the lower reported survivals. Bilaterality is not uncommon, and probably some of these have been labeled "recurrences" when arising after the original tumor identification. The tumors have a propensity for late recurrence after 10 vears or more from the original diagnosis. The authors who deny the existence of granulosa-theca cell tumors would not use this designa- tion and would classify them as Sertoli-Leydig cell tumors. The third member of the group, and much less frequent, are the Sertoli- Leydig cell tumors, which were previously called tubular adenomas or arrhenoblastomas, for the benign and malignant variants. Grosslv, these may have varving amounts of both solid and cystic elements. As the name implies, these tumors contain tubular elements lined by sustentacular cells of sex cord origin. They may show varying degrees of maturity among the cells of the t-ubules. The specific stromal elements (Leydig cells) have the abundant poorly demarcated cytoplasm and the large nuclei of the inter- stitial cell of the testis; they may also have Reinke crystalloids in the cytoplasm, a specific identifying feature of the Leydig cell (Figure 25). The cells of the better differentiated tubules can be shown to contain much fat; the more poorly differentiated tubular elements have little cytoplasm and no definite basement membrane. The more poorly differ-

4.~~~~~~~~t

40

w2' '' ss* 4se~~~~~~~~~fw i*' s s

Fge 25-Sertoli-Leydig cell tumor of the ovary, with primitive ducts surrounded by Leydig cells, which have increased lipid in the stroma on the left (X368) 424(40) CRAIG American Journal of Pathology entiated stromal elements take on a sarcomatoid pattern. The prognosis of this group of tumors is about the same as for granulosa cell tumors, but the malignant forms can be identified occasionally with greater precision; recurrence in the pelvis and abdomen is common. The fourth member of the group and most rare is the gynandroblas- toma, in which both primitive male and female sex cord elements are present, ie, granulosa as well as tubular. The fifth member of the group displays a spectrum of appearances from a hyperplastic reaction to tumor formation: the of pregnancy. This tumor is seen primarily in obese black women toward the end of pregnancy and in the puerperium. It consists of the excessive abnormal proliferation of theca interna cells; in the less florid cases in which there is only mild enlargement of the ovary, it can be seen to have proliferated and luteinized theca interna cells about each atretic and cystic atretic follicle. These, in the luteoma, proliferate to such an extent that they obscure their point of origin so that numerous solid masses of luteinized cells make up the tumor. It has an obvious multicentric origin. These tumors may secrete androgens predominantly, causing mild masculiniza- tion and . They will subside after pregnancy given sufficient time and should not be regarded as true tumors but as reaction to gonadotrophins from the placenta. Two allied forms of ovarian enlarge- ment can be seen in a) the ovarian hyperstimulation syndrome after administration of follicle-stimulating hormone and chorionic gonadotro- phin for nonovulation in infertility (here there is marked edema and many large cysts lined by granulosa cells are formed) and b) lutein cysts in the presence of aggressive hydatidiform moles and choriocarcinoma with very high gonadotrophin levels (the cysts are made up of cystic atretic follicles and, although with some luteinization of the theca, this is not as florid as in the luteoma of pregnancy). In the last member of this group, lipid cell tumor, the cells have the appearance of steroid-secreting elements with abundant floccular cyto- plasm without clearly defined cell borders and large round nuclei with vesicular chromatin. The origin of these tumors cannot be established but may be from Leydig cells, adrenal rests, or hilar cells. Two allied tumors, the hilar cell tumors and adrenal rest tumors, may invade and replace the ovary proper, although they do not arise there. The former, which have abundant irregular poorly defined eosinophilic cytoplasm and a large vesicular nucleus, arise from similar cells lying among the nerves and vessels of the ovarian hilus; they may contain Reinke crystalloids. They are androgen secretors and can be found chiefly among postmenopausal women, in whom hilar cell hyperplasia is more Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 425(41) February 1979 common. The adrenal rest tumor arises from nodules of adrenal cortical tissue Iying in the mesovarium. These rests, unlike the hilar cells, are well- encapsulated and have an organized vascular supply which is identical to that of the adrenal gland itself. The tumor cells approach the same appearance as the adrenal gland. Both androgen- and estrogen-secretory activity have been found in these tumors. Both are considered benign tumors. The next large group of tumors are those arising from germ cells and their derivatives. The most common neoplastic tumor of the ovary is the benign cvstic . Such tumors are found in children and through- out reproductive life. Thev contain large cvstic spaces filled with desqua- mated squamous cells and sebaceous debris. The cysts are lined by skin and contain adnexal structures, hair follicles, sebaceous glands, and sweat glands in the wall. In addition, benign possess a great variety of other tissues, most frequentlv respiratorv epithelium, bronchial glands, cartilage, smooth muscle, glial tissue, and bone. Less frequently, choroid plexus, tooth structures, thyroid tissue, striate muscle, and pigmented choroid tissue from the coverings of the eye are found in benign tera- tomas. Benign cystic teratomas of the ovary have a 46 XX karvotype. Because of their cellular isoenzyme patterns, they are considered homo- zvgotes and result from spontaneous proliferation of a haploid zvgote after the first meiotic division. Bilateralitv of benign teratomas occurs in as many as 15% of cases. Two special forms of benign teratomas are of interest because of their clinical effects. In each of these forms, there is often overgrowth of a single tissue so that onlv a small portion of the resulting tumor mass shows the usual admixture of mature teratomatous elements. The first of these, struma ovarui, is composed of benign thvroid tissue which in rare cases mav respond to thyroid-stimulating homone in the presence or absence of a normallv placed thyroid. The second form is the carcinoid tumor which can arise from the argentaffin cells of the intestinal or bronchial gland elements of the teratoma. The latter tumor can produce the carcinoid syndrome without metastases since, unlike similar tumors of the gastroin- testinal canal, their secretion does not pass through the portal circulation to be detoxified in the liver. Rarely in older women there may be a malignant degeneration of once benign epithelial or connective tissue in a benign cvstic teratoma. The most frequent of such transformations is seen in the squamous epithelial elements. Because of their tendency to spread to adjacent organs before producing clinical symptoms, these invasive squamous carcinomas have a poor prognosis. Two other elements of benign cystic teratomas which 426(42) CRAIG American Journal of Pathology were previously noted to form "one-sided teratomas" also are capable of forming malignant tumors with metastases; these are thyroid and carci- noid tumors of the ovary. Other malignant degenerations in otherwise benign teratomas have been seen: melanomas, basal cell carcinomas, intestinal adenocarcinomas, and chondrosarcomas. In contrast to the benign course of cystic teratomas, solid teratomas have a less happy outcome. These tumors may be quite large and are invariably slightly irregular in outline. On cross section they have a variegated appearance with highly cellular translucent embryonal tissue as well as more mature areas and even small s(uamous-lined cysts. Micro- scopicallv, large areas of such tumors consist of primitive neuroepithelial and glial tissue with frequent primitive neurorosettes containing mitoses. Other primitive stromal elements, eg, bone cartilage and undifferentiated mesenchvme, as well as immature embryonic glandular tissues of bron- chial origin, and smooth muscle are seen (Figure 26). These tumors rapidly invade the ovarian capsule and become adherent to other pelvic organs. Spread throughout the pelvis and abdominal cavity is common. A few solid teratomas of predominantly mature glial tissue exist; these have a better prognosis and, even with spread of proliferating glial tissue to the peritoneum, the patients may survive for many years. In general, how- ever, fewer than 50% of patients with immature solid teratomas will have a 5-year survival. Three other malignant tumors of the ovary which arise from primitive germ cells and form derivatives of the early blastocyst elements are , nongestational choriocarcinoma, and endodermal sinus tumor. The first approximates in form the inner cell mass of the blastocyst, with large polygonal cells forming small sheets of cells and lining irregular small spaces but with little polarity to the cell. These cells have large round nuclei and prominent chromatin patterns. They spread rapidly to regional aortic lymph nodes and peritoneum. Survivals for a 5-year period are virtually unknown. The second member of the group can only be diagnosed with certainty in the prepubertal girl, since in active reproductive life, the identical histology can be found in the tumor derived from an abnormal pregnancy. Like gestational , these tumors may be hemorrhagic and consist of cytotrophoblast and syncytial trophoblast cells which are found in the coverings of the blastocyst and chorionic villi. Because of their tend- ency to invade and line blood vessels, spread to the lung is early and com- mon. These two tumors produce the hormone chorionic gonadotrophin, and their growth and treatment regression can be monitored by radio- immunoassay of the hormone in the blood and urine. Although the true nongestational choriocarcinomas arising in the ovary resemble their gesta- Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 427(43) February 1979

- .W a v I .ul * .: ob '%r V. -10 11 0 .10 0."I-'..%. 4m 4lb- 40 . 0 0 .o It "I"J"Modo- 09, -

" Tw .- 'N .- CT4111911 ;i:ll--.1 "gr a V- 04% 6 jr.. 110, Ai"P 4w .?. -L 4. 46 100' ."r 0-...

Fiues 26A and B-Solid teratoma of the ovary with neurorosettes and primitive glial and epithelial elements. (x143) tional counterparts, they are less susceptible to control with chemothera- peutic agents. The third of these primitive embryonic tumors (endodermal sinus tu- mor) resembles in its arrangements the y-olk sac elements on the rat 428(44) CRAIG American Journal of Pathology placenta, the sinuses of Duhval, with mound-like epithelial cells lying on a well-defined basement membrane and lining a small space with a blood vessel in the center (glomeruloid bodies). Such tumors, as do their normal counterparts (yolk sac), secrete a-fetoprotein (also produced by the em- bryonic liver and gut), which can be detected in the patients' blood. All of these tumors are very uncommon and highly malignant with early spread; survivals are infrequent. The last group of germ cell tumors are those which are made up of germ cells themselves. The first of these is the which is an analogue of the seminoma in the male. While the latter grows at first within the lumens of the testicular tubules, the latter grows diffusely in the ovarian cortex. The dysgerminoma is composed of large round cells with very large nuclei which have a very prominent chromatin pattern; the cytoplasm has no polarity or relation to a basement membrane. The cells are arranged in sheets which are punctuated by other sheet-like collections of another distinct class of tumor cells which are much smaller with scant cytoplasm; these have the cytologic characteristics of lympho- cytes. These tumors, like the seminomas, metastasize early to the renal para-aortic lymph nodes via the ovarian vein lymphatics. The tumors may spread to the opposite ovary. They are radiosensitive. They occur pre- dominantly in the second and third decades, so that if the original tumor is small and no pelvic spread has occurred, radiotherapy of the hemipelvis, including the para-aortic nodes, with shielding of the uninvolved ovary, may be curative, with preservation of the child-bearing functions. With proper treatment, survival rates are high and recurrences are early if at all. There is an uncommon dysontogenic tumor that is seen most often in masculinized phenotypic females and less commonly in nonmasculinized phenotypic females; a similar tumor is found in hermaphroditic males. This tumor, a gonadoblastoma, is composed of poorly formed tubules lined by primitive Sertoli cells interspersed with primitive germ cells. Also within the tubules are collections of cells having the arrangements and the Call-Exner bodies found in granulosa cells. Outside the tubules there are cells with cytoplasmic features of Leydig or lutein cells. These tumors are usually medium-sized, up to 7.0 cm in diameter. In approximately one half of cases, in both males and females, the gonadoblastoma elements are infiltrated and overgrown by dysgerminoma (?seminoma) elements. Curi- ously, these primitive malignant elements do not worsen the prognosis of these tumors, which is excellent. The karyotypes associated with gonado- blastoma are 46 XY; mosaics which include XO/XY are the second most common karyotype. The majority of such tumors are quite small and are Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 429(45) February 1979 discovered during investigation of abnormal sexual status or of amenor- rhea. The ovary may be involved bv malignant metastatic tumors which cause significant enlargement of the ovary so that an may be the presenting abnormality of the primary tumor. Those tumors which metastasize from the gastrointestinal tract (stomach and large bowel) form smooth rounded masses, usually bilateral, replacing much of the ovarian tissue. Those, particularly of the stomach, are made up of diffuselv scat- tered single signet ring cells, with mucin-positive vacuoles (). The breast is the source of the primary in another large com- ponent of the metastatic tumors of the ovary; its localization mav be in part a result of increased estrogen or its precursors in the ovarian stroma. Converselv, both Krukenberg and breast tumors metastatic to the ovary may stimulate luteinization of the stroma cells, wvith resulting hyper- estrogenism. Other noteworthy primaries for ovarian metatases include endometrium, lvmphoma, and leukemia. In children, the latter may form the most common form of metastatic tumor of the ovary. The Pathoog of PreVancy The most common abnormality associated with pregnancy is spontane- ous death and expulsion of the products of conception before term. This event has been estimated to occur in nearly 40% of conceptions in humans, the great majority in the first trimester and nearlv 25% before the first missed period. Among these early pregnancy losses, demonstrable chromosomal abnormalities are present in 60%; predominantlv they are trisomies, deletions, triploids, and tetraploid changes in the chromo- somal structures. Only rarelv are chromosomal abnormalties in the first trimester specifically identifiable anatomically. These changes include hypoplasia of the chorionic villi with some of the trisomies, a generalized swelling (hvdatid change) of the chorionic villi with triploids and tetra- ploids, and a combination of a stunted embryo and well-developed villi with the X monosomv. Among the trisomies, the presence of trophoblast cells in clumps within the substance of the villi is said to be specific for E trisomv (other than E 16) and for C and D trisomvs (other than D 13). In the early studies of first trimester abortions, Mall, long before the recognition of chromosomal abnormalities, classified abortions by their gross anatomic features; this classification is still used in some laboratories. When the conceptus is completely submitted, if onlv villi remain, it is designated as a "Pathological Ovum, Group I"; all other classes for proper designation require an intact ovisac. With Class II onlv chorion and villi are present; Class III, villi, chorion, and amnion; Class IV, villi, chorion, 430(46) CRAIG American Journal of Pathology amnion, and umbilical cord; Class V, as with Class IV, but with a nodular embryo at the end of the umbilical stalk; Class VI, as with Class IV, but with a cylindric embryo; Class VII, a malformed embryo but with recog- nizable features; and Class VIII, a normally formed but macerated em- bryo within the amnion. In addition to the above changes, there are nonspecific alterations in the products of conception and decidua that are common to all instances of fetal death. The embryo rapidly becomes macerated (autolyzed) but, because the placental villi are usually continuously perfused with mater- nal blood in the intervillous space, they survive. The villous fetal circula- tion ceases and within hours of fetal death, the endothelial cells and fetal red blood cells undergo cytolysis and, within a day, the villous vessels disappear completely, so that these changes are evidence of fetal death although the embryo has not been identified. Soon after fetal death, because the circulation has stopped within the villous and fluid imbibed by pinocytosis of the syncytiotrophoblast cells is not carried away, the villi become swollen and hydropic, although they do not reach the proportions or size of a hydatidiform mole. Later, the villi lose fluid, become hyali- nized, eventually lose their trophoblast coverings through necrobiosis, and become "ghost villi." Intervillous thrombosis, amnion nodosum, and large subchorionic hematomas are found in the abortions remaining for a number of weeks in the uterus after fetal death (missed abortion). Changes in the decidua accompany abortion but are nonspecific. These include necrosis, acute and chronic inflammation, infarction, and hemor- rhage. All these changes may be found in normal pregnancy in a minor degree. Beyond the first trimester, changes in the placenta after fetal death are less dramatic, but loss of fetal villous vessels, shrinkage of the villi, and intervillous fibrin deposition are common. With long-standing intra- uterine death, one may find amnion nodosum, which is a deposition of desquamated amnion cells of fetal squames on the fetal surface of the placenta accompanied by erosion of the normal fetal surface and reaction on the part of the chorionic connective tissue. Collapse of the major chorionic vessels and disappearance of the fetal capillaries are well-recog- nized evidence of fetal death throughout pregnancy. Malformations of the Placenta Malformations of the placenta aside from those due to vagaries of positioning within the uterus are rare. The former include eccentricities of umbilical cord and implantation at the placental edge (marginal in- Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 431(47) February 1979 sertion), on the membranes (membranous insertion), or on the mem- branes overlving the cervical os (vasa praevia). Within the uterus the placenta mav implant on the cervix; in the lower segment, with a resulting placenta praevia which blocks the passage for the expulsion of the con- ceptus; or in the interstitial portion of the tube (an interstitial pregnancy), causing an increased susceptibility for abortion or rupture of the uterus. Two minor alterations of the placental form associated with an in- creased frequency of marginal hemorrhage and premature separation of the placenta are found in so-called circummarginate and circumvallate . Here the chorionic plate is restricted in diameter, and the peripheral cotyledons grow outward from the chorionic plate to lie be- neath the surface of the decidua (placenta extrachorialis) instead of the chorionic plate extending to the lateral boundary of the placenta. The circumvallate placenta has an easily discernible double membranous fold at the chorionic boundarv; that of the circummarginate placenta is less marked, but in each case decidua can be recognized beneath the periph- eral membranes within the lateral boundary of the placenta. Usuallv the chorion frondosum of the implanting blastocyst is restricted to one side of the uterus or even a fairlv small area of the uterine wall. Occasionallv, villi will form and imbed on both anterior and posterior endometrial surfaces. The result will be a placenta with a great chorionic plate but which is much thinner than usual (placenta membranacea). When reconstructed it can be seen to have villous structures on the external surface of two opposite faces of the chorionic sac. More often perhaps only a small portion of the placenta attaches to the opposing endometrial surface away from the main placental mass, forming a de- tached or succenturiate lobe. If the placental villi attach directly to the uterine muscle with no intervening decidua, the placenta will separate from the uterus onlv with great difficultv. Brisk bleeding will occur post partum, requiring hysterec- tomv. This condition is due to the abnormal thinness of the decidua as a result of vigorous curettage at a previous postpartum or postabortal bleed, implantation on a scar from cesarean section or myomectomv, or in- adequate regeneration of the endometrium in multiparas with a short interval between subsequent pregnancies. Actual invasion of the villi into (increta) or through (percreta) the myometrium is much less common. Too vigorous manipulation of the uterus in attempting to deliver the placenta mav cause uterine inversion. Retention of placental fragments is a cause of postpartum or postabortal bleeding. Inflammation of the decid- ua and myometrium in the region of the placental implantation may 432(48) CRAIG American Journal of Pathology cause lysis or inhibition of formation of intravascular clots in large myo- metrial sinusoids and cause late postpartum bleeding (subinvolution of the placental site). Circulatory Disorders of the'Placenta Because the placenta has a high reserve capacity, infarction of the placenta mav be extensive (up to one third of placental volume) without recognizable untoward result to the fetus. Infarction of the placenta is believed to be related to thrombosis of the spiral arteries of the decidua; the infarction almost uniformly is distributed with its base on the floor of the intervillous space with extensions to the chorionic plate. Here the villi undergo rapid necrosis and shrinkage with only a transient inflammatory reaction. Small infarcts at the margin of the placenta are common and usually of no clinical significance. Major placental infarction is found in mothers with advanced renal disease and in patients with eclampsia. Placental infarction is to be distinguished from intervillous thromboses, in which masses of thrombus are laid down between villi which are often pushed aside by the thrombus. These less often compromise placental function. A third disturbance to placental exchange is found with the deposition of fibrin about a small number of villi; here the fetal villous circulation continues as it does with thrombosis, but maternal perfusion is com- promised. Such lesions often accompany placental infarction. In "toxic" or premature separation of the placenta (abruption pla- centa), intervillous perfusion will also fail because of the destruction of the continuity between the maternal vessels and the intervillous space. A large amount of blood gathers as a clot behind the separated placenta or leaks from the cervix if the separation is marginal and near the cervical os. Aside from a statistical correlation with maternal cigarette smoking and eclampsia, the etiology of premature separation is not known. At times, premature separation is associated with a decreased fibrinogen level and coagulability of the blood; the uterus may contain many hemorrhages and be hard and tender (uterine apoplexy, Couvelaire uterus). Rarely the placenta may have the equivalent of an arteriovenous fistula in the fetal circulation because of the presence of a (chorangioma) or a generalized increase and dilatation of a large propor- tion of the villous vessels (chorangiosis); either condition may give rise to fetal heart failure and fetal hydrops. One other circulatory disturbance of importance arises in monozygotic twins, in which there are anastomoses between the circulations of the fetuses with vein-to-vein, artery-to-artery, or artery-to-vein connections. Vd. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 433(49) February 1979 The latter is the most important because most of the blood may pass to one twin, causing plethora in the recipient and anemia in the donor twin. When an artery-to-artery anatosmosis occurs, the heart of one twin may become dominant, with the failure of development of the other twin's heart and marked malformation of the acardiac twin, especially of the upper parts of the body. Infections of the Pacenta Placental infections are numerically overwhelmingly bacterial, and the route of transmission is almost always via the transcervical route from the vagina, occasionally across grossly intact but compromised membranes but much more frequently after rupture of the membranes as a result of premature dilatation of the cervix or labor. The amniotic sac (except in systemic infections of the mother) is usually involved first; the amniotic fluid forms a fine bacterial culture media. The membranes become sec- ondarily involved bv contiguity, with subsequent spread to the chorion, the chorionic vessels, the umbilical cord and vessels, and, finallv, the maternal vascular space. Such reactions elicit an acute response in the cord and membranes with many polvmorphonuclear cells and, rarely, mono- nuclear or plasma cells. In severe infections, bacterial necrosis of mem- branes with massive bacterial growth on the membrane surface can be expected. In such severe infections, when the maternal blood sinuses are involved, small purulent fibrin thrombi are formed in the sinuses and a lvmphocvtic infiltration occurs in the villous connective tissue cores. The rarity of the chronicity in the placental tissue reactions results from the lack of chronicitv in the infections, since labor soon follows infection in most cases. The origin of these infections in the vaginal flora plays a larger role in the identitv of the usual spectrum of bacteria found, which are largely the enteric organisms and, occasionally, clostridia. When the bacteria enter the maternal sinusoids of the placenta, maternal sepsis and septic shock rapidly follow. The fetus also becomes secondarily involved from the amniotic sac; the majoritv of these infections are acquired by pulmonary aspiration of the infected amniotic sac content and not via the bloodstream. Viral infections of the placenta are acquired both bv bloodstream (for cytomegallic, rubella, and vaccinia virus) and probablv by the cervical route (for cytomegallic virus and herpes). Virus infections are uncom- monly identified histologically in the placenta but are certainly present in all fetal infections. They may be identified by characteristic organisms in the cases of herpes or cytomegallic virus; a diffuse chronic villous inflam- mation may be present. 434(50) CRAIG American Journal of Pathology

Monilial infections arising from the vagina behave almost identially to bacterial infections, although secondary maternal systemic involvement is almost never seen; secondary yeast infection of fetal lung does occur. Placental Pathology Associated With Maternal Disease With maternal diabetes of greater than a mild degree of severity, changes can be expected in the placenta. These changes reflect not only the diabetic state but also the renal status of the mother. In uncompli- cated diabetes of moderate severity, the placenta is large and reflects the increased size of the fetus, which is dependent on the severity and the degree of control of the diabetic state. The placenta may weigh as much as 600 g and histologically is more immature than a placenta of a nondiabetic woman of similar gestational age, with persistence of Hof- bauer cells, a recognizable cytotrophoblast layer, villous budding, and a low ratio of the vascular bed area to the total villous cross section. When diabetes (particularly of juvenile onset) has resulted in renal glomerui- losclerosis (Kimmelstiel-Wilson's disease) and atherosclerosis, the pla- centa is smaller than normal and takes on the changes seen in other renovascular disease in pregnancy. In renal insufficiency of whatever cause, the changes in the placenta are only quantitatively different from those seen in a normally aging placenta. One will find a greater number and greater volume of infarcts, more deposition of intervillous fibrin coating the villi, and, because of the relatively poor perfusion of the remaining more normal areas of such a placenta, increased syncytial knotting, ie, larger and more numerous col- lections of syncytial cells in the intervillous spaces (the Tenney change). All these lesions are considered to be secondary to occlusive lesions in the spiral decidual arterioles secondary to proliferative endarteritis and depo- sition of lipid-laden macrophages in the media, leading to thrombosis. With the exception of syphilis, spread of systemic infectious disease to the placenta is rare; even here, documented cases in modern obstetric practice are most unusual and many of the pathologic conditions desig- nated "syphilis" in the older literature were probably labeled incorrectly. In mothers of blood groups 0 or Rh negative, sensitized by previous pregnancies or by transfusion to Rh, A or B antigens, the fetus may have erythroblastosis fetalis with anemia due to destruction of red blood cells by maternal antibodies crossing the placenta. The placenta in more severe cases will be enlarged late in pregnancy and show a relative histologic immaturity in comparison to the gestational age, as well as severe villous edema and extramedullary erythropoiesis. Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 435(51) February 1979 Tuwors of the Placenta The benign tumors of the placenta are confined to two kinds: The first is the chorangioma, which is found in and beneath the chorionic plate, a round fleshy mass with sharply circumscribed borders. It is composed of fairly closely packed slightly dilated blood vascular channels separated by a connective tissue stroma. The second benign tumor is the so-called transitional mole, which is in essence a pregnancy associated with a triploid chromosomal number. There may be a macerated or stunted embryo in a large amniotic sac, and the placenta may be enlarged due to extreme hydropic change in the villi so that they may easily be discerned with the naked eye. Not all villi are so affected. There is no excess or unusual proliferation of the trophoblastic cells; the "tumor" is more the result of swelling rather than proliferation of villi. The remaining tumors of the placenta, having normal chromosome complements, form a spectrum both behaviorally and histologically from a benign process to a highly malignant one. The benign tumors, the hydatidiform moles, cause rapid enlargement of the uterus, usually in the second trimester. They cause bleeding and may discharge tumor elements into the vagina. They form a large amorphous mass of grape-like grosslv visible villi with diameters up to 2 to 3 cm and, of course, are mixed with matemal blood from the maternal sinusoid in which they lie. The cho- rionic sac is small and inconspicuous and often never identified. The tumor microscopically is made up of immature avascular villi with varving degrees of trophoblastic proliferation on the surface and with islands of rapidly proliferating cytotrophoblast and maturing syncytiotrophoblast in the intervillous space (Figure 27). The greater degree of trophoblast proliferation and the higher the proportion of cytotrophoblast, the higher the grade of tumor (usually on a basis of 1 to 3). Such tumors usually stav within the confines of the uterus but may penetrate or grow through the uterine wall (invasive mole or chorioadenoma destruens). Historicallv, such patients died of uterine hemorrhage or from peritonitis due to penetration of bacteria through the compromized uterine wall. Since these tumors are universally susceptible to antitumor chemotherapy, that should no longer occur. Choriocarcinoma forms the malignant variant of these tumors. It is composed in almost all cases of pure cytotrophoblast and syncvtiotropho- blast elements with no villous formation. It thus mimics the trophoblast in the previllous ovum. These tumors invade the blood vessels activelv and cause their dilatation and proliferation by secretion of an angiogenesis factor. Choriocarcinomas metastasize to liver, lung, and brain. Chorio- 436(52) CRAIG American Journal of Pathology

Figure 27-Gestational choriocarcinoma in endometrial curettings. (Xl 13) carcinomas and hydatidiform moles produce chorionic gonadotrophin, and their clinical course can be monitored by estimation of the specific beta side chain by radioimmunoassay methods. This is of inestimable help in the successful treatment of these tumors by antitumor agents, for, even with metastases, nearly 90% of patients may be cured if treatment is begun within a few months of onset of the disease. Choriocarcinoma arises in approximately equal proportions of women with previously existing hydatidiform moles, spontaneous first trimester abortions, and normal term pregnancies. Although attempts have been made to predict the development of choriocarcinoma from observation of the histology of evacuated hydatidiform moles, this has proved of little value. The ovary in the presence of an active hydatidiform mole or choriocarcinoma may be enlarged due to the presence of numerous corpora lutea in various stages of maturation or to theca lutein cysts which are reactivated cystic atretic follicles with an atrophic granulosa layer and a greatly proliferated and luteinized theca interna layer. It has recently been determined by chromosome banding techniques that true gestational hydatidiform moles predominantly originate from sperm and represent a homozygous descendent of the male partner, although there must be some contribution to the process by the ova as well. Vol. 94, No. 2 PATHOLOGY OF FEMALE REPRODUCTIVE TRACT 437(53) February 1979 Bibliography Benirschke K. Driscoll SG: The Patholog- of the Human Placenta. Ne- York. Springer- V'erlag. 1967 Blaustein A: Pathology of the Female Genital Tract. Ne%^- York. Springer-Verial. 1977 Gompel C. Silverberg SG: Pathology in Gvnecolog! and Obstetrics. Second edition. Philadelphia. J B. Lippincott Co. 197,7 438(54) CRAIG American Journal of Pathology

[End ofArticle]