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Epidermal layers

Stratum Basalis - regenerative (stem cell) - layer, location of melanocytes and langerhans cells, hemidesmosomes between keratinocytes and basement membrane

Stratum spinosun - have dessmosomes between keratinocytes

Stratum corneum - keratin in anucleate cells

Atopic dermatitis

Eczematous dermatitis

pruritic, erythematous, oozing rash with vesicles and edema

arises upon exposure to allergens such as poision ivy and nickel (type IV hypersensitivity), irritant chemicals, drugs

treatment involved removal of offending agent and topical glucocorticoids if needed

Acne Vulgaris

Comedones (whiteheads and blackheads), pustules (pimples), and nodules, extremely common in aolescents

Due to chronic inflammation of hair follicles and sebaceous glands. Hormone associated increase in sebum production (sebacous glands have androgen receptors) and excess keratin production blocks follicles making comedones

Proprionibacterium acnes infection produces lipases that break down sebum releasing proinflammatory fatty acids results in pustule or nodule formation

treatment includes benzoyl peroxide (antimicrobial) and vitamin A derivatives (isotretinoin) which reduce keratin production


Well circumscribed, salmon colored plaques with silvery scale, usually on extensor surfaces and scalp, maybe pitting of nails. Due to excessive keratinocyte proliferation

possible autoimmune etiology, associated with HLA-C, lesions often in trauma areas

Acanthosis, parakeratosis, collections of neutrophils in the stratum corneum (Munro microabscesses), thinning of epidermis above elongated dermal papillae results in bleeding when scale picked off (Auspitz sign)

treatment - corticosteroids, PUVA (psoralen), or immune modulating

Lichen Planus

Pruritic, planar, polygonal, purple papules, often with reticular white lines om their surface (Wickham striae). Oral involvement manifests as Wickham striae


inflammation of dermal epidermal junction with "saw-tooth like appearance), individual necrotic keratinocytes,

dense band like lymphocytic infiltrate which hugs epidermis, shows hyperkeratosis, wedgeshaped hypergranulosis

Unknown etiology, associated with chronic hepatitis C virus infection

Pemphigus Vulgaris

autoimmune destruction of desmosomes (desmoglein 3) between keratinocytes. IgG antibody against desmoglein (type II hypersensitivity)

Presents as skin and oral mucosa bullae, acantholysis of stratum spinosum keratinocytes - suprabasal blisters. Basal layer cells remain attached to basement membrane via hemidesmosomes (tombstone appearance)m tin walled bullae easily rupture (Nikolsky sign) leading to shallow erosions with dried crusts

flaccid fragile bullae, scalp, face, axilla, groin, trunk, and pressure points

oral involvement very common

intraepidermal subraasilar blister, mixed dermal inflammatory infiltrate with eosinophils

acantholysis, eosinophlilic spongiosis

immunoflourensce highilights IgG surrounding keratinocytes in fish net patterened

Bullous Pemphigoid

Autoimmune destruction of hemidesmosomes between basal cells and the underlying basement membrane, due to IgG against basement membrane collagen.

Presents as blisters of the skin, no oral mucosa. Basal cell layer detached from basement membrane, tense bulae do not rupture easily, clnically milder than pemphigus vulgarus. immunoflorescence along basement membrane - linear

generally elderly, on extremities, intertriginous areas, abdomen and oral mucosa

subepidermal blister wihtout tombstones or acantholysis, blister contains edema fluid and eosinophils

Dermatitis Herpetiformis

Autoimmune deposition of IgA at the tips of dermal papillae. Presents as pruritic vesicles and bullae that are grouped (herpetiform), strong association with celiac disease, resolves with gluten free diet

vesicular dermatosis, pruritic, burning vesiles, especially on extensor surfaces of extremities (elbows/kneews), upper back, buttocks

subepidermal vesicles, neutrophlilc microabscess

granular IgA deposits in demrla papillae

Erythema Multiforme

Hypersensitivity reaction characterized by targetoid rash and bullae, targetoid due to central epidermal necrosis surrounded by erythema, papules, vesicles, bullae

Most commonly associated with HSV infection, also Mycoplasma, druge (penicillin and sulfonamides), autoimmune and malingnancy, idiopathic in 50% fo cases

Two more serious forms, Stevens Johnsons syndrome and Toxic epidermal necrolysis

histo - superficial perivascular lymphocytic infiltrate, usually mild, prominent edema of papillary dermis, degeneration and necrosis of keratinocytes leading to full thickness necrosis (start at basal layer)

Stevens-Johnson Syndrome

erythema multifora with mucosa/lip involvement and fever and ocular

fever, more in children, drugs are common cause (Bactrim and TMP-SMX)

Toxic epidermal necrolysis

diffuse sloughing of the skin resembleing a large burn, most often associated to adverse drug reaction

Seborrheic keratosis

benign squamous proliferation, common tumor in elderly. Presents as raised, discolored plaques on the trunk> extremities and face,

often has a coin like, waxy, stuck-on appearance, papules, smooth rough or greasy surface

Characterized by keratin psuedocysts

hyperkeratosis, acanthosis, basaloid keratinocytes, epidermal invaginations, keratin filled horn cysts, often contain melanin pigment

Leser Trelat sign

sudden onset of multiple seborrheic keratoses and suggests underlying carcinoma of the GI tract

Acanthosis Nigricans

Epidermal hyperplasia with darkening of the skin (velvet like skin), often axilla or groin

Associated with Insulin resistance (non insulin dependent diabetes), or malignancy (especially gastric carcinoma)

cutaneous marker for benign and malignant conditions (80% benign), may precede development of the associated condition

Basal cell carcinoma

malignant proliferation of basal cells of the epidermis, most common cutaneous malignancy

Risk factors - UVB induced DNA damage, prolong sunlight exposure, albinism, xeroderma pigmentosum

Elevated nodules with a central ulcerated crater (rodent ulcer) surrounded by telangectasia, pink, pearl like papule, smooth surface, retraction artifact

Nodules of basal cells with peripheral palasiding (outsie cells pallasiade to outside

Treatment is excision, metastasis is rare

Squamous cell carcinoma

Malignant proliferation of squamous cells, formation of keratin pearls. , more men than female, typically old, 2nd most common tumor arising in sun exposed sites

Risk factors - prolonged sun exposure, albinism, xeroderma pigmentosum, immunospuressive therapy, aresnic exposure, chronic inflammation (scar from burn or draining sinus tract), chronic and old burn scars

ulcerated, nodular mass, usually on face (classically involving lower lip) flesh colored erythematous, firm

hyperkeratosis, parakeratosis, acanthosis, dysplasia of entire epidermis, extension of tumor into dermis, squamous "pearls", solar elastosis

Treatment - excision, metastasis is uncommon

actinic keratosis

is a precursor lesion of squamous cell carcinoma, presents as hyperkeratotic, scaly plaque often on face, back, or neck

fair complexion individuals, chronically sun exposed areas, induced by UV radiation, can be thought of as precancerous

At risk with exposure to hydrocarbons and arsenicals

can be macule, pappule or scale

show hyperkeratosis, parakeratosis, dysplasia of lower epidermia, solar elastosis


well differentiated squamous cell carcinoma that develops rapidly and regresses spontaneously, presents as a cup shaped tumor filled with keratin debris.

usually on sun exposed skin, expecially face and dorsa of hands, very rarely aggessive

cup shape, keratin plug, glassy keratinocytes


responsiblefor skin pigmentation and are present in basal layer of epidermis

Derived from neural crest, Synthesize melanin in melanosomes using tyrosine via tyrosinase, pass melanosomes to keratinocytes


localized loss of skin pigmentation, due to autoimmune destruction of melanocytes

partial to complete loss of pigment producing melanocytes

all ages/races, macules and patches of pigment loss - hands, wrists, axillae, perioral.orbital, anogenital

koebnerization - when area of lesion is traumatized, more processes of lesion develop around it

may respond to light therapy (PUVA)

hard to tell sometimes in fair skin, show up after tanning


congenital lack of pigmentation, due to enzyme defect (usually tyrosinase) that impairs melanin production, may involve the eyes, or eyes and skin

increased risk of squamous cell carcinoma, basal cell carcinoma, and melanoma due to reduced protection againse UVB


freckle, small tan to brown macule, darkens when exposed to sunlight

due to increase number of MELANOSOMES, not melanocytes


mask like hyperpigmentation of the cheeks

cheeks temples and forehead

accentuated by sunlight, more common in women

OCPS, hydantoins, idiopathic causes

3 histopathological types - epidermal, dermal, and mixed

associated with pregnancy and oral contraceptives


mole, benign neoplasm of melanocytes

congenital nevus preset at birth - often with hair, Acquired later in life

Begins as nests of melanocytes at dermal epidermal junction (junctional nevus), most common in children. Grows by extension into the dermis (compound nerves), Junctional component is eventually lost resulting in an intradermal nevus, most common in adults

Flat macule or raised papule with symmetry, sharp borders, evenly distributed color, small diameter, cytologically bland melanocytes, no dermal mitotic figures, nuclei get smaller with descent into dermis, predominant nest pattern

Dysplasia may arise, Dysplastic nevus, which is precursor to melanoma


most common cause of death from skin cancer

risk factors - prolonged sunlight exposure, albinism, xeroderma pigmentosum, additional risk factor is dysplastic nevus syndrome, light skin, idoor occupations/out door hobbies, proximity to equator, xeroderma pigmentosa

ABCD - asymmetry, borders are irregular, color not uniform, diameter >6mm, enlargement of pre existing mole, itching or pain in mole

radial growth - growth horizontally along epidermis and superficial dermis, low risk for metastasis

Vertical growth - into deep dermis increased risk of metastasis, depth of extension (Breslow thickness) is the most important prognostic factor in predicting metastasis
- measure from stratum granulosum to lowest melanoma cell clarks level - anatomical location

superficial spreading - most common, dominant early radial growth phase

lentigo maligna melanoma - lentigous proliferation (radial), good prognosis

nodular - early vertical growth, poor prognosis
Acral lentiginous - arises on palms and soles, often dark skinned, not related to UV light exposure

favorable prognostic indicators - breslow <1.7mm, absence/low mitotic index, brisk tumor of infiltrating lymphocytes, no regression, female gender, location on extremity

deletions of p16INK4A, p14ARF, BRAF mutations

Dysplastic nevus syndrome

autosomal ddominant disordered characterized by formation of dysplastic nevi that may progress to melanoma

larger than acquired nevi (>5mm), variation in pigment with irregular borders
- isloated leisons not very significant, multiple more risk for melanoma,

usually compound or junctional = bridging of nests, shouldering, dermal fibroplasia, single cell lengitinous proliferation, irregular nuclear outlines with hyperchromasia, shoulders


Superficial bacterial infection, most often due to S aureus or S pyogenes, commonly affects children

erythematous macules that progress to pustules usually on face. Rupture of pustules results in erosions and dry, crusted, honey colored sreum


dermal and subcutaneous infection, usually due to S aureus or S pyogenes

red, tender, swollen rash with fever.
Risk factors- recent surgery, trauma, or insect bite
Can progressing to necrotizing fasciitis with necrosis of subcutaneous tissue due to infection with anaerobic flesh eating bacteria (CO2 production leads to crepitus, surgical emergency)

Staphyloccal scalded skin syndrome

Sloughing of skin with erythematous rash and fever, leads to significant skin loss

Due to S aureus infection, exfolative A and B toxins result in epidermolysis of the stratum granulosum

distinguished from toxic epidermal necrolysis by level of skin separation, TEN occurs at dermal-epidermal junction


wart. Fleshed colored papule with rough surface

due to HPV infection of keratinocytes, characterized by koilcytic change, hands and feet are common

Molluscum Contagiosum

Firm, pink, umbilicated papule due to pox virus. Affected keratinocytes show cytoplasmic inclusions (molluscum bodies)

Most often arise in chldren, also occur to sexually active adults and immunocompromised individuals

dome shaped papules with central keratin filled crater

face trunk and anogenital regions, easily spread through contact, DNA pox virus

Hematopoeitic Stem Cell

CD34 marker, can go to either two precursors, a myeloid or lymphoid stem cell.

lymphoid stem cell can go either B or T lymphoblast, to naive B or T cells, to mature cells

myeloid stem cell can go to erythroblast, myeloblast, monoblast, megakaryoblast, then to mature cells

WBC counts

normal is 5-10 thousand, leukopenia - <5000, leukocytosis >10,000


decreased number of circulating neutrophils, Causes are Drug toxicity (chemo) - damage to stem cells results in decreased production of WBCs, especially neutrophils. Severe infection via neutrophil movement into tissue, Gm-CSF or G-CSF can be used to boost production

supression of bone marrow production, dectruction of neutrophils (immune, splenomegaly) also overwhelming infection due to increased perpheral utilization


Decrease number of circilating lymphocytes, causes can be immunodeficieny (Digeorge or HIV), high cortisol state (exogenous or Cushings) induces apoptosis of leukocytes, autoimmune destruction (SLE), Whole body radiation - lymphocytes are highly sensitive to radiation]

neutrophilic leukocytosis

increased circulating neutrophils. Causes include bacterial infection or tissue necrosis 0 induces release of marginated pool and bone marrow neutrophils, including immature forms, immature cells are characterized by decreased Fc reeptors (CD16)

high cotrisol state - impair leukocyte adhesions, leading to release of marginated pool of neutrophils into blood

also caused by tissue necrosis


increase in ciruclating monocytes, causes include inflammatory states and malignancy


increased circulating eosinophils, causes include allergic
(type I) reactions, parasitic infections, and Hodgkins lymphoma, drug reactions, vascular disorders (Churg Strauss)


increased circulating basophils, classically seen in chronic myeloid leukemia

lymphocytic leukocytosis

increase in circulating lymphocytes causes iclude Viral infections - T cells proliferate, and BORDATELLA PERTUSSIS infection which prodouces lymphocytosis promoting facor which blocks circulating lymphocytes from leaving blood to enter lymph node, also fungal infections

Leukemoid reaction - very high white counts with circulating immature white cells (stimulates myeloid leukemia) (myelocyte with Dohle bodies - toxic granulations) - perforated abdominal wall and infarcted bowel have highest incidence of leukemoid rxn

Infectious Mononucleosis

EBV infection that results in a lymphocytic leukocytosis comprimised of CD8 T cells, CMV less common cause, EBV transmitted by saliva, adolescents

EBV - oropharynx(pharyngitis), liver (hepatitis with hepatomegaly and elevated liver enzymes), B cells

T cell response leads to lymphadenopathy due to T cell hyperplasia (paracortex), Splenomegaly T cell hyperplase in periarterial lymphatic sheath, high WBC count with atypical lymphocytes (reactive CD8 cells)

monospot test - detects IgM antibodies that cross react with horse or sheep RBC, typically positive 1 week after infection, negative test suggest CMV. Definitive diagnosis serology for EBV viral capsid antigen

Complications - increased risk splenic rupture (avoid contact for one year), rash if exposed to ampicillin, dormancy of virus in B cells lead to increased risk for recurrence and B cell lymphoma, especially in HIV

Acute Lekuemia

Neoplastic proliferation of blasts, >20% blasts in bone marrow

increased blasts crowd out normal hematopoeisis, present with acute presentation with anemia (fatigue), thrombocytopenia (bleeding), or neutropenia (infection)

blasts usually enter blood stream resulting in a high WBC count, large immature cells often with punched out nucleoli

divided into lymphoblastic or myelogenous leukemia

WBC can be high, normal, or low

typically short duration of symptoms, aggresive clinical course

Acute Lymphoblastic leukemia (ALL)

neoplastic accumulation of lymphoblasts (>20%) in bone marrow, most common malignancy of childhood 80% of child leukemia, peak incidence 2-10, more common in whites

positive for TdT in nuclear staining (DNA polymerase), absent in myeloblasts and mature lymphocytes

most commonly seen in children, associated with Down syndrome (arise after age of 5)

clinical - related directly to replacement of bone marrow by lymphoblasts
- pallor, weakness and lassitude due to anemia, petechial hemorrhage and mucosal bleeding, bond pain, fever due to neutropenia and infection, lymphadenopathy or hepatosplenomegaly, anterior mediastinal mass (T-ALL)

spleen liver and lymph nodes more common for leukemic infiltrates, also testicular enlargement

Hypercellular bone marrow, >25% blasts
divided into B ALL and T ALL

presentation can be leukemic or lymphoma (peripheral blood or bone marrow)

single best predictive indicator of remission and survival is cytogenetics

favorable - hyperdiploidy >50chromosomes, age 5-10, normal of low WBC

unfavorable - age< 2 years, presentation in adolescence/adulthood, blast >100,000, t(9,22)

B cell acute lymphoblastic leukemia

most common, characterized by lymphoblasts (Tdt positive) that express CD10, CD19, and CD20, excellent response to chemotherapy, prophylaxis to scrotum and CSF

85% of ALL

t(12,21) - good prognosis, more common in children

t(9,22) - poor prognosis, more common in adults (Ph+ ALL)

T cell acute lymphoblastic leukemia

lymphoblast (TdT+) express markings from CD2-CD8 (CD7),

usually present in teenagers as a thymic mass (called acute lymphoblastic lymphoma) T's

usually show clonal arrangements of T cell receptor genes, also IGH@gene rearrangements mal also occur in 20% of cases

considered higher risk that BALL

Acute Myeloid Leukemia

>20% myeloblasts in BM, positive cytoplasmic staining for myeloperoxidase (auer rods - crustal aggregates of MPO)

most common in older adults 50-60

subclassified based on cytogenetic abnormalities, some high yield subtypes are Acute promyelocytic leukemia, acute monocytic leukemia, acute megakaryoblastic leukemia

may arise from pre existing dysplasia (myelodysplastic disorder, especially with prior exposure to alkylating agents or radiotherapy)
- usually present with cytopenias, hypercellular bone marrow, abnormal maturation of cells, increased blast >20%. Most patients die from infection or bleeding, some progress to acute leukemia

often resembles acute infection, ulceration mucous membranes, bleeding, DIC, soft tissue masses of immature myeloid cells, anemia, thrombocytopenia

CBC, peripheral blood smear for myelobalsts, auer rods and nucleated RBC

auer rods - fused stacks of abnormal primary granules

MPO and Sudan black B - neutrophilic lineage

Nonspecific esterase - monocytic lineage

t(8,21) - good response to treatment
t(15,17) - promyelocytic - good prognosis due to all trans retinoic acid treatment
inv (16) - complete remission with cytarabine treatment

Acute promyelocytic leukemia

Characterized by t(15,17) (q22,q21) which involves translocation of the RAR (retinoic acid receptor) from 17 to 15, disruption blocks maturation and promyelocytes accumulate

classified as M3

abnormal promyelocytes have granules which INCREASE RISK FOR DIC, numerous auer rods

treat with all trans retinoic acid, binds altered receptor and causes blasts to mature and eventually die

acute monocytic leukemia

proliferation of monoblasts, usually lack MPO

classified as M5

blasts characteristically infiltrate gums. gum hypertrophy of new onset is strong clinical sign for AML monoblastic type

usually MPO negative, positive for nonspecific esterase

Acute megakaryoblastic leukemia

Proliferation of megakaryoblasts, lack MPO, associated with DOwn syndrome (before age of 5)

Chronic leukemia

neoblastic proliferation of mature circulating lymphocytes, high WBC count. Usually insidious onset and seen in older adults

Chronic Lymphocytic Leukemia

Neoplastic proliferation of naive B cells that co express CD5 (T cell) and CD20 (B cell, also 19, 23), urually low level of surface IG (IgM)

most common leukemia of western world

peak age 60-70, more common in males, 20% asymptomatic at presentation

lab - increased WBC, decreased nphil %, anemia, thrombocytopenia moderate or absent, hemmolytic aneia type with positive direct combs test

increased lymphocytes and smudged cells on blood smear, involvement of lymph nodes leads to generalized lymphadenopathy and is called small lymphocytic lymphoma

cracked earth or soccer ball nuclei

clinical - weakness, night sweats, weight loss as constitutional symptoms, prone to infection, bleeding

1/3 indolent, 1/3 indolent which becomes aggressive, 1/3 aggressive

origin cells may be naive B cell or post germinal center memory B cell

complications include - Hypogammaglobulinemia,
autoimmune hemolytic anemia, transformation to diffuse large B cell lymphoma (Richter transformation) - marked clinically by enlarging lymph node or spleen

Hairy Cell Leukemia

Neoplastic proliferation of memory B cells characterized by hairy cytoplasmic processes

age 55, M>F

presentation - middle aged male, pancytopenia, enlarged spleen, dry tap on bone marrow, hairy cells seen on BM aspiration
cells are positive for tartrate resistant acid phosphatase (TRAP)

Clinical features - splenomegaly (accumulation of hairy cells in red pulp), and dry tap on BM aspiration due to marrow fibrosis

excellent response to 2-CDA (cladribine) - adenosine deaminase inhibitor, adenosine accumulates to toxic levels in neoplastic B cells

diagnosis - fried egg cells seen in bone marrow, positive for TRAP, CD19,CD20, 11c markers

cells crowding splenic sinusoids create red cell lakes and massive enlargement

Adult T cell Leukemia/Lymphoma

Neoplastic proliferation of mature CD4 T cells, associated with HTLV-1, more common in Japan and Carribean

clinical features - rash, generalized lymphadenopathy with hepatosplenomegaly, and lytic bone lesions with hypercalcemia

Mycosis Fungoides

Neoplasticc proliferation of mature CD4 T cells that infiltrate the skin proucing localized skin rash plaques, and nodules. Aggregates of neoplsatic cells in epidermis are called Pautriet microabscesses

Cells can spread to involve blood, producing Sezary sydrome - Characteristic lymphocytes withcerebriform nuclei (Sezary cells) and are seen on blood smear

Myeloproliferative Disorders

Neoplastic proliferation of mature cels of myeloid lineage, usually late adulthood (50-60). Results in high WBC count with hypercellular bone marrow, all lineages are increased, classified based on dominant cell produced

Complications - increased risk for hyperuricemia and gout due to high turnover of cells. Progression to marrow fibrosis or transformation to acute leukemia

Chronic Myeloid Leukemia

Neoplastic proliferation of mature myeloid cells, especially granulocytes and precursors, basophiles are characteristically increased

driven by t(9,22) Ph which generates BCR-ABL fusion with increased tyrosine kinase activity, first line of treatment is imatinib which blocks TK activity, remission in 90%

Splenomegaly is common, enlarging spleen suggests accelerated part of disease, can transform to acute leukemia (AML(2/3) or ALL (1/3),

initially indolent with excessive numbers or mature granulocytes, may enter accelerated phase terminating in blast cris

peak age between 40,50

symptoms - 50% asymptomatic at time, energy loss, headache, weight loss, anorexia, abdominal discomfort (dragging sensation),

acelerated - account for 10-19% of WBCs in peripheral blood, blast crisis they account for 20% or greater, resembles AML, 70% time is myeloid

GLEEVAC is treatment

CML from leukemoid reaction

negative leukocute alkaline phosphatase (granulocytes in a leukemoid reaction are LAP positive)

increased basophils (absent in leukemoid)

t(9,22) - absent in leukemoid reaction

Polycythemia Vera

proliferation of mature myeloid, especially RBC, but granulocytes and platelets also increased, median age 60

Associated with JAK2 kinase mutation

Hyperviscour blood - blurry vision and headache, increased risk of venous thrombosis, hepatic vein (Budd Chiari), portal, dural sinus), Flushed face due to congestion (plethora), itching especially after bathing (histamine rxn from increased mast cells), GI discomfort

treatment is phlebotomy, 2nd line hydroxyurea, death occur in 1 year without treatment

3 stages
prepolycythemic - mild increase in WBC, may mimic essential thrombocythemia

proliferative - headache, dizziness, visual disturbances, plethora, cyanosis, hypertension, venous or arterial thrombosis, GI bleeding, pruritis, absolute increase in red cell mass with increased Hb/HC, hyperceuular bone marrow, sustaibable iron is absent, due to increased utilization of iron and GI blood loss

Spent - 10-15 years after onset of proliferative stage, marrow fibrosis with decreased marrow cellularity, HSM due to extrameddulary hematopoiesis, causing hepatosplenomegaly. Major symptoms relate to anemia, massive splenomegaly and bleeding

treatment - phlebotomy, blood transfusion, maybe JAK 2 inhibitors in future, transition to AML in 2%

death usually due to thrombosis or bleeding,

Polycythemia vera from reactive polycythemia

PV - EPO levels are decreased, SaO2 is normal

RP - SaO2 low form high altitude, EPO increased
from ectopic EPO (renal cell carcinoma), EPO high, SaO2 normal

Essential Thrombocythemia

proliferation of mature myeloid especially platelets, others also increased, platelets exceed 450,000 without known cause, megakaryocytic hyperplasia in bone marrow

JAK2 kinase mutation

Symptoms are related to increased risk of bleeding and or thrombosis, rarely progresses to marrow fibrosis or acute leukemia,

clinnical - hemorrhage, thrombosis, neurologi symptoms, erythromelalgia (throbbing aching or burning of extremities caused by occlusion of arterioles, moderate splenomegaly and hepatomegaly

sustained thrombocytosis, platelets display morphologic heterogeneity including giant platelt, median WBC count between 10 -14,000

BM - hypercellularity, megakaryocyte hyperplasia, clusteing

must exclude other myeloproliferative disorders

no significant risk for hyperuricemia or gout - no big turnover of nuclear material since platelets do not have nucleus

survival time 12-15 years


Proliferation of maturemyeloid, especially megakaryocytes, marrow fibrosis leads to distortion of marrow sinusoids

JAK2 kinase mutation in 50% cases

produce excess platelet derived growth factor causing marrow fibrosis

Clinical - splenomegaly due to extramedullary hematopoiesis,

leukoerythroblastic smear (teardrop RBCs, nucleate RBCs, immature granulocytes) - BM reticulin gates keep immature cells from leaving, when made in spleen there is no gate, also reticulin fibers make RBCs squeeze, resulting in tear drop

leukoerythroblastosis seen in peripheral blood, erythroid and granulocytic precursors, bone marrow is white on inspection of core biopsy

increased risk of infection, thrombosis, and bleeding

must rule out other causes of marrow fibrosis


large lymph nodes. Paniful LAD usually seen in lymph nodes draining a region of acute infection

Painless LAD can be seen with chronic inflammation, metastatic carcinoma, or lymphoma

in inflammation - lymph node enlargement is due to hyperplasia of particular regions of the lymph node (Follicular hyperplasia (B cell region) seen with rheumatoid arthritis and early HIV infection.

Follicular hyperplasia

B cell region, seen in rheumatoid arthritis and early HIV infection

Paracortex hyperplasia

T cell region, seein with viral infections

Sinus histiocyte hyperplasia

medulla, seen in lymph nodes draining area with cancer


Proliferation of lymphoid cells that forms a mass, may arise in lymph node or in extranodal tissue

divide into hodgkins and non hodgkins lymphoma

B symptoms - fever, night sweats, loss of appetite, weight loss,

biopsy tissue is necessary for diagnosis

NHK further divided
small B cells (more differentiated) - follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma.

intermediate sized B cells - Burket lymphoma

Large B cells - diffuse large B cell lymphoma

Non hodgkins lymphoma general

60% of lymphoma, lymphoid cells are malignant and make up most of the composition of the mass, 85% B cell, 15% T cell

present as painless lymphadenopathy, late adult hood

extranodal masses

spread is diffuse, often extranodal

has leukemic phase, staging is not very important

Hodgkins lymphoma general

40% of lymphoma, reed sternberg cells are malignant

mass is predominately reactive cells, (inflammatory cells and fibrosis). Painless lymphadeopathy with occasioal B symptoms, arises in young adults

typically contiguous, rarely extranodal, Stagin guides therapy,

No Leukemic phase

Follicular lymphoma

Proliferation of small B-cells (CD20) that form follicle like nodules. Clinically presents in late adulthood with lymphadenopathy

centrocytes - cleaved follicle center cells, centroblasts - large non cleaved follicle center cells

grading predicts clinical outcome - depends on # of centrobalsts per HPF - 0-5, 6-16,>15

positive for surface Ig, CD19m CD20, CD22, CD79a

t(14,18) - BCL2 on chromosome 18 translocates to Ig heavy chain on chromosome 14, overexpression of Bcl-2- which is a mitochondrial embrae stabilizer, inhibits apoptosis in follicle, where you want apoptosis occuring for selection

treatment - those who are symptomatic , lose dose chemo or rituximab (CD20 antibody)

Progression to diffuse large b cell lymphoma is important complication - presents as enlarging lymph node

almost exclusively effects adults - lymph nodes,s pleen, bm, waldeyer tonsilar ring. Indolent, not curable but manageable, can progress to DLBCL

Follicular lymphoma from reactive follicular hyperplasia

FL - disruptio of normal lymph node archeticture, lack of tingible macrophages (macrophages positive in follicular hyperplasia since apoptosis is going on)

Bcl-2 in follicles in FL, also monoclonality

Mantle Cell lymphoma

proliferation of small B cells (CD20) that expands the mantle zone, clinically present in late adult hood with painless lymphadenopathy, spleen, bonemarrow, GI, waldeyers

diven by t(11,14) - Cyclin D1 on 11 moved ti Ig heavy chain locus on 14, overexpressed cyclin D1 promotes cell transition from G1 to S, facilitates neoplastic formation

Marginal zone lymphoma

Proliferation of small B cells (CD20 that expands the marginal zone, associated with chronic inflammatory states such as Hashimoto thyroiditis, Sjogrn syndrome, and H pylori gastritis

marginal zone formed by post germinal center B cells

MALToma is marginal zone lymphoma in mucosal sites - gastric MaLToma may regress with H pylori treatment - most often stomach, lung, head anc neck, skin, tyoroid

Burkitts Lymphoma

proliferation of intermediate sized cells (CD20) associated with EBV

classically presents as extranodal mass in young child or adult

African type - Involes jawm Sporadic usualy involves abdomen

t(8,14) - translocation of c-myc to Ig heavy chain on chromosome 14, overexpression of c-myc promotes cell growth
high S phase, tumor lysis syndrome

monomorphic, medium sized cells, round nuclei, multiple basophilic nucleoli, cytoplasmic lipid vacuoles, numerous mitotic figures, "starry sky pattern"

Characterized by high mitotic index and starry sky appearance on microscopy (cells grow so fast they die, have clearer macrophages around

Diffuse Large B cell Lymphoma

Proliferation of large B cells that grow diffusely in sheets, most common form of non hodgkins lymphoma, nuclear size equal or exceeds normal macrophage, diffuse growth pattern

Arises sporadically or from transformation of low grade lymphoma, presents in late adulthood as enlarging lymp node or extranodal lymph node

surface Ig may be present, pan B cell markers (Cd19,2-,22,79a)

bcl-2 gene t(14,18)
bcl6 (3q27) - susceptible to chemotherapy, disease is potentially curable depending on stage

high grade and agressive, potentially curable depending on stage

Subsets - immunodeficiency assoiated and body cavity
(AIDS patients)

Hodgkin Lymphoma

Proliferation of Reed Sternberg cells - large B cells with multilobed nuclei and prominent nucleoli (owl eyed nuclei), positive for CD15 and CD30

RS cells secrete cytokines - occasionally result in B symptoms (fever ,chills, and night sweats), attract reactive lymphocytes, plasma cells, macrophages, eosinophils, ma lead to fibrosis

95% are B lineage

common age 15-35, age 55 and older, RS cells with background of reactive inflammatory cells, RS classically binucleated, eosinophils. After treatment,

B symptoms, painless enlargement of lymph nodes

staging most important prognostic indicator


nodular sclerosis - most common (70%) - classic presentation is enlarging cervical or mediastinal lymph node in young adult female,, lymph node divided by bands of sclerosis, RS cells are present in lake like spaces

Lymphocyte rich - best prognosis of all types

mixed cellularity - often associated with abunant eosinophils (Rs produce IL-5)

, lymphocyte depleted is most agressive, usually seen in elderly and HIV positive

Multiple Myeloma

malignant proliferation of plasma cells in bone marrow, most common PRIMARY malignancy of bone, metastatic cancer is most common overall, High serum plasma IL-6 sometimes present, stimulates plasma cell growth an Ig production

CLinical - bone pain with hypercalcemia - plasma cells activate RANK receptor on osteoclasts, leading to bone destruction, lytic punched out lesions seen on xray especially in skull and vertebrae, alkaline phosphatase not increased unless fracture present

seen as anemia and backpain in older individuals

elevated serum proetein - plasma cells produce Ig, M spike present on serum protein electrophoresis, most common due to monoclonal IgG or IgA

increased risk of infection - monoclonal Ab lacks antigenic diversity, most common cause of death in MM

Rouleax formation of RBCs - increased serum protein decreases charge between RBCS

clinical symptoms due to 3 main processes - plasma cell growth in tissues, especially bones, production of excessive Igs, often have abnormal physiochemical properties, suppression of nomrla humoral immunity

marrow plasmacytosis, monoclonal paraprotein, reduced normal immunoglobulin, normochromic normocytic anemia, high erythrocyte sedimentation rate, lytic bone lesions, bone pain and fatigue

triad - lytic bone leasions, monoclonal serum immunoglobulin documented by serum and urine proetin, dodumentation of incrased monoclonal plasma cells

chromosome - Ig heavy chain rearrangements on 14q32, dysregulation of D cyclins common, deletion of 13q

Primary AL amyloidosis - free light chains due to over production in serum and deposit in tissues

Proteinuria - free light chain is excreted in urine as Bence Jones proteins, deposition in kidney tubules leads to risk for renal failure (myeloma kidney)

Monoclonal Gammopathy of undetermined significance

MGUS, increased serum protein with M spike on SPEP, other features of MM are absent (no lytic bone lesions, hypercalcemia, AL amyloid, or bence jones proteinuria)

most comomn plasma cell neoplasm

serum M protein less than 3gm/dL

most die from unrelated causes
common in elderly, 1% of MGUS patients develop into MM each year

Waldenstrom Macroglobulinemia

B cell lymphoma with monoclonal IgM production

Clinical - generalized lymphadenopathy, lytic bone lesions are absent

Increased serum protein with M spike (compromised of IgM)

Visual and neurological spike (retinal hemorrhage or stroke, IgM pentamer causes serum hyperviscosiity), bleeding due to macroglobulin interference, cryoglobulinemia from precipitation of macroglobulins at low temperature

treated with plasma pheresis until symptoms controlled. can use anti CD20 antibody drugs. median survival aporoximately 4 years

bleeding - defective platelet aggregation due to viscous serum

Acute complicationg treated with plasmapheresis, removes IgM from serum

Langherhans cell histiocytosis

L cells - specialized dendritic cells found predominatelty in skin, derived from bone marrow monocytes, present antigen to naive T cells

neoplasti proliferation of langerhans cells, characteristic birbeck (tennis racket) granules are seen on EM, cells are CD1a and S1000 positive by immunohistochemistry

If named after soemone - malignant, and skin

2 people names - children <2
3 people names >3

letterer-siwe disease, eosinophilic granuloma, hand- Schuller-Christian disease

Letterer-Siwe disease

Malignant proliferation of langerhans cells, classic presentation is skin rash and cystic skeletal defects in an infant <2

multiple organs may be involved, rapidly fatal

Eosinophilic Granuloma

benign proliferation of Langerhans cells in bone

Classic presentation - pathologic fracture in adolescent, skin not involved

skin biopsy - langerhans cells with mixed inflammatory cells, including numerous eosinophils

Hand - Schuller -Christian Disease

Malignant proliferation of Langerhans cells

Classic presentation is scalp rash, lytic skull defects, diabetes insipidus, and exophthalmos in a child

Hypospadia/ Epispadia

hypo - abnormal urethral opening on ventral surface of penis, failure of urethral folds to close

Epi - abnormal urethralopening on dorsal surface of penis, due to abnormal positioning of genital tubercle

may be associated with other abnormalities like failure of normal descent of testes and malformations of urinary tract

may result in obstruction of sterility

Phimosis / paraphimosis

Phimosis - prepuce too small to permit normal retraction, may be a anomaly but common secondary to repeated infection that leads to scarring

paraphimosis - prepuce forcibly retracted leading to marked constriction and swelling of penis

Penile inflammation

Balanitis - infection of glans

Balanoposthitis - infection of glans and prepuce, usually associated with phimosis, chronic accumulation of smegma

can be caused by variety of organisms - Candida, anaerobes, Gardnerella, pyogenic bacteria

also STDs - syphilis, gonorrhea, chancroid, genital herpes, granuloma inguinale, lymphogranuloma venerem, herpes

Condyloma Acuminatum

Benign epitheliam tumor caused by HPV, particularly types 6 and 11, typically sexual transmission

Typically occurs around coronal sulcus and inner surface of prepuce. Tend to recur but do not evolve into invasive carcinoma

Gross - sessile or pedunculated, red papillary excrescences

Micro - branching, villous, papillary connective tissue stroma covered by hyperplastic epithelium with hyperkeratosis and acanthosis. Maturation is normal. Clear vacuolization of epithelial cells (koilcytosis) is present. Basement membrane intact with no evidence of invasion

koilocyte - nuclear enlargement and binucleation, hyperchromasia, halos

Carcinoma in Situ Male Genital

cytologic changes of malignancy confined to epithelium, no local invasion, malignant changes in epithelium with loss of surface maturation and cellular atypia with nuclear hyperchromatism and mitotic figures

2 lesions in males. Bowen disease and Bowenoid papulosis. Both have strong association with HPV (16)

characterixed by epidermal proliferation with numerous mitotic figures, cells are markedly dysplastic with large hyperchromatic nuclei and lack orderly maturation. Basement membrane is intact

Bowen Disease

carcinoma in situ on Skin of shaft, usually solitary lesions but can be multiple

thickened gray-white or red shiny plaques

Erythroplasia of Queyrat - Clinical term used for lesions on glans or prepuce. 10% progress to malignancy (leukplakia)

associated with HPV (16)

Bowenoid papulosis

Carcinoma in situ

patients typically younger sexually active adults,

multiple reddish brown papular verrucoid lesions,

almost never develop into cancer

associated with HPV (16)

Squamous cell carcinoma of the penis

uncommon - less than 1% of tumors in males

correlation between lack of circumcision and cancer (poor genital hygeine)

HPV type 16 and sometimes 18,31,33 in 50% of patients, smoking other risk factor. Ages 40-70, lack of circumsicison

Gross - slow growing lesion on glans or inner surface of prepuce near coronal sulcus. Papillary or flat which eventually ulcerates and erodes local tissue

Micro - squamous cell carcinoma with varying degrees of differentiation , can see histoplastic rxn and invasive tumor islands

variant - verrucous carcinoma - rarely metasatazies - has papillary surface growth pattern, locally invasive

Clinical - slow growing local metastasize, Mets to inginal and iliac lymph nodes. local mets 27% survival, no mets 66% 5 year

Testes Histo

composed of seminiferous tubules and supporting structures, seminiferous tubules are lined by germ cells in various stage of maturation. Supporting sex-cord cells known as sertoli cells

During ejactulation sperm enters seminal ampule where mixed with seminal fluid from seminal vesicles and prostate


Undescended testes, a complete or incomplete failure of intraabdominal testes to descend into scrotal sac. Approximately 1% of boys, may be associated with other genitourinary malformations. Asymptomatic, usually found during physical exam, may be palpable in inguinal canal

Often will descend on own in first year or can be surgically corrected by age 2(orchiopexy)

Most common unilateral, bilateral in 25% of cases

Micro - germ cell maturation arrest, hyalinized and thickening of basement membrane spermatic tubules, increase interstitial stroma, leydig cells prominent. contralateral testis may show deterioration

May be related to hernias, sterility and testicular cancer. Higher location of undescention greater the risk

even descended testical has higher risk

Testes and Epididymis Infection

Epididymal infections are more common. Gonorrhea/TB first in epididymis and then spread to testis.

Syphilis in testes first, then to epididymis

Mumps - cause of orchitis, usually develops 1 week after parotitis

nonspecific epididymitis and orchitis - often associated with UTI - gram negatives, chlamydia, Neisseria, E. coli, psuedomonas in older men. See congestion, edema, neutrophilic infiltrates, inflammation, chronic infections can lead to scarring and infertility

Granulomatous orchitis

unilateral testicular enlargement in middle aged men, sudden onset of tender testicular mass, sometimes with fever, confined to region of the seminiferous tubules

Testicular Torsion

Vascular disturbance secondary to twisting of spermatic cord and venous obstruction. Can occur in absence of injury, onset of sudden pain

usually due to congenital failure of testes to attach to inner lining of scrotum (via processus vaginalis)
true urologic emergency requiring surgical treatment. Microscopy can show varying changes from congestion to interstitial hemorrhage and necrosis

sudden testicular pain and absence of cremasteric reflex

2 types of Testicular tumors

Germ cell - seminoma, spermatocytic seminoma, embryonal carcinoma, Yolk sac tumor, choriocarcinoma, teratoma

Sex cord-Stromal Tumors - Leydig cell tumor, Sertoli cell tumor

Germ cell tumors

95% of testicular tumors, incidence 6/100,000, peak age 15-34 (most common tumor in age range) 10% of cancer deaths

two categories - one histological pattern (40%), and tumors showing more than one histo pattern (60%)

predisposing factors - cryptorchidism, genestic (isochromosome 12, 12p), testicular dysgenesis (feminization and Klinefelters)

pathogenesis: malignant transformation of germ cells results in an intratubular tumor known as carcinoma in situ or intratubular germ neoplasm. Develop in two directions
1) retain features of primitive gonocytes, forming a neoplasm of single cell type - seminoma
2) transform into a totipotential cell population that gives rise to non seminomatous tumors - embryonal, choriocarcinoma, teratoma, yolk sac tumor

Histo - cells are rounded, same size and shape

Patients typically precent wiht painless enlargement of testicle, biopsy not recommended because of tumor spillage so standard management is orchiectomy. Typically spread via lymphatics - para aortic nodes first. Hematogenous spread to lungs most common, followed by liver, brain, and bones

Non-seminomatous germ cell tumors - more aggressive in general, present with advanced disease, metastazie early

generally 90% can achieve remission

AFP - 30% of carcinoma, sign of yolk sac tumor
HCF - choriocarcinoma


Most common (50%) of germ cell tumors, 95% classic, 5% spermatocytic. Peak in thirties

Gross - homogenous, gray/white, lobulated cut surface, large, replaces entire testis, tunica albuginea intact, no hemorrhage or necrosis

rare cases produces beta HCG,

Microscopic - sheets of uniform large round polyhedral cells with distinct cell membranes, clear cytoplasm (abundant glycogen), Large central nucleus with one or two prominent nuclei.

Tumor cells stain positive for placental alkaline phosphatase. 15% contain syncytial giant cells that resemble syncytiotrophoblasts (secrete HCG). Well defined fibrous strands, septa infiltrated by lumphocytes and plasma cells

Immunohistochemical staining - placental alkaline phosphatase, OCy 3/4, NANOG, c-kit

tend to remain localized to testis for long time, spread via lymphatics, Extremely radiosensitive

can be seen in ovary and CNS

Spermatocytic Seminoma

occurs in older patients. Indolent tumors - almost never metastasizes

larger than classic seminoma, mixed population of cells, small cells resembling spermatocytes, medium sized cells and some giant cells. Arise only in testis (classic form can be seen in ovary and CNS). PLAP negative

Embryonal carcinoma

in 20-30 year olds, more aggressive than seminoma. more often component of mixed tumor. Immature, primitive cells that may produce glands, forms hemorrhagic mass with necrosis

gross - cut surface variegated, poorly demarcated gray white mass with hemorrhage and necrosis. May extend through tunica albuginea into epididymis/spermatic cord

Micro - glandular, alveolar, tubular, solid, papillary patterns. Primitive epithelial cells, considerable size variation, anaplastic, hyperchromatic nuclei, prominent nuclei, indistinct cell borders, mitotic figures

Immunohistochemistry - CD30, Cytokeratin, OCT 3/4, PLAP

aggresive with early hematogenous spread

increased AFP or beta -HCG may be present

Yolk sac (endodermal sinus) tumor

most common testicular tumor in infants and children up to 3 years of age. Good prognosis. Adults is more often component of mixed tumor

Gross- cut surface hemogenous, yellow/white, mucinous

Micro - lace like network of medium sized cuboidal or elongated cells. Structures resembiling primitive glomeruli (endodermal sinuses, Schiller -Duval bodies). Eosinophilic hyaline globules containing AFP highly characteristic. ALso Alpha 1 antitrypsin

AFP is tumor marker


Highly malignant, most aggresive, rare <1% of all germ cell tumors. more commonly a component of mixed tumors

Composed of both cytotrophoblast and synctiotrophoblasts elements

Can be seen in other sites, ovary, placenta, sites of germ cell rests (mediastinum, abdomen)

Gross - usually small, rarely larger than 5cm, hemorrhage and necrosis common

Microscopic - two cell types
Syncytiotrophoblast - large, many irregular or lobular hyperchromatic nuclei and abundant eosinophilic cytoplasm. Cytotrophoblast - more regular, polygonal with distinct cell borders and clear cytoplasm. Grows in cords or massed and have a single fairly uniform nucleus.

Tumor marker HCG - may lead to hyperthyroidism or gynecomastia


neoplasm exhibiting evidence of simultaneous differentiation along endodermal, ectodermal and mesodermal lines. Pure form seen more commonly in children, Adults - more often component of mixed tumor.

Post pubertal male - tumors should be considered malignant with capability to metastatsize

Gross- large heterogenous with sold, sometimes cartilaginous and cystic areas

Microscopic 3 variants
Mature - differentiated tissue, diagnosis of mature testicular teratoma should be made with caution in adults, likelihood of small hidden foci of immature cells

Immature - elements are incompletely differentiated. Poorly formed cartilage, neuroblast, mesenchyme etc

Teratoma with malignant transformation - clear evidence of malignancy in derivatives of one of more germ cell layers

Mixed Germ cell Tumors

60% germ cell neoplasms

Variable pattern - mix of teratoma, embryonal ca, yolk sac, and HCG containign giant cells.

teratocarcinoma - teratome + embryonal ca

metastases can contain any, all, or new components

must present % of each in tumor

Leydig cell tumor

Approximately 2% of all testicular tumors, usually benign, hormonally active producing androgens and soemtimes steroids

males between 20-60, present with testicular mass and hormonal changes (gynecomastia, sexual precocity in children

gross - usually <5 cm in diameter, golden brown homogenous cut surface

micro - large round or polygonal cells with abundant granular eosinophilic cytoplasm and central round nucleus, Cytoplasm contains crystalloids of Reinke in approx 25% of tumors

Clinical - most are benign, approximately 10% invsive

Sertoli Cell tumor


rare testicular tumors, u sually benign, hormonally active, rarely in sufficent quantity to produce feminization or rpecocious masculinization

most common in middle age men, present with testicular swelling, possibly gynecomastia

Gross - < 3 cm diameter, well circumscribed, solid, gray white cut surface

Micro - tumor cells are arranged in distinctive trabeculae with a tendency to form cordlike structures resembling immature seminiferous tubules. Tall columnar cells

Clinical - most are benign, occasionally anaplastic and pursue malignant case, variant of sertoli cell tumor with annular tubules associated with Peutz Jeghers syndrome

Testicular lymphoma

5% of testicular neoplasma. most common form in men older than 60

rarely limited to testis at discovery

usually diffuse large B cell lymphoma. poor prognosis

Glomeruli components

Capillary loops - (endothelium, basement membrane)


Visceral epithelium (foot processes, podocytes)

Parietal epithelium

Renal path affected compartments

Glomeruli, Tubules, Interstitum, blood vessels

Kidneys gross

retroperitoneal organs, extend from 12th throacic to 3rd lumbar vertebrae, each weighs about 150 gms.

Outer cortex - glomeruli and tubules
Inner medulla - loops of Henle and collecting ducts, divided into pyramids

Examination of Renal Tissue

Light microscope - up to 1000x

Immunofluorescence - look for proteins in kidney not present in undiseased states - (IgG, IgA, IgM), complement (C3, C4, C1q), and fibrinogen. Tissue is incubated in solution with Ab tag

Electron Microscopy - magnfies 3150 - 10,000X - can see podocyte foot processes, amyloid fibrils, basement membranes, granular electron dense deposit


elevation of blood urea nitrogen (BUN) and creatinine, due largely to decreased glomerular filtration rate.

Pre-renal - occurs when there is hypoperfusion of the kidney (hemmorhagic shock, volume depletion, CHF)

Renal - intrinsic disease of kidney (ATN, toxins, acute interstitial nephritis, glomerular dz)

post renal - occurs whenever urine flow is obstructed (prostate enlargement, stones, retroperitoneal fibrosis, cervix cancer)


azothemia + clinical signs and symptoms and biochemical abnormalities.

Hypothermia, glucose intolerance, hypertriglyceridemia, elevated serum phosphate, renal osteodystrophy, pericarditis, hypertension, nausea/vomiting/gastroenteritis, anemia, peripheral neuropathy, and pruritus

Acute renal failure

deterioration of renal function over a period of hours to days, resulting in failure of the kidney to excrete nitrogenous waste products and to maintain fluid and electrolyte homeostasis. Can be caused by glomerular, interstitial, vascular injury or acute tubular necrosis.

Usually reversible

Chronic renal failure

progressive destruction of nephron mass, characterized by prolonged signs and symptoms of uremia. End result of all renal diseases.

Glomerulonephritis is most common cause, others include diabetes mellitus, polycystic kidney disease, nephrosclerosis, pyelonephritis, interstitial nephritis

Different stages include diminished renal reserve, renal insufficiency, overt renal failure, end stage renal disease

Diminished renal reserve

GFR 35-50% of normal, BUN normal, patient asymptomatic

Renal insufficiency

GFR 20-35% of normal, azotemia, uremia, anemia, hypertension, polyuria, nocturia

Overt renal failure

GFR <20-25% of normal, edema, metabolic acidosis, hypocalcemia

End stage renal disease

GFR <5% , terminal stage uremia

Nephrotic Syndrome

Massive proteinuria (>3.5gm/24 hr)

hypoalbuminemia (plasma albumin <3gm/dL)

hypercoagulable state - loss of antithrombin III (breaks up thrombin and coag clotting factors)

generalized edema

Hyperlipidemia and lipiduria (oval fat bodies in urine)

Nephritic Syndrome

Hematuria (RBC and red cell casts)

Oliguria (rarely anuria)


Hypertension (classically transient)

some proteinuria, slight edema

Minimal change disease (Lipoid nephrosis)

Most common cause of NEPHROTIC syndrome in CHILDREN (60% in children, 10% adults), peak incidence 2-6 years

sometimes follows a respiratory infection or routine prophylactic immunization, can be associated with Hodkins disease and other lymphomas and leukemias in adults

Can follow NSAID therapy

Glomeruli are essentially normal in appearance, proximal tubule cells often laden with lipid reflecting tubular reabsorption of lipids that pass through diseased glomeruli

EM - GBM normal, uniform and diffuse loss of foot processes of visceral epithelial cells, may see vacuolization of epithelial cell cytoplasm and villous hyperplasia, no electron dense deposits

No immunoglobulin or complement deposits

Clinical - renal function normal, no hypertension or hematuria, highly selective proteinuria (albumin), Most children (>90%) respond rapidly to steroids. Overall excellent prognosis

Focal Segmental Glomerulosclerosis

Most common cause of NEPHROTIC syndrome in adults, any age can be affected.

Can occur idiopathic (10-15%) (more common in black and hispanic, questionable shared spectrum with minimal change disease) -

secondary to glomerular scarring in other forms of focal glomerulonephritis, loss of renal mass,

secondary to HEROIN abuse, HIV, infection, obesity, inherited mutations of podocyte proteins (podocin, alpha actinin), linked to chromosome 19, response to glomerular ablation nephropathy

nonselective proetinuria, more likely hematuria, reduced GFR, hypertension, and poor response to steroids. Primary glomerular lesion is visceral epithelial damage.

LM - Focal (not all glomeruli), segmental (portion of glomerulus). Usually initially involves juxtamedullary glomeruli. Sclerotic segments - collapse of basement membranes, increase in matrix and deposition of hyaline masses often with lipid droplets and foam cells. Normal glomeruli appear normal or increased mesangial matrix and mesangial proliferation, often hyaline thickening of afferent arterioles - may be missed if dont have enough glomeruli in specimen

EM - sclerotic and nonsclerotic areas show diffuse loss of foot processes and pronounced, focal detachment of the epithelial cells with denudation of underlying GBM. (hallmark of FSGS)

IF - IgM and C3 present within sclerotic areas, also in mesangium (pathoma says no)

tip lesion only - good prognosis. Collapsing variant - very bad (idiopathic, or HIV-nephropathy - sclerosis of entire glomerulus and endothelial tubuloreticular inclusions on EM)

best histologic correlation to prognosis is extent of sclerosis

children have better prognosis, little tendency of spontaneous remission. Responses to corticosteroid therapy are variably.

20% of pts follow rapid course leading to renal failure within 2 years. Recurs in 25-50% of transplant patients

Membranous Glomerulonephritis

85% are primary (idiopathic), 15% secondary (underlying malignant tumors (colon, lung, melanoma), SLE, HEP B and HEP C, infections (syphilis, schistosomiasis, malaria), metabolic disorders)

40% progress to renal insufficiency and 10% to renal failure

thought to be auto immune disease, but poor response to immunosupression

Immunecomplex mediated, accumulate on subepithelial side of basement membrane, no cellular proliferative or inflammatory response

LM: uniform, diffuse thickening of glomerular capillary wall with?without spikes (BM laid down between dense deposits). Eventually becomes sclerotic or hyalinized

EM: Dense deposits located between GBM and epithelial cell, BM material is laid down between deposits producing SPIKES - best seen on silver stain (deposits do not take up silver)
IF: even, diffuse, granular deposits of IgG and sometimes C3 along GBM, sparing mesangium

clinical - insidious onset, usually indolent course, nonselective proteinuria which DOES NOT RESPOND WELL TO STEROIDs.

Progression is associated with increased glomerular sclerosis, increased BUN, decreased in severity of proteinuria and development of HTN. WOmen and children better prognosis, only about 10% die or progress to renal failure within 10 years. rull out secondary causes

Membranoproliferative Glomerulonephritis

membrano - thickened capillary loops
proliferative - glomerular cell proliferation

accounts for 10-20% of NEPHROTIC syndrome in adults and children, principal presentation of nephrotic syndrome with nephritic component manifest by hematuria and less common proteinuria, Slowly progresses but doesnt remit, 50% with chronic renal failure in 10 years

High recurence rate in transplants
Type I, Type II - different etiologic mechanisms but similar clinical and LM findings

can be secondary to - chronic immune complex disease (SLE, HepB, HIV), partial lipodystrophy, A1AT deficiency, Malignant disaes, hereditary complement deficiencystates

LM: glomeruli are large and hypercellular, hypercellularity is produced by increase numbers of mesangial cells as well as infiltrating leukocytes and parietal epithelial cells. Changes impart lobular appearance to glomeruli. GBM thickened, glomerular capillary wall often shows double countour or tram track appearance - silver stain

Clinical - seen in older children/young adults. Nephrotic range proteinuria with nephritic component (hematuria), slowly progressive. 50% develop chronic renal failure within 10 years. Treated with corticosteroids and immunospuressive agents. High incidence of recurrence in transplant pts (type II)

Type I membranoproliferative glomerulonephritis

Majority of cases, associated with HBV and HCV, more associated with tram track

Immune comple mediated. Subendothelial and mesangial immune complexes which incite a proliferative/inflammatory response. Both classical and alternative complement pathways. Classification as idiopathic requires ruling out underlying causes

LM: glomeruli are large and hypercellular, increased number of mesangial cells and infiltrating leukocytes/parietal epithelial cells. Impart lobular appearance to glomeruli. GBM is thickened, glomerular capillary wall often shows double contour or tram track appearance - silver stain

EM - SUBENDOTHELIAL electron dense deposits, occasionally mesangial and subepithelial deposits

IF - C3 deposited in granular pattern along glomerular capillary walls and in mesangium

Clinical - seen in older children/young adults. Nephrotic range proteinuria with nephritic component (hematuria), slowly progressive. 50% develop chronic renal failure within 10 years. Treated with corticosteroids (POOR RESPONSE) and immunospuressive agents. High incidence of recurrence in transplant pts (type II)

Type II membranoproliferative glomerulonephritis

activation of alternative complement pathway. Decreased levels of factor B and properidin Circulating antibodies are directed at early alternitive pathway components, more than 70% have circulating Ab termed C3nephritic factor (C3neF) binds to C3 convertase. Results in persistent C3 degradation and hypocomplementemia (C1 and C4 normal levels) (C3a and C3b)

LM: glomeruli are large and hypercellular, hypercellularity is produced by increase numbers of mesangial cells as well as infiltrating leukocytes and parietal epithelial cells. Changes impart lobular appearance to glomeruli. GBM thickened, glomerular capillary wall often shows double countour or tram track appearance - silver stain. Sometimes see intramembranous ribbon like deposits

EM: dense homogenous deposits in lamina densa (dense deposit disease)

IF - C3 deposits in irregular granular/linear foci in basement membraneon either side, but not within dense deposits C3 present in mesangium in circular aggregates. IgG, C1q and C4 are absent

Clinical - seen in older children/young adults. Nephrotic range proteinuria with nephritic component (hematuria), slowly progressive. 50% develop chronic renal failure within 10 years. Treated with corticosteroids and immunospuressive agents. High incidence of recurrence in transplant pts (type II)

Diseases associated with Nephrotic presentatio

minimal change disease

focal segmental glomerulosclerosis

membranous glomerulonephritis

membranoproliferative glomerulonephritis

Acute Proliferative Glomerulonephritis

post streptococcal (most common), post infectious (persistent infecitons, infective endocarditis, deep seated abscess, infected shunts)

usually appears 1-4 weeks after group A beta-hemolytic strep infection (M PROTEIN) of pharynx or skin, commonly age 6-10 but can occur any age. Antibody mediated (certain strains of GAS 12,4 and 1), serum complement low, serologic increase in ASO titers

classic picture is child who develops malaise, fever, nausea, oliguria, and hematuria 1-2 weeks after sore throat. Urine contain red cells and casts, small amount protein, Can show peri orbital edema and hypertension (Nephritic syndrome picture)

LM: diffuse glomerular hypercellularity due to leukocyte inflitration and proliferation of endothelial, mesangial, and sometimes epithelial cells and endothelial swelling. Obliteration of capillary lumen. Also typially fibrin deposits in capillary lumens and mesangium, interstitial edema and inflammation, red cell casts in tubules

IF: focal granular deposits of IgG, IgM, and C3 in mesangium and along basement membrane

EM: discrete amorphous, electron dense deposits on epithelial side of GBM, producing humps. Deposits represent antigen-antibody complexes, may also see subendothelial and intramembranous deposits as well as swelling of endothelial and mesangial cells

most cases remit spontaneously, ret develop rapidly progressive glomerulonephritis or chronic glomerulonephritis, adults more common to develop rapidly progressing glomerulonephritis

Rapidly Progressive Glomerulonephritis

various etiologies, rapid and progressive loss of renal function with severe oliguria and death in weeks to months. 50% idiopathic

serum analysis for anti GBM, anti nuclear Ab and ANCA helpful in diagnosis of subtypes

I - anti GBM antibody 20%
II - Immune complex 25%
III - pauci-immune (anca, wegener) 50%

Gross - kidney enlarged, pale, often petechial hemorrhages

LM: crescent formation in glomeruli (fibrin and macrophages), formed by proliferation of parietal cells and migration of monocytes, macrophages and sometimes neutrophils and lymphocytes into Bowmans space. Fibrin also important component

IF: depends on etiology

EM: ruptures in GBM, may see electron dense deposits, cells which make up crescents

Clinical - rapid decline in renal function, frequently severe oliguria or anuria, hematuria, red cell casts in urine, moderate proteinuria, hypertension and edema. treatment includes plasmapheresis, steroids, cytotoxic agents. Some require dialysis or transplant despite therapy

Type I rapidly progressive glomerulonephritis

20% of RPGN

antibody against GBM, some patianets have cross reaction with pulmonary alveolar BM - pulmonary hemorrhage with renal failure - Goodpastures Syndrome - antigen is peptide within noncollagenous portion of colagen type IV


can treat with plasmapheresis

Gross - kidney enlarged, pale, often petechial hemorrhages

LM: crescent formation in glomeruli, formed by proliferation of parietal cells and migration of monocytes, macrophages and sometimes neutrophils and lymphocytes into Bowmans space. Fibrin also important component

IF: linear IgG and C3 in BM

EM: ruptures in GBM, may see electron dense deposits, cells which make up crescents

Clinical - rapid decline in renal function, frequently severe oliguria or anuria, hematuria, red cell casts in urine, moderate proteinuria, hypertension and edema. treatment includes plasmapheresis, steroids, cytotoxic agents. Some require dialysis or transplant despite therapy

Type II rapidly progressive glomerulonephritis


complication of immune complex nephritis of various etiologies - post infectious, SLE, IGA nephropathy, Henoch-Schonlein purpura - need to treat underlying disease

Gross - kidney enlarged, pale, often petechial hemorrhages

LM: crescent formation in glomeruli, formed by proliferation of parietal cells and migration of monocytes, macrophages and sometimes neutrophils and lymphocytes into Bowmans space. Fibrin also important component

IF: granular deposition - lumpy bumpy, subendothelial

EM: ruptures in GBM, may see electron dense deposits, cells which make up crescents

Clinical - rapid decline in renal function, frequently severe oliguria or anuria, hematuria, red cell casts in urine, moderate proteinuria, hypertension and edema. treatment includes plasmapheresis, steroids, cytotoxic agents. Some require dialysis or transplant despite therapy

Type III rapidly progressive glmoerulonephritis

50% of RPGN - pauci immune

lack of anti GBM or immune complex, antineutrophil cytoplasmic antibodies are present in serum (P-ANCA, C-ANCA)

can be idiopathic or related to systemic vasculitis (Wegeners, microscopic polyangitis), ANCA positive in 90% of idiopathic

Gross - kidney enlarged, pale, often petechial hemorrhages

LM: crescent formation in glomeruli, formed by proliferation of parietal cells and migration of monocytes, macrophages and sometimes neutrophils and lymphocytes into Bowmans space. Fibrin also important component

IF: negative
EM: ruptures in GBM, may see electron dense deposits, cells which make up crescents

Clinical - rapid decline in renal function, frequently severe oliguria or anuria, hematuria, red cell casts in urine, moderate proteinuria, hypertension and edema. treatment includes plasmapheresis, steroids, cytotoxic agents. Some require dialysis or transplant despite therapy

IgA Nephropathy (Bergers Disease)

Most common primary glomerulonephritis world wide. Primary disease as component of Henoch-Schonlein purpura or secondary to liver disease, inflammatory bowel disease, celiac disease and HIV

characterized by mesangial IgA deposits and IF necessary for definitive diagnosis (only IgA1 subclass forms the nephritogenic deposits) generation of nephritogenic IgA antibodies derived from mucosal antigen exposure than form immune complexes in circulation that deposit in glomeruli and mediate inflammation

EPISODIC HEMATURIA, comes and goes with infection due to mucosal infection

Clinical - Older children and young adults most common, Extremely variable Present with gross or microscopic hematuria during or shortly after URI. Hematuria lasts for several days and then subsides with recurrence every couple months. Slow progression to renal failure in 15-40% of pts, common recurrence in transplants (20-60%).

Worse prognosis - old age, heavy proteinuria, hypertension, crescent formation, vascular sclerosis

LM: very considerably, Glomeruli may be normal, or show mesangial widening and proliferation, can be segmental. Rarely crescentic glomerulonephritis

IF - MESANGIAL DEPOSITION of IgA, often codeposit with C3, properdin and low intensity IgG or IgM

EM: mesangial or paramesangial electron dense deposit

Henoch-Schonlein Purpura

Systemic IgA-mediated vasculitis. Purpuric skin lesions involving extensor surfaces of arms and legs as well as buttocks, abdominal pain, bleeding, vomiting, non migratory arthralgia

and renal abnormalities (gross or microscopic hematuria, proteinuria, or nephrotic syndrome, IgA deposited in glomerular mesangium)

do not need to have all symptoms, most common in children 3-8

LM: Renal lesions vary from mild focal to diffuse mesangial proliferation, may see crescent formation

IF: deposition of IgA and occasionally IgG and C3 in mesangial region

Benign Familial Hematuria

Thin basement membrane disease

fairly common disorder manifested clinically by familial asymptomatic hematuria, anomaly has been traced to genes encoding alpha 3 and 4 chains of type IV collagen

basement membrane is 150-250 nm (300-400 is normal) seen best by EM

asymptomatic hematuria, occasional mild proteinuria, renal function is normal, found on routine urinalysis, excellent prognosis

patients homozygous for defective gene resemble autosomal recessive Alports syndrome, may progress to renal failure

Alport syndrome

recurrent micro or macrohematuria, varying proetinuria, sensorineural deafness, cataracts, lens dislocation, slow progression to renal failure

males affected more, most are X linked but also AD and AR

defect in alpha 5 chain of collagen type IV, leading to abnormal synthesis of glomerular basement membranes

clinical - gross of microscopic hematuria, usually appear at 5-20 years with renal failure between 20-50 years

LM: mesangial hypercellularity and/or scarring, usually mild, tubular atrophy and interstitial fibrosis, foam cells

EM :GBM shows irregular foci of THINNING AND SPLITTING and lamination of lamina densa. not specific for Alports syndrome, most widespread and pronounced in pts with disorder

Chronic glomerulonephritis

End stage glomerular disease, casued by types (poststreptococcal, RPGN, MGN, FGS, MPGN, IgA)

most common causes are DM, hypertension, glomerular disease

Gross - shrunken kidney, granular surface, increase peripelvic adipose tissue

eventually see hyaline obliteration of glomeruli, transforming into acellular eosinophilic structures, may see arterial sclerosis, tubular atrophy, interstitial fibrosis, lymphocytic infiltration

develops insidiously and slowly progresses to death, most patients have hypertension

Clinical -
Uremia (nausea, anorexia, pericarditis, platelet dysfunction, encephalopathy with asterixis, deposition of urea crystals in skin).

Salt an water retention with resultant hypertension,

Hyperkalemia with metabolic acidosis (excretion problems),


hypocalcemia (decreased hydroxylation of vitamin D by PCT cells and hyperphosphatemia)

Renal osteodystrophy (hyperparathyroidism due to hypocalcemia (ostea fibrosis cystica, osteomalacia (cannot mineralize new bone), osteoporosis (slowly leak Ca)

treatment involves dialysis or renal transplant
Cysts develop with shrunken end stage kidneys during dialysis, increased risk for Renal cell carcinoma

Systemic Lupus Erythematous

kidney involved in 60-70% of cases,, 50% have glomerulonephritis

classifications I - normal histo
II - mesangial lupus glomerulonephritis
III - focal proliferative glomerulonephritis
IV - diffuse proliferative glomerulonephritis
V - membranous glomerulonephritis

IF - mesangial and peripheral granular IgG, IgA, IgM, and complement

EM - electron dense deposits in mesangium, intramembranous, subepithelial and subendothelial, all types show mesangial deposits

one of most common causes of death in lupus patients

Diabetic Glomerulosclerosis

major cause of renal morbidity and mortality, faliure occurs in 30-40% DM I and 5-10% DM II

two processes - metabolic defect from advanced glycosylation end products, produce GBM thickening and increased mesangial matrix. Hemodynamic effects - glomerular hypertrophy whihc leads to glomerulosclerosis

LM: BM thickening, diffuse or nodular glomerulosclerosis, ovoid hyaline masses in periphery of glomeruli, Tubules may show artophy, thickened BM, interstital fibrosis, hyalinization of arterioles

Glomerular efferent arteroiole more affected - leads to high glomerular filtration pressure, hyperfiltration leads to microalbuminemia (ACE inhibitors slow progression of hyperfiltration induced damage)

eventually progresses to nephrotic syndrome - sclerosis of the mesangium with formation of Kimmelstiel-Wilson nodules

IF: diffuse linear staining of GBM and tubular basement memrbanes for igG, albumin and sometimes IgM and C3

EM: thickened gbms, increased mesangial matrix

CLinical - microalbuminuria and increased GFR, then proteinuria that increases to nephrotic range. Loss of GFR leading to end stage renal disease. Often have hypertension

Renal amyloidosis

typically from light chains or amyloid A deposits

involved are AL amyloidosis, light chain deposition disease and light chain cast nephropathy

LM:homogeneous, amorphous pink deposits - changes in glomerulus, BV walls, tubule basement membranes and within tubule lumens - congo red stain (apple green birefrigence)

IF - kappa and light chains

EM - non branching, randomly oriented twisting fibrils, most often in mesangium

Clinical - proteinuria or the nephrotic syndrome with varying degress of renal insufficiency

Acute tubular Necrosis

Most common cause of acute renal failure (50% of ARF in hospitalizations

destruction of tubular epithelial cells and loss of renal function,

critical events - tubular injury leading to leakage of tubular fluid into interstitium and tubular obstrution with cast like material. Persistend and severe disturbances in blood flow (arteriolar vasoconstriction producing reduction in cortical blood flow, abnormal glomerular permeability)

2 types: ischemia - reversible lesion arising in settings of inadequate blood flow to kidneys

- toxic - direct tubular insult by drugs and toxic agents (aminoglycosides, cephalosporings, amphotericin, metals, organic solvents and glycols, insectisides, pigment , contrast agents, antineoplastic agents, mushroom poisoning)

Gross: kidneys may show icnreased size and weight

LM: ischemic - focal tubular epithelial necrosis at multiple points along nephron (PCT and loop of henle), hyaline casts, dialted with flattening of epithelium, loss of PAS positive brush border, interstitial edema and inglammation, leukocytes in vasarecta.

Toxic - PCT most commonly affected, typically non specific but some individual specific effects (Mercurary - large acidophilic inclusions, CCL4 - neutral lipids in injured cells, Ethylene glycol - marked balooning or hydropic degeneration - calcium oxylate crystals)

Three clinical stages (highly variable)
- initiation - 36 hrs, slight decrease in urine output
- maintence - worsening relan function, uremia, oliguria, hyperkalemia
Recovery - increase in urine volume, sometimes hypokalemia, typically recover if reach this stage

toxic cases recover 95% of time, ischemic with shock related may be 50% or better

Tubulointerstitial Nephritis

Disorders with diverse causes and different mechanisms

Acute - acute onset with rapid decline, interstitial edema, leukocyte infiltrate and focal tubular necrosis, caused by infections, drug reactions, associated with systemic disorders and uveitis (NSAIDS, penecillin, diuretics)

Chronic - insidious onset, slow decline inrenal function, mononuclear cell infiltrate, interstitial fibrosis and widespread tubular atrophy, causes include infections, drug reactions, obstruction, systemic disaeses, hereditary diseases, neoplasia, vascular


85% of cases casued by gram neg bacteria (E coli, Klebsiella, Enterobacter) - hematogenous spread (less common), or ascending from lower urinary tract, factos include obstruction, refluc, instrumentation, diabetes, immunosupression, and pregnancy

increased risk with vesicoureteral reflux

preent with fever, flank pain, WBC casts, and leukocytosis in addition to cystitis symptoms

Acute pyelonephritis

Acute supparative inflammation of kidney caused by infection

Flank pain, fever, dysuria, pyuria, bacteruria

Gross - Grayish white spots of inflammation and/or abscesses

LM - patchy interstitial inflammation, tubular necrosis with tubular abscesses, Glomeruli typically uninvolved escept in fungal infections or severe disease

3 main complications
- papillary necrosis - mainly diabetics and obstruction, distal 2/3 of renal papillae necrotic
- pyonephrosis - suppurative exudate fills renal pelvis, calyces, ureter, usually in complete obstruction
- preinephritis abscess - extension of supparative inflammation through capsule into perinephritic tissue

Patients often present with costovertebral angle tenderness and systemic evidence of inection, fever, malaise, bladder and urethral irritation, dysuria, treated with antibiotics, scarring and deformation occur upon healing

Chronic Pyelonephritis

chronic tubulointerstitial renal disorder in which chronic tubulointerstitial inflammation and renal scarring are associated with patholgic involvement of calyces and pelvis

chronic obstructive - predisposes to repeat infection

reflux nephropathy - most common, superimposition of UTI on vesicouretheral reflux and intrarenal reflux

Gross - irregular scarring, coasrse discrete corticomedullary scar overlying blunt deformedcalyx, scarring at upper and lower poles are characteristic of vesicoureteral reflux

microscopic - tubular atrophy, dilation, dilated tubules may be filled with colloid casts (thyroidization), chronic interstitial inflammation and fibrosis, inflammtion and fibrosis of calyceal mucosa, waxy casts

Insidioius onset of may present with manifestations of acute recurrent pyelonephritis. Can see proteinuria, pyuria or baxcteruria. Some develop FSGS which proceed to end stage renal disease

Drug induced Interstitial Nephritis

Common cause of acute renal failure - beta lactam antibiotics, NSAIDS, diuretics

3 ways of injury
- interstitial immunological rxn - acute hypersensitivity nephritis, begins about 2 weeks after exposure, fever, eosinophilia, rash, abnormalities, interstitial edema and infiltration by mononuclear cells including eosinophils. May see tubular necrosis and regeneration
- may cause acute renal failure
- subtle but cumulative injury over time leads to renal insufficiency (papillary necrosis and chronic tubulointerstitial nephritis)

drugs act as hapten binding component of tubular cells - become immunogenic. Injury mediated by IgE and/or T cell mediated immune rxn.

Analgesic Abuse Nephropathy

chronic renal disease, Phenacetin, acetominophen, aspirin, caffeine, codeine

chronic tubulointerstitial nephritis and renal papillary necrosis

more common in females, pts with recurrent headaches and muscle pain

Clinical- headaches, anemia, GI, hypertension, small percentage develop trasitional papillary carcinoma of the renal pelvis

Urate nephropathy

- acute uric acid nephropathy - precipation of uric acid crystals in tubules, mainly collecting ducts. Obstruction of nephrons and development of acute renal failure. Common in patients receiving chemo for leukemias and lymphomas

- chronic or gouty - deposition of monosidum urate crystals, tubular obstruction causes cortical atrophy and scarring

nephrolithiasis - uric acid stones

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