Systemic Pathology: Test #2

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SYSTEMIC PATHOLOGY TEST 2

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Urinary Tract
Male GU
Female GU

Vulva, Vagina, Cervix
Uterus
Ovary
Placenta and Gestation

The Breast

Hematology

Functional Hematologic Disorders
Neoplastic Hematologic Disorders

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URINARY TRACT

DEVELOPMENT:

KIDNEY:

Mesonephric Duct: Forms the ureter and Male GU tract.

Ampullary Bud comes off the duct at four weeks. It induces the surrounding mesenchyme to form the metanephric blastema, which ultimately will form the kidney.
INVERTED: The mesonephric duct rotates during development, such that the superior part winds up being inferior, and vice-versa

Superior Portion: Forms the inferior Vas Deferens and Ejaculatory Ducts.
Inferior Portion: Forms the superior Vas Deferens and Ureter.

The kidney later migrates from the pelvis to the retroperitoneum.

BLADDER: Urogenital Sinus is divided into two portions, to become the rectum and the bladder.

Urachus: The former umbilical artery normally closes near the superior part of the UG sinus. Normally it attaches onto the superior anterior part of the bladder.
Prostatic Epithelial Buds form from invaginations of the epithelia around the UG sinus.
Cloacal Membrane: It induces the formation of the muscles of the anterior wall of the abdomen and the anterior bladder.

CONGENITAL ANOMALIES:

PERSISTENT URACHUS: Occurs when the umbilical artery fails to close.

Urine may flow directly out of the umbilicus, but this is very rare.
Urachus may be closed at one or both ends, forming a urine-filled urachal cyst.
Urachal Adenocarcinoma can develop as a complication. This bladder tumor tends to be on the dome of the bladder, instead of the lateral and posterior wall, like most other tumors.

EXSTROPHY of BLADDER: Improper formation of the cloacal membrane, leading to absence of anterior abdominal wall and anterior part of bladder.

Posterior wall of bladder is exposed to environment ------> chronic inflammation and squamous metaplasia ------> increased risk of squamous or adenocarcinoma of bladder.
SYMPTOM: Epispadia of penis usually is also found.

EAGLE-BARRETT (PRUNE BELLY) SYNDROME: The Eagle-Barrett syndrome is a relatively rare condition in which there is failure of normal development of the abdominal muscles and the smooth muscle of the ureters and bladder.

SYMPTOMS:

Bilateral cryptorchidism
Talipes equinovarus (club feet) and hip dislocation
Ureteral reflux ------> advanced hydroureteronephrosis is present.

AGENESIS of the URETER: The mesonephric duct does not form the metanephric bud. It invariably results in agenesis of the kidney too.
URETERAL DUPLICATION: About 0.8% of population, based on autopsy studies.

Biphid Ureters: Two calyceal-systems give rise to two separate ureters, which then fuse before entering bladder.
Duplex Ureters: The two ureters don't merge, so one of them is in the wrong place.

ECTOPIC URETER: The one that is misplaced may go into ejaculatory duct, vas deferens etc. It must be surgically removed.
URETERAL SEAL: Diverticulum or herniation around the ureter. It is common in ectopic ureter and often gets obstructed.

UTEROPELVIC JUNCTION OBSTRUCTION: This is the most common cause of hydronephrosis in infants.

75% of cases: Usually a congenital deficiency of smooth muscle. Surgically treatable.
25% of cases: Kidney malrotation ------> ureter obstructed by blood vessels.

DIVERTICULUM of the RENAL CALYX: Uncommon and asymptomatic. Cystic dilatation of the single calyx of the kidney.
CONGENITAL MEGAURETER: Congenital hydronephrosis. Catch-all term for massive dilatation of the ureter.

Dysplastic Ureter: Deficiency of myosin in ureteral smooth muscle ------> absent peristalsis and resultant dilatation of both ureters.

URETERAL REFLUX: The trigone is the area surrounding the ureterocystic junction, the entrance of the ureters into the bladder. When it contracts, it should prevent reflux of urine into the ureters.

MUSCLE ARRANGEMENT: Ureters have helical, peristaltic muscle, while bladder wall is longitudinal muscle.

Waldeyer's Sheath is another investment of muscle surrounding the ureteral opening. When it contracts, it prevents reflux of urine through the ureters.
Long-term catheterization ------> weakening of the Trigone Muscle ------> ureteral reflux can occur.

MALPOSITIONED URETERS: Ureters that insert onto the bladder at too perpendicular of an angle.

The normal bladder looks like a volcanic cone, while the bladder with malpositioned ureters looks more bowl-shaped (like a stadium).

Golf-Hole appearance: On cystoscopy, this indicates both a malpositioned ureter and a weakened trigone. This leads to the worst case of ureteral reflux.

INFLAMMATORY DISORDERS:

FIBROEPITHELIAL POLYPS: Papillary projections, lined with transitional epithelium, with fibrovascular core.

EPIDEMIOLOGY: Occurs in young people.

CYSTITIS: Occurs in women because of short urethra.

PATHOGENESIS: Various causes

Urinary stones denude epithelium and expose the basement membrane, allowing bacteria to attach and predisposing to cystitis.
Bladder outlet obstruction, as in BPH.
Chemotherapy
Indwelling catheters
Adenovirus may cause cystitis in children, but viral cystitis is rare in adults.

BUGS:

Gram-negatives: E. Coli, Proteus, Pseudomonas, Klebsiella
Gram-positives: Staph Saprophyticus, Enterococci.

POLYPOID CYSTITIS: Polypoid lesions reflecting severe submucosal edema. Associated with indwelling catheters.

They usually go away after removal of the catheter.

EOSINOPHILIC CYSTITIS: Can occur in three situations:

Secondary to an allergic response in GI tract or peripheral eosinophilia (rare)
Secondary to a transurethral resection.
Adjacent to, and in response to, an invasive carcinoma. Always consider an invasive carcinoma when you see eosinophilic cystitis!

CHRONIC INTERSTITIAL CYSTITIS (HUNNER ULCER): Middle-aged women.

PATHOLOGY: Transmural, aseptic inflammation of bladder.

Urine cultures come back negative -- no bugs causing the inflammation.
Linear cracks in mucosa.
Ulcer: Bladder epithelium becomes denuded and can ulcerate. This can be treated with sulfa drugs.
Fibrosis prevents normal expansion of bladder. Cannot be treated.

TREATMENT: Give sulfa drugs, which aids in reepitheliazation of bladder. Theory is that they are unable to sulfonate the GAG's and glycoproteins on the epithelium, hence these drugs help.

The treatment allows reepitheliazation (heals the ulcer), but it does not stop the fibrosis.

MALAKOPLAKIA: Occurs with chronic cystitis.

PATHOLOGY: Looks like a chronic granulomatous response with no Giant Cells.

In bladder, grossly looks like a white or yellow, indurated lesion.
Michaelis-Guttmann Bodies: PAS-Positive, calcified inclusions inside macrophages. They are lysosomes containing bacteria fragments.

They stain positive for iron, PAS, and calcium.

It usually occurs in the bladder, but can occur anywhere else too, especially in the UG tract.

IATROGENIC CYSTITIS: Induced by radiation or chemotherapy. Also known as hemorrhagic cystitis.

Cyclophosphamide shows idiosyncratic reaction (not dose-dependant) with the bladder in some people.

PATHOLOGY: Edema, congestion, hemorrhage within four hours of administration of drug.

Radiation Cystitis: Edema, vacuolized cytoplasm, fibrosis, nuclear abnormalities.

OBSTRUCTION: Urinary obstruction can occur at the level of renal pelvis, ureter, ureterovesical junction, urinary bladder or the urethra. Such an obstruction may cause hydronephrosis, hydroureter and predispose to urinary infections.

PATHOGENESIS: Obstructions can be congenital, due to developmental anomalies or acquired; bilateral or unilateral.

EXTRINSIC: The ureter is compressed from outside

Pelvic tumors
Pregnancy
Retroperitoneal fibrosis
BPH: common.

INTRINSIC:

Ureteric tumors
Urinary stones: common
Blood clots
Detached renal papillae separated from the rest of the kidney by papillary necrosis.
Urethral strictures secondary to urethritis.

BENIGN LESIONS:

BRUNN LESIONS:

BRUNN BUDS: Invagination of surface epithelium into the lamina propria.
BRUNN NESTS: Invagination within the lamina propria. More progressed Brunn's Bud.
CYSTITIS CYSTICA: Results when Brunn's Nest closes over on itself, forming a cyst.

METAPLASIA:

CYSTITIS GLANDULARIS: Cystitis Cystica that has undergone metaplasia to form glandular tissue. Differs from Cystitis Cystica only in the nature of the epithelia.
COLONIC METAPLASIA: Bladder glands look like mucinous glands. Occurs in paraplegics, and it leads to higher risk for adenocarcinoma.
SQUAMOUS METAPLASIA: It happens with Schistosoma Haematobium infection, and it can lead to Squamous Cell Carcinoma.
NEPHROGENIC METAPLASIA: Makes the bladder glands look like renal tubules.

PATHOGENESIS: Occurs after surgeries, and is probably a result of healing process.
PATHOLOGY: Cuboidal epithelium, with normal urothelium on top.

INVERTED PAPILLOMA: Found near the trigone.

PATHOLOGY: In the polyp, transitional cell form back-to-back serpent-like glands. It looks like it would be cancerous, except they are lacking the thick epithelium (more than 8 cells thick) and fibrovascular stalks of cancerous papillomas.

BLADDER DIVERTICULUM: Outpocketings of bladder can result from increased cystic pressure, in elderly men with BPH.

Complication = urinary stones can develop in the diverticulum.

MISCELLANEOUS URINARY DEFINITIONS (MUD):

Calculi: A simple stone. Urinary calculi can occur in the renal collecting system, ureters or urinary bladder. These stones are composed of calcium oxalate, calcium phosphate, ammonium magnesium sulfate, urate crystals or cysteine.
Neurogenic Bladder: An abnormally functioning bladder that has lost its autonomic innervation usually following spinal cord injury.

Enuresis: Bed wetting. It is physiologic during the first 2 or 3 years of life. It may be functional or secondary to delayed neuromuscular maturation of the ureterovesical component, but it may present as a symptom of organic disease (e.g., infection, distal urethral stenosis in girls, posterior urethral valves in boys, neurogenic bladder).

Incontinence: The patient may lose urine without warning; this may be a constant or periodic symptom. The more obvious causes exstrophy of the bladder, epispadias, vesicovaginal fistula, and ectopic ureteral orifice. Injury to the urethral smooth muscle sphincters may occur during prostatectomy or childbirth.
Filariasis: An infection with Wuchereria bancrofti a threadlike nematode about 0.5 cm or more in length that lives in the human lymphatics. The patient suffers recurrent lymphadenitis and lymphangitis with fever and malaise. Not infrequently, inflammation of the epididymis, testis, scrotum, and spermatic cord occurs. Varying degrees of painless elephantiasis of the scrotum and extremities develop as obstruction to lymphatics progresses.
Nocturia: Urination at night. Nocturia may be a symptom of renal disease related to a decrease in the functioning renal parenchyma with loss of concentrating power. Nocturia can occur in the absence of disease in persons who drink excessive amounts of fluid in the late evening. Coffee and alcoholic beverages, because of their specific diuretic effect, often produce nocturia if consumed just before bedtime.
PNEUMATURIA: The passage of gas in the urine strongly suggests a fistula between the urinary tract and the bowel.

PATHOGENESIS:

Vesico-enteric Fistulas: Carcinoma of the sigmoid colon, diverticulitis with abscess formation, regional enteritis, and trauma cause most vesical fistulas.
Urethro-enteric Fistulas: Congenital anomalies account for most urethroenteric fistulas.

URINARY CANCERS:

TRANSITIONAL-CELL CARCINOMA of URETER: 90% of ureter tumors are transitional cell carcinomas.

EPIDEMIOLOGY: Tend to occur in 6^th to 7^th decade.
Squamous Cell and adenocarcinomas are rare in ureter, but carry a worse prognosis when found.

TRANSITIONAL CELL CARCINOMA of BLADDER:

EPIDEMIOLOGY: Predominantly a disease of white males.

4^th most common cancer in men, and 8^th most common in women. 10% of all cancers.

PATHOGENESIS:

Smoking by itself can account for 50% of bladder cancers.
Arylamines: 2-naphthylamine and 4-aminobiphenyl are two arylamines, known to be carcinogenic, which are found in cigarette smoke.

beta-Glucuronidases in the bladder cleave previously conjugated arylamines, making them once again toxic when they hit the bladder. This mechanism explains why arylamine toxicity is specific to the bladder.

Saccharin has been shown to cause bladder cancer in rats when fed large doses.
Occupational Hazard: Rubber workers, leather workers, chemical workers, textile workers, painters, have all been associated with increased risk.
Phenacetin: Analgesic. Abuse after 10 or 20 years can lead to bladder cancer.
Free Radicals: Overall, free radicals seem to often play a role. They can attack deoxyguanosine and deoxyadenosine, causing point mutations in ras and myc oncogenes.

THREE STAGES or SUBTYPES:

TRANSITIONAL CELL PAPILLOMA: Low Grade superficial tumor. 80% of transitional-cell tumors.

CLINICAL: Although this is a low-grade tumor, 80% of patients will have a recurrence of another tumor in the future.

Only 20-30% of these patients will ultimately progress to invasive cancer.

PATHOGENESIS: Genetic defect on chromosome 9.
PATHOLOGY: This tumor may be classified as malignant or benign, depending on who you ask.

TRANSITIONAL CELL CARCINOMA IN SITU: Intermediate grade carcinoma. Flat lesion traversing the mucosa.

CLINICAL: 80% of these patients will ultimately progress to invasive cancer.
PATHOGENESIS: Genetic defect in P53 gene, which is a different carcinogenesis than the papillary carcinoma above.
PATHOLOGY: Definitely malignant. The disease is diagnosed based on histology. The bladder wall isn't any thicker, but typical anaplasia is found.

DIFFUSE pattern carriers poor prognosis and is very likely to become invasive, while focal pattern is much better.

PAPILLARY TRANSITIONAL-CELL ADENOCARCINOMA: Invasive, high grade carcinoma, having invaded the muscularis layer.

PATHOLOGY: It is usually found on the lateral walls of the bladder, not the posterior wall.

It can be endophytic or exophytic.

STAGING:

Ta: Cancer is still within the mucosa. Recurrences are less common.
T1a: Cancer has passed the mucosa, into the lamina propria. Recurrences are common.

GRADING:

Grade 1: Basically normal urothelium, except (1) it is greater than 8 cell layers thick, and (2) there is usually a fibrovascular stalk.
Grade 2: Intermediate. The surface layer of this bladder tumor appears disorganized. The cells shows variation in size and shape and the polarity of the nuclei has been lost.

Tends to be papillary or endophytic.

Grade 3: Highest degree of anaplasia; variety in architecture of cells. Tends to be exophytic and invading.

TREATMENT: Radical cystectomy is normally performed if there is muscle invasion.

SQUAMOUS CELL CARCINOMA: Occurs with Schistosoma Haematobium.
ADENOCARCINOMA: Very rare. Likely to be urachal in origin (on dome of bladder) if it occurs.

URETHRA:

ANATOMY: Male Urethra

Prostatic Urethra

Contains urothelium (transitional cells)
Verumontanum (seminal colliculus): an elevated portion of the urethral crest upon which open the two ejaculatory ducts and the prostatic utricle.

Membranous Urethra

Pseudostratified Columnar Epithelia line the membranous urethra.
Cowper's Glands empty into the membranous urethra.

Penile Urethra

Pseudostratified Columnar line most of the penile urethra.
Non-keratinized stratified squamous epithelia line the fossa navicularis and urethral orifice.

CONGENITAL ANOMALIES:

URETHRAL DIVERTICULA: Mainly in women. Trauma may lead to sac-like evagination.
Duplications of Urethra: rare.
FIBROEPITHELIAL POLYPS: Congenital urethral polyps; arise in prostatic urethra near colliculus, and may cause obstruction. They can be removed surgically.
POSTERIOR URETHRAL VALVE: Mucosal folds projecting into the prostatic urethra, which may cause obstruction.

SYMPTOMS: Early on, dysuria and fever.

enuresis is seen in boys.
Late stage: Hematuria, inflammatory symptoms, eventually hydronephrosis.

EPIDEMIOLOGY: Not uncommonly seen in pediatric population.
TREATMENT: Vesiculotomy to relieve the pressure. Later trans-urethral resection, after the inflammation has healed.

URETHRITIS:

ACUTE URETHRITIS: Dysuria with urethral discharge.

PATHOGENESIS: Sexually transmitted, in males.

Neisseria gonorrhoeae = yellow discharge
Chlamydia Trachomatis, Ureaplasma urealyticum = white discharge.

EPIDEMIOLOGY: Transmission risk of 17-20% for the male, with unprotected sex.

REITER SYNDROME: In males, triad of urethritis, conjunctivitis, arthritis. Cause unknown. Treated conservatively. Disease waxes and wanes.
CARUNCLE: Polypoid or sessile lesion in distal urethra of women.

PATHOLOGY: Consists of granulation tissue covered with hyperplastic partially ulcerated transitional or squamous cell epithelium.
CLINICAL: Treated with topical creams or removed. It may spontaneously resolve.

POLYPOID URETHRITIS: Urethral counterpart to polypoid cystitis. Submucosal edema, associated with indwelling catheters.

NON-NEOPLASTIC DISEASES:

NEPHROGENIC METAPLASIA: Just as in bladder.

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MALE GU

SEX DISORDERS:

GENETIC SEX

TURNER SYNDROME: XO genotype.
MIXED GONADAL DYSGENESIS: 1 defined gonad plus a contralateral streak gonad. Increased incidence of germ cell tumors.
TRUE HERMAPHRODITE: Both ovarian and testicular tissue present.

PHENOTYPIC SEX:

MALE PSEUDOHERMAPHRODITISM: Testicular Feminization Syndrome, insensitivity to testosterone ------> phenotypic female with primary amenorrhea.
FEMALE PSEUDOHERMAPHRODITISM: Androgenital Syndrome, due to adrenal hypersecretion of androgens.

CRYPTORCHIDISM: Failure of testes to descend into scrotum.

SYMPTOMS: Infertility.

5-35X Risk of developing germ-cell tumors in untreated Cryptorchidism.

TREATMENT: Orchidopexy = repositioning of testes into scrotum surgically. Should treat as early as possible (less than 1 yr old) to prevent occurrence of germ-cell tumor.

ORCHITIS:

PATHOGENESIS: Often results from hematogenous spread of systemic diseases (bacteremia, viremia). Orchitis without epididymitis is thought to start this way.
GRAM(-) BACTERIAL ORCHITIS: Most common, often secondary to Syphilitic orchitis.
SYPHILITIC ORCHITIS:

GUMMAS: Granulomatous-type lesion in testicles, can occur with tertiary syphilis.

MUMPS ORCHITIS: Occurs in 20% of adult male Mumps cases. Usually only unilateral.
GRANULOMATOUS ORCHITIS: Non-caseating granulomas, may be an auto-immune reaction to sperm.
MALAKOPLAKIA: Can occur in testes, as in other locales.

TORSION of the TESTES:

PATHOGENESIS: Occurs when there is redundancy of the cord.
PATHOLOGY: Will result in infarct of testicle if not quickly resolved.

GERM-CELL TUMORS:

PATHOGENESIS: Cryptorchidism is a common risk factor for all germ-cell tumors.

They may occur in sites other tha gonads, such as mediastinum, sacrococcygeal region, or even cranium.

PATHOLOGY: LDH Type-I is elevated in many germ cell tumors.
SEMINOMA: Adults.

EPIDEMIOLOGY: Seminoma accounts for 40% of all testicular tumors. It has a peak incidence in the 35-45 years age group.
SUBTYPES:

CLASSIC SEMINOMA: Most common type. Can metastasize to regional lymph nodes.

5-15% of tumors contain scattered syncytiotrophoblast cells that secrete hCG.

ANAPLASTIC SEMINOMA: Different histologically, but same picture clinically as classic seminoma.
SPERMATOCYTIC SEMINOMA: The only testicular cancer to occur in elderly men. Is not known to metastasize.

PATHOLOGY: Polygonal neoplastic cells that have clear cytoplasm, contain glycogen and resemble fetal gonocytes.

Syncytiotrophoblastic Differentiation: Seminomas often secrete hCG (80% of time) because they show some differentiation into syncytiotrophoblast. This is not a choriocarcinoma because that would require both syncitio- and trophoblasts.
Gross: Yellow, no necrosis.
Lymphocytic Inflammation: the tumor cells are arranged into solid nests surrounded by fibrous septa that are infiltrated with lymphocytes.
Cancer cells are clear and contain glycogen, which stains PAS positive.
Granulomas can be formed in response to seminomas, as a response to tumor antigens.

TREATMENT: The tumor is radiosensitive and can be cured in over 90% of cases.
DDx = LYMPHOMA of TESTIS: In an older male, you must consider lymphoma as well as seminoma for any tumor in testis. In a younger male, it is mostly likely a seminoma.

EMBRYONAL CARCINOMA: Usually occurs in conjunction with seminomas. It would be rare to see it by itself.

EPIDEMIOLOGY: The tumor has a peak incidence in the 25-35 year age group. Pure embryonal carcinomas are rare accounting for about 10-15% of all germ cell tumors.
PATHOLOGY: Undifferentiated cells resembling early embryonic cells.

Gross: Yellow with brown discoloration. Necrosis.
No lymphocytes, unlike seminoma. More nuclear crowding.
Embryoid Bodies: Contained in the tumor, they mimic what the embryonic tissue looks like in the blastocyst stage.
Can further differentiate into other tumors:

Teratocarcinoma
Yolk-Sac Tumor
Choriocarcinoma

TERATOMA:

EPIDEMIOLOGY: Rare in the testis. Usually found in pre-pubertal children.
PATHOLOGY: Benign lesion containing all three germ-layers, often containing hair, skin, eyes, anything else.
SUBTYPES:

Mature Teratoma: Benign, tends to occur in children.
Immature Teratoma:
Teratoma with Malignant Transformation (Teratocarcinoma): Rare, malignant, and tends to occur in adults.

CLINICAL: Age is most important prognostic indicator. Children have a good prognosis, and adults have a poor prognosis.

ENDODERMAL SINUS (YOLK-SAC) TUMOR: Most common germ-cell tumor in children.

EPIDEMIOLOGY: Children under age 5.
PATHOLOGY:

Numerous histological patterns seen:

Reticulated
Microcystic
Papillary myxoid

Schiller-Duval Bodies: Often present, they resemble fetal glomeruli.
Alpha-Fetoprotein (AFP): Tumor cells secrete AFP. AFP can also be found in teratocarcinomas, indicating the similar lineage of the two tumors.

TREATMENT: Surgical resection.

TESTICULAR CHORIOCARCINOMA:

EPIDEMIOLOGY: Rare.
PATHOLOGY: Highly malignant, composed of cytotrophoblast and syncytiotrophoblast cells. Highly invasive cells cause hemorrhage and necrosis of tissues into which they have spread.

Human Chorionic Gonadotropin (hCG): Choriocarcinoma cells secrete hCG, which helps to identify them. This is explained by their syncytiotrophoblast origin.

STROMAL TUMORS:

LEYDIG CELL TUMOR: Most common stromal tumor of the testis. Usually benign.

EPIDEMIOLOGY: Accounts for 1-3% of all testicular tumors.
PATHOGENESIS: Unknown, but there is no association with Cryptorchidism.
PATHOLOGY: Only 10% of tumors in adults are malignant. Malignancy cannot be predicted histologically, but only by behavior of the cancer.

SERTOLI CELL TUMOR: Extremely rare. Usually benign (10% malignant).

SYMPTOMS:

Virilization is often seen in children
Gynecomastia may be present in 30% of adults. It can produce estrogen.

GONADOBLASTOMA: Rare.

EPIDEMIOLOGY / PATHOGENESIS: Almost exclusively seen in patients with some form of gonadal dysgenesis (testicular feminization).

The majority of these tumors occur in patients under 30 years of age.

SYMPTOMS: Four-fifths of patients with gonadoblastomas are phenotypic females.

Males typically have cryptorchidism or hypospadias.

TESTICULAR ADNEXAE:

TESTICULAR TUNICS:

VARICOCELE: Engorgement of veins in the pampiniform plexus of th testes.
HYDROCELE: Collection of clear, serous fluid in the scrotum. The fluid typically fills the space between the layers of the tunica vaginalis testis.
HEMATOCELE:
SPERMATOCELE:

EPIDIDYMITIS: Painful swelling of one or both epididymides with fever and a variable incidence of dysuria and pyuria. In young men, usually associated with sexually transmitted urethritis (N. gonorrhoeae or C. trachomatis), in older men, most often associated with prostatitis (infections with coliform bacilli).
TUMORS OF EPIDIDYMIS:

Adenomatoid tumors are most common and typically occur in the third and fourth decade of life.
Leiomyomas are the second most common tumor.

VASITIS NODOSA:
LIPOMAS: Typically benign and usually occur in spermatic cord.
SARCOMAS:

PROSTATE:

ANATOMY:

Anterior Zone: mostly stroma, little glands.
Peripheral Zone: 75% of all the glands in the prostate.

Location of most Prostatic Adenocarcinoma.

Central Zone
Periurethral Glands: A narrow sleeve of the proximal urethra.
Transitional Zone: Area surrounding prostatic urethra.

Location of most BPH

PROSTATITIS:

ACUTE BACTERIAL PROSTATITIS: Usually gram(-) bugs.

PATHOGENESIS: Often occurs secondary to bacteremia.
PATHOLOGY: Tender, swollen, indurated prostate. Purulent prostatic secretions, usually caused by infection with coliform bacilli.

Often accompanied by bacteriuria.

SYMPTOMS: Fever, chills, perineal pain.

CHRONIC PROSTATITIS: An imprecise term that encompasses a variety of syndromes.

PATHOGENESIS: Variable cause and clinical sequelae:

Chronic bacterial prostatitis
Chronic non-bacterial prostatitis
BPH: frequent complication.

PATHOLOGY: Lymphocytic infiltrate.
SYMPTOMS: Suprapubic pain, low back pain, dysuria, nocturia.

NON-BACTERIAL PROSTATITIS: Most common prostatitis.

PATHOGENESIS: Usually unknown. Abnormal numbers of inflammatory cells found in their prostatic secretions, but no causative infectious agent can be found by culture or other means.

Autoimmune: Theory = may be an autoimmune attack against prostate.
Trichomonas, Mycoplasma: They may be responsible for the prostatitis in a minority of cases.

DIAGNOSIS: Made by excluding other causes of prostatitis.

GRANULOMATOUS PROSTATITIS:

NON-INFECTIOUS: Inflammatory response to inspissated (thickened) concretions.

Allergic prostatitis often occurs here; eosinophils are common.

INFECTIOUS: Tubercular, fungal.

BENIGN PROSTATITIC HYPERPLASIA (BPH) (NODULAR HYPERPLASIA): BPH is not preneoplastic.

EPIDEMIOLOGY: 75% of men have it by age 80. Some people say even higher. Especially common in African American men.
PATHOGENESIS: Several theories

BPH may result from a combination of decreased testosterone and increased estrogen, occurring with old age. This may cause an increased sensitivity to DHT in the prostate.

PATHOLOGY: Both glands and stroma proliferate, with a significant (5:1) stromal component.

Gross:

Hyperplasia appears nodular, with even proliferation of stroma and glandular components.
Hyperplasia nearly always occurs in the transitional zone of the prostate, beginning around the prostatic urethra, and going out peripherally.

SYMPTOMS: Bladder-outlet obstruction. Hesitancy, dysuria, urgency, feeling of incomplete stream.

Rectal Exam: BPH feels like a soft padding over the base of the thumb. Cancer is rock-hard.

TREATMENT:

5-alpha-Reductase Inhibitors: Finasteride (Proscar) inhibits the peripheral conversion of testosterone to DHT, thereby blocking the growth-effect of DHT on the prostate.

Clinical Trials have shown it effective in reducing prostate size and alleviating symptoms.

Trans-Urethral Resection (TUR): Core out middle part of the urethra, to open up the lumen. This results in prostatic chips which can be sent into Surg.Path. for analysis.

PROSTATIC ADENOCARCINOMA:

EPIDEMIOLOGY: Common in U.S., rare in Asia. Incidence again highest in African American men.

Median age of diagnosis = 72 years old.

PATHOGENESIS:

Dietary (supposed): Increase in dietary fats, decrease in fish oils.
Testosterone makes the cancer grow, but there is no evidence that high DHT can cause the cancer.
It may just be a natural consequence of aging -- some carcinoma is found in 80% of old men at autopsy.
CYTOGENETIC Abnormalities: Variety of them are seen.

Chromosome 8p22 deletion found in 70% of cancers.
c-myc oncogene involvement.
POOR PROGNOSIS: Two abnormalities associated with poorer prognosis.

Aneuploidy of chromosomes 7 and 8 is associated with poor prognosis.
Chromosome 16 has Cadherin and Catenin proteins, which are associated with poor prognosis when present.

PATHOLOGY: Almost all carcinomas originate in the acini, in the Peripheral Zone of the prostate.

Gross: Usually yellow. It is solid -- not nodular as in BPH.
GLEASON GRADING:

Grades:

Grade 1: Near normal, minimal anaplasia.
Grade 2-4: Intermediate grades.
Grade 5: No acini exist at all, maximal anaplasia.

SCORE: Add the major pattern + minor pattern to get final score. Final score of 1 thru 10, with 10 being worst.

PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN): Pre-cancer. Lesion is confined to the acinus.

PATHOLOGY: The basal cell layer is maintained in PIN.

Basal-Cell-Specific Keratin: PIN will stain positive for it, since basal cells are present. Full carcinoma will stain negative, as basal cells are absent.

HISTOLOGICAL SUBTYPES:

Tufting: Most common
Micropapillary
Cribriform
Flat

EPIDEMIOLOGY: PIN develops early in life, from age 10-50.

PROSTATE SPECIFIC ANTIGEN (PSA): Used to diagnose prostate cancer, and distinguish it from BPH.

STRUCTURE: A glycoprotein (mol wt 33,000) that is secreted in the cytoplasm of prostatic cells.
FUNCTION: Serine protease functions normally in aiding liquefaction of semen.

NORMAL VALUES: Upper limit of normal

Young adults: between 0 and 4 ng/mL.
40-49 year-old: 2.5 ng/mL
50-59-year-old: 3.5 ng/mL
60-69-year-old: 4.5 ng/mL
70-79-year-old: 6.5 ng/mL

PSA DENSITY: PSA levels divided by volume of prostate, to normalize for BPH. Densities greater than 0.15 are associated with 60% chance of cancer.
TWO SUBTYPES: The two subtypes cannot currently be differentiated.

Complexed PSA: Associated with cancer
Free PSA: Associated with BPH.

X-RAY DIAGNOSIS: Bone metastases can be seen on X-Ray and result in an elevated Alkaline Phosphatase.

TRANS-URETHRAL SONOGRAPHY (TRUS): Diagnostic tool, to help diagnose cancers that aren't caught by PSA or rectal exam.

It can identify 60% of cancers even if they are nonpalpable, because of hypo-echogenic characteristics of these cancers. This is presumably because the compact, highly cellular nature of malignancy produces a minimal interphase between cells, and this creates minimal internal echoes. Transrectal ultrasound is also more accurate than DRE at detecting extracapsular extension.

SYMPTOMS:

Most cancers are indolent. Less than 1% of men diagnosed with Prostate Cancer actually die of the disease.
METASTASIS to bone, lung, liver, spleen. Bone is most common site of metastasis.

STAGING:

Stage A: Microscopic foci of anaplasia in an otherwise benign specimen.

A1: Focal anaplasia.
A2: Diffuse anaplasia.

Stage B: Clinically palpable nodule, but still confined to prostate.

B1: Focal lesion, one lobe.
B2: More than one lobe of prostate involved.

Stage C: Local invasion beyond the prostate capsule. No metastasis.
Stage D: Metastasis.

D1: Metastases to regional lymph nodes.
D2: Distant metastases.

CONGENITAL DISORDERS of PENIS:

PHIMOSIS: Congenital or acquired inability to retract the prepuce, in uncircumcised penises.
EPISPADIA: Urethra opens on dorsal aspect of penis. Surgically correctable and associated with infertility.

PATHOGENESIS: Often associated with Exstrophy of Bladder

HYPOSPADIA: Urethra opens on underside (ventral) aspect of penis. Surgically correctable and associated with infertility.

Most common of the congenital penile anomalies.

SEXUALLY TRANSMITTED PENILE LESIONS:

CONDYLOMATA ACUMINATA (VENEREAL WARTS): HPV, usually type 6 and 11.

PATHOLOGY: Condylomata resemble other warts and show acanthosis, papillomatosis, prominence of the granular layer, parakeratosis and keratosis. HPV can be demonstrated in the nuclei of the keratinocytes by immunofluorescence microscopy or electron microscopy.

GENITAL HERPES: Herpes simplex virus is a double-stranded DNA virus that may cause persistent or latent infections. Most genital herpes infections are due to type 2 virus, although infection due to type I herpes virus, which is commonly associated with oral infections, has been reported in 10-25% of cases of genital herpes.

PATHOLOGY: Vesicles grouped on an erythematous base, not following a neural distribution, and associated with a previous history of such eruptions are pathognomonic for genital herpes.

GRANULOMA INGUINALE: Granuloma inguinale, a sexually transmitted chronic infection of the skin and subcutaneous tissue of the genitalia, perineum, and inguinal area, has an incubation period of 2-3 months.

PATHOGENESIS: Calymmatobacterium granulomatis
SYMPTOM: A painful papule is the first sign of granuloma inguinale.

LYMPHOGRANULOMA VENEREUM: Chlamydia trachomatis, immunotypes Ll - L3.

SYMPTOMS: A papule or pustule appears 5-21 days after sexual exposure. The disease is characterized by a transient genital lesion followed by lymphadenitis and, possibly, rectal strictures.

CANCER of PENIS:

SQUAMOUS CARCINOMA IN SITU:

BOWEN DISEASE: Epidermal dysplasia on shaft of penis.

SYMPTOMS: Erythematous plaque

May progress to invasive cancer, but such progression occurs in only 10% of cases

ERYTHROPLASIA of QUEYRAT: Epidermal dysplasia on glans or prepuce.
BOWENOID PAPULOSIS:

PATHOGENESIS: HPV-16
PATHOLOGY: Lesions show less cytologic atypia than other forms of carcinoma in situ.
TREATMENT: Readily cured with topical antiviral ointments.

PENILE INTRAEPITHELIAL NEOPLASIA (PIN):

GIANT CONDYLOMA of BUSCHKE-LOWENSTEIN (VERRUCOUS CARCINOMA) Exophytic mass on gland of uncircumcised penis. Can be cured surgically.
SQUAMOUS CELL CARCINOMA:

EPIDEMIOLOGY: Rare in the US -- less than 0.5% of all cancers in males

Common in South America, Africa and Asia, where it may be 10-20% of Male-GU cancers.
Age = 6^th decade
Circumcision effectively prevents the disease, hence it is rare in U.S.

PATHOLOGY: Exophytic or endophytic with superficial ulceration.
PATHOGENESIS: One theory postulates that smegma (is that Yiddush?) accumulation under the phimotic foreskin results in chronic inflammation leading to carcinoma.

SCLEROSING LIPOGRANULOMA of SCROTUM:

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FEMALE GU

SEXUALLY TRANSMITTED INFECTIONS:

BACTERIAL:

GONORRHEA
SYPHILIS
GRANULOMA INGUINALE
CHANCROID: Chancroid is a sexually transmitted disease caused by Haemophilus ducreyi. It is a well-established cofactor for HIV transmission, and 10% of patients with chancroid may also have syphilis or herpesvirus infection . One or more painful, dirty-appearing chancroid ulcers appear after the first few days of infection.
GARDNERELLA
MYCOPLASMA
CHLAMYDIA

CHLAMYDIAL URETHRITIS:
LYMPHOGRANULOMA VENEREUM:

VIRAL:

HUMAN PAPILLOMAVIRUS (HPV) (CONDYLOMA ACUMINATUM):
HERPESVIRUS (HSV):
CYTOMEGALOVIRUS (CMV):
MOLLUSCUM CONTAGIOSUM:

PROTOZOA:

TRICHOMONIASIS:

PELVIC INFLAMMATORY DISEASE (PID):

OTHER VAGINAL INFECTIONS:

TUBERCULOSIS:
CANDIDIASIS:
ACTINOMYCOSIS:
TOXIC SHOCK SYNDROME:

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VULVA, VAGINA, CERVIX

VULVA:

BARTHOLIN'S GLAND CYST: Obstruction of Bartholin's gland ------> cyst formation, infection, abscess.

TREATMENT: Incision, drainage, antibiotics.

LICHEN SCLEROSIS:

PATHOLOGY: Painful white plaques on the vulva with atrophy.

Hyperkeratosis and blunting of rete ridges.
Homogenous, acellular zone in the upper dermis with a band of lymphocytes and plasma cells.

SYMPTOMS: Itching and dyspareunia.

SQUAMOUS HYPERPLASIA: Benign.

PATHOLOGY: Thickened epithelium, hyperkeratosis. Granulosa layer becomes hypercellular.

LEUKOPLAKIA: White patch on vulva. Differential diagnosis includes:

Lichen Sclerosis
Squamous Hyperplasia
Squamous Carcinoma In Situ
Squamous Cell Carcinoma

VULVAR TUMORS:

HIDRADENOMA:
SYRINGOMA:
VULVAR INTRAEPITHELIAL NEOPLASIA (VIN): Vulvar dysplasia. Precursor lesion of Squamous Cell Carcinoma of Vulva.

PATHOGENESIS: Related to HPV 6, 11, 16
SYMPTOMS: Macules, papules, or plaques.
GRADING:

VIN I: Most differentiated.
VIN II:
VIN III: Highest degree of atypia.

SQUAMOUS CELL CARCINOMA of VULVA:

EPIDEMIOLOGY: Most common cancer of the vulva (85%) and accounts for 3% of all genital cancers in women.
PATHOLOGY: Exophytic, ulcerative or endophytic. Usually is keratinizing.
SYMPTOMS: Pruritus, bleeding, ulcer, and a mass.

Prognosis is good: 90% survival with no metastasis.
Metastasis goes to inguinal or femoral nodes.

VERRUCOUS CARCINOMA (GIANT CONDYLOMA):

PATHOGENESIS: HPV 6
CLINICAL: Good prognosis.

EXTRAMAMMARY PAGET DISEASE: Rare

PATHOLOGY:

Paget Cells: Malignant, large, pale vacuolated cells, found scattered throughout the epidermis.
Usually remains confined to epidermis.
Stains: PAS-positive, mucin-positive

SYMPTOMS: Red, moist, weeping, pruritic lesion on labia majora.

Other malignancies often co-occur with Paget's. Check for other malignancies if you see the disease.

TREATMENT: Wide local excision. Usually curative.

MELANOMA: Very rare.

SYMPTOMS: ABCD

Asymmetry of lesion
Borders are elevated
Color is brown or black
Diameter is unusually large.

VAGINA:

CONGENITAL ANOMALIES:

CONGENITAL ABSENCE
SEPTATE VAGINA
IMPERFORATE HYMEN

ATROPHIC VAGINITIS: Diminished estrogenic stimulation post-menopausal leads to atrophy and possible superimposed infection. Can be prevented with Post-Menopausal Estrogen Replacement Therapy (ERT).
VAGINAL ADENOSIS: Change from normal squamous epithelium ------> glandular epithelium.

PATHOGENESIS: Associated with use of diethylstilbestrol (DES) during 10^th - 18^th weeks of pregnancy ------> female fetus will get Vaginal Adenosis.
SYMPTOMS: Appears as red area; glandular epithelium is not as thick.

Increased risk for vaginal adenocarcinoma, which is otherwise a rare a cancer.

VAGINAL TUMORS:

SQUAMOUS CELL CARCINOMA: The most common cancer of the vagina.

PATHOGENESIS: Associated with HPV infection.

Patients usually have had multiple sexual partners and early age at first intercourse.

STAGING: VAGINAL INTRAEPITHELIAL NEOPLASIA (VAIN) is the precursor lesion to Squamous Cell Carcinoma. Term encompasses vaginal dysplasia and carcinoma in situ.

VAIN I: Mild, well-differentiated.
VAIN II: Moderate
VAIN III: Severe anaplasia. Carcinoma in situ
VAIN IV: Invasive Carcinoma

PROGNOSIS: Excellent prognosis, for localized lesions with no metastases.

CLEAR CELL ADENOCARCINOMA:

PATHOGENESIS: Adenocarcinoma associated with in utero exposure to Diethylstilbestrol.
PATHOLOGY: "Clear cell" indicates glycogen-filled mucin-producing glandular cells.
TREATMENT: They are curable.

EMBRYONAL RHABDOMYOSARCOMA (SARCOMA BOTRYOIDES):

EPIDEMIOLOGY: Rare, exclusively in infants and young children
PATHOLOGY: Made of primitive embryonal rhabdomyoblasts.
SYMPTOMS: Confluent polypoid masses resembling a bunch of grapes, protruding from the vagina.
TREATMENT: Good prognosis. Conservative surgery followed by chemotherapy.

CERVIX:

Transformation Zone:

Squamocolumnar Junction: It can occur in the internal os or the external os.

Endocervical Ectropion: Reddish areas around the external os that are actually just extensions of columnar epithelium from the uterus. This is normal and can occur in women who have a transformation zone that is one the exocervix rather than endocervix.

Squamous Metaplasia: In women in whom columnar epithelium extends into the exocervix, the exocervical part can undergo squamous metaplasia, especially with age and childbirth. This effectively makes the squamocolumnar junction recede into the endocervix.
Transformation Zone: The area between the original squamocolumnar junction (before squamous metaplasia) and the new squamocolumnar junction is called the transformation zone.

BENIGN CERVICAL TUMORS:

ENDOCERVICAL POLYP: Benign polyps usually located in the os. They bleed; surgical excision is curative.
MICROGLANDULAR HYPERPLASIA: Closely packed glands without intervening stroma. Occurs with birth control pills or in pregnancy, it is caused by Progesterone and is not cancerous.
LEIOMYOMA: One tenth of all uterine leiomyomas occur in cervix.

CERVICAL CANCERS:

CERVICAL INTRAEPITHELIAL NEOPLASIA (CIN):

PATHOGENESIS: HPV 16, 18, 31, 33, 35

Patients usually have had multiple sexual partners and early age at first intercourse.

GRADES:

CIN-1: Mild dysplasia. Abnormal cells in the lower third of the epithelium.
CIN-2: Moderate dysplasia. Abnormal cells in the lower and middle thirds of the epithelium.
CIN-3: Severe dysplasia, or carcinoma in situ. Abnormal cells diffusely involve more than two thirds of the epithelium.

PATHOLOGY: You see the cytologic features of HPV: Dysplasia, hyperchromatin, viral inclusions.
TREATMENT: Varies according to the disease stage.

Cryosurgery
Cervical Conization: Removal of mucosal layer of cervical tissue.
Laser Vaporization
Hysterectomy

SQUAMOUS CELL CARCINOMA of CERVIX: Most common cancer of cervix.

PATHOGENESIS: Usually evolves from CIN.
PATHOLOGY: Exophytic, ulcerating or infiltrative lesion.

May be either keratinizing or non-keratinizing.
Keratin Pearls: Can see islands of squamous cells in the stroma, indicative of Squamous Cell Carcinoma.

SUBTYPES:

MICROINVASIVE SQUAMOUS CARCINOMA: Generally carries a better prognosis. Two criteria in order to call it microinvasive:

Tumor ends less than 3mm from the overlying epithelium.
No vascular or lymphatic invasion.

INVASIVE CARCINOMA: Tumor greater than 3mm deep, and/or vascular ot lymphatic invasion.

SYMPTOMS: Vaginal bleeding, discharge.

Metastasis: Tumor spreads by direct extension and through lymphatics.

TREATMENT: Varies with age. Same options as CIN. Radical hysterectomy is often required.

ADENOCARCINOMA of CERVIX:

EPIDEMIOLOGY: Incidence is going up. Traditionally sited as 10% of cervical cancers, but now it may be more like 30-40%.
PATHOGENESIS: HPV 16, 18 is implicated in pathogenesis. That explains the rising incidence of the cancer.
PATHOLOGY: Mucin producing glands with stromal invasion.

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UTERUS

CONGENITAL ANOMALIES:

UTERINE AGENESIS:
UTERUS DIDELPHYS: Completely double-uterus, from lack of fusion of the two Mullerian ducts.
UTERUS DUPLEX BICORNIS: Single Uterus with a common wall separating two endometrial cavities.
UTERUS SEPTUS: Single uterus with a partial remain septum separating two hemi-cavities. Patient is at increased risk for spontaneous abortion.
BICORNUATE UTERUS: Uterus with two horns and a single common cervix. Increased risk for premature birth.

ENDOMETRITIS: Inflammation of the uterus.

ACUTE ENDOMETRITIS: Usually caused by ascending infection (sexually transmitted), abortion, or instrumentation.
CHRONIC ENDOMETRITIS: Can be caused by IUD's, PID, abortion, instrumentation.
SYMPTOMS: Pelvis pain, bleeding.
TREATMENT: Often resolves on its own with menstruation to wash out the inflammation. If it doesn't, do cultures and give antibiotics.

ADENOMYOSIS: Endometrial glands and stroma located in the myometrium.

PATHOLOGY: Looks like red, soft areas in the myometrium.

It can be confused with invasive carcinoma. Examine it histologically to distinguish them.

SYMPTOMS: Can be asymptomatic, or dysmenorrhea.

ENDOMETRIOSIS: Presence of benign, ectopic endometrial tissue, outside the uterus.

PATHOGENESIS: Theories as to the cause:

Retrograde Menstruation: Most accepted theory. Some tissue goes back through fallopian tubes and seeds in peritoneum.
Intraoperative Implantation: Resulting from surgery; surgical implantation of ectopic tissue.
Lymphatic, Hematogenous Dissemination: Some endometrial cells may spread through circulation and seed elsewhere.
Celomic Metaplasia: Metaplasia of peritoneal lining to endometrial glandular cells.

PATHOLOGY:

Most common sites: ovaries, tubes, and broad ligaments. But, any site can be involved.
Mulberry nodules: Red-blue areas found during laparoscopy.
Hemosiderin-laden macrophages can also be found in the area, as the macrophages come in to try to clean up the mess.
Glands with Stroma: Endometriosis has normal-appearing tissue, glands with stroma. This distinguishes it from adenocarcinoma, which shows back to back glands, and little or no stroma.

SYMPTOMS: Dysmenorrhea, dysfunctional uterine bleeding (DUB), dyspareunia and infertility.

Infertility results from adhesions in the tube and oviduct.

MENSTRUAL SYMPTOMS:

Dysfunctional Uterine Bleeding (DUB): Abnormal vaginal bleeding, at any time, in which cause of the bleeding lies outside the uterus. The major cause is endometriosis.

PATHOGENESIS: Largely unknown. May result from endocrine disturbances.

Anovulatory Bleeding ("Breakthrough Bleeding"): Bleeding occurring in the absence of ovulation.

PATHOGENESIS: For whatever reason, no ovulation leads to excessive estrogen and no progesterone, which leads to abnormal development of spiral arteries. When the estrogen levels then drop, the abnormal arteries can infarct, thrombose, or hemorrhage.
AGE-GROUPS: Common causes of DUB change with age:

Newborn: Due to maternal estrogen.
Child: Tumors
Reproductive Age: Stress, nutritional, tumors, endocrine disorders
Peri-Menopausal, Post-Menopausal: Tumors

Dyspareunia: Pain during intercourse.
Dysmenorrhea: Painful menstruation, or pain during menstruation.
Menorrhagia: Excessive or profuse menses.

BENIGN UTERINE LESIONS:

ENDOMETRIAL POLYPS: Benign overgrowths, mostly located on the fundus.

PATHOLOGY: Endometrial glands, fibromatous stroma, and thick-walled, dilated blood vessels.
SYMPTOMS: Inter-menstrual bleeding is the most common symptom.
TREATMENT: Curettage is usually curative.

LEIOMYOMAS (FIBROIDS): The most common GYN tumor. Strictly benign.

PATHOLOGY: Firm, pale gray, well circumscribed whorled lesions, composed of smooth muscle fibers similar to the myometrium.

Locations:

Intramural: Located with myometrial wall.
Subserosal: Located outside the myometrium.
Submucosal: Located close to surface.

SYMPTOMS: Wide range of symptoms, from asymptomatic to abnormal uterine bleeding and pain requiring hysterectomy.
TREATMENT: Myomectomy.

UTERINE PRE-CANCER and CANCER:

ENDOMETRIAL HYPERPLASIA: Pre-cancerous condition leading to adenocarcinoma.

PATHOGENESIS: Related to excessive levels of estrogen.
SUBTYPES:

Simple Hyperplasia: Crowding of glands. Glands are proliferative (more than 50% of field) and show crowding, but no atypia.

Cystic Hyperplasia: "Swiss-Cheese" hyperplasia is a variant.
Only 1% of cases progress to adenocarcinoma.

Complex Hyperplasia: Crowding of glands, with branching and irregular patterns. Still no cellular atypia.

3% of cases progress to adenocarcinoma.

Atypical Hyperplasia: Complex hyperplasia with atypia nuclei -- mitotic figures, hyperchromatin, etc. Often see back-to-back glands.

Frequent progression to adenocarcinoma.
TREATMENT: This is usually cause for having the uterus removed. Milder cases can be treated with hormonal therapy (Tamoxifen?), to attempt to block the effects of estrogen on the uterus.

ENDOMETRIAL ADENOCARCINOMA: The most common GYN malignant cancer.

PATHOGENESIS: Related to excess estrogen. Most risk-factors relate to excess estrogen:

Nulliparity, early menarche or late menopause.
Diabetes, hypertension.
Smoking

PATHOLOGY:

Growth pattern can be polypoid or diffuse. Hemorrhage and necrosis is common.

SUBTYPES:

ENDOMETRIOID CARCINOMA: Most common subtype. Well-differentiated, resembling endometrium.
ENDOMETRIOID CARCINOMA with SQUAMOUS DIFFERENTIATION: About 30% of cases.
Papillary (Serous) Carcinoma: Very poor prognosis. Usually presents with metastasis at time of diagnosis.
Clear Cell Carcinoma:
Secretory Carcinoma:

GRADING: International Federation of Gynecologic Oncologists (FIGO)

FIGO 1: Well differentiated, nearly 100% glands.
FIGO 2: Moderately differentiated. Shows both glands and sheets of cells.
FIGO 3: Poorly differentiated. Sheets of anaplastic cells with mitotic figures.

SYMPTOMS: Abnormal uterine bleeding is common complaint. Occurs in peri-menopausal and post-menopausal women.

ENDOMETRIAL STROMAL SARCOMA: Rare stromal tumor, resembling leiomyomas. They do metastasize.
LEIOMYOSARCOMA: Malignant counterpart to leiomyoma. Rare.

PATHOLOGY: Malignant smooth muscle cells, showing mitosis, necrosis, increased cellularity.

Gross: Poorly circumscribed lesion.
SYMPTOMS: Same broad range of symptoms as with fibroids.
TREATMENT: Radical hysterectomy.

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OVERY and OVIDUCT

FALLOPIAN TUBES:

SALPINGITIS: Usually caused by Pelvic Inflammatory Disease.

COMPLICATIONS:

Hydrosalpinx: Dilation of lumen of tubes, filled with clear fluid.
Pyosalpinx: Pus in tube
Fibrosis
Tubo-ovarian Abscess

ECTOPIC PREGNANCY: Most often results from tubal strictures or fibrosis, secondary to PID.

CYSTIC LESIONS of OVARY:

SIMPLE CYSTS: Majority are benign, but can be malignant.

Follicle Cyst: It can release estrogens, and looks just like a Graafian Follicle.
Corpus Luteum Cyst: Can release progesterone. Occurs in reproductive women. It is usually filled with blood, can hemorrhage, and must be removed.
Epithelial-Inclusion Cyst:
Paratubal Cyst: Cyst attached to the tube.
Theca Lutein Cyst: Commonly associated with high levels of hCG (choriocarcinoma, hydatidiform mole)

POLYCYSTIC OVARY SYNDROME (PCO) (STEIN-LEVENTHAL DISEASE):

PATHOGENESIS: Obese women. Excess estrone production in adipose tissue triggers the change.

Adipose tissue ------> excess estrone ------> stimulation of GnRH and suppression of FSH ------> high LH/FSH ratio, which is characteristic of PCO.

SYMPTOMS: Classic triad of Hirsutism, Amenorrhea, Obesity.

Hirsutism: related to excess androgens
Amenorrhea, Infertility: Secondary to the screwed up LH/FSH ratio.

PATHOLOGY: Numerous subcortical cysts. No corpus luteum or corpus albicans can be found in ovary.

BENIGN OVARIAN TUMORS:

CYSTADENOMA: Benign tumor.

SEROUS CYSTADENOMA: Cystic benign tumor.

PATHOLOGY:

Unilocular
Lined by ciliated epithelium -- tubal-like cells.

MUCINOUS CYSTADENOMA: Have mucin glands, similar to the endocervix.

PATHOLOGY:

Multilocular.
Lined by columnar epithelium.

PSEUDOMYXOMA PERITONEI: Seeding of the tumor in the peritoneum.

PATHOLOGY: Massive accumulation of gelatinous material in the abdominal cavity.
PATHOGENESIS: Mucinous Cystadenoma of the ovary, or Mucocele in the appendix.
TREATMENT is surgical, and usually requires repeated operations.

BRENNER TUMOR: Benign tumor, usually discovered incidentally.

PATHOLOGY: Composed of islands of transitional-cells, within fibrous stroma.

BORDERLINE TUMOR: Tumor of low malignant potential. Excellent prognosis, despite histologic features that suggest malignancy. May be serous or mucinous.

OVARIAN ADENOCARCINOMA:

SUBTYPES:

SEROUS CYSTADENOCARCINOMA: Most common malignant ovarian tumor. 30% of ovarian cancers.

Papillary Projections are common, with hemorrhage and necrosis.
Multilocular, when it is malignant, as opposed to unilocular when it is benign.
Psammoma Bodies are laminated, calcified concretions characteristically found in this tumor.

MUCINOUS CYSTADENOCARCINOMA: Third most common.

Signet-Ring cells, or similar-looking cells, may be seen because these cells are mucin-producing.
Much larger than serous carcinomas.
Also multilocular.

ENDOMETRIOID ADENOCARCINOMA: Second most common.

Resembles endometrial cancer histologically. Slightly better prognosis, but still bad.

CLEAR CELL ADENOCARCINOMA: Rare.

May be associated with endometriosis
Very poor prognosis.

CLINICAL:

Bad prognosis. As a group these tumors are bad, because they usually don't present until late-stage.
CA-125 is a tumor-marker present in these tumors that is useful for tracking the tumor. It isn't too useful for diagnosis because it shows up in a lot of other instances, too.

STROMAL TUMORS: Mixed benign and malignant, mostly benign.

OVARIAN FIBROMA: Benign. Most common ovarian stromal tumor, and the only non-secreting one.

PATHOLOGY: Solid, firm benign ovarian stromal tumor, composed of well-differentiated fibroblasts and collagen stroma.

It is the only one that does not secrete hormones.

MEIGS SYNDROME: Ovarian Fibroma, Ascites, Pleural Effusion. This complication can be found with this tumor.

THECOMA: Benign.

PATHOLOGY: Circumscribed yellow-brown mass. Look similar to fibroma, but not as fibrotic.
SYMPTOMS: Occurs in peri- and post-menopausal women and produces lots of estrogen.

The excess estrogen can produce endometrial hyperplasia and may lead to cancer.

GRANULOSA CELL TUMOR: May be malignant or benign.

EPIDEMIOLOGY: Rare. Found in middle-aged women.
PATHOLOGY: It produces estrogen, like a Thecoma, so it is yellow.

Call-Exner Bodies: Characteristic histologic pattern of tumor, arranged into follicles.

CLINICAL: Malignancy cannot be determined histologically. Watch the behavior of the tumor; if it metastasizes, then it's malignant.

SERTOLI-LEYDIG CELL TUMORS: Rare tumor of "Low malignant potential."

SYMPTOMS: Occurs in younger age group.

Overall, 50% of patients present with hirsutism.
5-yr survival = 60-70%

SUBTYPES:

Sertoli-cell Tumor (Arrhenoblastoma):
Leydig-cell Tumor (Androblastoma): Tumor is androgen secreting, and patient will present with hirsutism.

OVARIAN GERM-CELL TUMORS: Malignant tumors are quite rare, compared to their incidence in the testis.

DYSGERMINOMA: Male counterpart to seminoma.

PATHOLOGY: Primordial germ cells

Clear glycogen-filled cytoplasm arranged in large nests.

SYMPTOMS: Occurs in younger women and has a very good prognosis.

ENDODERMAL SINUS (YOLK-SAC) TUMOR: Rare and highly malignant.

EPIDEMIOLOGY: Rare, usually happen in young patients 10-12.
PATHOLOGY: Tumor resembles the mesenchyme of the primitive yolk-sac.

alpha-Fetoprotein (AFP): Means of both diagnosing the tumor and monitoring it.
Schiller-Duval Bodies: Characteristic structure resembling fetal glomeruli.

TREATMENT: Surgery is usually curative. Good prognosis despite being highly malignant.

CHORIOCARCINOMA:

EPIDEMIOLOGY: Rare tumor, occurring in younger age groups.
PATHOLOGY: Very malignant, aggressive, and hemorrhagic.

Composed of neoplastic cytotrophoblastic and syncytiotrophoblastic cells.
Human Chorionic Gonadotropin (hCG): Tumors secrete hCG which aids in identification.

PATHOGENESIS: Can be derived from the placenta (gestational choriocarcinoma) or the ovary.

GONADOBLASTOMA
TERATOMA (DERMOID CYST): Benign. Relatively common (relative to the other ones)

PATHOLOGY: All three germ-layers. More than 90% contain skin, sebaceous glands and hair follicles. Can be very large.
EPIDEMIOLOGY: 25% of all ovarian tumors with a peak incidence in the third decade.
Struma Ovarii: Dermoid cyst containing thyroid tissue. It is a unique cause of hyperthyroidism and can actually lead to ectopic thyroid cancer.
SUBTYPES:

Mature Teratoma: Most common and with best prognosis. Contains mature tissues.
Immature Teratoma: Contains embryonal tissue in addition to the mature tissue, and is more solid. Often contains neural tissue. Has a poorer prognosis.

KRUKENBERG TUMORS: Tumors metastatic to the ovary, most often originating from stomach.

PATHOLOGY: Signet-Ring Cells, cells filled with glycogen, are usually seen, as the cancer cells are mucin-secreting.

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PLACENTA and GESTATION

PLACENTA:

INFECTIONS:

PATHOGENESIS: Placental infections result from complication of pregnancy.

Premature Rupture of Membranes (PROM) will result in ascending infection.
Induced abortions
Hematogenous spread: uncommon cause of placental infection.
Sexual intercourse during 3^rd trimester. Probably a good idea not to do that.

BUGS: Hemolytic Strep and anaerobic Strep are the top two.
TYPES:

Placentitis
Chorioamnionitis: Infection of fetal membrane
Funisitis: Infection of umbilical cord.

ARTERIO-VENUS SHUNTING: In monozygotic twins, sometimes one fetus will get the inordinate share of blood supply, resulting in complications (low birth weight, death) for the other twin.
ABRUPTIO PLACENTAE:
PLACENTA PREVIA: Embryo implants near the cervical opening, and placenta develops near the internal os.

SYMPTOMS: Post-partum bleeding is often very bad, as the placental vessels are easily sheared due to position of placenta.
TREATMENT: Pre-natal diagnosis (sonogram) can prevent bad complications at birth. Do elective C-Section.

PLACENTA ACRETA: Abnormal adherence of placenta to the uterine wall. Placenta can remain adherent after delivery.

SIMPLE PLACENTA ACRETA: Attachment of villi to the myometrium without further invasion.
PLACENTA INCRETA: Villi invade the underlying myometrium.
PLACENTA PERCRETA: Villi penetrate the full thickness of the uterine wall.
CLINICAL: Attached placenta can result in life-threatening bleeding and may require hysterectomy.

TOXEMIA of PREGNANCY:

PATHOGENESIS: Complex; multiple theories

Reduced resistance to the effects of Angiotensin II
Increased renin production.
Increased prostaglandins.
Placental production of a thrombogenic substance ------> possibly lead to DIC.

PATHOLOGY:

Thrombosis, DIC leads to infarction of kidney, liver, and other organs.
May infarct the placenta itself.

SUBTYPES:

PREECLAMPSIA: Mild toxemia.
ECLAMPSIA: Severe toxemia.

SYMPTOMS: Hypertension, proteinuria, edema, and in its most severe form, convulsions.

Risk at first pregnancy is much higher than with subsequent pregnancies.
Delivery usually makes the symptoms alleviate. The goal is to try to get to delivery (perhaps induce early) before the eclampsia becomes bad.

SPONTANEOUS ABORTION: A large number of spontaneous abortions are related to chromosomal abnormalities in the fetus.

Threatened Abortion: The pregnancy is hanging by a string. It may be able to be saved with some precautions.
Inevitable Abortion: No intervention possible.
Missed Abortion: Baby dies within the gestational sac and remains in the uterus. Curettage is required to evacuate the fetus.
Incomplete Abortion: Parts of the fetal material remain in uterus.

ECTOPIC PREGNANCY:

PATHOGENESIS: Fibrotic tubes from PID, usually.
SYMPTOMS: Rupture and hemorrhage of tubes are most feared complication. Rupture usually occurs by 12 weeks.

TROPHOBLASTIC DISEASE:

COMPLETE HYDATIDIFORM MOLE: Homozygous Diploid (XX, 46)

PATHOGENESIS: Results from the fertilization of an ovum that lacks functional DNA, hence all chromosomes are paternal.
EPIDEMIOLOGY:

Very young (younger than 15) and very old (older than 50) mothers are at increased risk.
Much more common in SE Asian women.

PATHOLOGY: Placenta has grossly swollen chorionic villi, resembling a bunch of grapes. Trophoblastic proliferation.

No embryo is present.
Very high hCG levels

SYMPTOMS: Present in second trimester of pregnancy with abnormal uterine bleeding.

COMPLICATION: Gestational choriocarcinoma can develop from it.

PARTIAL HYDATIDIFORM MOLE: Triploid (X, 63)

PATHOGENESIS: Results from either two sperm fertilizing the same egg, or one primary spermatocyte (still diploid) fertilizing an egg.
PATHOLOGY: Embryo starts developing, but dies at about 10 weeks.

INVASIVE MOLE (CHORIOADENOMA DESTRUENS): More aggressive disease, rare.

PATHOLOGY: Invasion of the myometrium, and very large amounts of hCG.

GESTATIONAL CHORIOCARCINOMA: Very rare.

PATHOGENESIS: Can arise from a complete hydatidiform mole.
PATHOLOGY: Very large, hemorrhagic tumor.

Contains both cytotrophoblast and syncytiotrophoblast, as all choriocarcinomas do.
No chorionic villi will be present.
Secretes hCG, as other choriocarcinomas do.

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THE BREAST

CONGENITAL DISORDERS:

SUPERNUMERARY NIPPLES: Nipples or whole breast tissue dispersed along the axillary breast-line: from axilla, down mid-clavicular line, converging on inguinal region.
CONGENITAL INVERSION

GYNECOMASTIA: Enlargement of the adult male breast usually caused by an excess of estrogenic hormones in circulation, as in cirrhosis or hormonally active tumors of the testis and adrenals.

GALACTOCELE: Cystic collection of milk, in lactating women. Milk collects and causes inflammation, to the point that it needs to be aspirated.

MASTITIS: Extreme breast tenderness encountered during lactation.

FIBROCYSTIC CHANGE: Very common.

EPIDEMIOLOGY: Mid to late reproductive years.
PATHOGENESIS: Normal cyclical effects of hormones and aging bring on the changes.
PATHOLOGY:

Histological Properties:

Cystic dilatation of terminal ducts
Relative increase in fibrous stroma
Variable proliferation of terminal duct epithelial elements.

Apocrine Metaplasia: Epithelial lining of cysts often show characteristic change. No relation to cancer.

SUBTYPES:

NON-PROLIFERATING FIBROCYSTIC CHANGE: No increased risk for cancer
EPITHELIAL HYPERPLASIA:

Epithelial Hyperplasia with Atypia: Shows a 4-5X increased risk for cancer.
Epithelial Hyperplasia without Atypia: 1.5-2X increased risk for cancer.

SCLEROSING ADENOSIS: Less common variant. Sclerosis and proliferation around the small lobules, which resembles carcinoma, but it isn't.

SYMPTOMS: Lumps and tenderness, which are hormone-sensitive and responsive to changes in the menstrual cycle. This distinguishes the lump from a carcinoma, which does change in size or tenderness with the menstrual cycle.

BENIGN TUMORS:

FIBROADENOMA:

PATHOLOGY: Composed of elongated ducts and hyperplastic stroma resembling intralobular connective tissue.
EPIDEMIOLOGY: Adolescents and young women. Most common benign neoplasm of the breast.
SYMPTOMS: Sharply circumscribed spherical nodule.

Freely mobile: The lump will move on palpation. This distinguishes it from a cancer, which is anchored to the stroma so it stays put.

INTRADUCTAL PAPILLOMA: Benign solitary lesions within the ducts.

EPIDEMIOLOGY: Middle-aged and older women.
SYMPTOMS: Nipple discharge, nipple retraction. The lump is generally right beneath the nipple.
TREATMENT: Surgical excision.

BREAST CANCER:

EPIDEMIOLOGY: Most common cancer of U.S. females, and 2^nd most common killer after lung cancer.

Peak ages of diagnosis: 45-49, 55-59.

PATHOGENESIS:

GENETIC FACTORS: Strong familial component.
HORMONAL FACTORS: Estrogen promotes breast cancer.

Thus, early menarche, late menopause, and nulliparity all increase the risk for breast cancer.
Multiparity and early menopause are both protective.

DIAGNOSIS: Non-mobile mass.

Mammography is especially useful in identifying microcalcification, which is characteristic of breast cancer.

CARCINOMA IN SITU: Risk for progressing to invasive cancer is 10X that of normal.

INTRADUCTAL CARCINOMA IN SITU: Arises in the terminal duct lobular unit, and has two subtypes.

COMEDOCARCINOMA: Composed of large, pleomorphic cells arranged around areas of central necrosis.

Comedos: Pimple-like. The necrotic material + PMN's can be squeezed from the tumor, just like pimples, hence the name. Also see atypia and necrosis, as would expect for carcinoma.
CLINICAL: It is easy to diagnose and carries a good prognosis.

PAPILLARY-CRIBRIFORM CARCINOMA: Tumor cells grow in papillary structures and form fenestrations within the distended ducts.

Cribriform: Glands are back-to-back and crowded, but still contained by the basement membrane.

LOBULAR CARCINOMA IN SITU: Arising in the terminal duct lobular unit.

Monotonous-looking cells, as compared to comedocarcinoma.

PAPILLARY CARCINOMA IN SITU: Rare and less dangerous tumor, originating in the larger branches of the duct system.

INVASIVE CARCINOMA:

DUCTAL CARCINOMA: The most common form of breast cancer, 65-80% of all cancers.

PATHOLOGY: Invasive carcinoma arising in terminal duct lobular unit.

Gross Specimen: Poorly defined nargins, firm, gray or white specimen, which cuts with characteristic gritty sensation.
Desmoplasia: Calcification occurs in response to the cancer, making the lump larger and more visible on X-ray.

LOBULAR CARCINOMA: Second most common cancer.

PATHOLOGY: Invasive carcinoma arising in lobular epithelium.

Indian Files: Characteristic cords of monotonous cells infiltrating between stromal fibers, found in Lobular Carcinoma.

MEDULLARY CARCINOMA: Third most common cancer.

SYMPTOMS: Well-behaved tumor. Lumpectomy is usually curative.
PATHOLOGY: Circumscribed mass that lacks calcification on mammography.

COLLOID (MUCINOUS) CARCINOMA: Uncommon invasive breast carcinoma. Also has good prognosis.
PAGET DISEASE of the NIPPLE: Uncommon form of Ductal Carcinoma, which extends outward to involve the epidermis, nipple, and areola. Inflammation around nipple is seen; poor prognosis.

TREATMENT: Lumpectomy, mastectomy, radical mastectomy (including lymph nodes) if necessary.

Tamoxifen: Estrogen antagonist. If the tumor is estrogen-receptor positive, then Tamoxifen works in 70% of cases.

Estrogen-receptor positivity correlates with a good prognosis. This means that the tumor-cells are better developed, and they responsible to Tamoxifen.

STAGING:

Stage I: Solitary tumor 2cm or smaller.
Stage II: Tumor 2-5cm, without nodal masses, or with unilateral moveable nodal metastases.
Stage III: Greater than 5cm, or with nodal metastasis, or any tumor with fixed nodal metastases, or any tumor with fixation to underlying chest-wall muscles.
Stage IV: Any tumor involving chest wall, nodes other than axillary nodes, edema of the arm (blocked lymphatics), or distant metastases.

METASTATIC PATTERNS: Axillary nodes ------> supraclavicular and infraclavicular nodes ------> internal mammary nodes ------>t; distant sites

Distant Sites: Lung and pleura, liver, bone, adrenals, skin.

PROGNOSIS:

GOOD PROGNOSIS:

Estrogen-sensitive tumor (indicates cell maturity, and sensitivity to Tamoxifen)
Early menopause, multiparity

BAD PROGNOSIS:

Late menopause, nulliparity or late age at first childbirth.
Cathepsin-D: Presence of this proteolytic enzyme correlates with bad prognosis, as it probably facilitates invasion of the tumor.
INFLAMMATORY CARCINOMA of BREAST: Occurs secondary to dermal lymphatic invasion by the malignant cells, blocking the lymphatic drainage of the skin leading to lymphedema and thickening of the skin. Later will see redness, swelling, and tenderness. Very bad prognosis.

Peau d'orange - orange peal appearance of skin.

PHYLLODES TUMOR (CYSTOSARCOMA PHYLLODES):

PATHOLOGY: A giant fibroadenoma. It may be benign or malignant.

Generally aggressive locally, but it does not metastasize.
Histology looks similar to a benign fibroadenoma, but the stroma is more hypercellular.

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FUNCTIONAL HEMATOLOGIC DISORDERS

Complete Blood Count (CBC)
Item	Normal Range	Comments
Hemoglobin (Hgb) (g/dL)	M: 13 - 17 F: 12 - 16	Absolute concentration of hemoglobin in blood.
Hematocrit (%)	M: 39 - 50% F: 35 - 48%	Percentage of the volume of plasma occupied by cells.
WBC	4,000 - 10,000	Up to 20,000: expected in reactive leukocytosis 50,000-100,000: leukemoid reaction, or CML
RBC	M: 4.5 million - 5.9 million F: 3.9 million - 5.3 million
Mean Cell Volume (MCV)	80 - 100	MCV = Hematocrit / RBC Count Abnormal Size = Microcytosis or macrocytosis
Mean Cell Hemoglobin (MCH)	25 - 35	MCH = Hemoglobin / RBC Count Abnormal Value = Hyperchromic or hypochromic
Mean Cell Hemoglobin Concentration (MCHC)	30 - 37%	MCHC = MCH / Hematocrit Basically the same as the MCH, except it takes the hematocrit into account.
Red-Cell Distribution Width (RDW)	11.5 - 15.5%	Sort of like a standard deviation; measure of the variability in red-cell size.
Platelets	150,000 - 450,000	Below 100,000: Increased bleeding time Below 50,000: Bleeding (ecchymoses, hematoma) on trivial trauma Below 10,000: Spontaneous bleeding, hemorrhage.

MYELOID SERIES:

Myeloblast
Promyelocyte: Has characteristic azurophilic granules, which contain a Tissue-Factor like substance which, when degranulated (as in AML), can lead to DIC.
Myelocyte
Metamyelocyte
Band Cell: Increased in a reactive leukocytosis with left shift.
Mature PMN

HEMOSTASIS:

PLATELET PLUG FORMATION: Mass of platelets form at site of injury.

PLATELET ADHESION: Allow platelets to stick to vessel wall.

Von Willebrand Factor, on endothelial cell basement membrane, is responsible for platelet adhesion. When it is exposed, platelets will adhere to vessel wall.
Glycoprotein Ib/IX is the platelet protein that is a receptor for Von Willebrand Factor.

PLATELET AGGREGATION: Activate platelets so that they stick to each other.

Several factors cause the platelets to clump together at the site of injury.

Collagen: Exposed collagen indicates injury.
ADP
Thrombin: The final product of the coagulation pathway causes platelets to stick together.

Glycoprotein IIb/IIIa: Platelet receptor which binds to Collagen, ADP, thrombin, causing cross-linking between platelets and thus allowing for aggregation. It also binds to fibrinogen to facilitate cross-linking.

Thromboxane-A₂ (TXA₂) activates these receptors, enabling them to cross-link.
Fibrin Degradation Products can block this glycoprotein, preventing platelet aggregation.

COAGULATION

INTRINSIC PATHWAY: XII, XI, IX, VIII, Kallikrein, Kininogen. Partial Thromboplastin Time measures its integrity.

Anionic Surfaces can activate one of three substances in order to start the Intrinsic Pathway: Pre-kallikrein, Kininogen, and Factor XII
Factor XII ------> Factor XI ------> Factor IX
Factor VIII, anionic phospholipid, and Ca⁺² are then required to activate Factor X

EXTRINSIC PATHWAY: Tissue Factor, VII. Prothrombin Time measures its integrity.

Tissue Factor ------> Factor VII ------> Factor X

COMMON PATHWAY: X, V, II, I. One way or another, common pathway starts when Factor X is activated.

Factor X converts Prothrombin (II) ------> Thrombin

Factor V, anionic phospholipid, and Ca⁺² are required as cofactors.

Thrombin converts Fibrinogen (I) ------> Fibrin
Fibrin cross-links platelets and forms cohesive plug.

FIBRINOLYSIS: Occurs concurrent with the healing process.

Plasminogen is converted to Plasmin by two factors:

Tissue Plasminogen Activator (tPA) is released by damaged endothelial cells.
Urokinase

BLEEDING TESTS:

BLEEDING TIME:

PROCEDURE: Simply measure the amount of time it takes the patient to stop bleeding, from have two 1mm incisions on forearm. Use filter paper to dop off the blood every 30 seconds.
NORMAL: 5-10 minutes.
ABNORMAL: Long bleeding times are seen with any disorder in forming a platelet plug:

Diseases affecting the blood vessel wall: vasculitis, amyloidosis, scurvy, hereditary hemorrhagic telangiectasia, Ehlers-Danlos syndrome
Diseases causing thrombocytopenia: chemotherapy, ITP, DIC, TTP
Drugs or diseases affecting platelet function: aspirin, ibuprofen, renal failure
Von Willebrand Disease.

PLATELET COUNT:

NORMAL: 150,000 - 450,000

Von Willebrand Disease, Aspirin, and Renal Failure all show normal platelet counts, but still have long bleeding times.

ABNORMAL:

Below 100,000: Bleeding time is affected.
Below 50,000: Bleeding with minor trauma will occur.
Below 20,000: Spontaneous bleeding will occur; transfusions required.

ACTIVATED PARTIAL THROMBOPLASTIN TIME (aPTT): Measures the integrity of the Intrinsic and Common Pathways.

PROCEDURE: Partial Thromboplastin is added to citrate-anticoagulated plasma. Partial Thromboplastin consists of:

Anionic surface (koalin, silica)
Phospholipid
Calcium

NORMAL: 30 second to form a clot in vitro
ABNORMAL: Hemophilia = defect in intrinsic pathway. 50-100 second to form clot.

Also abnormal in DIC, some cases of Von Willebrand Disease, and in Heparin therapy.

PROTHROMBIN TIME (PT): Measures the integrity of the Extrinsic and Common Pathways.

PROCEDURE: Complete thromboplastin is used, which is all of the reagents above, plus Tissue Factor.
NORMAL: 12-14 second to form a clot in vitro.
ABNORMAL: Vitamin-K Deficiency leads to deficiency of factors in the Extrinsic Pathway (Factor VII). Will show times of 18-20 seconds.

FIBRIN DEGRADATION PRODUCTS: They are elevated in Disseminated Intravascular Coagulation (DIC), which shows hyperactive fibrinolysis.

BLEEDING DISORDERS: Congenital and acquired diseases that lead to excessive bleeding or imbalances in hemostasis.

CONGENITAL DISORDERS:

VON-WILLEBRAND DISEASE:

PATHOGENESIS: Autosomal dominant (generally) deficiency of Von Willebrand Factor.

VWF is normally a carrier protein for Factor VIII, so its deficiency results in shorter half-life for Factor VIII. This is only symptomatic in severe cases.
VWF is required for initial platelet-plus formation.

SUBTYPES:

Type I: Partial quantitative deficiency
Type II: Qualitative deficiency, dysfunctional protein.
Type III: Complete absence, with recessive inheritance. Worst form.

SYMPTOMS: petechiae, ecchymosis, mucosal hemorrhage, and in some cases hemarthrosis and hematomas.

Periorbital Ecchymoses: Racoon Eyes are characteristic finding.

LABS: These patients will have abnormal bleeding time, but normal platelet count. May also see prolonged partial thromboplastin time.

BERNARD SOULIER SYNDROME (GIANT PLATELET SYNDROME): Deficiency of Glycoprotein Ib/IX, which is the Von Willebrand receptor on platelets.
GLANZMANN THROMBOASTHENIA: Abnormality in Glycoprotein Complex IIb/IIIa (Platelet receptor), which impairs clotting. You will see excessive bleeding but will have a normal platelet count.
HEMOPHILIA-A:

PATHOGENESIS: X-Linked. Deficiency of Factor-VIII, the cofactor required to convert Factor X ------> Factor Xa, in the Intrinsic Pathway.
SYMPTOMS:

Hemarthrosis: Joint and muscle bleeding with minor trauma, which chronically leads to osteoarthritis. You also see atrophy of muscle distal to the joint.
GI bleeds
Ecchymoses

LABS: Prolonged Partial Thromboplastin Time (PTT), indicating a defect in the Intrinsic Pathway.
TREATMENT: Concentrated Factor-VIII transfusions, or more recently, recombinant Factor-VIII.

HEMOPHILIA-B: X-Linked. Deficiency of Factor IX, the final intermediate in the Intrinsic Pathway.

EPIDEMIOLOGY: Rarer than Hemophilia-A
SYMPTOMS: Identical to Hemophilia-A
LABS: Prolonged Partial Thromboplastin Time (PTT), indicating a defect in the Intrinsic Pathway.

RENDU-OSLER-WEBER SYNDROME (HEREDITARY HEMORRHAGIC TELANGIECTASIA): Autosomal dominant.

SYMPTOMS: Recurrent spontaneous hemorrhages from trivial trauma. Epistaxis.

ACQUIRED DISORDERS:

VITAMIN-K DEFICIENCY: It will lead to a defect in many coagulation factors of the Extrinsic and Common Pathways.

PATHOGENESIS: Vit-K Deficiency is caused by broad-spectrum antibiotics (due to lost intestinal flora), malnutrition, and fat-malabsorption syndromes.
Vitamin K is normally involved in forming gamma-carboxyglutamate residues, which are required to chelate calcium in many calcium-dependent clotting factors.

SOURCES: 50% from diet, and 50% from intestinal bacterial flora.

Vitamin-K dependent factors:

Factor VII: EXTRINSIC pathway factor.
Factors V, X, II (Prothrombin), and I (Fibrinogen): COMMON pathway factors.

DISSEMINATED INTRAVASCULAR COAGULATION (DIC):

PATHOGENESIS: Caused by the pathologic release of pro-coagulant factors into the bloodstream, which sets off the clotting cascade in the bloodstream.

Over-activation of the clotting cascade ------> generation of excessive thrombin and plasmin ------> excessive fibrin degradation products.
Lots of things can set off the DIC:

AML, Type M3: The Promyelocytic azurophilic granules contain a tissue-factor like substance that can cause DIC when released.
Endotoxic infections, shock, and sepsis. Macrophages can release tissue factor in circumstances of shock.
Complications of pregnancy: Retained dead fetus, placental abruption.
Hemolytic Uremic Syndrome

LABS: Prolonged PTT, prolonged Prothrombin time, prolonged bleeding time, thrombocytopenia, and elevated fibrin degradation products.
TREATMENT: Try to treat the underlying cause. Beyond that, give platelets and plasma (to replace clotting factors), and heparin (to prevent further intravascular coagulation)

IDIOPATHIC THROMBOCYTOPENIA PURPURA (ITP): Autoimmune disease against platelets.

PATHOGENESIS: Anti-platelet auto-antibodies cause the widespread destruction of platelets ------> low platelet count.
LABS: Platelet count is low, but bleeding times are still relatively okay, because the remaining platelets are hyperfunctional.
SYMPTOMS: Petechiae, ecchymoses
SUBTYPES:

ACUTE ITP: Generally found in children.

PATHOGENESIS: Usually follows a viral infection.
SYMPTOMS: Sudden, fulminant onset of symptoms. The disease usually resolves after 6 months without treatment.
LABS: Level of thrombocytopenia is severe -- 20,000 platelets or less -- but the remaining platelets are hyperfunctional.

CHRONIC ITP: ITP lasting more than 6 months. Occurs in adults, usually females.

PATHOGENESIS: No preceding antigenic exposure. Associated with HIV infections, or other diseases, such as SLE, CLL, CML.
SYMPTOMS: Insidious onset showing mild to moderate thrombocytopenia. No spontaneous recovery; treatment is usually required.
TREATMENT: Disease usually responds to steroids; if that fails, do splenectomy.

THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP): Simultaneous thrombosis, blood clotting, and bleeding ------> end-organ infarcts.

PATHOGENESIS: Patients are thought to release an abnormally large amount of Von Willebrand Factor (large multimers of it), leading to intravascular activation of clotting cascade. The VWF molecule has molecular weight of around 10 million rather than 1 million. It can be idiopathic, or caused by several factors:

Pregnancy, post-partum state
Drugs: Cyclosporin, mitomycin
Infection: HIV, rickettsial
Collagen Vascular Diseases: Lupus, Sjögren
Certain Malignancies

PATHOLOGY:

Thrombocytopenia, anemia
Elevated creatinine and BUN, from renal failure.
Prolonged bleeding times.
Schistocytes (from microangiopathic hemolysis) found on blood smear.

SYMPTOMS: The disease is deadly if not treated, and treatment must be undertaken quickly. Classical pentad of findings:

Thrombocytopenia: Spontaneous platelet aggregation ------> low platelet count
Microangiopathic Hemolytic Anemia: RBC's are lysed in small vessels by the presence of intravascular fibrin clots.
Fever: It isn't known why, and not all patients will show it.
Neurologic Symptoms: Arteriolar thromboses in brain; similar to TIA's.
Renal Failure: Due to thrombosis in renal vasculature. Often a prominent symptom.

TREATMENT: Plasmapheresis. Machine filters out the clots and the extra large Von Willebrand Factor. Extra transfusions are required, too.

HENOCH-SCHONLEIN PURPURA (ALLERGIC PURPURA): Auto-immune attack against vessel-wall, leading to purpura. Often follows a drug-reaction.

ANEMIAS:

GENERAL PROPERTIES:

SYMPTOMS:

Fatigue
Pallor resulting form decreased perfusion of skin.
Light-headedness
Decreased renal perfusion ------> increased erythropoietin
Increased Cardiac Output and tachycardia, in compensation. This combined with myocardial hypoxia can lead to an MI or CHF.

CLASSIFICATIONS:

Hypoproliferative: Decreased production of red-cells.

Reticulocyte Index < 2%

Hyperproliferative: Increased destruction of red-cells.

Reticulocyte Index > 2%: Reticulocytes are signs of effective erythropoiesis and red-blood cell proliferation.
POLYCHROMASIA: The histological appearance of reticulocytes, which still have some residual RNA elements left in them. They appear in the standard Wright Stain blood smear.

SECONDARY ANEMIAS: Anemias occurring secondary to other, unrelated body systems.

Renal Failure: Due to lack of erythropoietin, renal failure almost always leads to anemia.
Anemia of Chronic Disease: Normocytic, normochromic anemia. Very common cause of anemia.

PATHOGENESIS: Abnormal or excessive utilization of iron, due to chronic infections (Histo, TB), chronic inflammation (SLE, Rheumatoid Arthritis), or neoplasia.
SYMPTOMS: Usually only a moderate anemia.
LABS: Patients will have low serum iron, but they will have adequate iron stores in bone marrow, which distinguishes it from iron-deficiency anemia.

Infiltrative Anemia: Anemia resulting when other things infiltrate the bone-marrow, pushing out normal cellular elements.

Metastatic Cancer to bone: Lung, breast, and prostate cancers often metastasize to bone.
Gaucher's Disease

APLASTIC ANEMIA: Deficiency or complete failure to produce all blood cells.

PATHOGENESIS: Several things can cause it. They are all external (environmental) causes.

Ionizing Radiation
Drugs: Chemotherapy, benzene, chloramphenicol, gold, anti-convulsants, insecticides.
Viruses: Parvovirus B-19, HCV, HIV-1

PATHOLOGY: Pancytopenia. The blood-cells that are there retain normal morphology.

PURE RED CELL APLASIA: Anemia due to isolated depletion of erythroid precursors in the marrow, and may be acute or chronic.

PATHOLOGY: Normochromic anemia, normocytic or macrocytic.

Reticulocytes are decreased or absent because it is hypoproliferative.

SUBTYPES:

ACUTE PRCA: Acute pure red cell aplasia often follows a viral illness, notably Parvovirus B19 infection.
CHRONIC PRCA:

CHRONIC INHERITED PRCA (DIAMOND-BLACKFAN ANEMIA): Quite responsive to steroids.
CHRONIC ACQUIRED PRCA: Immunologic etiology, and may be seen in association with thymoma.

TREATMENT: Removal of thymus may result in clinical remission.

IRON-DEFICIENCY ANEMIA:

PATHOGENESIS: Several causes.

Most common cause = chronic or acute blood loss ------> intracellular fluid goes into vascular space to replace lost fluid ------> relative anemia results.
Growth, pregnancy, lactation.
Inadequate dietary intake.
Increased metabolic requirements, neoplasia.

PATHOLOGY: Microcytic, hypochromic anemia. Low serum iron.

Bone-Marrow will show absence of iron.
Ferritin: Low serum ferritin indicates low body stores of iron. Ferritin is a storage-protein found in liver, in Kupffer cells.

However, ferritin is an acute-phase protein, so there are some acute conditions in which ferritin may be high (inflammation, hepatitis) anyway. Therefore, don't rely on ferritin to make the diagnosis of iron-deficiency anemia.

Transferrin: These carrier proteins will be unsaturated and available to bind iron, hence the Total Iron Binding Capacity (TIBC) is increased with anemia.

SYMPTOMS: General anemia symptoms. Can see pica, a craving to eat clay.

Koilonychia: Spoon-shaped nails can be seen.
Thrombocytosis: May see increased platelets in chronic anemia, due to general Over-activation (via erythropoietin) of the bone marrow.

MEGALOBLASTIC ANEMIA: Macrocytic, hyperchromic anemia.

PATHOGENESIS: The nuclear development of the RBC can't keep up with the cytoplasmic growth, because of faulty DNA synthesis.

Folate Deficiency:

Usually dietary, as in alcoholism
Increased metabolic demand, as in pregnancy
Malabsorption (as in Sprue)

B-12 Deficiency:

Autoimmune Gastritis ------> Pernicious Anemia
Fish Tapeworm, Diphyllobothrium Latum
Malabsorption: Sprue, ileitis, ileal resection.

PATHOLOGY:

Morphologic Abnormalities:

Large RBC's with nuclear-cytoplasmic dyssynchrony
Tear-Drop Cells
Hypersegmented Neutrophils: One of the earliest signs of disease. 5 or 6 lobes.
Ovalocytes: The large RBC's tend to have an oval-shape.
Howell-Jolly Bodies: Nuclear fragments seen in Megaloblastic anemia.

LABS: Reticulocyte count is low, because this is a hypoproliferative anemia. Erythropoiesis is ineffective.

THALASSEMIAS: Deficient production of hemoglobin.

EPIDEMIOLOGY: Mediterranean, middle east.
SYMPTOMS: Hypochromic, microcytic anemia, owing to deficient production of hemoglobin.
PATHOLOGY:

Heinz Bodies, precipitated red blood cells, may be found.
Target Cells, due to increased membrane : cytoplasm ratio, can also be seen.

alpha-THALASSEMIA: Deficient production of the alpha-globin chain.

SYMPTOMS: There are four alpha-genes, and severity of disease depends on how many of those genes are deleted. If all four are deleted, death in utero is inevitable.

beta-THALASSEMIA: Deficient production of the beta-globin chain.

SYMPTOMS: Both excess hemolysis and ineffective erythropoiesis occurs, with homozygous trait.

Excess alpha-chains precipitate in RBC's, leading to hemolysis.
HETEROZYGOUS TRAIT: Very mild, with an increased amount of Hemoglobin A₂ (alpha₂,delta₂), because it doesn't contain the beta-chain.

TREATMENT: Transfusion therapy, plus iron chelators to prevent secondary iron overload from the therapy.

MEMBRANE-DEFECTS: Defects in RBC shape

HEREDITARY SPHEROCYTOSIS:

PATHOGENESIS: Deficiency in spectrin, plus a variety of other possible problems, leads to spherical shape of RBC's.
PATHOLOGY: RBC's can be sequestered in spleen and prematurely removed from circulation.

Normocytic, hyperchromic (no central pallor -- for unknown reasons) anemia.

SYMPTOMS: Hemolytic jaundice, hyperproliferative anemia, splenomegaly.

Pigment gallstones may result from the hemolytic jaundice.

TREATMENT: Splenectomy is usually curative, since the spleen is responsible for removing the spherocytes.

HEREDITARY ELLIPTOCYTOSIS
ACANTHOCYTOSIS

GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY:

PATHOGENESIS: X-Linked Recessive.

G6PD is an enzyme of the Hexose Monophosphate Shunt pathway. It maintains Glutathione in its reduced (active) form. Deficiency of this enzyme makes the RBC susceptible to oxidative damage.

PATHOLOGY:

Heinz Bodies are bodies of denatured or precipitated hemoglobin, found in this disease as well as other diseases.

SYMPTOMS: Hemolytic anemia brought on by infection or drugs.

FAVISM: Susceptibility to eating Fava beans ------> potentially lethal hemolytic anemia.

HEMOGLOBINOPATHIES: Normal levels of hemoglobin, but defects in Hgb structure.

HEMOGLOBIN-C DISEASE: Second most common hemoglobinopathy.

PATHOGENESIS: Substitution of Glu ------> Lys at 6^th position of beta-chain.
SYMPTOMS: Chronic, mild hemolytic anemia.
PATHOLOGY: See lots of target cells -- formed by excess hemoglobin-accumulation in center of cell, giving bulls-eye appearance.

SICKLE CELL DISEASE:

EPIDEMIOLOGY: Endemic to Sub-saharan Africa, due to heterozygous advantage conferred against Falciparum Malaria. The advantage is thought to be that infected RBC's preferentially sickle and are thus taken to the spleen and sequestered, limiting the spread of infection.
PATHOGENESIS: Point-mutation of Glu ------> Val at 6^th position of beta-globin chain.
PATHOLOGY: Deoxygenation (low oxygen tension) causes the HbS to polymerize ------> RBC becomes rigid and non-deformmable ------> RBC gets stuck in the microvasculature causing micro-infarcts.

The cells can be fine for quite some time, as they go through cycles of deoxygenation and reoxygenation. After several cycles they may become deformed, and wind up in the spleen or in an end-organ.
Howell-Jolly Bodies: Nuclear fragments seen in RBC's.

SYMPTOMS:

SICKLE CRISIS: Accelerated sickling of cells due to low O₂-tension.

Infarctive Crisis: Most common type of crisis. End-organ infarcts.
Aplastic Crisis: Some bacterial infection can depress erythropoiesis, which, when combined with normal rate of hemolysis, can lead to Aplastic crisis.
Sequestration Crisis: Reactive hyperplasia of spleen, with sudden pooling of RBC's and rapid fall in hematocrit. Most common cause of death in early life from Sickle Cell.

SPLEEN: Small and fibrotic in chronic disease, due to repeated infarcts. Poor splenic function leads to propensity for infections.
Osteomyelitis from infections and microinfarcts in bone marrow.
Hemolytic Jaundice is frequently seen, which can lead to Pigment (Bilirubin) Gallstones.
CNS: Strokes, ischemic attacks, neurologic complications.
CV: MI, CHF, Cardiomegaly.

PATHOLOGY: Heinz Bodies, precipitated hemoglobin inside RBC's, are commonly found with hemoglobinopathies.

HEMOLYTIC ANEMIAS: Hyperproliferative anemias that result from destruction (either mechanical or immune-mediated) of RBC's.

PATHOLOGY:

Howell-Jolly Bodies: Nuclear fragments seen in RBC's, often found in hemolytic anemias.

TRAUMATIC HEMOLYTIC ANEMIAS:

MICROANGIOPATHIC HEMOLYSIS: RBC's being damaged by intravascular fibrin-clots, in small vessels. DIC, TTP, HUS.
MACROANGIOPATHIC HEMOLYSIS: Damage by artifical heart valves.
PATHOLOGY: SCHISTOCYTES are broken-up red blood cells that result from mechanical hemolysis, classically found in microangiopathic and macroangiopathic anemias.

ERYTHROBLASTOSIS FETALIS: Hemolytic disease in the fetus or neonate due to maternal antibodies against fetal RBC's. Hemolytic disease may occur when the maternal antibody is against a fetal antigen of the RH or ABO blood group system. Alloimmunization of RH negative mother by fetal Rh positive cells may occur at delivery, and therefore, it is future pregnancies which are at risk of developing hemolytic disease. The use of RhoGam has greatly reduced the incidence of RH hemolytic disease.
PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH):

PATHOGENESIS: Deficiency of functional Decay Accelerating Factor (DAF) on RBC membranes ------> complement is unregulated and disinhibited ------> complement-mediated lysis of RBC's ensues.

Actual genetic defect is not in DAF itself, but in some downstream function needed to get DAF into the membrane

LABS: The hemolysis can affect all cell-types. Can see thrombocytopenia and granulocytopenia, as well as anemia.
SYMPTOMS: Classic symptom is periodic morning red urine.

AUTOIMMUNE HEMOLYTIC ANEMIA:

COOMBS TEST: Add Anti-Rabbit IgG to RBC's and see if you get agglutination. You can then later determine if it is Warm or Cold autoantibodies.
PATHOGENESIS: Can be idiopathic, or secondary to some cause.

SECONDARY AUTOIMMUNE HEMOLYTIC ANEMIA: Various causes

Drug-induced Hemolytic Anemia: alpha-Methyldopa is the classic drug which leads to autoantibodies and can result in hemolytic anemia (1% incidence). Also quinidine.
SLE
Cancers, especially CLL.

PATHOLOGY:

Polychromasia (high reticulocyte count) indicates effective erythropoiesis.
Spherocytes are found in autoimmune hemolytic anemia.
LDH is elevated.

SUBTYPES: Come in the warm and cold flavors:

WARM-REACTING HEMOLYTIC ANEMIA: Hemolysis occurs at 37C.

PATHOGENESIS: 50% idiopathic, and most others associated with CLL or Lymphocytic Lymphoma.
PATHOLOGY: Usually IgG antibodies directed against the Rh antigen on RBC's. Cells will be destroyed by macrophages in the spleen, which recognize the Fc portion of IgG. It is not complement-fixing.

COLD-REACTING HEMOLYTIC ANEMIA: Hemolysis only occurs at cool temps less than 37C

PATHOLOGY: Usually IgM antibodies, directed against the I (blood-type) antigens on RBC's. It is complement-fixing, and is sequestered by Kupffer cells in the liver.

HYPERSPLENISM:

PATHOGENESIS: Often caused by portal hypertension or liver disease.
SYMPTOMS: Triad of findings

Splenomegaly
Peripheral cytopenia of varying degrees, due to inappropriate sequestration of cells in the big spleen. Can see thrombocytopenia, anemia, granulocytopenia.
Compensatory bone-marrow hyperplasia (polychromasia, possible left shift).

HEMOGLOBINS:

Hemoglobin-A alpha₂, beta₂ Predominant hemoglobin in adults

Hemoglobin-A₂ alpha₂, delta₂ Found in normal adults

Hemoglobin-F alpha₂, gamma₂ Fetal (cord) hemoglobin, with higher O₂-binding affinity

Hemoglobin-S alpha₂, beta₂
(beta: Glu-6 ---> Val)
Sickle-Cell Hemoglobin. Sickle crisis can result from low O₂-tension.

Hemoglobin-C alpha₂, beta₂
(beta: Glu-6 ---> Lys)
Hemoglobin-C Disease. Second most common hemoglobinopathy.

Selected Cluster Designation (CD) Markers:

CD3 T-Cell Receptor (TCR), common to all T-Cells.

CD4 T-Cell Helper

CD8 T-Cell Suppressor, Cytotoxic T-Cells

CD10 CALLA: Common Acute Lymphoblastic Leukemia (ALL) Antigen.

CD20 B-Cell marker

CD34 Stem-Cell Marker

CD45 LCA: Leukocyte Common Antigen, common to all leukocytes.

MYELODYSPLASIA: A group of disorders that are considered to be pre-Leukemic -- precursors to acute leukemia.

Refractory Anemia: Unexplained, normocytic, normochromic anemia with less than 5% blasts.
Refractory Anemia with Excess Blasts (RAEB): Refractory Anemia with 5-20% blasts. Greater than 30% blasts is diagnostic of AML.
PATHOLOGY: Tend to have some immature red-cells in bone-marrow.

Ring Sideroblasts are red-cells with iron-laden mitochondria forming rings around the rim of the nucleus. The rings stain with Prussian Blue.

NON-NEOPLASTIC WBC ABNORMALITIES:

AGRANULOCYTOSIS: Bad reaction to certain drugs. Severe pancytopenia.
REACTIVE LEUKOCYTOSIS: Physiologic response to infections, showing high WBC count with a left shift (i.e. excess bands, some metamyelocytes).

LEUKEMOID REACTION: A reactive leukocytosis showing a huge increase in the WBC-count, to 50,000 - 100,000. It must be distinguished from Chronic Myelogenous Leukemia, which will show a similar WBC count with similar differential.

Toxic Granulation: The presence of this characteristic finding in the cells can be used to distinguish the Leukemoid Reaction from CML. This is seen especially in burn patients, sepsis, and severe infection.
Dohle Bodies: Can also use this finding to rule out CML.
Leukocyte Alkaline Phosphatase activity is high in the leukemoid reaction, but not in CML.

NEUTROPHILIC DISORDERS:

CHRONIC GRANULOMATOUS DISEASE
MYELOPEROXIDASE DEFICIENCY
CHEDIAK-HIGASHI SYNDROME

BENIGN LYMPHADENOPATHIES:

ACUTE LYMPHADENITIS:

CAT-SCRATCH DISEASE: Bartonella Henselae infection.

PATHOLOGY: Follicular Hyperplasia, with suppurative, necrotizing granulomatous inflammation. It looks histologically identical lymphogranuloma venereum (Chlamydia Trachomatis L1-L3).

CHRONIC LYMPHADENITIS:

PATHOGENESIS: You can't tell what is causing it by the histology. Non-specific findings. Some etiologies:

INFECTIOUS MONONUCLEOSIS: Shows follicular hyperplasia, indicating a T-Cell proliferation.

Also see Atypical Lymphocytes, characteristic of Infectious Mono.
SYMPTOMS: Pharyngitis, maybe hepatosplenomegaly, lymphadenopathy, particularly of posterior cervical nodes.

Rheumatoid Arthritis
AIDS Lymphadenopathy: Generalized lymphadenopathy maybe the presenting symptom in HIV infection.

DERMATOPATHIC LYMPHADENOPATHY: Reactive changes in lymph nodes secondary to a chronic dermatosis.

LANGERHANS CELL HISTIOCYTOSIS (HISTIOCYTOSIS X):

Langerhans Cells: Tissue macrophages, derived from bone marrow, found in the skin. Analogous cells are found all over body, such as Kupffer Cells of liver and Mesangial Cells of kidney.
PATHOGENESIS: Some people think it is a clonal proliferation, but pathogenesis remains uncertain.
SUBTYPES:

EOSINOPHILIC GRANULOMA (Unifocal): 75% of cases. Mildest form, affecting young males. Often affects lungs, but can affect bones.
HAND-SCHULLER-CHRISTIAN DISEASE (Multifocal): Same histopathology, but multifocal. Often affects pituitary gland, but can also affect bones.

SYMPTOMS: Characteristic triad of Diabetes Insipidus, Exophthalmos, Bony Lesions. But all three only occur in 15% of cases.

LETTERER-SIWE DISEASE (Disseminated): Presents with skin rash. Rapidly fatal disease identified in infants.

PATHOLOGY:

Birbeck Granules: Look like tennis-rackets. Characteristic granules that help to identify Langerhans Histiocytes.
GRANULOMA: Eosinophils and Langerhans Cells make up the characteristic granulomas, found in all forms of the disease.

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HEMATOLOGIC NEOPLASMS

MYELOPROLIFERATIVE DISORDERS:

GENERAL PROPERTIES:

PATHOLOGY:

Basophilia is characteristically found in all of the myeloproliferative disorders.
Tear-Drop Cells are characteristically found.

SYMPTOMS:

Varying degrees of splenomegaly (extreme in Myeloid Metaplasia)
Varying degrees of cytopenia: anemia, thrombocytopenia, leukopenia.

CHRONIC MYELOGENOUS LEUKEMIA (CML):

PATHOGENESIS: Philadelphia Chromosome is found in all cases of CML. It may, however, result from a few different translocations.

t(9:22), abl:bcr is the most common and classic translocation. abl is fused to bcr on Chromosome 22, such that bcr drives the over expression of the abl gene.

abl codes for Tyrosine Kinase Activity. Hyper activation leads to uncontrolled growth and cancer.

The initial error occurs in a multipotential stem-cell, and the cancer can manifest in all subsequent cell-lineages.

SYMPTOMS: Splenomegaly, lymphadenopathy. Median 5-yr survival is 3-4 years.

Chronic Phase: Insidious. Fatigue, fever, sweating.
Blast Crisis: Leukemic conversion occurs in 70% of cases ------> rapidly progressive anemia, neutropenia, thrombocytopenia.

It usually converts to AML (rapid death in matter of months), or it can convert to ALL.

DIAGNOSIS / PATHOLOGY:

Leukocytosis: Sustained leukocytosis > 20,000 shows left-shift with myelocyte bulge (too many myelocytes in peripheral blood). Normally peripheral blood should have no myelocytes.
Leukocyte Alkaline Phosphatase (LAP): It is absent (low score), which distinguishes CML from reactive leukocytosis and from the other myeloproliferative disorders.

CML shows fewer than 30% blasts, or else the diagnosis is changed to AML.
All cell types can be seen in the peripheral blood.

Basophilia

TREATMENT:

Interferon-alfa has been used recently, to suppress proliferation of progenitor cells.
Bone-marrow transplant is improving the outlook of CML.

POLYCYTHEMIA VERA: Idiopathic, erythropoietin-independent growth of red-cells.

PATHOLOGY:

Pancellular hyperplasia -- increase in all cell-types: erythrocytosis, thrombocytosis, leukocytosis.

DIAGNOSIS:

High hematocrit: Male > 54%, Female > 51%
Pancytosis with normal differential. Most or all cell-counts are mildly high, and there is no left shift. This distinguishes it from CML, where you see a marked left shift.
Decreased or normal erythropoietin.
LAP is variable, but not absent as in CML.

SYMPTOMS: Median survival is 13 years.

Proliferative Phase: Chronic hyperviscosity, major thrombotic complications. Gastric ulcers, intermittent claudication.
Spent Phase: Red cells settle down, and you can see a post-proliferative reactive myeloid metaplasia (myelofibrosis).
Progression:

AML progression can occur in 1-3% of cases.
Can also progress to AMM (myelofibrosis).

TREATMENT: Repeated phlebotomy to remove excess red cells, plus iron supplements to replace iron lost from treatments.

IDIOPATHIC THROMBOCYTHEMIA:

PATHOGENESIS: Idiopathic increase in Megakaryocytes, leading to increased platelets.
PATHOLOGY:

Megakaryocytes show bizarre (malignant) morphologies.

SYMPTOMS: Median survival 5-8 years (Rubin says 10 years)

Patients may have a thrombotic or bleeding tendency.
Leukemic conversion occurs in 2-5% of patients.
Microcytic hypochromic anemia is common.

DIAGNOSIS: Diagnose by exclusion. Exclude all the other reasons for having high platelets, and you are left with essential thrombocythemia.

Platelet count of 1 - 3 million or more.

AGNOGENIC MYELOID METAPLASIA (AMM) (IDIOPATHIC MYELOFIBROSIS):

PATHOGENESIS: Reactive fibrosis in the bone-marrow.

Clonal hemopoietic cells proliferate initially, and they can go into peripheral blood. In response to this, polyclonal activation of fibroblasts occurs. They secrete collagen in the bone marrow, causing fibrosis.

Fibroblasts are thought to be responding to growth signals, (PDGF, TGF-beta) sent out by platelets and megakaryocytes.

AMM can also occur as a response to the other myeloproliferative disorders (CML, Polycythemia Vera). It can be a common endpoint to any of the myeloproliferative disorders.

PATHOLOGY:

Extramedullary Hematopoiesis occurs in liver and spleen, because the bone marrow is fibrotic and non-functional.
Leukoerythroblastic Reaction: The space-occupying myelofibrosis causes immature blood cells to be kicked out into the blood in disproportionate numbers. Specifically you see:

Promyelocytes (immature granulocyte)
Nucleated RBC (immature RBC)

SYMPTOMS:

Leukocytosis: Especially early on, you will see high WBC count. Later on as the fibrosis becomes really bad, the WBC may actually be low.

This distinguishes Myelofibrosis from Hair Cell Leukemia, which shows splenomegaly, dry tap, and leukopenia.

Massive Splenomegaly: The biggest spleens you'll ever see.
Dry Tap: Bone-marrow tap is difficult to do and is almost always dry, due to fibrosis in marrow.

TREATMENT: No specific treatment.

Splenic radiation and splenectomy are often done.
Bone marrow transplantation shows mixed results.

ACUTE MYELOGENOUS LEUKEMIA (AML):

EPIDEMIOLOGY: Most common leukemia found in adulthood. 4% of newly diagnosed adult cancers.
PATHOGENESIS: Clonal disorder arising from an aberrant myeloid precursor cell, which includes myeloblasts, monoblasts, erythroblasts, and megakaryoblasts. Possible causes:

Myelotoxic agents: Benzene, and chemotherapeutic alkylating agents are most important ones.
Radiation
Down Syndrome has propensity to lead to AML. Other chromosomal abnormalities too.
Myelodysplastic Disorders (Refractory Anemias) are considered to be pre-leukemic. It basically is finding the same anemias, but with the greater than 30% blasts needed to make a diagnosis.

PATHOLOGY:

AUER RODS: Structures characteristic of myeloblasts. Found in AML but not ALL.

SUBTYPES: FAB divides it into 8 Subtypes: M0, M1 - M7

M0 AML: Minimal differentiation, with no cytochemical markers.
M2 AML: AML Without Maturation. Most common subtype.
M3 AML: ACUTE PROMYELOCYTIC LEUKEMIA (APL)

SYMPTOMS: DIC. Promyelocytes will show azurophilic granules and Auer rods, which contain a Tissue-Factor-like substance. When degranulated, this leads to DIC, a very common complication of APL.
PATHOGENESIS: t(15:17) is the characteristic translocation. It is treated with retinoic acid, different than other subtypes.

M5 AML: Monocytic Leukemia. Clinically most severe type.

Non-Specific Esterase is a stain that is specific for monocytes, diagnostic of AML Subtype M5.

DIAGNOSIS: Leukocytosis, with greater than 30% blasts are present in the bone marrow or blood.

TDT-Negative: Terminal Deoxynucleotidyl Transferase is not present in myeloid cells, distinguishing it from the lymphoid cells (ALL).

SYMPTOMS: Granulocytopenia, anemia, thrombocytopenia. All the myeloblasts encroach on normal bone marrow function.

GRANULOCYTIC SARCOMA (CHLOROMA): Discrete tumor masses infiltrated into soft tissues. Occurs especially in bones around face and lymph nodes.

Stains positive (red) with Chloroacetate Esterase, which is the diagnostic stain.

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL):

EPIDEMIOLOGY: Childhood. Most common childhood malignancy. 3500 new cases diagnosed in 1995 in USA.
PATHOGENESIS: The c-myc gene is involved, as in Burkitt Lymphoma.
IMMUNOTYPES: Several different cell-types can yield ALL. Flow Cytometry can be used to identify the specific type.

B-Cell ALL: More common, better prognosis. Subtypes are Pre-Pre-B-ALL, Pre-B-ALL, and Mature B-ALL (worst prognosis)
T-Cell ALL: More common in adolescents, worst prognosis.
Null Cell ALL

SUBTYPES: 3 Subtypes proposed by the French-American-British (FAB) Group:

L1 LYMPHOBLASTS: Small, plain cells.

CLINICAL: Best prognosis, common in the children 3-7 age group.

L2 LYMPHOBLASTS: Contain prominent nucleoli.

CLINICAL: Found in infants younger than 1, or common in adolescents (T-Cell immunotype) or in adults.

L3 LYMPHOBLASTS: Burkitt's Leukemia. Identical histology to Burkitt's Lymphoma. Larger cells with vacuoles in cytoplasm, and showing characteristic starry sky appearance.

CLINICAL: Poor prognosis, found in children 6-11 years of age.

SYMPTOMS:

Hepatosplenomegaly
Generalized Lymphadenopathy, particularly cervical nodes.
Normocytic normochromic anemia, thrombocytopenia, neutropenia.
May have CNS involvement.
Metastasis to testes is common in kids, which changes how the disease would be treated.

PATHOLOGY:

60% of cases have cytogenetic abnormalities. Hyperdiploidy is a common abnormality and is a favorable prognostic indicator.

DIAGNOSTIC CRITERIA: Greater than 30% blasts must be present in the bone marrow or peripheral blood.

TDT-Positive: Terminal Deoxynucleotidyl Transferase is present in the lymphoid cells, distinguishing it from the myeloid cells (AML).
Myeloperoxidase-negative: Only granulocytes have myeloperoxidase.
PAS-Positive: Lymphoblasts in general stain positive for PAS.

PROGNOSTIC FACTORS:

Clinical Features	Favorable Prognosis	Unfavorable Prognosis
FAB Subtype	L1	L2, and especially L3
Immunotype	B-Cell (Pre-Pre-B-All, Pre-B-All)	T-Cell ALL Mature B-Cell ALL
WBC Count at Diagnosis	Less than 10,000	Greater than 50,000
Age	Children 3-7 (will probably be L1 subtype)	Children less than 1 (L2 subtype), or older than 10 (L3 subtype)
Race	White	Black
Sex	Female	Male
Organ Involvement	Minimal	Prominent
Cytogenetic Abnormalities	Hyperdiploidy

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL):

EPIDEMIOLOGY: The most common hematologic cancer in the United States. Found in old folks.
PATHOGENESIS: CLL is a clonal proliferation of immunologically incompetent small lymphocytes, which are almost always of B-cell phenotype. It is the most common leukemia in Western countries, occurs in the older population and has an indolent course, with a mean survival of 6 years. CLL involves the bone marrow and peripheral blood, with an absolute lymphocyte count above 5000 /l, and may infiltrate the liver, spleen and lymph nodes as well as other organs.
SUBTYPES: B-Cell CLL is by far (~95%) the most type of CLL in the USA.
PATHOLOGY:

Lymphocytosis: High lymphocyte-count diagnostic of CLL

Lymphocytes above 15,000 is diagnostic.
Lymphocytes between 5,000 - 15,000 is diagnostic, if monoclonality is present.

Pan-T-Cell Marker CD5 is expressed, which indicates that it is in immature B-Cell (but still not a blast).
Smudge-Cells: Cell appearance characteristic of CLL.

SYMPTOMS: Indolent course, mean survival of 6 years.

Immunodeficiency: Results from:

Hypogammaglobulinemia and granulocytopenia ------> pyogenic infections.
Impaired cellular immunity, due to too many CD8 Suppressor cells, and not enough CD4 cells.

Thrombocytopenia
Coombs-positive hemolytic anemia

PROGNOSIS: Bad prognostic indicators include:

Diffuse, as opposed to interstitial or nodular histological patterns in the bone marrow.
The presence of chromosomal abnormalities.

HAIRY-CELL LEUKEMIA: A rare chronic lymphocytic leukemia of B-Cells.

EPIDEMIOLOGY: The mean age is 50-60 years old, with a male predominance.
PATHOLOGY: Low-grade B-Cell leukemia. Diffuse infiltrate of hairy cells into bone marrow and spleen.

Hairy Cells: Cytoplasmic projections on cell-surface of B-Cells.
Tartrate-Resistant Acid Phosphatase (TRAP): Hairy-Cells are TRAP-Positive.

This distinguishes the cells from neutrophils which are TRAP-negative.

SYMPTOMS:

Presenting Symptoms: Classic symptoms, found in a middle-aged man.

Massive Splenomegaly: Due to infiltration of hairy cells into spleen
Pancytopenia
Dry Tap: Bone-marrow tap is dry, due to reactive fibrosis in the bone marrow.
No lymphadenopathy

Prognosis: Chronic and indolent course, but aggressive in 15% of cases. Death usually by infection.

TREATMENT:

2-CDA: 2-Deoxycoformycin is a recent treatment that has greatly improved the survival in these patients.
Interferon alfa also used, to inhibit proliferation of hairy cells.

MULTIPLE MYELOMA: 90% of plasma cell cancers are Multiple Myeloma.

PATHOGENESIS: Several causative factors

Genetic predisposition
Chronic antigenic stimulation: chronic stimulation of B-Cells can cause plasma cell malignancy.
Chromosomal abnormalities

OTHER PLASMA CELL CANCERS:

EXTRAMEDULLARY PLASMACYTOMA: 5% of cancers. Plasma-cell cancer usually occurring in upper respiratory tract. Up to 20% of cases progress to Multiple Myeloma.
Solitary Osseus Myeloma: 5% of cancers. Single lytic lesion of bone.

PATHOLOGY: Monoclonal spikes in the Protein Electrophoresis are found, indicating an abundance of a single type of antibody.

ROULEAUX: Paraproteins from the monoclonal antibodies tend to make red-blood cells stick together, giving the characteristic "roll-of-coins" appearance.
Bence-Jones Proteins: Immunoglobulin light-chains present in the urine.
Russell Bodies: Eosinophilic cytoplasmic inclusions of excess immunoglobulin.
Dutcher Bodies: Eosinophilic nuclear inclusions of excess immunoglobulin.

SYMPTOMS:

Lytic Bone Lesions: Characteristic lesions due to cancer cells secreting an osteoclast-activating factor.
Amyloidosis is characteristic of Multiple Myeloma. Amyloidosis of Multiple Myeloma is considered to be a primary amyloidosis, since the origin of the amyloid is directly related to the increase in immunoglobulins.
Light-Chain Cast Nephropathy: Severe renal involvement, causing mesangioproliferative glomerulonephritis and tubulointerstitial inflammation.

DIAGNOSIS:

Sheets of plasma cells found in the bone marrow.
Significant Monoclonal M-Component found in serum or urine.

Monoclonal Gammopathy of Unknown Significance (MGUS) is part of the differential diagnosis. It is diagnosed when a monoclonal spike is found in the absence of the other diagnostic features. MGUS later advances to full-blown Multiple Myeloma in many cases.

Radiologic demonstration of lytic bone lesions, or diffuse demineralization of bone.

NON-HODGKIN LYMPHOMAS:

STAGING: Progression of tumor is generally: Start in lymph node ------> spleen ------> liver ------> bone marrow ------> peripheral blood. Only rarely do the tumors disseminate through peripheral blood.
SYMPTOMS: Painless lymphadenopathy, splenomegaly

"B" SYMPTOMS: Weight loss, fever, night sweats, fatigue. General symptoms of a malignancy; when they are prominent they are almost always associated with a worse prognosis.

PATHOGENESIS: Several disorders are associated with increased risk of Non-Hodgkin Lymphoma

Sjögren Syndrome
HIV: Particularly Burkitt Lymphoma
Congenital immune deficiency syndromes (Wiskott-Aldrich, Ataxia Telangiectasia, SCID, Chediak-Higashi)
Hodgkin's Disease (post-treatment, resulting from chemotherapy)

International Working Formulation: Classifies lymphomas into low, intermediate, high grades, based on the rate of growth and aggressivity of the tumor

Low-Grade: Proliferative index < 5%. Indolent course. Tough to treat by chemotherapy because it's slow-growing.
Intermediate-Grade: Proliferative Index 5-10%
High-Grade: Proliferative Index > 10%, often much greater than 10%, as in Burkitt Lymphoma. Aggressive course, but easier to treat by chemotherapy.

PATHOLOGY:

Nodular (Follicular): Mostly low-grade. Histological pattern carrier a better prognosis.

Follicular Large Cell Lymphoma is the only follicular tumor placed in the intermediate grade category; all others are low-grade.

Diffuse: Mostly high grade, carrying a worse prognosis.

LOW-GRADE LYMPHOMAS:

SMALL LYMPHOCYTIC LYMPHOMA (SLL): Equivalent to Chronic Lymphocytic Leukemia (CLL)

SYMPTOMS: Low-grade, indolent lymphoma.

One third will see dissemination to blood ------> clinical picture identical to CLL.

WALDENSTROM MACROGLOBULINEMIA: SLL with Plasmacytoid Differentiation most often presents with a monoclonal gammopathy -- secretion of monoclonal IgM. SYMPTOMS:

Hyperviscosity Syndrome is seen secondary to the monoclonal gammopathy: Peripheral neuropathy, headache, deafness, paresis, coma.

It is caused by high molecular weight paraprotein in the blood.
Tendency to bleed, due to reduced Factor VIII (which is mopped up by all the extra paraprotein).

Mean survival = 4-5 years

MALT LYMPHOMA (MALTOMA):
FOLLICULAR (CENTER-CELL) LYMPHOMAS: Follicular (as opposed to diffuse) generally indicates high level of differentiation, slow growth, and a low-grade.

PATHOGENESIS:

t(14:18) translocation results in over-expression of bcl-2 oncogene. This results in inhibition of apoptosis ------> uncontrolled growth. Found in 90% of cases.

PATHOLOGY: Generally, the larger the cells, the more aggressive is the tumor.
SUBTYPES:

FOLLICULAR SMALL-CLEAVED CELL LYMPHOMA:
FOLLICULAR MIXED SMALL CLEAVED AND LARGE-CELL LYMPHOMA:

INTERMEDIATE-GRADE LYMPHOMAS:

FOLLICULAR LARGE-CELL LYMPHOMA: This is the only subtype of follicular lymphoma associated with an aggressive clinical course (hence it is intermediate grade). It may be classified with the other follicular lymphomas in future.
DIFFUSE LARGE CELL LYMPHOMA: Relatively common tumor. Sometimes grouped with the High-Grade Immunoblastic Lymphoma.

PATHOLOGY: Both CLEAVED and NON-CLEAVED cells are present.
SYMPTOMS: They are intermediate grade, yet they are still fairly aggressive.

Extranodal Sites: Tumor usually presents at an extranodal site, such as stomach, terminal ileum, thyroid, bone marrow.
Can be widespread at time od diagnosis, hence prognosis ain't so good.

HIGH GRADE LYMPHOMAS:

LARGE-CELL IMMUNOBLASTIC LYMPHOMA:

PATHOGENESIS: Can be associated with auto-immune disorders (RA, Sjögren's), or other immune disorders.

AIDS patients often get this lymphoma.

PATHOLOGY:

Immunoblasts are identified by huge nucleoli in the center of the cell.

LYMPHOBLASTIC LYMPHOMA: Analogous tumor to Acute Lymphocytic Leukemia.

EPIDEMIOLOGY: Adolescent and young-adult males.
PATHOLOGY: Usually T-Cell lineage, which distinguishes this tumor from most others.

Sea of blasts, immature cells.
TDT-Positive, as the cells are of lymphocytic lineage.

SYMPTOMS: Often presents as big mass in mediastinum, suggesting origin the thymus.

Often spreads to bone marrow and disseminates as Leukemia.
Late spread shows involvement of CNS and leptomeninges.
Overall poor prognosis.

DIFFUSE SMALL NON-CLEAVED CELL LYMPHOMA (BURKITT LYMPHOMA): Extremely fast-growing B-Cell Lymphoma, analogous to Acute Lymphocytic Leukemia (ALL), Type L3 (Burkitt's Leukemia).

PATHOGENESIS:

c-myc: Translocation t(8,14) is present in 80% of cases. c-myc is activated by its proximity to the heavy-chain gene. This results in a dominant monoclonal colony of B-Cells, which are selected for based on the mutation.
EBV: EBV infection occurs in 80% of endemic Burkitt lymphomas, in children in Africa.
HIV: Burkitt Lymphoma is the most common lymphoma seen in AIDS population.

PATHOLOGY: Burkitt Lymphoma is the fastest growing tumor known to mankind.

Starry sky: Characteristic appearance of Burkitt's. This appearance results from tingible-body macrophages, which swallow up dead tumor cells, throughout the tumor.

SUBTYPES:

Endemic Burkitt Lymphoma: Africa; 80% EBV. Lymphadenopathy presents as mass in jaw, in children in Africa.
Sporadic Burkitt Lymphoma: USA; Only 15% EBV. Often present with abdominal masses rather than mass in jaw.
Burkitt-Like Lymphoma: Rare

MISCELLANEOUS LYMPHOMAS:

CUTANEOUS T-CELL LYMPHOMA (MYCOSIS FUNGOIDES): Primary lymphoma of the skin.

PATHOGENESIS:
PATHOLOGY: T-Cell origin.

Epidermotropism: T-Cells migrate up into the epidermis.
Pautrier Microabscesses: Characteristic microabscesses of cancer cells, found in epidermis, in late-stage disease.

SYMPTOMS: Has a chronic, indolent course.

STAGES of Disease:

Patch Stage: Benign chromic dermatoses. Cannot yet be diagnosed as Mycosis Fungoides.
Plaque Stage: Well demarcated plaque; can usually be diagnosed at this stage.
Tumor Stage: Microabscesses and epidermotropism occur. Most common on face and in body folds; frequently ulcerate.

SÉZARY SYNDROME: Generalized erythroderma (intense and widespread reddening of skin), secondary to leukemic dissemination of the cancer.

Sézary Cells in blood have a perinuclear ring of PAS-positive vacuoles.

Pruritus and recurrent cutaneous infections are the most common chronic symptoms.

ADULT T-CELL LEUKEMIA / LYMPHOMA: Caused by the HTLV retrovirus, endemic to Carribean and West Africa. Disease is widespread and prognosis is poor.

EQUIVALENT NEOPLASMS:

Leukemia Lymphoma

Chronic Lymphocytic Leukemia (CLL) (Low-Grade)
Small Lymphocytic Lymphoma (SLL)

Acute Lymphoblastic Leukemia (ALL) (High-Grade)
Lymphoblastic Lymphoma

Acute Lymphoblastic Leukemia (ALL), Type L3 = Burkitt Leukemia (High-Grade)
Diffuse Small Non-Cleaved Lymphoma = Burkitt Lymphoma

HODGKIN'S -vs- NON-HODGKIN

Clinical Feature Hodgkin's Disease Non-Hodgkin's Lymphoma

Lymphadenopathy Localized lymphadenopathy Generalized Lymphadenopathy

Spread of Tumor Always an orderly, contiguous spread Spreads everywhere unpredictably

Involved nodes Mesenteric nodes, Waldeyer's Ring Predominantly Waldeyer's Ring

Extranodal Involvement Uncommon Common (30% of cases)

HODGKIN'S LYMPHOMA:

EPIDEMIOLOGY: Relatively rare disease.

Bimodal Age Distribution: 15-35, than older than 50.

15-35: Generally get the Nodular Sclerosis subtype, with a good prognosis.
> 50: Generally get the Mixed Cellularity subtype, with a worse prognosis.

PATHOLOGY: The entire disease is based on the histopathology, the presence of characteristic Reed-Sternberg cells.

REED-STERNBERG CELL: Large, binucleated cell with giant eosinophilic inclusions. Resembles owl's eyes.

Latest research says it probably is a B-Cell lineage, but origin is still uncertain.
Reed-Sternberg Cells are the only malignant cells. All other cells express disease only in their reaction to Reed-Sternberg cells.

PROGNOSIS:

Histologic Subtype: Generally, the more background (non-malignant) lymphocytes you have in the tumor, the better the prognosis.
B-Symptoms: The presence of fever, night sweats, correlates with a bad prognosis.
Ann-Arbor Staging System: Stages I-IV, used to stage Hodgkin's Disease. Stage at diagnosis correlates with prognosis.

Stage-I: Single node, or single primary site.
Stage-II: Two or more sites, on the same side of the diaphragm, or localized contiguous involvement.
Stage-III: Both sides of diaphragm, involving spleen.
Stage-IV: Disseminated.

SUBTYPES:

LYMPHOCYTE-PREDOMINANT: Least common subtype; good prognosis. This may later by grouped with Non-Hodgkin's B-Cell Lymphomas.

CLINICAL: Excellent prognosis, because of lots of non-malignant lymphocytes and few Reed-Sternberg cells.

MIXED CELLULARITY: Found in 40's to 50's; intermediate prognosis.
LYMPHOCYTE DEPLETED: Found in elderly men. Poorest prognosis.
NODULAR SCLEROSIS: Good prognosis.

SYMPTOMS: Usually found in young women.

Often presents with mediastinal lymphadenopathy, which distinguishes it from other forms of Hodgkins. Can also present with standard cervical lymphadenopathy.

PATHOLOGY:

LACUNAR CELL is a unique form of Reed-Sternberg cell, pathognomonic for this subtype of Hodgkin's Disease.

SYMPTOMS: Lymphadenopathy.

Immunodeficiency: Usually presents at time of diagnosis. They're not sure which comes first -- the disease or the immune deficiency.
Anergy to skin tests is often noted at diagnosis, or as time progresses.
B-Symptoms correlate with poor prognosis and are present in 40%.

TREATMENT: Chemotherapy is usually effective. But, secondary malignancies subsequent to the chemotherapy are especially high with Hodgkin's Disease.

Common Secondary Tumors: AML, and Non-Hodgkin's Lymphoma.

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Hemoglobin-A	alpha₂, beta₂	Predominant hemoglobin in adults
Hemoglobin-A₂	alpha₂, delta₂	Found in normal adults
Hemoglobin-F	alpha₂, gamma₂	Fetal (cord) hemoglobin, with higher O₂-binding affinity
Hemoglobin-S	alpha₂, beta₂ (beta: Glu-6 ---> Val)	Sickle-Cell Hemoglobin. Sickle crisis can result from low O₂-tension.
Hemoglobin-C	alpha₂, beta₂ (beta: Glu-6 ---> Lys)	Hemoglobin-C Disease. Second most common hemoglobinopathy.

CD3	T-Cell Receptor (TCR), common to all T-Cells.
CD4	T-Cell Helper
CD8	T-Cell Suppressor, Cytotoxic T-Cells
CD10	CALLA: Common Acute Lymphoblastic Leukemia (ALL) Antigen.
CD20	B-Cell marker
CD34	Stem-Cell Marker
CD45	LCA: Leukocyte Common Antigen, common to all leukocytes.

Leukemia	Lymphoma
Chronic Lymphocytic Leukemia (CLL)	(Low-Grade) Small Lymphocytic Lymphoma (SLL)
Acute Lymphoblastic Leukemia (ALL)	(High-Grade) Lymphoblastic Lymphoma
Acute Lymphoblastic Leukemia (ALL), Type L3 = Burkitt Leukemia	(High-Grade) Diffuse Small Non-Cleaved Lymphoma = Burkitt Lymphoma

Clinical Feature	Hodgkin's Disease	Non-Hodgkin's Lymphoma
Lymphadenopathy	Localized lymphadenopathy	Generalized Lymphadenopathy
Spread of Tumor	Always an orderly, contiguous spread	Spreads everywhere unpredictably
Involved nodes	Mesenteric nodes, Waldeyer's Ring	Predominantly Waldeyer's Ring
Extranodal Involvement	Uncommon	Common (30% of cases)