Diseases of the liver and pancreas

Functional Endometrial Disorders
(Dysfunctional Uterine Bleeding)

• 
  During active reproductive life
  
• 
  Pituitary and ovarian hormones > Endometrium sheds and regrows
  
• 
  Alterations may result in a spectrum of disturbances
  

• 
  Atrophy
  
• 
  Abnormal proliferative or secretory patterns
  
• 
  Hyperplasia
  

• 
  Occurrence of excessive bleeding during or between menstrual periods – most common problem
  
• 
  Causes of abnormal bleeding from the uterus are many and varied
  
• 
  Largest single group is dysfunctional uterine bleeding
  

• 
  Abnormal bleeding in the presence of a functional disturbance rather than an organic lesion of the endometrium or uterus
  

Dysfunctional Uterine Bleeding - Anovulatory Cycle

• 
  Mostly is due to the occurrence of an anovulatory cycle
  
• 
  Most common at menarche and the perimenopausal period
  
• 
  Results in excessive and prolonged estrogenic stimulation without the development of the progestational phase that regularly follows ovulation
  
• 
  Failure of ovulation results in prolonged, excessive endometrial stimulation by estrogens
  
• 
  Endometrial glands undergo mild architectural changes, including cystic dilatation (persistent proliferative endometrium)
  
• 
  Less commonly, lack of ovulation is the result of
  

• 
  An endocrine disorder
  
• 
  Thyroid disease
  
• 
  Adrenal disease
  
• 
  Pituitary tumors
  

• 
  Primary lesion of the ovary
  

• 
  Functioning ovarian tumor (granulosa—theca cell tumors)
  
• 
  Polycystic ovaries
  

• 
  Generalized metabolic disturbance
  

• 
  Marked obesity
  
• 
  Severe malnutrition
  
• 
  Chronic systemic disease
  

• 
  In most patients, however, anovulatory cycles are unexplainable
  

Oral Contraceptives and Induced Endometrial Changes

• 
  Oral contraceptives containing synthetic or derivative ovarian steroids induces a wide variety of endometrial changes, depending on the steroid used and the dose.
  
• 
  A common response pattern is a discordant appearance between glands and stroma usually with inactive glands amidst a stroma showing large cells with abundant cytoplasm reminiscent of the decidua of pregnancy. When such therapy is discontinued, the endometrium reverts to normal. All these changes have been minimized with the newer low-dose contraceptives.
  

Adenomyosis

• 
  Definition: Some endometrial glands extending beneath this interface to form nests deep within the myometrium
  

• 
  Endo-myometrial interface is usually sharply demarcated
  

• 
  Cause: Unknown
  
• 
  Incidence: ~15 to 20% of uteri
  
• 
  Result: Causes expansion (enlargement) of the uterine wall
  
• 
  Gross Examination: Numerous small cysts
  
• 
  Microscopically:
  
• 
  Irregular nests of endometrial stroma, with or without glands
  
• 
  Arranged within the myometrium, separated from the basalis by at least 2 to 3 mm
  

Consequences:

• 
  Shedding of the endometrium during the menstrual cycle
  
• 
  Hemorrhage within these small adenomyotic nests results in:
  

• 
  Menorrhagia
  
• 
  Colicky dysmenorrhea
  
• 
  Dyspareunia
  
• 
  Pelvic pain
  

• 
  Particularly during the premenstrual period.
  

Endometriosis

• 
  Presence of endometrial glands or stroma in abnormal locations outside the uterus
  
• 
  Seen in active reproductive life
  
• 
  Most often in the third and fourth decades
  
• 
  It occurs in the following sites, in descending order of frequency:
  

• 
  Ovaries
  
• 
  Uterine ligaments
  
• 
  Rectovaginal septum
  
• 
  Pelvic peritoneum
  
• 
  Laparotomy scars
  
• 
  Rarely in the umbilicus, vagina, vulva, or appendix
  
• 
  Three potential explanations exist to explain the origin of these dispersed lesions
  

Regurgitation theory:

• 
  Retrograde menstruation through the fallopian tubes occurs regularly even in normal women
  
• 
  Could mediate spread of endometrial tissue to the peritoneal cavity
  

Metaplastic theory:

• 
  Endometrium could arise directly from coelomic epithelium
  

Vascular or lymphatic dissemination theory:

• 
  Explains the presence of endometriotic lesions in the lungs or lymph nodes
  

Morphology

• 
  Foci of endometrium is under the influence of the ovarian hormones
  

• 
  Therefore undergo the cyclic menstrual changes with periodic bleeding
  

• 
  Produces nodules
  
• 
  Red-blue to yellow-brown appearance
  
• 
  On/just beneath the serosal surfaces in the site of involvement
  
• 
  In extensive disease
  

• 
  Organizing hemorrhage causes extensive fibrous adhesions between tubes, ovaries, and other structures and obliteration of the pouch of Douglas
  

• 
  Ovaries may become markedly distorted by large cystic spaces (3 to 5 cm in diameter) filled with brown blood debris to form so-called “chocolate cysts”
  
• 
  A histologic diagnosis of endometriosis is satisfied if two of the three following features are identified:
  

• 
  Endometrial glands
  
• 
  Stroma
  
• 
  Hemosiderin pigment
  

• 
  Ovary sectioned to reveal large endometriotic cyst
  
• 
  Contains necrotic brown blood (chocolate cyst)
  

• 
  Lining of an endometrial cyst
  

• 
  Endometrial gland (right)
  
• 
  Endometrial stroma with plump stromal cells
  

charecteristic of decidual changes (left)

• 
  Macrophages containing hemosiderin (centre)
  

Clinical features

• 
  Severe dysmenorrhea
  
• 
  Dyspareunia
  
• 
  Pelvic pain owing to
  

• 
  Intrapelvic bleeding
  
• 
  Periuterine adhesions
  

• 
  Pain on defecation
  

• 
  Rectal wall involvement
  

• 
  Dysuria
  

• 
  Involvement of the serosa of the bladder
  

• 
  Intestinal disturbances may appear when the small intestine is affected
  
• 
  Menstrual irregularities are common
  
• 
  Infertility is the presenting complaint in 30 to 40% of women
  

Endometrial hyperplasia

• 
  Is another cause of abnormal bleeding
  
• 
  Differs from typical anovulation by the degree of glandular epithelial alterations in the endometrium
  
• 
  There is a relationship with endometrial carcinoma
  
• 
  Related to an abnormally high, prolonged level of estrogenic stimulation with diminution or absence of progestational activity
  
• 
  Occurs most commonly
  

• 
  Around menopause
  
• 
  In association with persistent anovulation in younger women.
  

• 
  Conditions leading to hyperplasia include
  

• 
  Polycystic ovarian disease–including Stein-Leventhal syndrome–
  
• 
  Functioning granulosa cell tumors of the ovary
  
• 
  Excessive cortical function (cortical stroma hyperplasia)
  
• 
  Prolonged administration of estrogenic substances (estrogen replacement therapy)
  

Morphology

• 
  Endometrial hyperplasia exhibits a continuum of alterations in gland architecture, epithelial growth pattern and cytology, and the grade increases as a function of the severity of these changes.
  
• 
  Lower grade hyperplasias
  
• 
  Include simple hyperplasia and complex hyperplasia
  
• 
  Simple hyperplasia
  
• 
  Also known as cystic or mild hyperplasia
  
• 
  Characterized by the presence of architectural alterations in glands of various sizes, producing irregularity in gland shape with cystic alterations.
  
• 
  The epithelial growth pattern and cytology are similar to proliferative endometrium, although mitoses are not as prominent
  
• 
  The stroma between glands also is frequently increased
  
• 
  These lesions uncommonly progress to adenocarcinoma
  
• 
  cystic hyperplasia frequently evolves into cystic atrophy in which the epithelium and stroma become atrophic. Complex hyperplasia, also known as adenomatous hyperplasia without atypia, exhibits an increase in the number and size of endometrial glands, with gland crowding and a disparity in their size and irregularity in their shape. The glands undergo “budding” with finger-like outpouchings into the adjacent endometrial stroma. The lining epithelium may appear more stratified than simple hyperplasia but is regular in contour and devoid of conspicuous cytologic atypia (see Figure 23.28B ). In the absence of cytologic atypia, less than 5% of these lesions evolve into carcinoma.
  

Simple (cystic) hyperplasia

• 
  Higher grade hyperplasias are usually termed atypical hyperplasia, or adenomatous hyperplasia with atypia. In addition to glandular crowding and complexity, epithelial lining is irregular, characterized by stratification, scalloping, and tufting. Importantly, there is cellular atypia with cytomegaly, loss of polarity, hyperchromatism, prominence of nucleoli, and altered nuclear cytoplasmic ratio (see Figure 23.29 ). Mitotic figures are common. Predictably, in the most severe forms, cytologic and architectural atypia may resemble frank adenocarcinoma, and an accurate distinction between atypical hyperplasia and cancer may not be made without hysterectomy (see Figure 23.30 ). In one study, 23% of patients with atypical hyperplasias eventually developed adenocarcinoma.55 In another study in which atypical hyperplasias were treated with progestin therapy alone, 50% persisted despite therapy, 25% recurred, and 25% progressed to carcinoma.56
  

Carcinoma of the endometrium

• 
  Uncommon in women younger than 40 years of age
  
• 
  Peak incidence 55- to 65-year-old woman
  
• 
  A higher frequency of this form of neoplasia is seen with
  

• 
  Obesity
  
• 
  Diabetes (abnormal glucose tolerance is found in more than 60%)
  
• 
  Hypertension
  
• 
  Infertility
  

• 
  Women who develop cancer of the endometrium tend to be single and nulliparous and to give a history of functional menstrual irregularities consistent with anovulatory cycles
  

• 
  In terms of potential pathogenesis, two general groups of endometrial cancer can be identified
  
• 
  The first and the most well studied develops on a background of prolonged estrogen stimulation and endometrial hyperplasia. Both conditions–hyperplasia and cancer–appear related to obesity and anovulatory cycles.
  
• 
  Additional support includes the following:
  

• 
  Women with ovarian estrogen-secreting tumors have a higher risk of endometrial cancer
  
• 
  Endometrial cancer is extremely rare in women with ovarian agenesis and in those castrated early in life
  
• 
  Estrogen replacement therapy is associated with increased risk in women, and prolonged administration of DES to laboratory animals may produce endometrial polyps, hyperplasia, and carcinoma
  
• 
  In postmenopausal women, there is greater synthesis of estrogens in body fats from adrenal and ovarian androgen precursors, a finding that may partly explain why there is increased risk of endometrial cancer with age and obesity.
  

• 
  Endometrial carcinomas that are associated with the aforementioned risk factors tend to be well differentiated and mimic normal endometrial glands (“endometrioid”) in histologic appearance. This group of tumors is generally associated with a more favorable prognosis, as described subsequently.62
  
• 
  A second and not insignificant subset of patients with endometrial cancer less commonly exhibits the stigmata of hyperestrinism or pre-existing hyperplasia and acquires the disease at a somewhat older age on average. In this group, tumors are generally more poorly differentiated, including tumors that resemble subtypes of ovarian carcinomas (serous carcinomas). Overall these tumors have a poorer prognosis than endometrioid tumors, and the factors predisposing to their development are obscure
  

Endometrial Polyp

• 
  Benign; arise in fundus
  
• 
  Women over 40
  
• 
  Cause vaginal bleeding (menorrhagia)
  
• 
  Not precancerous but may harbor an adenocarcinoma
  
• 
  Usually sessile masses composed of hyperplastic endometrium which is cystic
  

Endometrial Polyp

• 
  Endometrial polyps cause vaginal bleeding and must be differentiated from uterine cancer
  

Endometrial Hyperplasia

• 
  Abnormal proliferation of endometrial glands
  
• 
  Due to prolonged estrogenic stimulation
  

• 
  unopposed estrogen therapy
  
• 
  hyperestrinism (Stein-Leventhal or granulosa cell tumors of ovary)
  

• 
  Clinically present with vaginal bleeding
  

Endometrial Hyperplasia
WHO Committee Classification

• 
  Simple hyperplasia without atypia (SH)-(Cystic hyperplasia): large dilated glands, minimal glandular complexity, no cytologic atypia; 1% progress to adenocarcinoma
  
• 
  Simple hyperplasia with atypia (SAH)-no previous category in old classificati
  
• 
  Complex hyperplasia without atypia-CH (adenomatous hyperplasia without atypia): complex glands with crowding but no atypia; 3% progress
  
• 
  Complex hyperplasia with atypia-(CAH) (Atypical Hyperplasia): more glands, crowding with back-to-back glands; atypia; 33% chance of progression-(progression takes 4 years)-15-33% of patients will have a well-differentiated adenocarcinoma in the hysterectomy specimen
  

Endometrial Hyperplasia

A,B.Simple Endometrial Hyperplasia

• 
  Large, dilated glands with minimal glandular complexity and minimal proliferation
  

C.Complex hyperplasia

• 
  Complex glands with crowding
  

ID/CC:

A 60 year old obese, nulliparous white female presents with intermittent postmenopausal vaginal bleeding of three months’ duration

HPI: she has a history of diabetes, hypertension, and infertility with polycystic ovaries; menopause began at 56 years of age

PE: Uterus is not enlarged on bimanual palpation; remainder of physical exam unremarkable

Imaging stripe: US-Pelvic: thickening of endometrial
Endmetrial Carcinoma:
* MC invasive cancer of the female genital tract; best prognosis of gynecologic cancers

Endometrial Carcinoma

• 
  Risk Factors:
  

• 
  Hyperestrinism or prolonged estrogenic stimulation of endometrium
  
• 
  Obesity
  
• 
  Nulliparity
  
• 
  Diabetes
  
• 
  Hypertension
  
• 
  Infertility
  
• 
  Breast Cancer; Colon Cancer
  
• 
  Low fiber/High fat diet
  
• 
  Early menarche or late menopause
  

• 
  Granulosa cell tumors of ovary
  
• 
  Tamoxifen (a nonsteroidal hormone with antiestrogenic effect in reproductive age women)
  
• 
  Has a weak estrogenic effect in postmenopausal women. Over 80 cases of endometrial carcinoma have been reported in women with breast cancer who have been treated with tamoxifen
  
• 
  Endometrial or clear cell carcinomas of ovary
  

• 
  Peak age Overall: 55-65 years
  
• 
  Fungating, polypoid tumors presenting with VAGINAL BLEEDING
  
• 
  MC site of metastasis-lung
  
• 
  Depth of myometrial invasion and stage are key prognostic factors
  
• 
  MC histologic type: Endometrioid Adenocarcinoma (more solid areas reflect poor differentiation)-low grade, estrogen related, usually associated with endometrial hyperplasia, occurs in younger perimenopausal women
  

• 
  Other types: Serous, Adenosquamous, Cell cell carcinomas: more aggressive, older women, unrelated to estrogen
  

Endometrial Carcinoma: #1 cause of post menopausal

• 
  A large, fungating mass is filling the endometrial cavity.
  

ID/CC A 39 year old black female presents with a several-month long history of profuse menstruation and frequent menstrual periods

HPI Further questioning also reveals painful periods and increasing urinary frequency. She has a history of infertility and recurrent spontaneous abortions.
PE Enlarged, irregular uterus on bimanual palpation with several masses on posterior wall

LEIOMYOMA OF UTERUS

• 
  Fibroid tumor: benign tumor of smooth muscle origin; MC uterine tumor
  
• 
  MC overall tumor in women
  
• 
  MC location- uterus; second-stomach
  
• 
  More common in blacks
  
• 
  Estrogen-sensitive-may enlarge during pregnancy
  
• 
  If subendometrial-present with vaginal bleeding
  

Leiomyoma of Uterus

A well-circumscribed A small intramyometrial composed of interlacing bundles

leiomyoma leiomyoma of smooth muscle cells with rare

mitotic figures

ID/CC A 60 year old woman visits her gynecologist because of a foul-smelling, blood-tinged purulent vaginal discharge
HPI She has never been married and has never been pregnant. She is hypertensive and takes oral hypoglycemic agents for diabetes
PE VS: BP normal at present. PE: overweight; fleshy, bulky, fungating tumor protruding from cervical os on vaginal speculum exam

Leiomyosarcoma of Uterus

• 
  MC uterine sarcoma
  
• 
  Arises de novo and not from leiomyoma
  
• 
  Mean age of patients is > 50; more common in Blacks
  
• 
  Bulky tumor with areas of necrosis and hemorrhage
  
• 
  Look for increased numbers of mitoses per high powered field and atypical mitoses
  

Salpingitis

• 
  Most often associated with inflammation of ovaries and other adjacent tissue (PID)
  
• 
  Most infections are polymicrobial
  
• 
  Chlamydia trachomatis is most common followed by Neisseria gonorrhea
  
• 
  Others including anaerobes, Bacteroides, Clostridium, Mycoplasma hominis, Ureaplasma urealyticum
  
• 
  Anaerobes
  
• 
  TB in underdeveloped countries
  

Acute Salpingitis

• 
  A normal fallopian tube distention of the fimbriae with acute
  

inflammatory cells

• 
  Higher magnification of acute salpingitis. “violin-string” adhesions in
  

Fitz-Hugh-Curtis syndrome


Pelvic Inflammatory Disease

• 
  Causes:
  
• 
  Ascending infection via sexual intercourse
  
• 
  IUDs
  
• 
  Postpartum endometritis
  
• 
  Curettage from abortion that becomes infected
  
• 
  Complications
  
• 
  ectopic pregnancy, infertility, tubo-ovarian abscesses, pyosalpinx, peritonitis, bacteremia, Fitz-Hugh-Curtis (perihepatitis, “violin-string” adhesions) syndrome, bowel obstruction
  

ID/CC A 25 year old woman presents with amenorrhea of six weeks’ duration and pelvic pain over the past day

HPI She has a history of vaginal spotting off and on for the past two weeks and has been using an IUD for the past three years. She has no history of vaginal discharge and no urinary symptoms, and her previous menstrual history is normal. She has had multiple bouts of PID.

PE VS: normotension. PE: pallor; abdominal distention and decreased bowel sounds; cervical motion tenderness; uterus soft and slightly enlarged on pelvic exam; soft, tender boggy mass in right adnexa and pouch of Douglas

Labs CBC: anemia. ß-hCG levels lower than expected for this period of gestation; culdocentesis reveals presence of blood in the cul-de-sac;

Imaging US-pelvic: no products of conception in uterus

PathologyArias-Stella reaction without villi

Ectopic Pregnancy

• 
  95% occur in fallopian tube due to previous PID
  
• 
  Produce hematosalpinx
  
• 
  MC cause is chronic salpingitis; PID
  
• 
  Clinical presentation
  
• 
  Abdominal pain-sudden onset-may be hypogastric
  
• 
  Anomalous uterine bleeding following a period of amenorrhea
  
• 
  Rupture is most common cause of death in early pregnancy
  
• 
  Differential: Acute appendicitis, Torsion of ovarian cyst or ruptured ovarian cyst, PID, Mesenteric Lymphadenitis
  
• 
  DX: Ultrasound, Serum beta hCG, unclotted blood in rectovaginal pouch
  

Ectopic Pregnancy

• 
  An ectopic pregnancy showing a developing fetus.
  

Fallopian tube tumors

• 
  Adenomatoid tumor: MC benign tumor of the fallopian
  
• 
  Adenocarcinoma
  

• 
  Most often results from direct extension or metastasis from tumors originating elsewhere
  

Fallopian Tube Tumors

• 
  This is an example of an adenocarcinoma of the fallopian tube which is the most common primary tumor