IHC: CK7, CK20, CDX2, Ca 19.9 (Neg: Ca-125)

Molecular: KRAS common (No BRAF, No assw BRCA 1/2)

Assw myeloproliferytive neoplasms (Idiopathic myelofibrosis MC, CML)

HP: megakaryotypic atypia

SFT

 mesenchymal chondrosarcoma

synovial sarcoma

Cytokeratins, EMA (neg: CD34, WT1)

CD99 +

Vimentin/Cytokeratin Co-Expression

Carcinomas?

Sarcomas?

Vimentin/Cytokeratin Co-Expression

Carcinomas? RCC, Endometrial, Serous ovarian, Thyroid (papillary, anaplastic), Mesothelioma (biphasic),

Sarcomatoid (spindle cell carcinoma)

Sarcomas?

Synovial sarcoma, DSRCT, Malignant Rhabdoid Tumor, Epithelioid sarcoma, Epithelioid angiosarcoma

Ewing Sarcoma

Synovial sarcoma

Mesenchymal chondrosarcoma

DSRCT (variable)

Melanoma (variable)

Desmoplastic Small Round Cell Tumor IHC?

Epithelial (CAM 5.2, AE1/AE3, EMA)

WT1

NSE

Desmin (dot-like)

Myogenin/MyoD1 NEGATIVE

Neuroblastoma IHC?

+: NSE, Neurofilament, CD56, NCAM, Synaptophysin, chromogranin

Negative: CD99, CK (Small cell carcinoma), CD45, S100 (melanoma), MyoD1/myogenin

1.Histiocyte predominant villitis (villous Hofbaeur cells)

2. proliferative endovasculitis (concentric mural sclerosis of stem arterieis)

3.Necrotizing periphlebitis of umbilical cord (necrotic cell debris and eosinophilic material surrounding the umbilical vein)

• Recurrent bacterial infections

• Inflammatory lesions lack neutrophils

• But, ↑ neutrophils in the circulation

• ↓ Beta chain of CD11/CD18 integrin on polys

• Neutrophils can roll but do not stick

• Transfuse patients with normal neutrophils and

they can transmigrate

Defect in chemotaxis and lysosomal degranulation into

phagosomes

• Defects in cells w granules

• Such as melanosomes  --- oculocutaneous albinism

• Lymphoproliferative disorders

• Defect in NADPH oxidase system

• Marked decrease in ability to kill microorganisms

• Young, men with infections and granulomas at autopsy

• Test: Nitroblue tetrazolium

Decay accelerating factor

(Cannot turn off complement)

-MC defect: B cell progenitor kinase, long arm (Xq22)

-Tx: IVIG

-CD19 positive B cells are absent in peripheral blood

-Recurrent upper respiratory infections, Giardia infestations

-Presents approximately 2-6 months of age (after maternal antibody wanes)

• Good:
• t(12;21) (p13;q22); TEL/AML1
• Hyperdiploid > 50
• Age 4-10

• Hypodiploid
• t(9:22) (q34;q11.2); BCR/ABL
• 11q23; MLL
• t(1;19) (q 23;p13.3); PBX/E2A

Ewings T(11;22) EWS/FLI-1
           T(21;22) EWS/ERG
          
DSRCT T(11;22) EWS/WT-1

Clear cell sarcoma T(12;22) EWS/ATF-1
                                        EWS/TEC\

Myxoid liposarcoma T(12;16) EWS/CHOP

                                         EWS/FUS

Alveolar soft part sarcoma T(X;17) ASPL/TFE3

Synovial sarcoma T(X;18) SYT/SSX1
                                      SYT/SSX2

Rhabdomyosarcoma T(1;13) PAX7/FKRH
                               T(2;13) PAX3/FKRH

DFSP T(17;22) CALIA1/PDGFß

LG fibromyxoid sarc T(7;16) FUS/CREB

Tumor Suppressor Genes

•  Rb gene (retinoblastoma) 13q14
•  p53 gene (G1 arrest apoptosis) 17p13.1

• APC gene (adenom. polyposis coli) 5q21
• NF-1 gene (neurofibromatosis) 17q11
• NF-2 gene (neurofibromatosis) 22q12
• DCC gene (deleted in colon CA) 18q21
• WT-1 gene (Wilms’ tumor) 11p13
• VHL gene (von Hippel-Lindau) 3p25

Epstein-Barr Virus
• Burkitt’s Lymphoma, especially endemic
• PTLD
• Nasopharyngeal CA
• Hodgkin lymphomas
• Primary effusion lymphoma
• Angioimmunoblastic T cell lymphoma
• Aggressive NK/T cell lymphoma

Transient Hypogammaglobulinemia ofInfancy

 Presents approximately 5-6 months
 IgG low, IgM and IgA may be normal
to low
 Recurrent upper respiratory infections
 CD19 positive B cells ARE present
 Hypogammaglobulinemia may last up
to 2 years.
 Cause is undefined

Selective IgA Deficiency

 Most common primary immune deficiency. Occurs in 1in 700.
 IgA levels <5 mg/dl, IgG and IgM are usually normal.
 A concomitant IgG2 deficiency may be present.

 Patients are at risk for an allergic, nonhemolytic
transfusion reaction if antibodies
to IgA are produced. This may give a serum
sickness type of reaction to a whole blood or
plasma transfusion, or an Arthus (IgG) or
anaphylactic (IgE) type of reaction to a
subsequent transfusion.

Common Variable Hypogammaglobulinemia

 mc adults (any age)
 ~ IgG subclass deficiency but more severe
 May be a B or T cell defect
– Th1 imbalance with elevated IL12 and gamma interferon
– Autosomal recessive, ICOS defect

X-linked Hyper IgM Deficiency

 first year of life
 IgM levels are normal to elevated
(100-1000 mg/dl)
 IgG, IgA and IgE levels are low.
 CD4 cell increase may occur

Hyper IgM, 2

gene (Xq26 ) coding for the T cell protein, CD154 (CD40 Ligand)molecule.
– CD154 binds to CD40 initiating class switching
in B cells
– This defect prevents T cells from inducing B
cells to undergo a class switch. Thus the B cells
produce IgM, without switching to another
isotype.
 Autosomal recessive form does exist, involving the TNFRSF5 gene

DiGeorge Syndrome

(Congenital thymic aplasia or hypoplasia)

   quickly after birth
   third and fourth pharyngeal pouches (low set ears, notched ear pinnae).
 Two candidate genes- (Tbx1) chromosome 22 missing and one gene (Crkol, 10p13)

 Hypoparathyroidism and congenital heart disease
 CD3 positive T cells levels are low/absent
 Opportunistic infxns:Pneumocystis, Candida,viruses

Association

Adrenal cortical adenomas Small cell lung
CA from excess ACTH (cortisol)

Association

Adrenal cortical adenomas producing
excess aldosterone (hypernatremia,
hypokalemia, HTN)

Fibrosarcoma

Solitary fibrous tumor

HCC

[insulin, insulin like GF]

• Renal cell carcinoma

• Cerebellar hemangioblastoma

• HCC

• Leiomyoma

• Solitary fibrous tumor

Gastric Ca

Lung Ca

Uterine Ca

• 1 – NF1 gene (17q)

• 2 – NF2 gene (22q)

• Multiple NFs (plexiform NFs),
schwannomas (bilateral acoustics in 2),
gliomas, pheochromocytomas, somatostinomas

Tuberous Sclerosus

Chromosomes 9 & 16
• Cortical tubers, sclerosis, SEGAs, cardiac
rhabdomyomas, pulm LLM, AMLs, sebaceous
adenomas, ash green patches, subungual
fibromas

von Hippel Lindau
• 3p25
• RCC (bilateral), papillary cystadenoma of
pancreas, pheos
• Cavernous hemangiomas/hemangioblastomas of:
• Retina
• Cerebellum/brainstem
• Hemangiomas/cysts of:
• Pancreas
• Skin
• Liver
• Kidney

Gardner’s Syndrome

• Loss of regulation
• FAP & jaw osteomas, desmoids, cysts of skin
• Soft tissue tumors (desmoplastic fibromas)

Cowden Syndrome
• 10q23 (same as MEN II – MEN I 11p13)
• 9q22.3
• FAP with increased risk of breast, thyroid CA
• Trichilemommas

• Hamartomatous polyps, mostly small bowel
• Oral mucocutaneous hyperpigmentation
• SCTAT/Large cell calcifying Sertoli tumors
• Adenoma malignum of cervix
• Increased risk of breast, lung, ovary, pancreas
and uterine CA; rare malignant transformation in
GI tract

• FAP with brain tumors (astrocytomas – GBMs)
• HNPCC genes
• DNA mismatch/repair defect

• FAP (hamartomatous polyps) with skin & nail
changes

• 11p13
• Parathyroid adenomas/hyperplasia
• Pituitary adenomas/hyperplasia
• Pancreas adenomas/carcinomas/hyperplasia
• Adrenal hyperplasia
• Thyroid C-cell hyperplasia

• MEN II (Sipple Syndrome)
• 10q12 (RET oncogene)
• Parathyroid adenomas/hyperplasia
• Adrenal pheochromocytomas
• Thyroid medullary carcinomas

• MEN IIB/III
• MEN IIA with mucocutaneous ganglioneuromas
and marfanoid habitus (RET (different locus)

-Lymphocytes, macrophages and eosinophils

-No neutrophils
(polys indicate ischemia, antibody mediated rejection or infection.)

-No plasma cells (they indicate a Quilty lesion or PTLD)

Myocarditis General Causes

– Infections

– Cardiac allograft rejection

– Collagen vascular diseases

– Drug hypersensitivity

– Sarcoidosis

If not completely excised it may recur and/or develop atypia. Some consider it a form of low-grade carcinoma. The epithelial cells are characteristically S100 positive and ER negative.

NOmyoepithelial layer and should never invade nerves.

sclerosing adenosis

relative risk of IDC?

BpAg1 and BpAg2

(hemidesmosomes)

(also in pemphigus gestationis, cicatricial pemphigoid)

Epidermolysis bullosa acquisitiva

Bullous SLE

Myocarditis

Viral

Bacteria

Parasites

Myocarditis

Viral - Coxsackie A & B, CMV, HIV

Bacteria - Lyme, Diphteria

Parasites - Chagas, Toxoplasmosis, Trichinosis

Hypersensitivity myocarditis
 Interstitial infiltrate of macrophages,
eosinophils
 No or little necrosis
 No granulomas, but multinucleated cells
may be present
 Fewer clinical manifestations than other
forms of myocarditis
 Associated with long list of drugs
(classically, methyldopa)

Dilated Cardiomyopathy
– Progressive cardiac hypertrophy, dilation,
and systolic dysfunction (pump failure)
 Causes
– Postviral myocarditis (late stage)
– Postpartum
– Alcohol toxicity
– Familial
– Drug (Adriamycin)
– Idiopathic

Arrthymogenic RV Dysplasia

-Uncommon, familial form that affects
young adults causing sudden death
 RV is markedly thinned & replaced by
fat

Restrictive Cardiomyopathy

Gross
– Varies depending on cause
– Atrial dilation (bilateral)
– Endocardium thickened and opaque
– Valvular thickening
– Mural thrombi may be present
 Microscopic
– Dense endocardial fibrosis, extending into
subendocardial myocardium

X-linked recessive form of sphingolipidosis due to
deficiency of alphagalactosidase A
 angiokeratomas, renal insufficiency & cardiac
failure
 Histology: vacuolated myocytes
 EM shows intralysosomal dense lamallae with
concentric or packed arrangment (Zebra bodies)

Adriamycin:
– 1.7% incidence of toxicity
– Grading scheme based on
sarcotubular dilatation
(vacuolization) and
myofibrillar loss:
– process all for EM

 Cutaneous & cardiac myxomas
 Spotty skin pigmentation (lentigines & blue nevi)
 Endocrine overactivity – Adrenal, testicular,
thyroid & pituitary

 Multiple pulmonary chondromas
 GISTs of the stomach
 Extra-adrenal paragangliomas
 AD
 2p16

Most common primary cardiac tumor of infancy and childhood
May be isolated but >50% associated with TS
Eosinophilic, polygonal cells with large
glycogen-rich cytoplasmic vacuoles
with stranding “spider cells”

 IL-2 receptor gamma chain mutation
(Xq13); also affects receptors for IL-4, 7, 11
and 15.
 Adenosine deaminase deficiency (20q13,
AR)
 Thymic dysplasia- Nezelof’s syndrome
 Treatment- aggressive anti-microbial; bone
marrow transplant.

-shortly after birth to 6 months of age.
 Bacterial, fungal, viral and protozoan
infections.
 T, B, and LGL are low or absent

 Can be class I or class II deficiency
 Lack of either class I (rarer) or class II antigens on the lymphocyte surface.
 BMT may be helpful
 Autosomal recessive disorder
– Class 1 deficiency- TAP1, TAP2 genes
– Class II deficiency- MHC2TA, RFXANK genes

  first year of life
 X-linked disease
 Eczema, thrombocytopenia, recurrent
pyogenic infections
 IgE and possible IgA are elevated. IgM is
usually low
 T cells are present but with a reduced
response to mitogens.
 Defect is in a protein called WASP
(Xp11.22) (Wiskott Aldrich Syndrome
Protein)

 2-6 years
 AR disorder consisting of
ataxia, telangiectasias and recurrent sino
pulmonary disorder.
 IgA is often absent; IgE may be low. CD4
cells are reduced in numbers and function.
 Lymphoreticular malignancies common.
 Defect is in the  (ATM) on chromosome 11.
 Treat infections aggressively, no live or
attenuated vaccines.

 Defect in CD18 gene (21q22.23),
preventing proper LFA-1 adhesion molecule
formation. This molecule is important in
allowing neutrophils to migrate out of blood
vessels into the tissues.
 AR disease
 Recurrent soft tissue infections; impaired
wound healing.

 Presents by 2 years of age
 X-linked (2/3) or AR (1/3).
 Lymphadenitis, hepatosplenomegaly,
pneumonia are presenting symptoms.
 Diagnosis includes Nitroblue
tetrazolium reduction assay or newer,
flow cytometric assays

 Lupus or lupus like illness
 C3 deficiency may also include
recurrent encapsulated organism
infection

 C1 Esterase Inhibitor Deficiency
(Type 1)
– Functional and quantitative assays
available for C1INH

 Type 3- Factor XII mutation
– Factor XII SNP assay available

Molecular mimicry
– Exogenous Ag has similar structure to
self
– Examples
 Strep and rheumatic fever
 Mycoplasma and autoimmune hemolytic
anemia
 EBV peptide and Sm in SLE

Leukocyte Adhesion

Deficiency, Type I

Defect in CD18 gene (21q22.23),

preventing proper LFA-1 adhesion molecule

formation. This molecule is important in

allowing neutrophils to migrate out of blood

vessels into the tissues.

 Autosomal recessive disease

 Recurrent soft tissue infections; impaired

wound healing

 Multisystem inflammatory disease following

group A streptococcal pharyngitis.

 3% of patients with group A streptococcal

pharyngitis

 All 4 valves (MV > AV > TV > PV)

 Obliterated zona spongiosis by fibrosis and

neovascularization, no myxoid substance

 S. aureus – 

 S. epidermidis – 

 S. viridans – 

 Enterococci – 

 S. bovis – 

 Pneumococcus – 

 G negative – 

 Fungal – 

 S. aureus – IVDA

 S. epidermidis – prosthetic valves

 S. viridans – Sub acute

 Enterococci – normal/damaged valves

 S. bovis – colon CA

 Pneumococcus – alcoholics

 G negative – IVDA, DM,

immunocompromised

 Fungal – IVDA, immunocompromised

 5-10% of cases

 Prior treatment

 Fastidious organisms

– HACEK, mycobacteria

 Intracellular organisms

– Rickettsia, Q-fever, Whipple’s

 Hypercoagulable states

 Deposition of fibrin + platelets on

leaflets of cardiac valves.

 Thrombus on surface

 No microorganisms

 Lupus erythematosus

 Vegetations covering both sides of valve

surfaces

 Fibrinoid necrosis & inflammation

Presents by 2 years of age

 X-linked (2/3) or autosomal recessive

(1/3).

 Lymphadenitis, hepatosplenomegaly,

pneumonia are presenting symptoms.

 Diagnosis includes Nitroblue

tetrazolium reduction assay or newer,

flow cytometric assays

 C1 Esterase Inhibitor Deficiency

(Type 1)

– Functional and quantitative assays

available for C1INH

 Type 3- Factor XII mutation

– Factor XII SNP assay available

Strep and rheumatic fever

 Mycoplasma and autoimmune hemolytic

anemia

 EBV peptide and Sm in SLE

Autoantibodies

– ANA and anti-DNA- Kunkel, 1957

 ANA currently tested on HEp-2 cells (IFA)

or ELISA

 Anti DNA usually detected by Crithidia

luciliae (IFA) or ELISA (Farr type assay)

 Diagnosis

– 11 criteria

– 4 must be positive for diagnosis

 Anti Cyclic Citrullinated Peptide

 More sensitive and specific for RA

than RF

 Level may correlate with disease

activity

– 80% female, any age

– Raynaud’s phenomena and swollen digits

– Pulmonary disease

– Poly arthralgias

Anti-RNP (without anti-Sm)

– Dry mouth and eyes (SICCA)

– Keratoconjunctivitis

– Secondary to lymphocyte infiltration

Sjogren’s prepcipitins (ENAs)

– SSA (Ro)

– SSB (La)

– Not specific for SS