The Female Reproductive Genital Tract Notes

The Female Genital Tract

Vulva

Normal Structure

• The vulva consists of structures of ectodermal origin labia majora, labia minora, mons pubis, clitoris, vestibule, hymen, Bartholin’s glands and minor vestibular glands.
• The mons pubis and labia majora are covered externally by skin with hair follicles, sebaceous glands and sweat glands including apocrine glands.
• The inner surface of labia majora, labia minora and vestibule are covered by stratified squamous epithelium. The clitoris is made up of vascular erectile tissue.
• Bartholin’s or vulvovaginal glands are located on each side of the mass of tissue forming labia majora. The glands are racemose type and their secretions are released during sexual excitement.
• Since the vulva is of ectodermal origin, the common inflammatory conditions affecting it are similar to those found on the skin generally.
• A few specific conditions such as Bartholin’s cyst and abscess, vulvar dystrophy and certain tumours are described below.

Read And Learn More: Systemic Pathology Notes

Miscellaneous Conditions

Bartholin Cyst And Abscess

Bartholin cyst results following obstruction of its duct. Obstruction incites inflammation of Bartholin vulvovaginal glands (Bartholin adenitis) due to bacterial infection, notably gonorrhoeal infection. Infection may be acute or chronic.

• Acute Bartholin adenitis occurs from obstruction and dilatation of the duct by an infection resulting in the formation of a Bartholin’s abscess. The condition presents with intense pain, swelling and fluctuant mass which can be incised and drained.
  • Microscopically, it shows the usual appearance of acute suppurative inflammation with neutrophilic infiltration, hyperaemia, oedema and epithelial degeneration.
• Chronic Bartholin adenitis results from a less virulent infection so the process is slow and prolonged.
  • Alternatively, the chronic process evolves from repeated attacks of less severe acute inflammation which may be short of abscess formation and resolves incompletely.
  • In either case, the chronic inflammatory process terminates into a fluid-filled Bartholin cyst.
  • The resulting cyst may be quite large, 3-5 cm in diameter and readily palpable in the perineum, but may remain asymptomatic for years.
    • Microscopically, the cyst shows variable lining varying from the transitional epithelium of the normal duct to squamous or cuboidal lining because of increased intracystic pressure. The cyst wall may show chronic inflammatory infiltration and a few mucus-secreting acini.

Non-Neoplastic Epithelial Disorders

The older nomenclature vulvar dystrophy has been replaced by a more descriptive and clinically relevant term, non-neoplastic epithelial disorders of vulval skin and mucosa of the vulva.

• The term is applied to chronic lesions of the vulva characterised clinically by white, plaque-like, pruritic mucosal thickenings and pathologically by disorders of epithelial growth.
• Clinicians often use the term ‘leukoplakia’ for such white lesions. But white lesions may represent other depigmented conditions as well such as vitiligo, inflammatory dermatoses, carcinoma in situ, Paget’s disease, or even invasive carcinoma, and thus the use of the term leukoplakia by pathologists is not recommended.

Currently, non-neoplastic epithelial disorders of the skin of the vulva include the following two lesions:

1. Lichen sclerosis (older term: atrophic dystrophy).
2. Squamous hyperplasia or keratosis (older term: hyperplastic dystrophy, or lichen simplex chronicus).

The two types of lesions may coexist in the same patient called mixed vulvar dystrophy.

Lichen Sclerosus:

• Lichen sclerosis may occur anywhere in the skin (page 816) but is more common and more extensive in the vulva in post-menopausal women.
• The lesions appear as multiple, small, coalescent, yellowish-blue macules or papules which produce thin and shiny parchment-like skin.
• The lesions may extend from the vulva onto the perianal and perineal areas. Clinically, the patient, usually a post-menopausal woman, complains of intense pruritus which may produce excoriation of the affected skin.
• Eventually, there is progressive shrinkage and atrophy resulting in the narrowing of the introitus, clinically referred to as kraurosis vulvae.

Morphologic Features Microscopically, the following characteristics are seen.

1. Hyperkeratosis of the surface layer.
2. Thinning and atrophy of the epithelium with the disappearance of rete ridges.
3. Amorphous homogeneous and hyalinised dermal collagen due to degeneration.
4. The scattered chronic inflammatory infiltrate in the mid-dermis.

Lichen sclerosis is not a premalignant lesion and responds favourably to topical treatment with androgens.

Squamous Hyperplasia

Squamous hyperplasia, simply called keratosis, is characterised by white, thickened vulvar
lesions which are usually itchy. The cause is unknown but is a reactive change due to irritation.
Symptomatic relief results from the use of topical treatment with corticosteroids.

Morphologic Features The histologic characteristics are as under.

1. Hyperkeratosis and hypergranulosis.
2. Hyperplasia of squamous epithelium with elongation of rete ridges (i.e. acanthosis).
3. Increased proliferation of squamous layers but the absence of dysplasia and atypia to distinguish from vulval intraepithelial neoplasia.
4. The mild chronic inflammatory infiltrate in the underlying dermis.

Squamous hyperplasia is not a precancerous condition. However, a variant having marked acanthosis, parakeratosis and a verruciform architecture called vulval acanthosis with altered differentiation (VAAD), does not have HPV association but may be the forerunner for HPVnegative vulval cancer.

Vulval Tumours

Vulva is the site of a variety of benign and malignant neoplasms which are in common with skin neoplasms elsewhere in the body.

• These include papillomas, fibromas, neurofibromas, angiomas, lipomas, sweat gland tumours, squamous cell carcinoma, verrucous carcinoma, malignant melanoma and mesenchymal sarcomas.
• However, a few tumours peculiar to the vulva such as
  1. Stromal polyps
  2. Papillary hidradenoma,
  3. Condyloma acuminatum,
  4. Extra-mammary Paget’s disease,
  5. Vulval carcinoma and Intra-epithelial neoplasia are discussed below.

1. Stromal Polyps:

Stromal (fibroepithelial) polyps or acrochordons may form in the vulva or vagina. There may be single or multiple polypoid masses.

• Histologically, they are covered by an orderly stratified squamous epithelium. The stroma consists of loose fibrous and myxomatous connective tissue with some adipose tissue and blood vessels.

2. Papillary Hidradenoma (HIDRADENOMA PAPILLIFERUM):

This is a benign tumour arising from the apocrine sweat glands of the vulva. Most commonly, it is located in the labia or in the perianal region as a small sharply circumscribed nodule.

• Histologically, the tumour lies in the dermis under a normal epidermis. The tumour consists of papillary structures composed of a fibrovascular stalk and is covered by a double layer of epithelial cells a layer of flattened myoepithelial cells and an overlying layer of columnar cells.

3. Condyloma Acuminatum:

• Condyloma acuminates or anogenital warts are benign papillary lesions of squamous epithelium which can be transmitted venereally to male sex partners.
• They may be solitary but more frequently are multiple forming soft warty masses. The common locations are the anus, perineum, vaginal wall, vulva and vagina. They are induced by human papillomavirus (HPV), particularly types 6 and 11.

• Histologically, they are identical to their counterparts on male external genitalia.
  • The features consist of a tree-like proliferation of the stratified squamous epithelium, showing marked acanthosis, hyperkeratosis, parakeratosis, papillomatosis and perinuclear vacuolisation of epithelium called koilocytosis, indicative of HPV infection.
  • The papillary projections consist of the fibrovascular stoma. Condylomas are benign lesions and regress spontaneously except in immunosuppressed individuals.

4. Extra-Mammary Paget’S Disease:

Paget’s disease of the vulva is a rare condition which has skin manifestations like those of Paget’s disease of the nipple. The affected skin, most often on the labia majora, appears as a map-like, red, scaly, elevated and indurated area.

• Histologically, extra-mammary Paget’s disease is identified by the presence of large, pale, carcinoma cells lying singly or in small clusters within the epidermis and adnexal structures.
  • These cells characteristically have a halo which stains positively with periodic acid-Schiff (PAS), alcian blue and mucicarmine and is thus believed to be of apocrine epithelial origin.
  • Unlike Paget’s disease of the breast in which case there is always an underlying ductal carcinoma, extra-mammary Paget’s disease is confined to the epidermis in most cases and only a small proportion of cases have an underlying adenocarcinoma.
  • The prognosis is good if there is no invasion but occasional cases progress into invasive carcinoma.

5. Vulval Intraepithelial Neoplasia And Invasive Carcinoma:

• Vulval intraepithelial neoplasia (VIN) and invasive squamous cell carcinoma are morphologically similar to those in the cervix and vagina.
• The etiologic role of certain viruses in carcinogenesis, particularly high-risk HPV types 16 and 18, in these sites is well documented.
• VIN is often multifocal within the vulva and may be multicentric as well with involvement of the contiguous cervix and vagina.
  Mention has already been made about the preceding stage of vulval epithelial disorders, particularly the VAAD variant of keratosis, in the development of these lesions.
• Vulval carcinoma constitutes 3% of all female genital tract cancers. While VIN occurs in reproductive age, the development of vulval cancer or VIN is in the 4th to 6th decade.
  • Grossly, VIN and vulval carcinoma in the early stage is a ‘white’ lesion (leukoplakia) while later the area develops an exophytic or endophytic (ulcerative) growth pattern.
    • The traditional VIN lesion, described as Bowen’s disease of the vulva, is generally a slightly elevated, velvety, plaque lesion.

Microscopically, just as in the cervix, VIN may also range from VIN I to VIN III, a higher grade also called Bowen’s disease (in situ carcinoma).

• Vulvar cancer is a squamous cell type with varying degrees of anaplasia and depth of invasion depending upon the stage. HPV-positive tumours are more often basaloid, poorly-differentiated squamous cell carcinoma while HPV-negative is a well-differentiated keratinising type.
• Verrucous carcinoma is a rare variant which is a fungating tumour but is locally malignant. Clinical staging for vulval carcinoma based on tumour size (< or > 2 cm) and extent of spread has been described by the Cancer Committee of the International Federation of Gynaecology and Obstetrics.

Diseases of the Vulva:

• Bartholin’s adenitis is a bacterial infection of Bartholin’s gland and may be acute or chronic.
• Vulvar dystrophies or leukoplakias are chronic pruritic nonneoplastic epithelial disorders of vulval skin and mucosa of the vulva which may be lichen sclerosus (or atrophic dystrophy) and squamous hyperplasia (or keratosis or hyperplastic dystrophy, or lichen simplex chronicus).
• Stromal (fibroepithelial) polyps or acrochordons may form in the vulva or vagina.
• Condyloma acuminates or anogenital warts are benign papillary lesions of squamous epithelium which can be transmitted venereally to male sex partners.
• Vulval intraepithelial neoplasia (VIN) and invasive squamous cell carcinoma are morphologically similar to those in the cervix and vagina.
• There is an etiologic role of high-risk HPV types 16 and 18 in most cases.

Vagina

Normal Structure:

• The vagina consists of a collapsed cylinder extending between the vestibule externally and the cervix internally.
• Histologically, the vaginal wall consists of 3 layers: an outer fibrous, a middle muscular and an inner epithelial. The muscular coat has a double layer of smooth muscle.
• The epithelial layer consists of stratified squamous epithelium which undergoes cytologic changes under hormonal stimuli.
• Oestrogen increases its thickness such as during reproductive years, whereas the epithelium is thin in childhood, and atrophic after menopause when oestrogen stimulation is minimal. Primary diseases of the vagina are uncommon.
• The only important clinicopathologic conditions which require elaboration here are vaginitis and certain tumours.

Vaginitis And Vulvovaginitis

Since the vulva and vagina are anatomically close to each other, often inflammation of one affects the other location. Certain other infections are quite common in the vulva and vagina as follows:

1. Bacterial examples are streptococci, staphylococci, Escherichia coli, and Haemophilus vaginalis.
2. Fungal example Candida albicans.
3. Protozoal example Trichomonas vaginalis.
4. Viral example Herpes simplex.

• The most common causes of vaginitis are Candida (moniliasis) and Trichomonas (trichomoniasis). The hyphae of Candida can be seen in the vaginal smears.
• Similarly, the protozoa, Trichomonas, can be identified in smears (Appendix I). These infections are particularly common in pregnant and diabetic women and may involve both the vulva and vagina.
• However, the adult vaginal mucosa is relatively resistant to gonococcal infection because of its histology.

Tumours And Tumour-Like Conditions

Vaginal cysts such as Gartner’s duct (Wolffian) cysts lined by glandular epithelium and vaginal inclusion cysts arising from the inclusion of vaginal epithelium are more common benign vaginal tumours and tumour-like conditions.

• Other uncommon benign tumours are papillomas, fibromas, lipomas, angiomas and leiomyomas and resemble their counterparts elsewhere in the body.
• Primary malignancies of the vagina are rare and include carcinoma (squamous cell carcinoma and adenocarcinoma) and embryonal rhabdomyosarcoma (sarcoma botryoides).

Carcinoma Of Vagina:

Primary carcinoma of the vagina is an uncommon tumour. Squamous cell dysplasia or vaginal intraepithelial neoplasia occurs less frequently as compared to the cervix or vulva and can be detected by Pap smears as discussed in Appendix I. Invasive carcinoma of the vagina includes two main types:

1. Squamous cell carcinoma of the vagina constitutes less than 2% of all gynecologic malignancies and is similar in morphology as elsewhere in the female genital tract. The role of HPV types 16 and 18 in its aetiology and the possibility of an extension from cervical carcinoma to the vagina have been emphasised.
2. Adenocarcinoma of the vagina is much less frequent than squamous cell carcinoma of the vagina. It may be endometrioid or mucinous type.
   • The significance of the association of diethylstilbestrol administered during pregnancy to the mother with the development of adenocarcinoma of the vagina in the daughter has been discussed in neoplasia. The clinical staging of carcinoma of the vagina proposed by FIGO is given in.

Embryonal Rhabdomyosarcoma (Sarcoma Botryoides):

• This is an unusual and rare malignant tumour occurring in infants and children under 5 years of age. The common location is an anterior vaginal wall.
• Similar tumours may occur in the urinary bladder, head and neck region (orbit, nasopharynx, middle ear, oral cavity) and biliary tract.

Morphologic Features Grossly, the tumour is characterised by a bulky and polypoid grape-like mass (botryoides = grape) that fills and projects out of the vagina.

Histologically, the features are as under:

1. Groups of round to fusiform tumour cells characteristically lie underneath the vaginal epithelium, called the cambium layer of tumour cells.
2. The central core of polypoid masses is composed of loose and myxoid stroma with many inflammatory cells.

The tumour invades extensively in the pelvis and metastasises to regional lymph nodes and distant sites such as to lungs and liver. Radical surgery combined with chemotherapy offers some benefits.

Diseases of the Vagina:

1. The most common causes of vaginitis are Candida (moniliasis) and Trichomonas (trichomoniasis).
2. Vaginal cysts include Gartner’s duct (Wolffian) cyst lined by glandular epithelium and vaginal inclusion cyst.
3. Primary cancers of the vagina are uncommon and include squamous cell carcinoma, adenocarcinoma of the vagina and embryonal rhabdomyosarcoma (sarcoma botryoides).

Cervix

Normal Structure:

The cervix consists of an internal os communicating with the endometrial cavity above, and an external os opening into the vagina below.

• Ectocervix (exocervix) or portion vaginalis is part of the cervix exposed to the vagina and is lined by stratified squamous epithelium, whereas the endocervix is continuous with the endocervical canal and is lined by a single layer of tall columnar mucus-secreting epithelium.
• The endocervical mucosa is thrown into folds resulting in the formation of clefts and tunnels, commonly referred to as cervical glands that secrete mucus.
• The junction of the ectocervix and endocervix—junctional mucosa, consists of a gradual transition between squamous and columnar epithelia (squamocolumnar junction) and is a clinically and pathologically significant landmark.
• The cervical mucosa undergoes changes under the influence of hormones and during pregnancy. The cervical mucus varies during the menstrual cycle, being viscus after menses, but under the influence of oestrogen becomes thin which on drying forms the fern-like pattern on the glass slide.

Lesions of the cervix are rather common. Of great significance are cervicitis, certain benign tumours, dysplasia, carcinoma in situ and invasive carcinoma.

Cervicitis:

• Some degree of cervical inflammation is present in virtually all multiparous women and some nulliparous women. The normal intact ectocervical stratified epithelium is usually more resistant to infection whereas the endocervical columnar epithelium bears the brunt of the initial inflammation.
• Cervicitis may be specific or nonspecific, acute or chronic. Specific cervicitis may be caused by tuberculosis, syphilis, granuloma inguinale, lymphogranuloma venereum, chlamydia and chancroid.
• Nonspecific cervicitis is more frequent and is generally divided into acute and chronic forms, the latter being quite common.

Acute Cervicitis:

Acute cervicitis is usually associated with puerperium or gonococcal infection. Other causes are primary chancre and infection with herpes simplex.

Grossly, the cervix shows everted endocervical mucosa which is red and oedematous.

Histologically, there is infiltration of the subepithelial and periglandular tissue with neutrophils, and there is oedema and congestion. The mucosa may be ulcerated and haemorrhagic.

Chronic Cervicitis:

• Chronic nonspecific cervicitis is encountered quite frequently and is the common cause of leucorrhoea. The most common organisms responsible for chronic cervicitis are the normal mixed vaginal flora that includes streptococci, enterococci and staphylococci.
• Other infecting organisms include gonococci, Trichomonas vaginalis, Candida albicans and herpes simplex. Factors predisposing to chronic cervicitis are sexual intercourse, the trauma of childbirth, instrumentation and excess or deficiency of oestrogen.

Grossly, there is an eversion of the ectocervix with hyperaemia, oedema and granular surface. Nabothian (retention) cysts may be grossly visible from the surface as pearly grey vesicles.

Histologically, chronic cervicitis is characterised by extensive subepithelial inflammatory infiltration of lymphocytes, plasma cells, large mononuclear cells and a few neutrophils.

• There may be the formation of lymphoid follicles termed follicular cervicitis. The surface epithelium may be normal or may show squamous metaplasia.
• The squamous epithelium of the ectocervix in cases of uterine prolapse may develop surface keratinisation and hyperkeratosis, so-called epidermidisation.
• Areas of squamous metaplasia and hyperkeratosis may be mistaken on a cursory microscopic look for a well-differentiated squamous carcinoma.

Tumours And Tumour-Like Lsions

• Both benign and malignant tumours are common in the cervix. In addition, the cervix is the site of ‘shades of grey’ lesions that include cervical dysplasia and carcinoma in situ (cervical intraepithelial neoplasia, CIN), currently termed squamous intraepithelial lesions (SIL).
• Benign tumours of the cervix consist most commonly of cervical polyps. Microglandular hyperplasia is a benign lesion that can be confused with endocervical adenocarcinoma.
• Uncommon benign cervical tumours are leiomyomas, papillomas and condyloma acuminatum which resemble in morphology with similar tumours elsewhere in the genital tract. The most common malignant tumour is squamous carcinoma of the cervix.

Cervical Polyps:

Cervical polyps are localised benign proliferations of endocervical mucosa though they may protrude through the external os. They are found in 2-5% of adult women and produce irregular vaginal spotting.

Morphologic Features Grossly, a cervical polyp is a small (up to 5 cm in size), bright red, fragile growth which is frequently pedunculated but may be sessile. Microscopically, most cervical polyps are endocervical polyps and are covered with endocervical epithelium which may show squamous metaplasia.

Less frequently, the covering is by the squamous epithelium of the portion vaginalis. The stroma of the polyp is composed of loose and oedematous fibrous tissue with variable degrees of inflammatory infiltrate and contains dilated mucus-secreting endocervical glands.

Microglandular Hyperplasia

• Microglandular hyperplasia is a benign condition of the cervix in which there is a closely packed proliferation of endocervical glands without intervening stroma.
• The condition is caused by progesterone stimulation such as during pregnancy, postpartum period and in women taking oral contraceptives. Morphologically, the condition may be mistaken for well-differentiated adenocarcinoma.

Squamous Intraepithelial Lesion (SIL)(CERVICAL INTRAEPITHELIAL NEOPLASIA, CIN):

Terminology:

Presently, the terms dysplasia, CIN, carcinoma in situ, and SIL are used synonymously as follows:

Dysplasia The term ‘dysplasia’ (meaning ‘bad moulding’) has been commonly used for atypical cytologic changes in the layers of squamous epithelium, the changes being progressive. Depending upon the thickness of squamous epithelium involved by atypical cells, dysplasia is conventionally graded as mild, moderate and severe.

• Carcinoma in situ is the full-thickness involvement by atypical cells, or in other words carcinoma confined to layers above the basement membrane. At times, severe dysplasia may not be clearly demarcated from carcinoma in situ.
• It is well-accepted that invasive cervical cancer evolves through progressive stages of dysplasia and carcinoma in situ.

CIN An alternative classification is to group various grades of dysplasia and carcinoma in situ together into cervical intraepithelial neoplasia (CIN) which is similarly graded from grade I to According to this concept, the criteria are as under:

• CIN-1 represents less than one-third involvement of the thickness of epithelium (mild dysplasia).
• CIN-2 is one-third to two-thirds involvement (moderate dysplasia).
• CIN-3 is full-thickness involvement or equivalent to carcinoma in situ (severe dysplasia and carcinoma in situ).

SIL Currently, the National Cancer Institute (NCI) of the US has proposed The Bethesda System (TBS) for reporting cervical and vaginal cytopathology.

According to the Bethesda system, based on cytomorphologic features and HPV types implicated in their aetiology, the three grades of CIN are readjusted into two grades of squamous intraepithelial lesions (SIL) low-grade SIL (L-SIL) and high-grade SIL (H-SIL) as under

• L-SIL corresponds to CIN-1 and is a flat condyloma, having pilocytic atypia, usually related to HPV 6 and 11 infections (i.e. includes mild dysplasia and HPV infection). About 10% of cases of L-SIL may progress to H-SIL.
• H-SIL corresponds to CIN-2 and 3 and has abnormal pleomorphic atypical squamous cells. HPV 16 and 18 are implicated in the aetiology of H-SIL (i.e. includes moderate dysplasia, severe dysplasia, and carcinoma in situ).
  • Approximately, 10% of cases of H-SIL may progress to invasive cervical cancer over a period of about two years. A comparison of these terminologies.
  • Progressive grades of dysplasia/CIN/SIL is a classical example of the progression of malignancy through stepwise epithelial changes and it can be detected early by a simple Papanicolaou cytologic test (‘Pap smear’) (Appendix I).
  • The use of a Pap smear followed by colposcopy-directed biopsy confirms the diagnosis which has helped greatly in instituting early effective therapy and thus has reduced the incidence of cervical cancer in many developed countries. CIN or SIL can develop at any age though it is rare before puberty.
  • Low-grade reversible changes arise in young women between 25 and 30 years of age, whereas progressively higher grades of epithelial changes develop a decade later. Hence, the desirability of periodic Pap smears on all women after they become sexually active.

Etiopathogenesis:

The biology of CIN/SIL and its relationship to invasive carcinoma of the cervix is well understood by epidemiologic, virologic, molecular, immunologic and ultrastructural studies.

1. Epidemiologic studies: Based on the epidemiology of a large population of women with cervical cancer, several risk factors have been identified which include the following 4 most important factors:

1. Women have an early age of sexual activity.
2. Women have multiple sexual partners.
3. Women with persistent HPV infection with high-risk types of oncogenic virus.
4. Potential role of high-risk male sexual partners such as promiscuous males having previous multiple sexual partners, having a history of penile condyloma, or males who had a previous spouse with cervical cancer.

In addition to the above factors, other epidemiologic observations reveal a high incidence of cervical cancer in lower socioeconomic strata, in multiparous women, cigarette smoking women, users of oral contraceptives, HIV infection and immunosuppression, while a low incidence is noted in virgins and nuns.

2. Virologic studies: Human papillomavirus (HPV) infection is strongly implicated in the aetiology of cervical cancer. By recombinant DNA hybridisation techniques, the following observations have been documented:

1. High-risk type HPV, most commonly of types 16 and 18 (in 70% of cases), and less often types 31, 33, 52 and 58, are present in 70-100% of cases of cervical cancer.
2. Low-risk type HPV types 6 and 11 are found most frequently in condylomas.
3. Mixed high and low-risk types of HPV may be found in dysplasias. Besides HPV, a few other viruses which may adversely affect the prognosis but do not have an etiologic relationship are HIV, HTLV-1 and EBV infection.

3. Molecular studies: Immunohistochemical, cytogenetic and molecular studies have shown that low-risk HPV types do not integrate into the host cell genome, while high-risk HPV types are integrated into the nucleus of cervical epithelial cells.

• Upon integration, the protein products of HPV- 16 and 18, E7 and E6 proteins respectively, inactivate tumour suppressor genes, p53 and RB-1 gene, thus permitting uncontrolled cellular proliferation.
• It has been possible to document that morphologic abnormalities in cervical lesions have a good correlation with underlying cellular events by use of techniques such as proliferation cell nuclear antigen (PCNA), p16, p53 and p63 expression, and nucleolar organizer region (AgNOR).
• However, all women who harbour HPV infection with high-risk type do not develop invasive cancer of the cervix. Women who have persistence of this infection or those who have another cofactor such as cigarette smoking or immunodeficiency, are at greater risk to develop progression of lesions.

4. Immunologic studies: Circulating tumour-specific antigens and antibodies are detected in patients with cervical cancer. Antibodies to virus-specific antigens are identified on tumour cells and in sera of such patients.

5. Ultrastructural studies: Changes observed on ultrastructural studies of cells in CIN/SIL reveal increased mitochondria and free ribosomes, and depletion of normally accumulated glycogen in the surface cells.

The latter change forms the basis of Schiller’s test in which the suspected cervix is painted with a solution of iodine and potassium iodide. The cancerous focus, if present, fails to stain because of a lack of glycogen in the surface cells.

Morphologic Features Grossly, no specific picture is associated with cellular atypia found in dysplasias or carcinoma in situ except that the changes begin at the squamocolumnar junction or transitional zone.

The diagnosis can be suspected clinically on the basis of visual inspection tests of the cervix done on bedside visual inspection with 5% acetic acid (VIA) and visual inspection with Lugol’s iodine (VILI); the latter was earlier called Schiller’s test.

Histologically, the distinction between various grades of CIN is quite subjective, but, in general, dysplastic cells are distributed in the layers of squamous epithelium for varying thickness, and accordingly graded as mild, moderate and severe dysplasia, and carcinoma in situ.

• In mild dysplasia (CIN-1), there are koilocytes in the upper layers of the epithelium while the abnormal cells extend up to one-third of thickness from the basal to the surface layer and;
• In moderate dysplasia (CIN-2) up to two-thirds;
• In severe dysplasia (CIN-3), these cells extend from 75-90% thickness of epithelium; and
• In carcinoma in situ (included in CIN-3), the entire thickness from the basement membrane to the surface shows dysplastic cells.
  • The atypical cells migrate to the surface layers from where they are shed off (exfoliated) into vaginal secretions and can be tested by Pap smear.
  • The individual dysplastic or abnormal cells in these grades of atypia show various cytologic changes such as crowding of cells, pleomorphism, high nucleocytoplasmic ratio, coarse and irregular nuclear chromatin, numerous mitoses and scattered dyskaryotic cells.
  • The diagnosis of dysplasia and carcinoma in situ or CIN/SIL is best made by exfoliative cytologic studies discussed in Appendix I. The degree of atypicality in the exfoliated surface epithelial cells can be objectively graded on the basis of 3 principal features:
    1. More severe nuclear dyskaryotic changes such as increased hyperchromasia and nuclear membrane folding.
    2. Decreased cytoplasmic maturation i.e. less cytoplasm as the surface cells show less maturation.
    3. In lower grades of dysplasia (CIN-1/L-SIL), predominantly superficial and intermediate cells are shed off whereas in severe dysplasia and in carcinoma in situ (CIN-3/H-SIL) the desquamated cells are mainly small, dark basal cells.
    4. The lesions of SIL in cytology have a histologic correlation with colposcopy-directed cervical biopsy in 70-90% of cases.

Cervical Screening and the Bethesda System:

• Naked eye visual inspection of the uterine cervix with either acetic acid (VIA) or with Lugol’s iodine (VILI) under intense illumination provides simple tests for the early detection of cervical precancerous lesions and invasive cervical cancer.
• VILI is similar to earlier Schiller’s test. The basis for the appearance of the ‘act white’ area as suspicion in VIA is the coagulation of increased nuclear DNA in precancerous and cancerous areas which assume a white appearance compared to pink normal squamous mucosa and reddish normal columnar mucosa.
• With the introduction of effective Pap screening programmes in developed countries, the incidence of invasive cervical cancer has declined greatly. However, still worldwide cervical cancer remains the third most common cancer in women, next to breast and lung cancer.
• Although accurate statistics are not available from India, but it is perhaps the leading cause of death in women. In the Pap screening programme, patients having abnormal Pap smears are appropriately followed up and, therefore, it requires an understanding of the Bethesda system by the clinician as regards the value and limitations of cytology reports prepared by the cytologist/cytotechnician.
• Cervical screening recommendations include annual cervical smears in all sexually active women having any risk factors listed above.
• However, if three consecutive Pap smears are negative in ‘high-risk women’ or satisfactory in ‘low-risk women’, the frequency of Pap screening is reduced. There is no upper age limit for cervical screening.

The broad principles of The Bethesda system (TBS) of cytologic evaluation are as under:

1. Pap smears are evaluated as regards adequacy of the specimen (i.e. satisfactory for evaluation, satisfactory but limited—removed now, or unsatisfactory for evaluation giving a reason).
2. A general diagnosis is given in the form of a normal or abnormal smear.
3. Descriptive diagnosis is given in abnormal smears that include benign cellular changes, reactive cellular changes, and abnormalities of epithelial cells.
4. Cellular abnormalities of both squamous and glandular cells include:
5. ASCUS (atypical squamous cells of undetermined significance), L-SIL (mentioning HPV infection and CIN-1 present or not), H-SIL (stating CIN-2 or CIN-3) and squamous cell carcinoma, and
6. Atypical glandular cells and atypical glandular cells favour neoplastic, endocervical adenocarcinoma in situ and adenocarcinoma.

Invasive Cervical Cancer:

• Invasive cervical cancer is the second most common cancer (after breast cancer) and the third leading cause of cancer mortality in women worldwide.
• The incidence of invasive carcinoma of the cervix has shown a declining trend in developed countries in the last half of the century due to increased use of the Pap smear technique for early detection and diagnosis but the incidence remains high in developing countries with low living standards and inadequate healthcare.
• The risk factors and etiologic factors are the same as for CIN discussed above. The peak incidence of.

Morphologic Features Grossly, invasive cervical carcinoma may present 3 types of patterns: fungating, ulcerating and infiltrating.

• The fungating or exophytic pattern appearing as cauliflower-like growth infiltrating the adjacent vaginal wall is the most common type.
• Characteristically, cervical carcinoma arises from the squamocolumnar junction. The advanced stage of the disease is characterised by widespread destruction and infiltration into adjacent structures including the urinary bladder, rectum, vagina and regional lymph nodes.
• Distant metastases occur in the lungs, liver, bone marrow and kidneys.

Histologically, the following patterns are seen:

1. Squamous cell carcinoma: Invasive cervical cancer in about 80% of cases is squamous
cell carcinoma.

• The most common pattern (70%) is moderately differentiated non-keratinising large cell type and has a better prognosis.
• Next in frequency (25%) is well-differentiated keratinising squamous cell carcinoma. Poorly-differentiated squamous cell carcinoma (5%) has primitive appearing tumour cells with scant cytoplasm and hyperchromatic nuclei, high mitotic activity and little or no keratin.

2. Neuroendocrine carcinoma: This is a small cell undifferentiated carcinoma which is less common (5%) and has a poor prognosis.

3. Adenocarcinoma: Adenocarcinomas comprise about 10-15% of cases. These may be well-differentiated mucus-secreting adenocarcinoma, or clear cell type containing glycogen but no mucin. Adenocarcinoma of the cervix has a poor prognosis.

4. Others: Remaining 5% of cases are a variety of other patterns such as adenosquamous carcinoma, verrucous carcinoma and undifferentiated carcinoma.

Clinical Staging: Clinical staging of cervical cancer described by the FIGO classification is widely adopted by clinicians and pathologists and is given.

Diseases of the Cervix:

• Cervicitis may be specific or nonspecific, acute or chronic.
• Cervical polyps are localised benign proliferations of endocervical mucosa.
• L-SIL corresponds to CIN-1 and is a flat condyloma, having pilocytic atypia, usually related to HPV 6 and 11 infection.
• H-SIL corresponds to CIN-2 and 3 and has abnormal pleomorphic atypical squamous cells. HPV 16 and 18 are implicated in the aetiology of H-SIL.
• The introduction of an effective Pap screening programme and The Bethesda system of reporting for smears in developed countries has resulted in a lowered incidence of invasive cervical cancer.
• Invasive cervical cancer in about 80% of cases is squamous cell carcinoma, most commonly moderately differentiated non-keratinising type.

Body Uterus (Endometrium Histogenesis)

Normal Structure

The myometrium is the thick muscular wall of the uterus which is covered internally by uterine mucosa called the endometrium. The endometrium extends above the level of the internal os where it joins the endocervical epithelium.

• The myometrium is capable of marked alterations in its size, capacity and contractility during pregnancy and labour.
• The endometrium responds in a cyclic fashion to the ovarian hormones with resultant monthly menstruation and has a remarkable regenerative capacity. The lesions pertaining to the corpus uteri and the endometrium are numerous and constitute the vast majority of gynecologic conditions.
• However, some of the important pathologic entities are discussed below, but first, the cyclic changes in the normal menstrual cycle are briefly reviewed.

Effects Of Hormones:

In addition to the changes that take place during the normal menstrual cycle, the endometrium undergoes morphologic changes when hormonal preparations are administered, or during pregnancy and menopause.

Normal Cyclic Changes:

The normal endometrial cycle begins with a proliferative phase lasting for about 14 days under the influence of oestrogen, followed by ovulation on or around the 14th day, and a consequent secretory phase under the influence of progesterone. The cycle ends with endometrial shedding and the next cycle begins anew.

The histologic changes in different phases of the menstrual cycle vary.

Histologically, normal endometrium in different phases of the menstrual cycle undergoes cyclic changes during reproductive years. Essentially, three structures of the endometrium undergo changes the endometrial lining epithelium, endometrial glands and stroma:

• Epithelial lining: undergoes an increase in its thickness from cuboidal to tall columnar appearance at ovulation and subsequently regresses.
• Endometrial glands: with their lining provide most of the information on the phase of the menstrual cycle. In the immediate postmenstrual period, the glands are straight and tubular, having columnar lining with basal nuclei. This phase is under the predominant influence of oestrogen and lasts for about 14 days and is called the proliferative phase.
  • The evidence of ovulation is taken from the appearance of convolutions in the glands and subnuclear vacuoles in the cells indicative of secretions. The secretory changes remain prominent for the next 7 days after ovulation for implantation of the ovum if it has been fertilised.
  • Otherwise, the secretory activity wanes during the following 7 days with increased luminal secretions and a frayed and ragged luminal border of the cells lining the glands.
  • This phase is under the predominant influence of progesterone and is called the secretory phase. Eventually, the endometrium is sloughed away at menstruation followed by the beginning of the fresh cycle.
• Endometrial stroma: in the pre-ovulatory phase or proliferative phase is generally dense and compact, composed of oval to spindled cells. In the post-ovulatory phase or secretory phase, the stroma is loose and oedematous, composed of large, pale and polyhedral cells.
  • The true decidual reaction of the stroma occurs if the pregnancy has taken place. However, the decidual reaction may be suggested in the absence of pregnancy due to extreme response to progesterone.
  • Thus, it may be impossible to distinguish an advanced progestational endometrium from early pregnancy except for the presence of trophoblastic tissue.

Effect Of Oestrogen And Progesterone:

• Oestrogen produces the characteristic changes of the proliferative phase at the time of menopause and in young women with anovulatory cycles as occurs in Stein-Leventhal syndrome. The therapeutic addition of progesterone produces a secretory pattern in an oestrogen-primed endometrium.
• Oestrogen-progesterone combination hormonal therapy is employed for the control of conception. The sequential type of oestrogen-progesterone oral contraceptives acts by producing prolonged oestrogenic effects past the time of ovulation and implantation so that the secretion is delayed until about the 25th day, followed by progestational effects and shedding.
• Repeated cyclic administration with combination therapy such as after long-term use of oral contraceptives produces inactive-looking, small and atrophic endometrial glands and compact decidua-like stroma.

Effect Of Pregnancy:

• The implantation of a fertilised ovum results in the interruption of the endometrial cycle. The endometrial glands are enlarged with abundant glandular secretions and the stromal cells become more plump and polygonal with increased cytoplasm termed decidual reaction.
• About 25% of cases of uterine or extrauterine pregnancy show a hyperactive secretory state called the Arias-Stella reaction.
• It is characterised by hyperchromatic, atypical, tall cells lining the glands and the glandular epithelium may show multilayering and budding which may be mistaken for an adenocarcinoma.

Effect Of Menopause:

• The onset of menopause is heralded by hormonal transition and consequent varying morphologic changes in the endometrium. Most commonly, the senile endometrium, as it is generally called, is thin and atrophic with inactive glands and fibrous stroma.
• However, some of the glands may show cystic dilatation. Sometimes, retrogressive hyperplasia is seen which is characterised by a Swiss-cheese pattern of glands resembling endometrial hyperplasia but composed of inactive retrogressive lining epithelium.
• There is an intermingling of cystic and dilated glands with small and atrophic glands. Postmenopausal endometrium may show actual active hyperplasia under the stimulatory influence of post-menopausal oestrogen originating from the ovary or adrenal gland.

Dysfunctional Uterine Bleeding (DUB):

• Dysfunctional uterine bleeding (DUB) may be defined as excessive bleeding occurring during or between menstrual periods without a causative uterine lesion such as a tumour, polyp, infection, hyperplasia, trauma, blood dyscrasia or pregnancy.
• But it occurs most commonly in association with anovulatory cycles when the ovarian function is waning (menopause). Anovulatory cycles are also seen at the other extreme of menstrual life when the ovarian function is first beginning i.e. menarche.
• Anovulation is the result of prolonged and excessive oestrogenic stimulation without the development of the progestational phase. The causes for anovulation at different ages are as follows:
  1. In pre-puberty: precocious puberty of hypothalamic, pituitary or ovarian origin.
  2. In adolescence: anovulatory cycles at the onset of menstruation.
  3. In reproductive age: complications of pregnancy, endometrial hyperplasia, carcinoma, polyps, leiomyomas and adenomyosis.
  4. At premenopause: anovulatory cycles, irregular shedding, endometrial hyperplasia, carcinoma and polyps.
  5. At perimenopause: endometrial hyperplasia, carcinoma, polyps and senile atrophy.
  6. It has been observed that women who ovulate may also occasionally have anovulatory cycles. In addition to anovulatory cycles, DUB may occur in an inadequate luteal phase that manifests clinically as infertility (ovulatory dysfunctional bleeding). In such cases, the premenstrual endometrial biopsy shows a histologic lag of more than 2 days.

Endometritis And Myometritis:

Inflammatory involvement of the endometrium and myometrium are uncommon clinical problems; myometritis is seen less frequently than endometritis and occurs in continuation with endometrial infections. Endometritis and myometritis may be acute or chronic.

• The acute form: generally results from 3 types of causes—puerperal (following full-term delivery, abortion and retained products of conception), intrauterine contraceptive device (IUCD), and extension of gonorrheal infection from the cervix and vagina.
• The chronic form: is more common and occurs by the same causes which result in the acute phase. In addition, tuberculous endometritis is an example of specific chronic inflammation, uncommon in Western countries but not so uncommon in developing countries. Its incidence in India is reported to be approximately 5% of women.

Morphologic Features: In acute endometritis and myometritis, there is progressive infiltration of the endometrium, myometrium and parametrium by polymorphs and marked oedema.

Chronic nonspecific endometritis and myometritis are characterised by the infiltration of plasma cells along with lymphocytes and macrophages. Tuberculous endometritis is almost always associated with tuberculous salpingitis and shows small caseating granulomas.

Adenomyosis

Adenomyosis is defined as the abnormal distribution of histologically benign endometrial tissue within the myometrium along with myometrial hypertrophy. The term adenomyoma is used for actually circumscribed mass made up of endometrium and smooth muscle tissue.

• Adenomyosis is found in 15-20% of all hysterectomies. Pathogenesis of the condition remains unexplained. The possible underlying cause of the invasiveness and increased proliferation of the endometrium into the myometrium appears to be either metaplasia or oestrogenic stimulation due to endocrine dysfunction of the ovary.
• Clinically, patients of adenomyosis generally complain of menorrhagia, colicky dysmenorrhoea and menstrual pain in the sacral or sacrococcygeal regions.

Morphologic Features Grossly, the uterus may be slightly or markedly enlarged. On the cut section, there is the diffuse thickness of the uterine wall with the presence of coarsely trabecular, ill-defined areas of haemorrhages.

Microscopically, the diagnosis is based on the finding of normal, benign endometrial islands composed of glands as well as stroma deep within the muscular layer.

The minimum distance between the endometrial islands within the myometrium and the basal endometrium should be one low-power microscopic field (2-3 mm) for making the diagnosis. Associated muscle hypertrophy is generally present.

Endometriosis:

• Endometriosis refers to the presence of endometrial glands and stroma in abnormal locations outside the uterus. Endometriosis and adenomyosis are closely interlinked, so much so that some gynaecologists have termed adenomyosis as endometriosis interna and the other category termed as endometriosis externa for a similar appearance at the extrauterine sites.
• However, the two differ as regards age, fertility and histogenesis and thus endometriosis should be regarded as a distinct clinicopathologic entity.
• The chief locations where the abnormal endometrial development may occur are as follows (in descending order of frequency): ovaries, uterine ligaments, rectovaginal septum, pelvic peritoneum, laparotomy scars, and infrequently in the umbilicus, vagina, vulva, appendix and hernial sacs.
• The histogenesis of endometriosis has been a debatable matter for years. Currently, however, the following 3 theories of its histogenesis are described:

1. 1. Transplantation or regurgitation theory is based on the assumption that ectopic endometrial tissue is transplanted from the uterus to an abnormal location by way of fallopian tubes due to the regurgitation of menstrual blood.
   2. Metaplastic theory suggests that ectopic endometrium develops in situ from local tissues by metaplasia of the coelomic epithelium.
   3. Vascular or lymphatic dissemination explains the development of endometrial tissue at extrapelvic sites by these routes.

Endometriosis is characteristically a disease of the reproductive years of life. Clinical signs and symptoms include intrapelvic bleeding from implants, severe dysmenorrhoea, pelvic pain, dyspareunia and infertility.

Morphologic Features Grossly, the appearance of endometriosis varies widely depending upon the location and extent of the disease.

• Typically, the foci of endometriosis appear as blue or brownish-black underneath the surface of the sites mentioned. Often, these foci are surrounded by fibrous tissue resulting in adherence to adjacent structures.
• The ovary is the most common site of endometriosis and shows numerous cysts varying in diameter from 0.1 to 2.5 cm. Ovarian involvement is often bilateral. Larger cysts, 3-5 cm in diameter, filled with old dark brown blood form ‘chocolate cysts’ of the ovary.
• Histologically, the diagnosis is simple and rests on the identification of foci of endometrial glands and stroma, old or new haemorrhages, haemosiderin-laden macrophages and the surrounding zone of inflammation and fibrosis.

Endometrial Hyperplasias:

• Endometrial hyperplasia is characterised by the exaggerated proliferation of glandular and stromal tissues. It is commonly associated with prolonged, profuse and irregular uterine bleeding in a menopausal or postmenopausal woman.
• It may be emphasised here that the syndrome of DUB with which endometrial hyperplasia is commonly associated is a clinical entity, while hyperplasia is a pathologic term. Hyperplasia results from prolonged oestrogenic stimulation unopposed with any progestational activity.
• Such conditions include Stein-Leventhal syndrome, functioning granulosa-theca cell tumours, adrenocortical hyperfunction and prolonged administration of oestrogen.

Classification:

• Certain types of endometrial hyperplasias are regarded as the forerunner of endometrial cancer. In order to successfully identify the disease at the precancerous stage, different classification systems of endometrial hyperplasias have been proposed in the past.
• Over the years, the WHO-1994 classification has been widely used by clinicians and gynecologic pathologists over the years and it divided endometrial hyperplasia into 4 categories:

1. 1. Simple hyperplasia without atypia
   2. Complex hyperplasia without atypia
   3. Simple hyperplasia with atypia
   4. Complex hyperplasia with atypia

• Categories in this classification were found to be descriptive morphology while the diagnostic criteria were not fully defined, and therefore not always helpful in the clinical management of patients.
• The drawbacks of the WHO-1994 classification have been overcome by the WHO-2014 classification scheme that divides endometrial hyperplasia simply into two categories:

1. Hyperplasia without atypia (or benign hyperplasia)
2. Atypical hyperplasia (or endometrial intraepithelial neoplasia i.e. EIN).

Morphologic Features:

• Modified and objective pathological criteria for diagnosis of these two categories of the WHO-2014 classification have been laid down which are prognostically relevant. Besides morphology, the current classification also includes molecular changes in the categories of endometrial hyperplasias.
• Corresponding terminologies used in the two classification systems and their salient features are summarised.
• Morphologic features of the WHO-2014 classification of endometrial hyperplasia are given below.

Hyperplasia Without Atypia (BENIGN HYPERPLASIA): This entity includes two categories of previous classification simple hyperplasia without atypia and complex hyperplasia without atypia. Its features are as under:

1. Pattern:

1. There is increased glandular density; gland to stroma ratio >1 (in disordered proliferative this ratio is <1).
2. Glands are round to elongated, without complexity in architecture, placed back-to-back but with a small amount of intervening stroma.

2. Cytologic features:

1. The morphology of epithelial cells in the crowded area is not different from the non-crowded areas in the biopsy. In other words, cellular morphology in glands is like a proliferative phase.
2. Individual epithelial cells do not have any cytologic atypia

3. Genetic changes: These cases have low levels of somatic mutations in scattered glands. Atypical Hyperplasia (Endometrial Intraepithelial Neoplasia, Ein) The term EIN has been found more acceptable for atypical endometrial hyperplasias which were previously grouped under two types of simple hyperplasia with atypia, and complex hyperplasia with atypia. Its main features are as under:

1. Pattern;

1. Endometrial glands occupy more than 50% of the total surface; i.e. glands to stroma ratio >1.
2. Individual glands may vary in shape and show branching.

2. Cytologic features:

1. Cellular features differ between crowded and non-crowded areas.
2. Individual epithelial cells show cytologic atypia loss of nuclear polarity, nuclear enlargement, irregularly distributed coarse chromatin, and altered cytoplasmic differentiation.

3. Genetic changes: Genetic mutations present in endometrial carcinoma are frequently present in EIN. These include microsatellite instability (MSI), PAX2 inactivation, and mutations in PTEN, KRAS and bβ-catenin.

Hyperplasia without atypia has an excellent prognosis; <1% of cases may develop endometrial carcinoma later. EIN may progress or may have coexistent endometrial carcinoma in 15-45% of cases.

Tumours Of Endometrium And Myometrium

Tumours arising from endometrium and myometrium may be benign or malignant. They may originate from different tissues as under:

• Endometrial glands endometrial polyps, endometrial carcinoma.
• Endometrial stroma stromal nodules, stromal sarcoma.
• Smooth muscle of the myometrium leiomyoma, leiomyosarcoma.
• Mullerian mesoderm mixed mesodermal or mullerian tumours.

Out of these, endometrial polyps, endometrial carcinoma, leiomyomas and leiomyosarcomas are relatively more common and are described below.

Endometrial Polyps:

• ‘Uterine polyp’ is a clinical term used for a polypoid growth projecting into the uterine lumen and may be composed of benign lesions (for example endometrial or mucous polyp, leiomyomatous polyp and placental polyp), or malignant polypoid tumours (example endometrial carcinoma, choriocarcinoma and sarcoma).
• The most common variety, however, is the one having a structure like that of the endometrium and is termed an endometrial or mucus polyp. They are more common in the perimenopausal age group.
• Small endometrial polyps generally remain asymptomatic and are detected incidentally. The larger ones may ulcerate, degenerate and result in clinical bleeding.

Morphologic Features Grossly, endometrial polyps may be single or multiple, usually sessile and small (0.5 to 3 cm in diameter) but occasionally they are large and pedunculated.

Histologically, they are essentially made up of a mixture of endometrial glands and stroma. The histologic pattern of the endometrial tissue in the polyp may resemble either functioning endometrium or hyperplastic endometrium of cystic hyperplasia type, the latter being more common.

The stroma often contains thick-walled blood vessels. Rarely, a large endometrial polyp may undergo malignant change.

Endometrial Carcinoma:

• Carcinoma of the endometrium, commonly called uterine cancer, occurs more commonly in developed countries and is the most common pelvic malignancy in females in the United States but is less common in Asia where cervical cancer continues to be the leading cancer in women.
• Whereas the decline in the incidence of cervical cancer in developed countries is due to aggressive cervical screening programmes leading to early detection and cure of in situ stage, increased frequency of endometrial carcinoma in these countries may be due to the longevity of women’s life to develop this cancer of older females.
• It is primarily a disease of postmenopausal women, the peak incidence at onset being 6th to 7th decades of life and is uncommon below the age of 40 years.
• The most important presenting complaint is abnormal bleeding in postmenopausal women or excessive flow in the premenopausal years.

Aetiology: A few factors associated with the increased frequency of its development are as follows:

1. Chronic unopposed oestrogen excess
2. Obesity
3. Diabetes mellitus
4. Hypertension
5. Nulliparous state
6. Heredity.

There is irrefutable evidence of the relationship between endometrial carcinoma with prolonged oestrogenic stimulation as under:

1. Endometrial carcinoma has an association with atypical endometrial hyperplasia (discussed earlier) in which there is unopposed chronic hypoestrogenism and frequent anovulatory cycles.
2. In postmenopausal years when endometrial carcinoma occurs characteristically, there is the excessive synthesis of oestrogen in the body from adrenal as well as ovarian sources.
3. Women having oestrogen-secreting tumours (for example granulosa cell tumour) have an increased risk of developing synchronous endometrial cancer.
4. Patients receiving prolonged exogenous oestrogen therapy are at higher risk of developing this cancer.
5. Women with breast cancer receiving tamoxifen for prolonged periods have a 2-fold increased risk of developing uterine cancer.
6. Prolonged administration of oestrogen to laboratory animals can produce endometrial hyperplasia and carcinoma.
7. Women with gonadal agenesis rarely develop endometrial carcinoma.

The role of heredity in endometrial cancer is supported by higher incidence in hereditary non-polyposis colon cancer (HNPCC) syndrome (having simultaneous cancers of the colon and endometrioid adenocarcinoma) and in Cowden syndrome (having simultaneous cancers of the breast, thyroid, and endometrium).

Pathogenesis: In order to explain pathogenesis, two major types of endometrial carcinoma are distinguished: type I and type 2:

Type 1 tumours: are predominant (80-85%) and are oestrogen-dependent and develop through a hyperplasia-carcinoma sequence.

• Morphologic types included in type I are endometrioid and mucinous carcinoma.
• These cases often have an association with factors having long-term unopposed oestrogen stimulation example obesity, polycystic ovary syndrome, exogenous oestrogen administration etc.
• Atypical hyperplasia (EIN) is a forerunner of endometrial carcinoma in these cases
• Common mutations seen in these cases are PTEN, KRAS and βb-catenin and PAX2 inactivation.
• Type 2 tumours comprise 10-15% and are independent of oestrogen and thus unrelated to endometrial hyperplasia.
• Type 2 morphologic types of endometrial cancer are serous, clear cell, undifferentiated and carcinosarcoma.
• Papillary serous endometrial carcinoma is associated with a mutation in the p53 tumour suppressor gene. The preinvasive precursor stage of serous adenocarcinoma has also been seen.

Morphologic Features Grossly, endometrial carcinoma may have 2 patterns localised polypoid tumour, or a diffuse tumour; the latter being more common. The tumour protrudes into the endometrial cavity as an irregular, friable and grey-tan mass.

• Extension of the growth into the myometrium may be identified by the presence of soft, friable and granular tissue in the cut section.
• In advanced disease, the involvement may extend beyond the physiologic limits into the cervical canal, into the peritoneum, besides lymphatic metastases and haematogenous metastases to distant sites such as lungs, liver, bones and other organs.

Histologically, most endometrial carcinomas are adenocarcinomas, commonly termed endometrioid adenocarcinomas due to their resemblance with normal endometrium. Depending upon the pattern of glands and individual cell changes, these may be well-differentiated, moderately differentiated or poorly differentiated.

• Well-differentiated adenocarcinoma is characterised by an increase in the number of glands which are closely packed sometimes showing ‘back-to-back crowding’ due to obliterated intervening stroma.
• The glandular epithelium shows stratification, formation of tufting and papillae and atypical changes.
• Most growths are well-differentiated. Moderately-differentiated adenocarcinoma shows all the above features along with the presence of some solid sheets of malignant cells.

• Poorly-differentiated adenocarcinoma is characterised by the presence of solid sheets and ribbons of malignant epithelial cells which show marked cytologic atypia and frequent mitoses. The glandular pattern is hard to find.

Cases can also be categorised by FIGO histologic grading as follows:

FIGO G1: Well-differentiated (predominantly glandular).

FIGO G2: Moderately-differentiated (glandular and partly solid areas).

FIGO G3: Poorly differentiated (predominantly solid).

Papillary serous carcinoma: of the endometrium resembling its ovarian counterpart is distinct since it occurs in the background of atrophic endometrium and is more aggressive.

Uncommon histologic variants: of endometrial carcinoma are adenocarcinoma with squamous metaplasia (adenoacanthoma), adenosquamous carcinoma (when both components are frankly malignant), squamous carcinoma, clear cell carcinoma, mucinous adenocarcinoma, small cell carcinoma and undifferentiated carcinoma.

Carcinoma of the endometrium is categorised into four stages as per the FIGO classification given.

Leiomyoma:

• Leiomyomas or fibromyomas, commonly called fibroids by gynaecologists, are the most common uterine tumours of smooth muscle origin, often admixed with variable amounts of fibrous tissue components. About 20% of women above the age of 30 years harbour uterine myomas of varying sizes.
• The vast majority of them are benign and cause no symptoms. Malignant transformation occurs in less than 0.5% of leiomyomas. Symptomatic cases may produce abnormal uterine bleeding, pain, symptoms due to compression of surrounding structures and infertility.
• The cause of leiomyomas is unknown but the possible stimulus to their proliferation is oestrogen. This is evidenced by an increase in their size during pregnancy and high dose oestrogen therapy and their regression following menopause and castration.
• Other possible factors implicated in its aetiology are human growth hormone and sterility.

Morphologic Features: Leiomyomas are most frequently located in the uterus where they may occur within the myometrium (intramural or interstitial), the serosa (subserosal), or just underneath the endometrium (submucosal).

Subserosal and submucosal leiomyomas may develop pedicles and protrude as pedunculated myomas. Leiomyomas may involve the cervix or broad ligament.

Grossly, irrespective of their location, leiomyomas are often multiple, circumscribed, firm, nodular, grey-white masses of variable size. On the cut section, they exhibit a characteristic whorled pattern.

Histologically, they are essentially composed of 2 tissue elements whorled bundles of smooth muscle cells admixed with variable amounts of connective tissue. The smooth muscle cells are uniform in size and shape with abundant cytoplasm and central oval nuclei.

• Cellular leiomyoma has a preponderance of smooth muscle elements and may superficially resemble leiomyosarcoma but is distinguished from it by the absence of mitoses (see below).
• The pathologic appearance may be altered by secondary changes in the leiomyomas these include hyaline degeneration, cystic degeneration, infarction, calcification, infection and suppuration, necrosis, fatty change, and rarely, sarcomatous change.

Leiomyosarcoma:

• Leiomyosarcoma is an uncommon malignant tumour as compared to its rather common benign counterpart. The incidence of malignancy in pre-existing leiomyoma is less than 0.5% but primary uterine sarcoma is less common than that which arises in the leiomyoma.
• The peak age incidence is seen in the 4th to 6th decades of life. The symptoms produced are nonspecific such as uterine enlargement and abnormal uterine bleeding.

Morphologic Features Grossly, the tumour may form a diffuse, bulky, soft and fleshy mass, or a polypoid mass projecting into the lumen

Histologically, though there are usually some areas showing the whorled arrangement of spindle-shaped smooth muscle cells having large and hyperchromatic nuclei, the hallmark of diagnosis and prognosis is the number of mitoses per high power field (HPF).

• The essential diagnostic criteria are more than 10 mitoses per 10 HPF with or without cellular atypia or 5-10 mitoses per 10 HPF with cellular atypia. More the number of mitoses per 10 HPF, the worse the prognosis.
• Leiomyosarcoma is liable to recur after removal and eventually metastasise to distant sites such as the lungs, liver, bone and brain.

Diseases of Endometrium and Myometrium:

• Endometrium undergoes morphologic changes when hormonal preparations are administered, or during pregnancy and menopause.
• Adenomyosis is the abnormal distribution of histologically benign endometrial tissue within the myometrium.
• Endometriosis refers to the presence of endometrial glands and stroma in abnormal locations outside the uterus.
• Endometrial hyperplasia is characterised by the exaggerated proliferation of glandular and stromal tissues due to prolonged oestrogenic stimulation. A new classification of endometrial hyperplasia divides it into benign hyperplasia (hyperplasia without atypia) and endometrial intraepithelial neoplasia (EIN) (or atypical hyperplasia).
• Endometrial cancer is a disease of post-menopausal women and is more common in developed countries. It occurs more commonly in a background of EIN (atypical hyperplasia) hence related to prolonged oestrogenic stimulation.
• Leiomyomas or fibroids are the most common benign uterine tumours of smooth muscle origin while leiomyosarcoma is its uncommon malignant counterpart.

Fallopian Tubes

Normal Structure

• The fallopian tube or oviducts are paired structures, each extending from the superior angle of the uterus laterally to the region of the ovaries and running in the superior border of the broad ligaments forming mesosalpinx.
• Each tube is 7-14 cm long and is divided into 4 parts interstitial portion in the uterine cornua wall narrow isthmic portion; wider ampullary region and funnel-like distal infundibulum.
• The infundibulum is fringed by fimbriae, the longest of which called fimbria ovarica is attached to the ovary.

Histologically, the wall of the tube has 4 coats—serous forming the peritoneal covering, subserous consisting of fibrovascular tissue, muscular composed of longitudinal and circular smooth muscle layers, and tubal mucosa having 3 types of cells namely: ciliated, columnar and dark intercalated cells.

The tubal serosal covering may contain tiny nodular masses of mesothelial cells forming Walthard’s cell rests. The major conditions involving the fallopian tubes are inflammations, ectopic tubal gestation, and endometriosis.

Inflammations

Salpingitis And Pelvic Inflammatory Disease:

• Pelvic inflammatory disease (PID) by definition is a clinical syndrome characterised by signs and symptoms of ascending infection beginning in the vulva or vagina and spreading through the entire genital tract.
• Although ascending route of infection is the most common mode of spread, PID may occur following abortion and puerperium, with the use of intrauterine contraceptive devices, or from local intra-abdominal infections such as appendicitis with peritonitis. In addition, haematogenous spread may occur, though this route is more important in the pathogenesis of tuberculosis.
• Most commonly, PID occurs as a venereally-transmitted infection, chiefly caused by Chlamydia trachomatis and Neisseria gonorrhoeae. Post-abortal and postpartum infections are mainly caused by staphylococci, streptococci, coliform bacteria, clostridia and pneumococci.
• Patients generally complain of lower abdominal and pelvic pain which is often bilateral, dysmenorrhoea, menstrual abnormalities and fever with tachycardia. Long-standing chronic PID may lead to infertility and adhesions between the small intestine and pelvic organs.

Morphologic Features Grossly, the fallopian tubes are invariably involved bilaterally. The distal end is blocked by inflammatory exudate and the lumina are dilated. There may be the formation of a loculated tubo-ovarian abscess involving the tube, ovary, broad ligament and adjacent part of the uterus.

Microscopically, the appearance varies with the duration of the inflammatory process.

1. The process begins with acute salpingitis characterised by oedema and intense acute inflammatory infiltration of neutrophils involving the tubal mucosa as well as the wall. The lumen is filled with purulent exudate consisting of leucocytes and sloughed-off epithelial cells.
2. The purulent process may extend to involve the tube as well as the ovary causing salpingooophoritis and forming a tubo-ovarian abscess.
3. The escape of purulent exudate into the peritoneal cavity produces pelvic peritonitis and pelvic abscess.
4. Pyosalpinx is a distension of the fallopian tube with pus due to an occluded fimbrial end.
5. End-result of pyosalpinx after resorption of the purulent exudate is hydrosalpinx in which the tube is thin-walled, dilated and filled with clear watery fluid.
6. Acute salpingitis may resolve with treatment but some cases pass into chronic salpingitis with infiltration of polymorphs, lymphocytes and plasma cells and fibrosis.
7. Salpingitis isthmic nodosa used to be considered another manifestation of chronic salpingitis but the currently accepted pathogenesis of this lesion appears to be similar to that of adenomyosis.
8. Nevertheless, the appearance is characterised by multiple nodules containing spaces which are lined by benign tubal epithelium. Inflammatory changes are scanty or absent.

Tuberculous Salpingitis:

• Tuberculous salpingitis is almost always secondary to focus elsewhere in the body. The tubercle bacilli reach the tube, most commonly by haematogenous route, generally from the lungs, but occasionally from the urinary tract or abdominal cavity.
• Tubal tuberculosis is always present when there is tuberculosis of other female genital organs such as of endometrium, cervix and lower genital tract.
• Though infrequent in developed countries of the world, the incidence of tubal tuberculosis in developing countries like India is estimated to be about 5%; concomitant involvement of endometrium is present in about 80% of cases. It affects more commonly young women in their active reproductive life and the most common complaint is infertility.

Morphologic Features Grossly, the tube is dilated and contains purulent exudate though the fimbrial end is generally patent. The tubal peritoneum as well as the peritoneum in general is studded with yellowish tubercles.
Microscopically, typical caseating granulomas and chronic inflammation are identified in the tubal serosa, muscular and mucosa.

Ectopic Tubal Pregnancy

The term ectopic tubal pregnancy is used for the implantation of a fertilised ovum in the tube. Though ectopic pregnancy may rarely occur in the uterine horn, cornu, ovary and abdominal cavity, tubal pregnancy is by far the most common form of ectopic gestation.

• Several factors which predispose to ectopic tubal pregnancy are PID, previous tubal surgery, use of IUCD and congenital anomalies of the female genital tract. The most frequent site of tubal pregnancy is the ampullary portion and the least common is interstitial pregnancy.
• Ectopic tubal pregnancy is a potentially hazardous problem because of rupture which is followed by intraperitoneal haemorrhage.

Tumours And Tumour-Like Lesions

Tumours in the fallopian tubes are rare. Relatively more common are tumour-like conditions such as hydatids of Morgagni or parovarian cysts which are unilocular, thin-walled cysts hanging from the tubal fimbriae.

Rare tumours include adenomatoid tumours, leiomyomas, teratomas, adenocarcinomas and choriocarcinoma all of which are similar in morphology to such tumours elsewhere in the body.

Diseases of the Fallopian Tube:

• Pelvic inflammatory disease (PID) is a clinical syndrome characterised by signs and
  symptoms of ascending infection beginning in the vulva or vagina and spreading through
  the entire genital tract.
• Tuberculous salpingitis is almost always secondary to focus elsewhere in the body.
• Ectopic tubal pregnancy is the implantation of a fertilised ovum in the tube.

Ovaries

Normal Structure

The ovaries are paired bean-shaped organs hanging from either tube by a mesentery called the mesovarium, the lateral suspensory ligament and the ovarian ligament.

The lateral suspensory ligament of the ovary contains blood vessels, lymphatics and plexuses of nerves. Each ovary measures 2.5-5 cm in length, 1.5-3 cm in breadth and 0.7-1.5 cm in width and weighs 4-8 gm.

Histologically, the ovarian structure consists of covering by coelomic epithelium, an outer cortex and an inner medulla.

Coelomic epithelium: The surface of the ovary is covered by a single layer of cuboidal epithelial cells.

Cortex: During active reproductive life, the cortex is broad and constitutes the predominant component of the ovary. The cortex contains numerous ovarian follicles and their derivative structures.

• Each follicle consists of a central germ cell ovum surrounded by specialised gonadal stroma. This stroma consists of granulosa cells encircling the ovum and concentrically arranged plump spindle-shaped theca cells.
• In infancy, the granulosa cells form a single layer of cuboidal cells around the ovum but later form several layers. Granulosa cells may form Call-Exner bodies normally as well as in certain neoplastic conditions.
• Call-Exner bodies have a central small round mass of dense pink material surrounded by a rosette of granulosa cells. The granulosa component is avascular and draws its nutrition from the highly vascular theca component.
• The theca component has 2 parts—luteinised theca layer called theca interna, and the outer condensed ovarian stroma called theca externa. Granulosa cells and follicle-associated (luteinised) theca cells produce oestrogen.
• A fully mature ovarian follicle called Graafian follicle bursts releasing the ovum and becomes transformed into corpus luteum which is the principal source of progesterone that brings about a secretory endometrial pattern.
• The corpus luteum is later replaced by corpus albicans. In addition to specialised gonadal stroma and follicles, the cortex contains unspecialised ovarian stroma consisting of spindle-shaped connective tissue cells and smooth muscle fibres.

Medulla: The ovarian medulla is primarily made up medulla and may also contain clusters of hilus cells (or hilar-Leydig cells) which may have an androgenic role in contrast to the oestrogenic role of the ovarian cortex.

The major pathologic lesions of the ovary are the non-neoplastic cysts and ovarian

Non-Neoplastic Cysts

The most common non-neoplastic cysts of the ovary are tubo-ovarian inflammatory mass (discussed already) and follicular and luteal cysts. The polycystic ovarian disease of Stein-Leventhal syndrome is another cause of cystic ovary.

Follicular And Luteal Cysts:

Normally follicles and corpus luteum do not exceed a diameter of 2 cm. When their diameter is greater than 3 cm, they are termed as cysts.

• Follicular cysts are frequently multiple, filled with clear serous fluid and may attain a diameter of up to 8 cm. When large, they produce clinical symptoms.
  • Histologically, they are lined by granulosa cells. Occasionally, however, there may be difficulty in distinguishing between a large cyst of coelomic epithelial origin (serous cyst) lined by flattened epithelial cells and a cyst of follicular origin. Such cases are appropriately designated as ‘simple cysts’.
• Luteal cysts are formed by rupture and sealing of the corpus haemorrhagic. The wall of these cysts is composed of yellowish luteal tissue (lutein = yellow pigment).

Histologically, luteal cysts are commonly lined by luteinised granulosa cells. Lining by predominantly luteinised theca cells may also be seen in cystic ovaries in association with hydatidiform mole and choriocarcinoma, and rarely, in normal pregnancy.

Corpus albicans cyst is a variant of corpus luteum cyst in which there is hyalinisation in the wall and distension of the cavity with fluid.

Polycystic Ovary Disease (Stein-Leventhal Syndrome):

• Polycystic ovary syndrome (PCOS) is a syndrome characterised by oligomenorrhoea, anovulation, infertility, hirsutism and obesity in young women having bilaterally enlarged and cystic ovaries. The principal biochemical abnormalities in most patients are excessive production of androgens and low levels of pituitary follicle-stimulating hormone (FSH).
• These endocrinologic abnormalities were previously attributed to primary ovarian dysfunction as evidenced by excellent results from wedge resection of the ovary.
• The current concept of the pathogenesis of PCOS is the unbalanced release of FSH and LH by the pituitary. FSH is inhibited to low levels by testosterone but the level of LH is sufficient to cause luteinisation of ovarian theca and granulosa cells which then secrete androgen inappropriately and produce an abnormal state of anovulation.
• A hereditary basis for the syndrome has been suggested in some cases.

Morphologic Features Grossly, the ovaries are usually involved bilaterally and are at least twice the size of the normal ovary. They are grey-white in colour and studded with multiple small (0.5-1.5 cm in diameter) bluish cysts just beneath the cortex. The medullary stroma is abundant, solid and grey.

Histologically, the outer cortex is thick and fibrous. The subcortical cysts are lined by prominent luteinised theca cells and represent follicles in various stages of maturation but there is no evidence of corpus luteum.

Ovarian Tumours

Both benign and malignant tumours occur in the ovaries. About 30% of all cancers in women occur in the ovary. The ovary is the third most common site of primary malignancy in the female genital tract, preceded only by endometrial and cervical cancer.

Ovarian cancer is more common in developed countries, especially of surface epithelial and stromal origin. However, in many Asian countries, germ cell tumours have a high incidence.

Clinical Features And Classification:

• In general, benign ovarian tumours are more common, particularly in young women between the age of 20 and 40 years, and account for 80% of all ovarian neoplasms.
• Malignant tumours may be primary or metastatic, the ovary being a common site for receiving metastases from various other cancers. Some ovarian tumours are bilateral. Primary malignant ovarian tumours are more common in older women between the age of 40 and 60 years.

1. 1. Most benign and malignant ovarian tumours are discovered when they grow sufficiently to cause abdominal discomfort and distension.
   2. Urinary tract and gastrointestinal tract symptoms are frequently associated due to compression by the tumour.
   3. Ascites are common in both benign and malignant ovarian tumours.
   4. Menstrual irregularities may or may not be present.
   5. Certain specific tumours have distinctive features such as elaboration of hormones.
   6. Malignant tumours usually spread beyond the ovary to other sites before the diagnosis is made.

The current WHO-2014 classification with minor modifications is compiled. According to this classification, various groups of ovarian tumours arise from normally occurring cellular components of the ovary and are named accordingly. These groups are as under:

1. Surface epithelial-stromal tumours
2. Sex cord-stromal tumours
3. Germ cell tumours
4. Germ cell-sex cord-stromal tumours
5. Haematolymphoid tumours
6. Metastatic cancer from a nonovarian primary

Aetiology:

Unlike the other two female genital cancers (cervix and endometrium), not much is known about the aetiology of ovarian tumours. However, a few risk factors have been identified as under:

1. Nulliparity: There is a higher incidence of ovarian cancer in unmarried women and married women with low or no parity.

2. Heredity: About 10% of cases of ovarian cancer occur in women with a family history of ovarian or breast cancer. Women with hereditary breast-ovarian cancer susceptibility have a mutation in tumour suppressor BRCA genes—BRCA-1 (located on chromosome 17q) and BRCA-2 (located on chromosome 13q). The risk in BRCA-1 carriers is higher compared to that in BRCA-2 carriers.

• Interestingly, men in such families have an increased risk of prostate cancer. In addition to BRCA mutation, other molecular abnormalities in ovarian cancers include mutation of the p53 tumour suppressor gene and overexpression of ERBB-2 and K-RAS genes.

3. Complex genetic syndromes: Besides the above two main factors, several complex genetic syndromes are associated with ovarian tumours:

1. Lynch syndrome is associated with an increased risk of ovarian cancer.
2. Peutz-Jeghers syndrome with ovarian sex cord-stromal tumours.
3. Gonadal dysgenesis with gonadoblastoma.
4. Nevoid basal cell carcinoma with ovarian fibromas.

Pathogenesis:

• Although ovarian cancer is clinically considered as one disease, different morphologic types listed in the current WHO classification of ovarian tumours have different pathogenesis, variable biologic course and distinct molecular changes, which are required to be understood for the future introduction of targeted therapies for specific tumour types.
• Specific tumour typing is also important for advising particular genetic testing for tumour predisposition. In brief, the pathogenesis of surface epithelial tumours and germ cell tumours of the ovary is as follows.

Pathogenesis Of Surface Epithelial Tumours: Histologic subtypes in this group have distinctive precursor and molecular changes:

1. Low-grade serous carcinoma: It evolves through precursor stages, serous cystadenoma borderline tumour-carcinoma sequence. Common mutations in this group are KRAS or BRAF, or both.
2. Mucinous carcinoma: This too evolves through a sequence of precursor stages of mucinous cystadenoma-borderline tumour-mucinous carcinoma. Common mutations in the mucinous group are KRAS and p53.
3. Low-grade endometrioid carcinoma: The forerunner conditions for this group are endometriosis and endometrial-like hyperplasias. Common molecular changes in endometrioid tumours are microsatellite instability and mutations in β-catenin and PTEN.
4. High-grade endometrioid carcinoma: These cases may have been preceded by epithelial inclusion cysts in the affected ovary. Several molecular changes have been reported in these cases: mutations in p53, PIK3CA, and BRCA1 and BRCA2 abnormalities.
5. Clear cell carcinoma: A proportion of patients having these tumours had preceding endometriosis. Common genetic abnormalities in clear cell carcinomas are loss of heterozygosity, PTEN mutation and PIK3CA amplification.

Pathogenesis Of Ovarian Germ Cell Tumours Unlike testicular germ cell tumours, the histogenesis of ovarian germ cell tumours remains incompletely understood.

presents a simplified schematic diagram illustrating the possible pathways of ovarian germ cell tumour development which are briefly described below.

1. Parthenogenic activation of the oocyte: Oocyte activation by some unknown mechanism creates a progeny of embryonal cells which undergo a malignant transformation:

1. Malignant embryonal cells result in embryonal carcinoma directly.
2. These malignant embryonal carcinoma cells may further transform into yolk sac elements or into non-gestational choriocarcinoma.
3. Alternatively, embryonal cells may differentiate towards various forms of teratoma and its further malignant transformation (i.e. somatic cancers such as carcinomas, and sarcomas).

2. Malignant transformation of the ovarian germ cell: Pathogenesis of dysgerminoma is by a different mechanism:

1. It is derived from the malignant transformation of oocytes.
2. Other germ cell tumours may also originate indirectly from the transformation of dysgerminoma cells into malignant embryonal cells.

3. Combined pathway: Mixed germ cell tumours are derived from a combination of various germ cell tumour elements derived from either oocyte activation, or its malignant transformation.

Surface Epithelial-Stromal Tumours:

• Tumours derived from the surface (coelomic) epithelium called common epithelial tumours form the largest group of ovarian tumours. This group constitutes about 60-70% of all ovarian neoplasms and 90% of malignant ovarian tumours.
• The common epithelial tumours are of 3 major types—serous, mucinous and endometrioid, though mixtures of these epithelia may occur in the same tumour. These tumours frequently have prominent cystic components which may have a single or multiple locations and hence the descriptive prefix cystadenoma- in these tumours.
• In addition, surface epithelial tumours may differentiate along urothelium to form Brenner tumours, and along mesonephros pattern forming clear cell (mesonephros) adenocarcinoma.
• Depending upon the aggressiveness, the surface epithelial tumours are divided into 3 groups: clearly benign, clearly malignant, and borderline (or atypical proliferating or low-grade)malignant tumours. In general, the criteria for diagnosis of these 3 grades of aggressiveness are as follows:

1. Clearly benign tumours: are lined by a single layer of well-oriented columnar epithelium. Papillary projections, if present, are covered by the same type of epithelium without any invasion into the fibrovascular stromal stalk.

2. Clearly malignant tumours: have anaplastic epithelial component, multilayering, loss of basal polarity and unquestionable stromal invasion. The prognosis of these tumours is very poor.

3. Borderline (atypical proliferating) tumours: tumours with low malignant potential have some morphological features of malignancy, apparent detachment of cellular clusters from their site of origin and essential absence of stromal invasion.

• Morphological features of malignancy which may be present in varying combinations include.
• stratification (2-3 layers) of the epithelial cells but generally maintained basal polarity of nuclei, moderate nuclear abnormalities, and some mitotic activity. This group has a much better prognosis than frankly malignant tumours of the ovary.
• Based on this categorisation of biological behaviour, groups of surface epithelial ovarian tumours are described here.

Serous Tumours:

• Serous tumours comprise the largest group constituting about 50% of all surface ovarian tumours and 40% of malignant ovarian tumours. They are called serous tumours because of the presence of clear, watery, serous fluid in these predominantly cystic tumours.
• About 60% of serous tumours are benign, 15% borderline and 25% malignant. Only 20% of benign tumours occur bilaterally, whereas 65% of both borderline and malignant serous tumours have bilateral ovarian involvement.
• Serous tumours occur most commonly in 2nd to 5th decades of life, the malignant forms being more frequent in later life.

Histogenesis of the serous tumours is by metaplasia from the surface (coelomic) epithelium
or mesothelium which differentiates along tubal-type of epithelium.

Morphologic Features Grossly, benign, borderline and malignant serous tumours are large (above 5 cm in diameter) and spherical masses. Small masses are generally unilocular while the larger serous cysts are multiloculated similar to the mucinous variety, or may have one large loculus and many daughter loculi in its wall.

These serious variants contain serous fluid rather than the viscid fluid of mucinous tumours. Malignant serous tumours may have solid areas in the cystic mass.

Exophytic as well as intracystic papillary projections may be present in all grades of serous tumours but are more frequent in malignant tumours termed papillary serous cystadenocarcinomas.

1. Histologically, the features are as follows: Serous cystadenoma: is characteristically lined by properly-oriented low columnar epithelium which is sometimes ciliated resembling tubal epithelium. Microscopic papillae may be found. Tumours having prominent stromal tissue are called serous cystadenofibroma
2. Borderline (atypical proliferating) serous tumour: usually has epithelial hyperplasia in the form of stratification (2-3 layers), tufting, cribriform and micropapillary arrangement. Detached cell clusters are often present.
   • The epithelial cells show mild to moderate cytologic atypia and minimal mitotic activity but there is the absence of stromal invasion or destruction.
3. Serous cystadenocarcinoma: has multilayered malignant cells which show loss of polarity, the presence of solid sheets of anaplastic epithelial cells and definite evidence of stromal invasion.
   • Papillae formations are more frequent in malignant variety and may be associated with psammoma bodies but the mere presence of psammoma bodies is not indicative of malignancy.

Mucinous Tumours:

• Mucinous tumours are somewhat less common than serous tumours and constitute about 30% of all ovarian tumours. Over 80% are benign, 10-15% are borderline (atypical proliferating) and 5% are malignant. These predominantly cystic tumours contain mucin which was previously described as pseudomucin.
• In mucinous tumours associated with mucinous ascites ( pseudomyxoma peritonei), it is important to assess the state of the appendix because mucinous tumours of the ovary and appendix are clearly linked. As compared with serous tumours, mucinous tumours are more commonly unilateral.
• Benign mucinous tumours occur bilaterally in 5% of cases while the vast majority of bilateral borderline and malignant mucinous tumours are metastatic to the ovaries.
• Thus, in general, the diagnosis of primary ovarian mucinous adenocarcinoma should be generally made after excluding metastatic tumours to the ovary, while bilateral mucinous adenocarcinoma of the ovary is invariably metastatic deposits to the ovary.
• Another variant of mucinous carcinoma metastatic to the ovary having peculiar features, the Krukenberg tumour, is discussed on page 786. Mucinous tumours occur principally between 2nd and 5th decades of life. Mucinous cystadenocarcinoma usually develops in women above the age of 40 years.

Morphologic Features Grossly, mucinous tumours are much larger than serous tumours. They are smooth-surfaced cysts with characteristic multilocation containing thick and viscid gelatinous fluid.

Benign tumours generally have thin walls and septa dividing the loculi are also thin and often translucent, but malignant varieties usually have thickened areas. In younger patients, an element of teratoma may be recognised in the firm areas of the tumour.

Histologically, the most distinctive feature is the characteristic tall columnar nonciliated epithelium similar to the intestinal l type or endocervical (Mullerian) type, lining the loculi. Other features are as under:

1. Mucinous cystadenoma is lined by a single layer of these cells having basal nuclei and apical mucinous vacuoles. There is very little tendency for papillary proliferation of the epithelium. Tumours with more abundant stroma are called mucinous cystadenofibromas.
2. Borderline (atypical proliferating) mucinous tumour is identified by the same histologic criteria as for borderline serous tumour i.e. stratification (usually 2-3 cells thick) of typical epithelium without stromal invasion.
3. Mucinous cystadenocarcinoma likewise is characterised by the piling up of malignant epithelium, at places forming solid sheets, papillary formation, adenomatous pattern and infiltration into stroma with or without pools of mucin.

Endometrioid Tumours:

• Endometrioid tumours comprise about 5% of all ovarian tumours. Most of them are malignant accounting for about 20% of all ovarian cancers. Benign and borderline forms are very rare.
• They are called endometrioid carcinomas because of the close resemblance of histologic pattern to that of uterine endometrioid adenocarcinoma. About 40% of ovarian endometrioid carcinomas have bilateral involvement. About 15-30% of cases have coexistent endometrial adenocarcinoma.
• Histogenesis of these tumours in a majority of cases is believed to be from ovarian coelomic epithelium differentiating towards the endometrial type of epithelium.
• In view of the presence of endometriosis in a few cases of endometrioid tumours, the suggestion of malignant transformation of endometriosis has been proposed.

Morphologic Features Grossly, these tumours are partly solid and partly cystic and may have foci of haemorrhages, especially in the benign variety.

Histologically, endometrioid adenocarcinoma is distinguished from serous and mucinous carcinomas by a typical glandular pattern that closely resembles that of uterine endometrioid adenocarcinoma. There may be foci of squamous metaplasia justifying the diagnosis of adenoacanthoma.

Papillary patterns and foci of serous and mucinous carcinoma may also be found. Benign variety closely resembles endometriosis with cystic change. There are no clearly defined criteria for borderline endometrioid tumours.

Clear Cell (Mesonephroid) Tumours:

• Clear cell (mesonephros) tumours are almost always malignant and comprise about 5% of all ovarian cancers; a rare benign variety is called clear cell adenofibroma. They are termed clear cell or mesonephros carcinomas because of the close histologic resemblance to renal adenocarcinoma.
• They have also been called mesonephros or mesonephric carcinoma because of their questionable relationship to the mesonephric structures. Clear cell carcinoma is frequently associated with endometriosis.

Morphologic Features Grossly, these tumours are large, usually unilateral, partly solid and partly cystic. Less than 10% are bilateral.

Histologically, clear cell or mesonephroid carcinoma is characterised by tubules, glands, papillae, cysts and solid sheets of tumour cells resembling cells of renal adenocarcinoma i.e. clear cells having abundant eosinophilic cytoplasm rich in glycogen.

Brenner Tumour:

• Brenner tumours are uncommon and comprise about 2% of all ovarian tumours. They are characteristically solid ovarian tumours. Less than 10% of Brenner’s tumours are bilateral. Most Brenner tumours are benign.
• Rarely, a borderline form is encountered called proliferating Brenner tumour while the one with carcinomatous change is termed a malignant Brenner tumour.
• Histogenesis of the tumour is from coelomic epithelium by metaplastic transformation into transitional epithelium (urothelium).

Morphologic Features Grossly, Brenner’s tumour is typically a solid, yellow-grey, firm mass of variable size. Occasionally, a few scattered tiny cysts may be present on the cut section.

Histologically, Brenner’s tumour consists of nests, masses and columns of epithelial cells, scattered in the fibrous stroma of the ovary.

These epithelial cells resemble urothelial cells which are ovoid in shape, having clear cytoplasm, and vesicular nuclei with characteristic nuclear grooves called ‘coffee-bean’ nuclei.

Germ Cell Tumours:

• Ovarian germ cell tumours arising from germ cells which produce the female gametes (i.e. ova) account for about 15-20% of all ovarian neoplasms. The neoplastic germ cells may follow one of the several lines of differentiation as already discussed and illustrated schematically.
• Nearly 95% of them are benign and occur chiefly in young females, the vast majority of them being benign cystic teratomas (dermoid cysts). The remainder is malignant germ cell tumours comprising a variety of morphologic forms occurring chiefly in children and young adults and are highly aggressive tumours.
• Most germ cell tumours of the ovaries have their morphologic counterparts in the testis sometimes germ cell tumours also occur at extragonadal sites (for example mediastinum, retroperitoneum, sacrococcygeal region, and pineal gland).
• However, their frequency is. nancy at different sites varies example benign cystic teratoma or dermoid cyst that is so common in ovaries is extremely rare in the testis.

Teratomas:

• Teratomas are tumours composed of different types of tissues derived from the three germ cell layers ectoderm, mesoderm and endoderm, in varying combinations.
• In view of the wide spectrum of tissue elements found in these teratomas, their histogenesis has been a matter of speculation for a long time. Cytogenetic studies have revealed that these tumours arise from a single germ cell (ovum) after its first meiotic division.
• Teratomas are divided into 3 types mature (benign), immature (malignant), and monodermal teratomas.

Mature (Benign) Teratoma: Vast majority of ovarian teratomas are benign and cystic and have the predominant ectodermal elements, often termed clinically as dermoid cysts.

Infrequently, mature teratoma may be solid and benign and has to be distinguished from immature or malignant teratoma. Benign cystic teratomas are more frequent in young women during their active reproductive life. The tumour is bilateral in 10% of cases.

Grossly, benign cystic teratoma or dermoid cyst is characteristically a unilocular cyst, 10-15 cm in diameter, usually lined by the skin and hence its name. On sectioning, the cyst is filled with paste-like sebaceous secretions and desquamated keratin admixed with masses of hair.

The cyst wall is thin and opaque grey-white. Generally, in one area of the cyst wall, a solid prominence is seen (Rokitansky’s protuberance) where tissue elements such as a tooth, bone, cartilage and various other odd tissues are present. Less often, the cyst may contain mucoid material.

Microscopically, the most prominent feature is the lining of the cyst wall by stratified squamous epithelium and its adnexal structures such as sebaceous glands, sweat glands and hair follicles.

• Though ectodermal derivatives are the most prominent features, tissues of mesodermal and endodermal origin are also commonly present. Various other tissue components frequently found in teratomas are bronchus, intestinal epithelium, cartilage, bone, tooth, smooth muscle, neural tissue, salivary gland, retina, pancreas and thyroid tissue.
• Thus, viewing a benign cystic teratoma in different microscopic fields reveals a variety of mature differentiated tissue elements, producing kaleidoscopic patterns.
• Less than 1% of patients with a dermoid cyst develop malignant transformation of one of the tissue components, most commonly squamous cell carcinoma.

Immature (MALIGNANT) Teratoma: Immature or malignant teratomas of the ovary are rare and account for approximately 0.2% of all ovarian tumours.

They are predominantly solid tumours that contain immature or embryonal structures in contrast to the mature or adult structures of benign teratomas. They are more common in prepubertal adolescents and young women under 20 years of age.

Grossly, malignant teratoma is a unilateral solid mass which on cut section shows a characteristic variegated appearance revealing areas of haemorrhages, necrosis, tiny cysts and heterogeneous admixture of various tissue elements.

Microscopically, parts of the tumour may show mature tissues, while most of it is composed of immature tissues having an embryonic appearance.

Immature tissue elements may differentiate towards cartilage, bone, glandular structures, neural tissue etc, and are distributed in spindle-shaped myxoid or undifferentiated sarcoma cells.

• An important factor in grading and determining the prognosis of immature teratoma is the relative amount of immature neural tissue.
• Immature neural tissue can undergo maturation even at the site of metastases over a period of years. Immature teratoma may contain areas of other germ cell tumours such as endodermal sinus tumours, embryonal carcinoma and choriocarcinoma.

Grade I tumours having relatively mature elements and confined to the ovary have a good prognosis, whereas grade III immature teratomas with metastases have an extremely poor prognosis.

Monodermal (Specialised) Teratoma: Monodermal or highly specialised teratomas are rare and include 2 important examples struma ovarii and carcinoid tumour.

• Struma ovarii It is a teratoma composed exclusively of thyroid tissue, recognisable grossly as well as microscopically. Most often, the tumour has the appearance of a follicular adenoma of the thyroid. Rarely, struma ovarii may be hyperfunctioning and produce hyperthyroidism.
• Carcinoid tumour This is an ovarian teratoma arising from argentaffin cells of intestinal epithelium in the teratoma. Ovarian carcinoids may also hyperfunction and produce 5-HT and consequent carcinoid syndrome.

Struma-carcinoid This is a rare combination of struma ovarii and ovarian carcinoid.

Dysgerminoma:

Dysgerminoma is an ovarian counterpart of seminoma of the testes. Dysgerminomas comprise about 2% of all ovarian cancers. They occur most commonly in the 2nd to 3rd decades. About 10% of them are bilateral. About 10% of patients with dysgerminoma have elevated hCG levels in the plasma. All dysgerminomas are malignant and extremely radiosensitive.

Morphologic Features Grossly, dysgerminoma is a solid mass of variable size. The cut section of the tumour is grey-white to pink, lobulated, soft and fleshy with foci of haemorrhages and necrosis.

Histologically, their structure is similar to that of the seminoma of the testis. The tumour cells are arranged in diffuse sheets, islands and cords separated by scanty fibrous stroma.

The tumour cells are uniform in appearance and large, with vesicular nuclei and clear cytoplasm rich in glycogen. The fibrous stroma generally contains lymphocytic infiltrate and sometimes may have sarcoid-like granulomas.

Endodermal Sinus (Yolk Sac) Tumour:

Endodermal sinus tumour or yolk sac tumour is the second most common germ cell tumour occurring most frequently in children and young women. More often, endodermal sinus tumour is found in combination with other germ cell tumours rather than in pure form.

The tumour is rich in alpha-fetoprotein (AFP) and α-1-antitrypsin. The tumour is usually unilateral but may metastasise to the other ovary. It is a highly aggressive and rapidly growing tumour.

Morphologic Features Grossly, the tumour is generally solid with areas of cystic degeneration.

Histologically, like its testicular counterpart, the endodermal sinus tumour is characterised by the presence of papillary projections having a central blood vessel with a perivascular layer of anaplastic embryonal germ cells.

Such structures resemble the endodermal sinuses of the rat placenta (Schiller-Duval body) from which the tumour derives its name. It is common to find intracellular and extracellular PAS-positive hyaline globules which are composed of AFP

Choriocarcinoma:

Choriocarcinoma in females is of 2 types gestational and non-gestational. Gestational choriocarcinoma of placental origin is more common and considered separately later.

Pure primary non-gestational choriocarcinoma of ovarian origin is rare while its combination with other germ cell tumours is seen more often. The patients are usually young girls under the age of 20 years.

Morphologically, ovarian choriocarcinoma is identical to gestational choriocarcinoma. Ovarian choriocarcinoma is more malignant than that of placental origin and disseminates widely via the bloodstream to the lungs, liver, bone, brain and kidneys. The marker for both types of choriocarcinoma is hCG.

Other Germ Cell Tumours:

Certain other germ cell tumours occasionally encountered in the ovaries are embryonal carcinoma, polyembryoma and mixed germ cell tumours. All these tumours are morphologically identical to similar tumours occurring in the testes.

Sex Cord-Stromal Tumours:

Sex cord-stromal tumours of the ovaries comprise 5-10% of all ovarian neoplasms. They arise from specialised ovarian stromal cells of the developing gonads.

Thus, these include tumours originating from granulosa cells, theca cells and Sertoli-Leydig cells. Since sex cord-stromal cells have functional activity, most of these tumours elaborate steroid hormones which may have feminising effects or masculinising effects.

Granulosa-Theca Cell Tumours:

Granulosa-theca cell tumours comprise about 5% of all ovarian tumours. The group includes pure granulosa cell tumours, pure thecomas, a combination of granulosa-theca cell tumours and fibromas.

Granulosa Cell Tumour: Pure granulosa cell tumours may occur at all ages. These tumours invade locally but occasionally may have more aggressive and malignant behaviour. Recurrences after surgical removal are common.

Most granulosa cell tumours secrete oestrogen which may be responsible for precocious puberty in young girls, or in older patients may produce endometrial hyperplasia, endometrial adenocarcinoma and cystic disease of the breast. Rarely, granulosa cell tumours may elaborate androgen which may have a masculinising effect on the patient.

Grossly, a granulosa cell tumour is a small, solid, partly cystic and usually unilateral tumour. The cut section of solid areas is yellowish-brown.

Microscopically, the granulosa cells are arranged in a variety of patterns including micro- and macrofollicular, trabecular, bands and diffuse sheets.

• The microfollicular pattern is characterised by the presence of characteristic rosette-like structures, Call-Exner bodies, having a central rounded pink mass surrounded by a circular row of granulosa cells.
• Morphologic appearance alone is a poor indicator of clinical malignancy but the presence of metastases and invasion outside the ovary are considered better indicators of aggressive behaviour.

Thecoma: Pure thecomas are almost always benign. They occur more frequently in postmenopausal women. Thecomas are typically oestrogenic.

Endometrial hyperplasia, endometrial carcinoma and cystic disease of the breast are some of its adverse effects. Occasionally a thecoma may secrete androgen and cause virilisation.

Grossly, the thecoma is a solid and firm mass, 5-10 cm in diameter. The Cut section is yellowish).

Microscopically, thecoma consists of spindle-shaped theca cells of the ovary admixed with a variable amount of hyalinised collagen. The cytoplasm of theca cells is lipid-rich and vacuolated which reacts with lipid stains.

Granulosa-Theca Cell Tumour: A mixture of both granulosa and theca cell elements in the same ovarian tumour is seen in some cases with the elaboration of oestrogen.

Fibroma Fibromas of the ovary are more common and account for about 5% of all ovarian tumours. These tumours are hormonally inert but some of them are associated with pleural effusion and benign ascites termed Meig’s syndrome.

Grossly, these tumours are large, firm and fibrous, usually unilateral masses.

Histologically, they are composed of spindle-shaped well-differentiated fibroblasts and collagen. Sometimes, the combination of fibroma and thecoma is present called fibrosarcoma

Sertoli-Leydig Cell Tumours:

Tumours containing Sertoli and Leydig cells in varying degrees of maturation comprise SertoliLeydig cell tumours, also called neuroblastomas or arrhenoblastomas. Characteristically, they produce androgens and masculinise the patient. Less often, they may elaborate on oestrogen. Their peak incidence is in the 2nd to 3rd decade of life.

Grossly, the Sertoli-Leydig cell tumour resembles a granulosa-theca cell tumour.

Histologically, these tumours recapitulate to some extent the structure of the testis. Three histologic types are distinguished:

1. Well-differentiated neuroblastoma is composed almost entirely of Sertoli cells or Leydig cells forming well-defined tubules.
2. Tumours with intermediate differentiation have a biphasic pattern with the formation of solid sheets in which abortive tubules are present.
3. Poorly-differentiated or sarcomatoid variety is composed of spindle cells resembling sarcoma with interspersed scanty Leydig cells.

Gynandroblastoma:

Gynandroblastoma is an extremely rare tumour in which there is a combination of patterns of both granulosa-theca cell tumour and Sertoli-Leydig cell tumour. The term gynandroblastoma stands for a combination of female (gyn) and male (andro).

Miscellaneous Tumours:

Lipid Cell Tumours: There is a small group of ovarian tumours that appears as soft yellow or yellow-brown nodules which on histologic examination are composed of large lipid-laden cells.

These cells resemble Leydig, lutein and adrenal cortical cells. Examples of these tumours are hilus cell tumours, adrenal rest tumours and luteomas. These tumours elaborate steroid hormones and are responsible for various endocrine dysfunctions such as Cushing’s syndrome and virilisation.

Gonadoblastoma: This is a rare tumour occurring exclusively in dysgenetic gonads, more often in phenotypic females and in hermaphrodites. Dysfunctions include virilism, amenorrhoea and abnormal external genitalia.

Microscopically, gonadoblastoma is composed of a mixture of germ cell and sex cord components.

Metastatic Tumours:

• About 10% of ovarian cancers are secondary carcinomas. Metastasis may occur by lymphatic or haematogenous route but direct extension from adjacent organs (for example uterus, fallopian tube and sigmoid colon) occurs frequently. Bilaterality of the tumour is the most helpful clue to the diagnosis of metastatic tumour.
• The most common primary sites from where metastases to the ovaries are encountered are carcinomas of the breast, genital tract, gastrointestinal tract (for example stomach, colon appendix, pancreas, biliary tract) and haematopoietic malignancies.

Krukenberg Tumour:

Krukenberg tumour is a distinctive bilateral tumour metastatic to the ovaries by the trans coelomic spread. The tumour is generally secondary to a non-ovarian primary, most often gastric carcinoma but other primary sites where signet ring carcinomas occur (for example colorectal, breast, appendix, pancreaticobiliary and endometrial cancers) may also produce Krukenberg tumours in the ovary. Metastatic mucinous ovarian tumours have to be distinguished from primary mucinous ovarian carcinoma; salient contrasting features are given.

Grossly, the Krukenberg tumour forms moderately large, rounded or kidney-shaped, firm, multinodular masses in both ovaries. The cut section shows a grey-white to yellow, firm, fleshy tumour and may have areas of haemorrhage and necrosis.

Microscopically, it is characterised by the presence of mucin-filled signet ring cells which may lie singly or in clusters. It is accompanied by a cellular proliferation of ovarian stroma in a storiform pattern.

FIGO staging of ovarian cancer is given.

Diseases of Ovaries:

• Non-neoplastic lesions of the ovary are tubo-ovarian inflammatory mass, follicular and luteal cysts, and polycystic ovarian disease of Stein-Leventhal syndrome.
• Tumours derived from the surface (coelomic) epithelium called common epithelial tumours form the largest group of ovarian tumours and include serous and mucinous tumours which may be benign, borderline or malignant. Other types are endometrioid, clear cell type and Brenner.
• Germ cell tumours of the ovary are similar to testicular germ cell tumours but nearly 95% of them are benign and occur chiefly in young females, the vast majority of them being benign cystic teratomas (dermoid cysts).
• Sex cord-stromal tumours of the ovaries are less frequent and include tumours originating from granulosa cells, theca cells and Sertoli-Leydig cells.
• About 10% of ovarian cancers are secondary carcinomas; an important example of bilateral signet ring carcinoma metastatic to the ovary, commonly from the GI tract and breast.

Placenta

Normal Structure

• At term, the normal placenta is a blue-red, rounded, flattened and discoid organ 15-20 cm in diameter and 2-4 cm thick. It weighs 400-600 gm or about one-sixth the weight of the newborn.
• The umbilical cord is about 50 cm long and contains two umbilical arteries and one umbilical vein attached to the foetal surface.
• The placenta is derived from both maternal and foetal tissues. The maternal portion of the placenta has irregular grooves dividing it into cotyledons which are composed of sheets of decidua basalis and remnants of blood vessels.
• The foetal portion of the placenta is composed of numerous functional units called chorionic villi and comprise the major part of the placenta at term. The villi consist of a loose fibrovascular stromal core and a few phagocytic (Höffbauer’s) cells.
• The villous core is covered by an inner layer of cytotrophoblast and an outer layer of syncytiotrophoblast. The basement membrane separating the foetal capillaries in the villous core and the trophoblast forms zones where nutrients and metabolites are transported between the mother and the foetus.
• Such zones are called vasculosyncitial membranes. The placenta secretes a number of hormones and enzymes into the maternal blood.
• These include human chorionic gonadotropin (hCG), human placental lactogen (HPL), chorionic thyrotropin and adrenocorticotropin hormone which partake in oestrogen and progesterone metabolism.
• Diseases related to pregnancy and the placenta are numerous and form the subject matter of discussion in obstetrics. Certain conditions such as inflammation of the placenta and chorionic membranes (placentitis and chorioamnionitis), placental gross abnormalities (for example placenta accreta, placenta praevia and twin placenta etc), toxaemia of pregnancy (eclampsia and preeclampsia) and products of gestation seen in abortions need mere mention only here.
• However, gestational trophoblastic diseases resulting from benign and malignant overgrowth of trophoblast hydatidiform mole (complete and partial mole) and choriocarcinoma respectively, are significant morphologic lesions and are discussed below and their features contrasted.

Hydatidiform Mole

The word ‘hydatidiform’ means a drop of water and ‘mole’ for a shapeless mass. A hydatidiform mole is defined as an abnormal placenta characterised by 2 features:

1. Enlarged, oedematous and hydropic change of the chorionic villi which become vesicular.
2. A variable amount of circumferential trophoblastic proliferation.

• • Most workers consider hydatidiform mole as a benign tumour of placental tissue with the potential for developing into choriocarcinoma, while some authors have described mole as a degenerative lesion though capable of neoplastic change. The incidence of molar pregnancy is high in teenagers and in older women.
  • For unknown reasons, the frequency of hydatidiform mole varies in different regions of the world; the incidence in Asia and Central America is about 10 times higher than in the United States. The incidence is higher in poorer socioeconomic classes of people.
  • The hydatidiform mole may be non-invasive or invasive. Two types of non-invasive moles are distinguished complete (classic) and partial. Pathogenesis of these 2 forms is different:

Complete (classic) mole: by cytogenetic studies has been shown to be derived from the father (androgenesis) and has 46, XX or rarely 46, XY chromosomal pattern. Complete mole bears a relationship to choriocarcinoma.

Partial mole: is mostly triploid (69, XXY or 69, XXX) and rarely tetraploid. Partial mole rarely develops into choriocarcinoma.

• Clinically, the condition appears in the 4th-5th month of gestation and is characterised by an increase in uterine size, vaginal bleeding and often with symptoms of toxaemia.
• Frequently, there is a history of the passage of grape-like masses per vaginum. About 1% of women with molar pregnancy develop it again in a subsequent pregnancy.
• The single most significant investigation forming the mainstay of management is the serial determination of β-hCG which is elevated more in both blood and urine as compared with the levels in normal pregnancy. Removal of the mole is accompanied by a fall in β-hCG levels.
• A more ominous behaviour is associated with no fall in β-hCG levels after the expulsion of the mole. About 10% of patients with complete moles develop into invasive moles and 2.5% into choriocarcinoma.

Morphologic Features: The pathologic findings in non-invasive (complete and partial) and invasive moles are different

Complete (Classic) Mole Grossly, the uterus is enlarged and characteristically filled with grape-like vesicles up to 3 cm in diameter. The vesicles contain clear watery fluid. Rarely, a macerated foetus may be found.

Microscopically, the features are quite typical. These are as under:

1. Large, round, oedematous and acellular villi due to hydropic degeneration forming central cisterns.
2. Decreased vascularity of villous stroma.
3. Trophoblastic proliferation in the form of masses and sheets of both cytotrophoblast and syncytiotrophoblast is generally circumferential around the villi.

Partial Mole Grossly, the uterus is generally smaller than expected and contains some cystic villi, while part of the placenta appears normal. A foetus with multiple malformations is often present.

Microscopically, some of the villi show oedematous change while others are normal or even fibrotic. Trophoblastic proliferation is usually slight and focal.

Invasive (Destructive) Mole (Chorioadenoma Destruens) Grossly, invasive mole shows the invasion of the molar tissue into the uterine wall which may be a source of haemorrhage. Rarely, molar tissue may invade the blood vessels and reach the lungs.

Microscopically, the lesion is benign and identical to a classic mole but has the potential for haemorrhage. It is always associated with persistent elevation of β-hCG levels.

Choriocarcinoma:

• Gestational choriocarcinoma is a highly malignant and widely metastasising tumour of trophoblast (non-gestational choriocarcinoma is described on page 784). Approximately 50% of cases occur following hydatidiform mole, 25% following spontaneous abortion, 20% after an otherwise normal pregnancy, and 5% develop in an ectopic pregnancy.
• Choriocarcinoma follows the geographic pattern of hydatidiform mole, being more common in Asia and Africa than in the United States and Europe.
• Clinically, the most common complaint is vaginal bleeding following a normal or abnormal pregnancy. Occasionally, the patients present with metastases in the brain or lungs.
• The diagnosis is confirmed by the demonstration of persistently high levels of β-hCG in the plasma and urine. Widespread haematogenous metastases are early and frequent in choriocarcinoma if not treated; these are found chiefly in the lungs, vagina, brain, liver and kidneys.

Morphologic Features Grossly, the tumour appears as a haemorrhagic, soft and fleshy mass. Sometimes, the tumour may be small, often like a blood clot, in the uterus. Microscopically, the characteristic features are as under:

1. Absence of identifiable villi.
2. Masses and columns of highly anaplastic and bizarre cytotrophoblast, intermediate trophoblast and syncytiotrophoblast cells are intermixed.
3. Invariable presence of haemorrhages and necrosis.
4. Invasion of the underlying myometrium and other structures, blood vessels and lymphatics.

• • Gestational choriocarcinoma and its metastases respond very well to chemotherapy while non-gestational choriocarcinoma is quite resistant to therapy and has a worse prognosis.
  • With hysterectomy and chemotherapy, the cure rate of choriocarcinoma has remarkably improved from a dismal 20 to 70% 5-year survival rate and almost total cure in localised tumours.
  • The effectiveness of treatment is also monitored by serial β-hCG determinations. Death from choriocarcinoma is generally due to fatal haemorrhage in the CNS or lungs or from pulmonary insufficiency

Diseases of the Placenta:

• Hydatidiform mole is a benign or degenerative condition of the placenta characterised by a hydropic change in the villi and circumferential trophoblastic proliferation. It may be noninvasive or invasive, the former being complete (classic) or partial mole.
• Gestational choriocarcinoma is a highly malignant and widely metastasising tumour of trophoblast but responds better to chemotherapy compared to gonadal choriocarcinoma.