Diseases of the liver and pancreas

Non-neoplastic Epithelial Disorders

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  Characterized by opaque, white, scaly, plaque-like mucosal thickenings that produce vulvar discomfort and itching (pruritus)
  
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  Non specific inflammatory alterations of vulva can be classified as:
  
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  Lichen sclerosus: a characteristic disorder manifested by subepithelial fibrosis
  
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  Squamous hyperplasia: characterized by epithelial hyperplasia and hyperkeratosis
  

Lichen sclerosus Squamous Hyperplasia

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  Fibrosis (arrow) Epithelial hyperplasia
  
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  Thinning of epithelial layer Dermal chronic inflammation
  

Vulval Tumors

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  Benign Tumors
  

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  Papillary Hidradenoma
  
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  Condyloma Acuminatum
  

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  Malignant Tumors
  

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  Carcinoma and Vulvar Intraepithelial Neoplasia(VIN)
  
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  Extramammary Paget’s Disease
  
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  Malignant Melanoma
  

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  Vulva contains modified apocrine sweat glands
  
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  Vulva may contain tissue closely resembling breast (“ectopic breast”)
  
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  Develops two tumors with counterparts in the breast
  

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  Papillary hidradenoma is identical in appearance to intraductal papillomas of the breast.
  
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  Paget’s disease
  

Hidradenoma

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  Presents as a sharply circumscribed nodule
  
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  Most commonly on the labia majora or interlabial folds
  
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  May be confused clinically with carcinoma
  

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  because of its tendency to ulcerate
  

Histologically:

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  Tubular ducts lined by a single or double layer of nonciliated columnar cells
  
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  Layer of flattened “myoepithelial cells” underlying the epithelium
  

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  Characteristic of sweat glands and sweat gland tumors
  

Condyloma Acuminatum

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  Benign raised or wart-like (verrucous) conditions of the vulva occur in three forms.
  
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  Condyloma acuminatum, a papillomavirus-induced squamous lesion also called “venereal wart.”
  
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  Mucosal polyps, which are benign stromal proliferations covered with squamous epithelium
  
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  Syphilitic condyloma latum
  
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  Are sexually transmitted
  
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  Benign tumors
  
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  Have a distinctly verrucous gross appearance
  
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  May be solitary , frequently multiple
  
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  Involve perineal, vulvar, and perianal regions as well as the vagina and, less commonly, the cervix
  
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  Lesions are identical to those found on the penis and around the anus in males
  

A,B. External genitalia (female)

C. Cytoplasmic Vacuolization (Koilocytosis) – Marker for cytopathic effect of viruses

D. Koilocytosis

Condyloma Acummantum (cont.)

Histologically:

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  Consist of branching, tree-like proliferation of stratified squamous epithelium supported by a fibrous stroma
  
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  Acanthosis, parakeratosis, hyperkeratosis, and, most specifically, nuclear atypia in the surface cells with perinuclear vacuolization (called koilocytosis) are present.
  
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  Condylomata are caused by the human papillomavirus, specifically types 6 and 11,20 which are associated with benign warts and replicate in the squamous epithelium.
  
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  Are not considered to be precancerous lesions
  
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  Are a marker for sexually transmitted disease
  

Malignant Tumors

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  Carcinoma and Vulvar Intraepithelial Neoplasia (VIN)
  
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  Extramammary Paget’s Disease
  
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  Malignant Melanoma
  

Carcinoma and Vulvar Intraepithelial Neoplasia (VIN)

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  Is an uncommon malignancy
  
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  >65% occur in women over age 60 years
  
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  85% of these malignant tumors are squamous cell carcinomas
  
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  In terms of etiology, pathogenesis, and clinical presentation, vulvar squamous cell carcinomas may be divided into two general groups:
  

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  Associated with papillomavirus
  
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  Asssociated with vulvular dystrophies
  

Associated with papillomaviruses

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  Coexists with or is preceded by a defined precancerous change, called vulvar intraepithelial neoplasia (VIN)
  
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  Also known as carcinoma in situ or Bowen’s disease
  
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  VIN is characterized by
  
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  Nuclear atypia in the epithelial cells
  
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  Increased mitoses
  
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  Lack of surface differentiation
  
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  Based on the severity of atypia, VIN may be graded as
  
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  I (mild)
  
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  II (moderate)
  
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  III (severe)
  
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  Lesions usually present as white or pigmented plaques on the vulva
  

Associated with vulvar “dystrophies”

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  Squamous cell hyperplasia / lichen sclerosus
  
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  Etiology is unclear
  
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  Infrequently associated with papillomaviruses
  

Morphology

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  Begin as small areas of epithelial thickening that resemble leukoplakia
  
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  In the course of time, progress to create firm, indurated, exophytic tumors or ulcerated, endophytic lesions
  
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  Are misinterpreted as dermatitis, eczema, or leukoplakia for long periods.
  
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  Clinical manifestations
  
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  Pain, local discomfort, itching, and exudation because superficial secondary infection is common
  

Histologically

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  Tumors associated with human papillomavirus or VIN tend to be poorly differentiated
  
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  Others are usually well differentiated, with the formation of keratohyaline pearls and prickle cells
  

Cancer of the Vulva Squamous Cell Carcinoma of Vulva Epithelial Pearl –

Squamous Cell Carcinoma

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  Risk of metastatic spread is linked to
  

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  Size of tumor
  
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  Depth of invasion
  
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  Involvement of lymphatic vessels
  

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  Inguinal, pelvic, iliac, and periaortic lymph nodes are most commonly involved
  
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  Dissemination to the lungs, liver, and other internal organs
  
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  Lesions less than 2 cm in diameter have a 60 to 80% 5-year survival rate after treatment with one-stage vulvectomy and lymphadenectomy
  
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  Larger lesions with lymph node involvement yield a less than 10% 5-year survival rate.
  

Extramammary Paget’s Disease

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  Rare lesion of the vulva usually on the labia majora
  
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  Manifests as a pruritic red, crusted, sharply demarcated, map-like area
  
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  Diagnostic microscopic feature:
  

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  Presence of large, anaplastic tumor cells lying singly or in small clusters within the epidermis and its appendages
  
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  These cells are distinguished by a clear separation (“halo”) from the surrounding epithelial cells
  
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  Finely granular cytoplasm containing PAS, alcian blue, or mucicarmine-positive mucopolysaccharide.
  

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  Prognosis : Poor
  

A.Note the appearance like an eczematoid rash (fiery red background mottled with white hyperkeratotic islands)

B.Large Clear Tumor cells within squamous epithelium
Malignant Melanoma

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  Melanomas of the vulva are rare
  
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  Peak incidence is in the sixth or seventh decade
  
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  Overall survival rate is < 32%
  
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  Prognosis depends on depth of invasion,
  
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  > 60% mortality for lesions invading deeper than 1 mm
  

Lesion stains with S100 which helps to

differentiate it from Paget’s disease


Vagina

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  Congenital Anomalies
  
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  Premalignant and Malignant Neoplasms
  

Congenital Anomalies

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  Atresia
  
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  Total absence of the vagina
  
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  Septate, or double, vagina
  

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  Arises from failure of total fusion of the müllerian ducts
  
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  Accompanies double uterus (uterus didelphis)
  

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  Gartner’s duct cysts
  

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  Common lesions
  
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  Found along the lateral walls of the vagina
  
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  Derived from wolffian duct rests
  
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  Are 1- to 2-cm, fluid-filled cysts that occur submucosally
  

Premalignant and Malignant Neoplasms

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  Benign tumors of the vagina
  

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  Occur in reproductive-age women
  
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  Consist of skeletal muscle (rhabdomyomas)
  
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  Stromal (stromal polyps) tumors
  
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  Leiomyomas
  
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  Hemangiomas
  

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  Malignant tumors
  

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  Carcinoma
  
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  Embryonal rhabdomyosarcoma (sarcoma botryoides)
  

Adenocarcinoma

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  Are rare
  
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  Have received attention because of the increased frequency of clear cell adenocarcinomas in young women whose mothers had been treated with diethylstilbestrol (DES) during pregnancy (for a threatened abortion)
  
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  < 0.14% of such DES-exposed young women develop adenocarcioma
  
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  Tumors are usually discovered between the ages of 15 and 20
  
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  Composed of vacuolated, glycogen-containing cells, hence the term “clear cell”
  
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  Because of its insidious, invasive growth, vaginal cancer
  

(squamous and adenocarcinoma) is difficult to cure.

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  Early detection by careful follow-up is mandatory in DES-exposed women
  

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  Treatment: Surgery and irradiation
  

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  Clear cell Carcinoma showing vacuolated tumor cells forming glands 
  

Morphology

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  Most often located
  

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  On the anterior wall of the vagina
  
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  Usually in the upper third
  

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  Vary in size from 0.2 to 10 cm in greatest diameter.
  
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  A probable precursor of the tumor is vaginal adenosis
  
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  A condition in which glandular columnar epithelium of müllerian type either appears beneath the squamous epithelium or replaces it.
  
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  Adenosis presents clinically as red, granular foci contrasting with the normal pale pink, opaque vaginal mucosa.
  
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  Microscopically the glandular epithelium may be either
  

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  Mucus-secreting, resembling endocervical mucosa
  
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  Tuboendometrial, often containing cilia
  

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  Adenosis has been reported in 35 to 90% of the offspring of estrogen-treated mothers
  

Vaginal Adenosis

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  Red granular patches on the vaginal mucosa on the left
  

Embryonal Rhabdomyosarcoma

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  Also called sarcoma botryoides
  
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  Very uncommon vaginal tumor
  
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  Most frequently found in infants and in children under the age of 5
  
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  Consists predominantly of malignant embryonal rhabdomyoblasts
  
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  Is thus a type of rhabdomyosarcoma
  
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  Gross:
  
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  Tumor tends to grow as polyploid, rounded, bulky masses that sometimes fill and project out of the vagina
  
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  Have the appearance and consistency of grape-like clusters (hence the designation “botryoides,” grape-like)
  
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  Histologically:
  
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  Tumor cells are small and have oval nuclei, with small protrusions of cytoplasm from one end, so they resemble a tennis racket
  
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  Treatment: Conservative surgery + chemotherapy
  

Sarcoma Botyroides


Cervix

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  Inflammations
  

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  Acute and Chronic Cervicitis
  
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  Endocervical Polyps
  

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  Intraepithelial and Invasive Squamous Neoplasia
  

Chronic Cervicitis

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  Chronic inflammation, sometimes ulceration with repair, atypia or dysplasia, nabothian cysts (from endocervical glands)
  
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  Backache is a common symptom
  

Chronic Cervicitis Chronic Cervicitis

Nabothian Cysts

A.Endocervical glands blocked by inflammation or scarring.

B.Chronic inflammation underlies an area of cervical dysplasia
Cervix - Intraepithelial and Invasive Squamous Neoplasia

Risk factors for cervical cancer:

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  Early age at first intercourse
  
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  Multiple sexual partners
  
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  Male partner with multiple previous sexual partners
  
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  Other risk factors (are subordinate to these three influences, primarily multiple sexual partners)
  

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  Oral contraceptive use
  
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  Cigarette smoking
  
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  Parity
  
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  Family history
  
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  Associated genital infections
  
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  Lack of circumcision in the male sexual partner.
  

Pathogenesis

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  Human papillomavirus is linked to cervical cancer
  
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  Human papillomavirus DNA is detected in
  

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  ~ 85% of cervical cancers
  
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  ~ 90% of cervical condylomata and precancerous lesions
  

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  Specific human papillomavirus types are associated with
  

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  Cervical cancer (high risk) - Types 16, 18, 31, and 33
  
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  Condylomata (low risk) - Types 6, 11, 42, and 44
  
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  Human papillomavirus is not the only factor
  
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  A high percentage of young women are infected with one or more human papillomavirus types during their reproductive years, and only a few develop cancer.
  
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  Factors influencing whether the human papillomavirus infection remains subclinical (latent), turns into a precancer, or eventually progresses to cancer:
  

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  Other co-carcinogens
  
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  Immune status of the individual
  
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  Nutrition
  

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  ~15% of cervical cancers are not associated with human papillomavirus, implying other modes of cancer development, including host gene mutations
  

Postulated Steps In Pathogenesis

Cervical Intraepithelial Neoplasia

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  Pre-cancerous lesion:
  

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  May exist in the noninvasive stage for as long as 20 years
  
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  Shed abnormal cells - detected on cytologic examination
  
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  Represent a continuum of morphologic change with relatively indistinct boundaries
  
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  Do not invariably progress to cancer
  
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  May spontaneously regress
  
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  Risk of cancer increasing with the severity of the precancerous change
  
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  Associated with papillomaviruses
  

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  Papanicolaou smear screening is an effective method in preventing cervical cancer
  

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  Reason: Majority of cancers preceded by a precancerous lesion
  

A.Normal exfoliated superficial squamous cervical epithelial cells

B.Papanicolou Smear – CIN I

C.Papanicolou Smear – CIN II

D.Papanicolou Smear – CIN III Note the increase in Nuclear-Cytplasmic Ratio

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  Cervical intraepithelial neoplasia (CIN) classification
  

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  CIN grade I: Mild dysplasia
  
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  CIN grade II
  
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  CIN grade III: Carcinoma in situ
  

CIN I

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  Extreme low end of the spectrum of morphologic change
  
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  Lesions indistinguishable histologically from condylomata acuminata
  
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  Exhibit koilocytotic atypia (viral cytopathic effect) with few alterations in the other cells in the epithelium
  

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  Viral Cytopathic Effect of HPV in Condyloma
  

CIN II

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  Appearance of atypical cells in the lower layers of the squamous epithelium
  
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  Atypical cells show changes characteristics of malignant cells:
  
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  Change in nucleocytoplasmic ratio
  
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  Variation in nuclear size (anisokaryosis)
  
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  Loss of polarity
  
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  Increased mitotic figures
  
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  Hyperchromasia
  

CIN III

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  Progressive loss of differentiation with involvement of more and more layers of the epithelium
  
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  Until totally replaced by immature atypical cells, exhibiting no surface differentiation
  

Salient Points of CIN

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  CIN almost always begins at the squamocolumnar junction, in the transformation zone.
  
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  Lowest grade CIN lesions, including condylomata, mostly do not progress
  
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  Lesions containing greater degrees of cellular atypia are at greater risk
  
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  One-third of CIN I and two-thirds of CIN II lesions persist or progress to high grade
  
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  Not all lesions begin as condylomata or as CIN I
  

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  May enter at any point in the spectrum, depending on the associated human papillomavirus type and other host factors
  

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  Lesions that have completely evolved (CIN III) constitute the greatest risk
  
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  CIN III is most frequently associated with invasive cancer
  

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  May develop in from a few months to over 20 years.45
  

Normal Cervical Epithelial Cervical Cancer Transformation Zone

Squamous Cell Carcinoma

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  Squamous cell carcinoma may occur at any age
  

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  From the second decade of life to senility
  

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  Peak incidence is occurring at an increasingly younger age:
  

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  40 to 45 years for invasive cancer
  
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  30 years for high-grade precancers
  

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  Represents the combination of
  
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  Earlier onset of sexual activity (i.e., earlier acquisition of human papillomavirus infection)
  
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  Active Papanicolaou smear screening programs
  

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  Detecting either cancers or precancerous lesions at an earlier point in life
  

Squamous Cell Carcinoma Epithelial Pearls

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  Invasive cervical carcinoma manifests in three distinctive patterns:
  

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  Fungating (or exophytic)
  

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  Most common variant
  
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  Produces mass that projects above the surrounding mucosa
  

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  Ulcerating
  
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  Infiltrative cancer
  

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  Advanced cervical carcinoma extends by direct continuity
  
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  Involve every contiguous structure
  

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  Peritoneum
  
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  Urinary bladder
  
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  Ureters
  
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  Rectum
  
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  Vagina
  

• 
  Local and distant lymph nodes are also involved
  
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  Distant metastasis - Liver, lungs, bone marrow, and other structures
  

Normal Cervix (Nulliparous) Cervical Carcinoma Cervical Carcinoma

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  Histologically:
  
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  ~95% of squamous carcinomas composed of relatively large cells
  

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  Keratinizing (well-differentiated)
  
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  Nonkeratinizing (moderately differentiated)
  

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  <5% are poorly differentiated small cell squamous
  
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  More rarely small cell undifferentiated carcinomas (neuroendocrine or oat cell carcinomas)
  

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  Resemble oat cell carcinomas of lung
  
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  Unusually poor prognosis owing to early spread by lymphatics and systemic spread
  

Cervical cancer Staging

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  Stage 0: Carcinoma in situ (CIN III).
  
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  Stage I: Carcinoma confined to the cervix.
  
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  Ia: Preclinical carcinoma, i.e., diagnosed only by microscopy but showing:
  
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  Ia1: Minimal microscopic invasion of stroma (minimally invasive carcinoma) .
  
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  Ia2: Microscopic invasion of stroma of less than 5 mm in depth (microinvasive carcinoma).
  
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  Ib: Histologically invasive carcinoma of the cervix that is greater than stage Ia2.
  
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  Stage II: Carcinoma extends beyond the cervix but not onto the pelvic wall. Carcinoma involves the vagina but not the lower third.
  
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  Stage III: Carcinoma has extended onto pelvic wall. On rectal examination, there is no cancer-free space between the tumor and the pelvic wall. The tumor involves the lower third of the vagina.
  
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  Stage IV: Carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum. This stage obviously includes those with metastatic dissemination.
  

Extensive Spread

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  10-25% of cervical carcinomas constitute adenocarcinomas, adenosquamous carcinomas, undifferentiated carcinomas, or other rare histologic types.
  
• 
  Adenocarcinomas tend to have a less favorable prognosis than squamous cell carcinoma of similar stage
  
• 
  Clear cell adenocarcinomas of the cervix in DES-exposed women are similar to those occurring in the vagina
  

Clinical Course – Precancer / Precursors

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  Cancer of the cervix and its precursors evolve slowly over the course of many years
  
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  During this interval, the only sign of disease may be the shedding of abnormal cells from the cervix
  
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  Periodic Papanicolaou smears
  

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  Performed on all women after they become sexually active
  
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  Detects the possible presence of a cervical precancer or cancer
  
• 
  It does not make an absolute diagnosis
  

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  Colposcopic examination of the cervix
  

• 
  CIN lesions are characterized by white patches on the cervix following the application of acetic acid
  

• 
  Clinically overt cervical cancers produce
  

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  Irregular vaginal bleeding
  
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  Leukorrhea
  
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  Bleeding
  
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  Pain on coitus
  
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  Dysuria
  

Treatment

• 
  Depend on the stage of the neoplasm
  
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  Treatment of precursors
  

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  Papanicolaou smear follow-up (for mild lesions)
  
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  Cryotherapy
  
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  Laser
  
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  Wire loop excision
  
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  Cone biopsy
  

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  Invasive cancers
  

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  Hysterectomy
  
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  Radiation for advanced lesions
  

Prognosis

• 
  Prognosis and survival for invasive carcinomas depends on the stage at which cancer is first discovered
  
• 
  With current methods of treatment, there is a 5-year survival rate:
  
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  Stage I - 80 to 90%
  
• 
  Stage II - 75%
  
• 
  Stage III - 35%
  
• 
  Stage IV - 10 to 15%
  

• 
  Die as a consequence of local extension of the tumor–
  

• 
  Into and about the urinary bladder and ureters, leading to ureteral obstruction, pyelonephritis, and uremia–rather than distant metastases