FEMALE REPRODUCTIVE SYSTEM – PATHOLOGY 3

DUB, ENDOMETRIOSIS ,ENDOMETRITIS, ADENOMYOSIS,

ENDOMETRIAL HYPERPLASIA,ENDOMETRIAL CARCINOMA , TUMORS
OF MYOMETRIUM, TURNER SYNDROME

DR. INDU
PROF. PATHOLOGY
LEARNING OBJECTIVES

• Discuss in detail about Dysfunctional Uterine bleeding

• Describe endometriosis, endometritis and adenomyosis

• Explain endometrial hyperplasia

• Describe microscopic features of leiomyoma

• Discuss about endometrial carcinoma and leiomyosarcoma

 Dysfunctional Uterine bleeding

Definition:
Bleeding unrelated to any anatomic cause; Caused by hormonal imbalance
• Anovulatory DUB
• Inadequate luteal phase
• Irregular shedding of endometrium
 Dysfunctional Uterine bleeding

Age group Causes of abnormal uterine bleeding

Prepuberty Precocious puberty (Hypothalamic, pituitary or ovarian origin)

Adolescence DUB Anovulatory cycle, coagulation disorders

Complications of pregnancy: (abortion, trophoblastic disease, ectopic pregnancy)

Organic lesions : polyps, leiomyoma, endometrial hyperplasia, Ca endo
Reproductive age group
DUB: Anovulatory cycles and ovulatory dysfunctional bleeding (inadequate luteal
phase)

DUB: Anovulatory cycle; irregular shedding

Perimenopausal
Organic lesions (hyperplasia, carcinoma, polyps)
Endometrial atrophy
Post menopausal Organic lesions (hyperplasia, carcinoma, polyps)
 Anovulatory DUB Inadequate luteal phase

• Occurs at extremes of reproductive life 1)Ovulatory type of DUB

Menarche to age 20 years 2)Inadequate maturation of the corpus luteum

Perimenopausal period Inadequate synthesis of progesterone

• Excessive estrogen stimulation relative to Delay in development of secretory phase

progesterone Decreased serum 17 hydroxyprogesterone on
• Absent secretory phase of the cycle day 21

• Produces endometrial hyperplasia and bleeding

Irregular shedding of endometrium

1)Ovulatory type of DUB

2)Persistent luteal phase with continued secretion of progesterone
3)Mixture of proliferative and secretory glands in the menstrual effluent
Endometritis
Acute : Bacterial - parturition/ miscarriage/ C. trachomatis and N. gonorrhoea

• Predominant inflammatory infiltrate – Neutrophils in the superficial endometrium and glands ;

stromal lympho-plasmacytic infiltrate

Chronic – lymphocytes (normally present) and plasma cells. Prominent lymphoid follicles seen in
Chlamydial infection

Clinical features:

• Fever, abdominal pain, menstrual abnormalities, vaginal discharge

Complications – infertility & ectopic pregnancy

& lymphocytes

Plasma cells and lymphocytes

Chronic Endometritis: Tuberculosis
 Endometriosis
Defined by presence of endometrial gland and stroma in a location outside
the uterus.

 Infertility, dysmenorrhea & pelvic pain , Dyspareunia, Painful defecation,

dysuria

 Involves ovaries, uterine ligaments, rectovaginal septum, cul-de sac;

peritoneal cavity, large and small bowel and appendix; mucosa of the
cervix, vagina and fallopian tube or laparotomy scar.

 Distant areas such as lung, heart, skeletal muscle bone

 Endometriosis - Pathogenesis

1. Metaplastic differentiation of
celomic epithelium
2. Lymphatic dissemination
3. Regurgitation of endometrial fluid
4. Dissemination through pelvic vein
Chocolate cyst of the ovary
 Endometriosis ovary - microscopy

Section showing the endometrial glands and stroma (both components are
necessary to make a histologic diagnosis of endometriosis. If only the glands
were present, it could be mistaken for metastatic well-
differentiated adenocarcinoma. Clinical history is important to the surgical
pathologist in a case like this.
 Adenomyosis
 Penetration / growth of endomerial gland and stroma into myometrium (internal
endometriosis) 2-3mm from basalis

 Coexist with endometriosis ; hyperestrogenic conditions; Age -30-40 yrs

 Bleeding ;No typical cyclical changes associated with menstruation

 Localized swelling in myometrium called endometrioma (adenoma) a misnomer

Clinical d/d : Fibroid

Clinical features: Menorrhagia. Pelvic pain, Dysmenorrhea
Adenomyosis – enlarged uterus
 Endometrial Hyperplasia
Etiology: Prolonged estrogen stimulation
Causes :
Polycystic ovary ( Stein – Leventhal syndrome)
Functional Granulosa -Theca cell tumor
Perimenopausal ( increased estrogen and failure of ovulation )
Prolonged administration of “estrogen alone” pills
• Obesity; Early menarche / late menopause/Nulliparity
Pathogenesis: Inactivation of tumor suppressor gene PTEN

Patients with Cowden syndrome( germline mutation of PTEN have a

high incidence of endo ca
 Morphology
Hyperplasia is classified based on architectural overcrowding and the presence or absence of
atypia :

 Simple endometrial without atypia - No risk of endometrial carcinoma (PTEN )

 Hyperplasia with Atypia - risk of endometrial carcinoma (8%)

 Complex hyperplasia without atypia - <3% risk of endometrial carcinoma (hMLH1)

 Complex hyperplasia with atypia- 20- 50% risk of endometrial carcinoma associated with
(KRAS)

 Monitor with serial biopsy. Endometrial carcinoma grade 1 ( β katenin and PI3K CA)
 Complex hyperplasia without atypia
Simple cystic hyperplasia

• Increased number of cystically dilated glands

Increased number of dilated glands with branching
• No glandular crowding Glandular crowding
• increased gland to stroma ratio
Complex hyperplasia with atypia -
Atypical hyperplasia

Clinical features and treatment

 Irregular Bleeding
 Menometrorrhagia
 T/T progestin therapy alone ? 50%
recurrence ; 25% progress to endometrial
carcinoma(Increased risk for progression to
endometrial adenocarcinoma)
 In young women trial with progestin
•
 Hysterectomy
Glandular crowding with back to back arrangement of glands,
• minimal connective tissue
• Glands lined by dysplastic cells - cellular atypia
• Increased risk of endometrial cancer ( 20-25%)
 Polyp &Tumors of the Uterus
Benign:
• Endometrial polyp
• Leiomyoma
Malignant:
• Leiomyosarcoma (rare)

• Endometrial carcinoma

• Malignant mixed mullerian tumor (MMMT)

• Tumors of the endometrium with stromal differentiation: Adenosarcoma and stromal

tumors
Endometrial Polyp (benign)
 Clinical : Benign polyps may cause
uterine bleeding.
 Arise from the basalis
 0.5-3 cm but may be larger
 M/E: cystically dilated Endometrial
glands; stromal cells are
monoclonal and constitute the
neoplastic component of the polyp
 Any age, commonly detected in
peri menopausal women
 Risk of carcinoma: Rare
 Leiomyoma( Fibroid)
• Benign smooth muscle tumor
• More common in black Americans than whites
• Estrogen , OCPs stimulate their growth
• Increases in size as the pregnancy progresses ( if present in a pregnant lady)
Leiomyoma- types

Submucosal
Intramural
Subserosal
 Tumor characteristics
Leiomyoma - gross
1. Degeneration – Red degeneration, cystic degeneratio
2. Dystrophic calcification
3. Hyalinization – reason for the term fibroid
4. Usually do not transform into leiomyosarcoma

Clinical features:

Menorrhagia – when located in submucosa

Obstructive delivery

complications
1. Dragging sensation / low back pain
2. Bleeding (menorrhagia)
3. Infertility
4. Spontaneous Abortion
5. Pain : due to red degeneration
6. ( Ischemic necrosis) within a large leiomyoma.
Well circumscribed rubbery white – tan masses 7. rarely: Sarcomatous change
Cut surface showing whorled appearance
Leiomyoma - microscopy

Left - Well differentiated spindle shaped smooth muscle cells, arranged haphazardly
giving rise to the whorled appearance. Areas of hyalinization +.
Right - Whorl pattern
 Leiomyosarcoma

Most common sarcoma of the uterus

Malignant tumor of the smooth muscle-

large bizarre giant cells ,spindle cells.

Tumor necrosis, cytological atypia/

increased mitotic activity

Recurrence after removal is common.

Metastasize widely
 Endometrial Carcinoma

7% of all invasive cancer in women

Most frequent invasive cancer of female genital tract in US
Age – 55-65yrs
2 types - different histologically and pathogenetically
Perimenopausal  Endometrioid carcinoma (75-80%) Type I – PTEN mutation
(common), P53 ( Rare)
Older post menopausal  Serous carcinoma (20%) Type II- TP53 mutation(Common), PTEN
Risk factors for endometrioid: Increased estrogenic stimulation*;
*All risk factors for endometrial hyperplasia
Characteristics of type I and type II endometrial cancers
Characteristics Type I Type II
Age 55-65 65-75
Clinical setting Unopposed estrogen, obesity, ATROPHY, THIN PHYSIQUE
hypertension diabetes

Morphology Endometrioid Serous clear, cell

Precursor Endometrial hyperplasia Endometrial intraepithelial Ca

Molecular genetics PTEN, PIK3CA, KRAS, β katenin, p53, aneuploidy, PIK3CA

p53

Behavior Indolent, spreads via lymphatics Aggressive, spread via

intraperitoneal and lymphatics
Types of endometrial cancer

• Well differentiated – most common type

• Adenoacanthoma – contains foci of benign squamous tissue –

no prognostic significance

• Adenosquamous carcinoma – contains foci of malignant

squamous cells – worse prognosis

• Papillary adenocarcinoma – highly aggressive tumor

 Morphology

Type I - Endometrioid
Gross - localized polypoid tumor or diffuse tumor involving the endometrial surface
Micro - Glandular pattern ; Grade 1-3 ; well differentiated; moderately and poorly differentiated
20% can show foci of squamous differentiation
 Spread by direct myometrial invasion; late stage lymphatic spread

Type II - Clear cell

Gross - large bulky tumors deeply invasive in the myometrium
Micro - papillary growth pattern
classified as grade 3
 Endometrial carcinoma - gross

Large exophytic mass filling the uterine cavity and infiltrating the
Large exophytic mass filling the uterine cavity and infiltrating the
walls with areas of necrosis
walls with areas of necrosis
 Endometrial carcinoma - microscopy

Left - Low magnification. Showing highly hyperchromatic malignant cells infiltrating the myometrium
Right - High magnification. Gland forming malignant cells with nuclear atypia, hyperchromatism and
loss of polarity . Back to back appearance of glands seen
Endometrial carcinoma - Clinical features
• Age : 55-65 years
• Post menopausal bleeding /Abnormal excessive bleeding - RED FLAG SIGN
• Marked leucorrhea
• Uterus is palpably enlarged and fixed
• Diagnosis is by biopsy or curettage
• Prognosis: no current screening test
• Depends on staging (invasion of myometrium prognostically significant)
• Treatment and prognosis:
Type I : Stage 1 (grade 1or2) surgery alone or followed by radiotherapy; 90%;Stage II –III < 50% 5 year
survival
Type II : <30% survival at 5years
 CONGENITAL AND DEVELOPMENTAL ANOMALIES

1. Involution of Wolffian (mesonephric) system leaves residual structure :

• Vaginal wall – Gartner duct cyst

• Fallopian tube – Hydatid cyst of Morgagni

2. Androgen Insensitivity : 46 XY –Lacks functional androgen receptors

• Normal female external genitalia ( distal vagina)

• Normal testes in inguinal canal (produces testosterone from Leydig cells)

• Absence of any internal genitalia ( Sertoli cells MIF –cause of involution of Mullerian in utero (male genitalia do
not develop in absence of testosterone effect)

• Normal breast development [ Testosterone is converted to estrogen]

Turner Syndrome : 46N,XO ; primary amenorrhea; short stature; spaced nipples; webbed
neck – lymphangioma

• Coarctation of aorta

• Streak ovaries ,less estrogen – under developed breasts ; pubic hair normal

• Elevated TSH/LH ( hypergonadotropic hypogonadism )

Kallmann syndrome
• Defect of hypothalamus producing GnRH ( Hypogonadotropic hypogonadism)
• Anosmia
• Migration defect of hypothalamus nuclei
FSH/LH - reduced