FLASHPATHH a z e m A l i

SARCOIDOSISH a z e m A l i

CLINICAL• Chronic, Multi-systemic, Granulomatous disease of

unknown origin

• Lung and hilar lymph nodes are involved in 90% of cases– Other affected organs include Eye, skin, bone, liver and spleen

• Common in adults between 20 – 40 years

• Common in females

• Common in blacks, Scandinavians– Rare in Asians

CLINICAL• General manifestations: variable

– Fever, fatigue, weight loss, night sweating• Lung: 90%

– Interstitial lung disease (dyspnea, cough, chest pain)• Lymph node: 90%

– LN enlargement– Commonly mediastinal and hilar lymph nodes, but can affect any LN

• Chest x-rays bilateral hilar lymphadenopathy is common finding• Liver and spleen: 20%

– Hepatosplenomegaly• Bone: 20%

– Circumscribed bone lesions by x-rays– Commonly phalangeal bones of the hands and feet

CLINICAL• Skin: 30 – 50%

– Erythema nodosum– Subcutaneous nodules

• Eye: 30 – 50%– Uveitis– Corneal opacities– Glaucoma– Dry eyes due to lacrimal gland involvement

• If sarcoidosis involves both lacrimal and salivary glands Mikulicz syndrome• Other organs: rare

– Heart: myocarditis and dilated cardiomyopathy– Skeletal muscle: myositis– Endocrine glands: hypofunction (especially pituitary glands)– Kidneys: tubulointerstitial nephritis– CNS: aseptic meningitis

CLINICALRadiologic staging of sarcoidosis• Stage 0: Normal chest X-ray

• Stage 1: Hilar/mediastinal adenopathy alone (good)

• Stage 2: Hilar/mediastinal adenopathy + interstitial pulmonary infiltrate (intermediate)

• Stage 3: Interstitial pulmonary infiltrate only (bad)

• Stage 4: End-stage fibrosis with honeycombing (poor)

CLINICALFate of sarcoidosis:• 65 – 70% recovery

– Either spontaneous or in response to steroids/immunosuppressive drugs– With minimal or no residual manifestations

• 20% progressive, permanent loss of functions– Pulmonary functions– Visual functions

• 10 – 15% death– Lung fibrosis and cor pulmonale (mainly) – Cardiac involvement– CNS involvement

PATHOGENESISMost probably autoimmune (helper T cells disorder)• Excessive accumulation of CD4+ T cells

– Marked increase in CD4/CD8 T-cell ratio (up to 15 : 1)• Increased levels of TH1-drived cytokines

– Such as IL-2 more T cells expansion– Also IFN-γ macrophage activation

• Increased levels of macrophage-drived cytokines– Such as IL-8, TNF, macrophage inflammatory protein 1α– Recruitment of more T cells and macrophages

TNF in particular is released at high levels by activated alveolar macrophages, and the TNF concentration in the bronchoalveolar fluid is a marker of disease activity

GranulomasFormation

GROSSLymph nodes:• Enlarged, firm, white (or black = anthracosis)• Mainly involve hilar/mediastinal lymph nodes

Lung:• No gross abnormalities• Focal lesions (up to 1 cm) within lung parenchyma

– Around bronchi and blood vessels• End-stage fibrosis and honeycombing

Other organs:• Either no gross abnormalities or focal lesions

MICROSCOPYGranulomas:• Well-formed and sharply circumscribed• Non-caseating

– Small foci of necrosis may be seen in some cases– Infections must be ruled out

• Composed mainly of epithelioid histiocytes• Also multinucleated giant cells and T lymphocytes

– Sarcoidosis granulomas are usually Naked• i.e. composed mainly of epithelioid macrophages, surrounded by minimal lymphocytes

• Chronic lesions heal by fibrosis– Start at periphery of granulomas (concentric fibrosis)– Later on totally replace it by hyaline scar

MICROSCOPY• Characteristic intracellular inclusions within the giant cells

– Non-specific (may be seen in other granulomatous diseases)1. Schaumann bodies:

– Laminated concretions– Composed of calcium and proteins

2. Asteroid bodies:– Eosinophilic Stellate inclusions

MICROSCOPY3. Hamazaki-Wesenberg bodies

– Oval, yellow-brown bodies– Represent large lysosomes with hemosiderin/lipofuscin– Related to extensive hemorrhage– Positive for (GMS and Ziehl-Neelsen stains !!)– Frequently appear to bud (simulating yeast !!)

4. Calcium oxalate– Irregular birefringent crystals– Difficult to be seen without polarization

MICROSCOPY• Lung

– Granulomas mainly follow the lymphatics• Involve bronchovascular bundle, interlobular septa and pleura

– Love the submucosa of bronchi & bronchioles• Easily caught by bronchoscopic biopsy

– End-stage complications:• Intestinal lung fibrosis• Pulmonary hypertension

– Abnormal calcification:• Metastatic “within normal tissues”• Dystrophic “within old fibrosis”

MICROSCOPY• Lymph nodes

– Granulomas cause total effacement of architecture

• Skin– Granulomas mainly involve the dermis / S.C fat

• Eye– Granulomas mainly involve the conjunctiva and lacrimal gl.– These are common sites for biopsy to confirm sarcoidosis

• Liver– Granulomas mainly involve the portal tracts

• Spleen– Granulomas mainly involve the white pulps

VARIANTSNecrotizing sarcoid granulomatosis• Very rare variant

• Extensive, confluent noncaseating granulomas– Form a large nodular collection of granulomatous inflammation

• Extensive vasculitis of pulmonary arteries and veins– Either by giant cells or granulomas within vessel wall

• Widespread necrosis of lung tissue– Either within granuloma or lung parenchyma supplied by diseased vessels

• Infections should be ruled out

• Grossly appears as circumscribed white nodules (+/- necrosis)

• Responds well to steroids / immunosuppressive drugs or surgical removal (Excellent prognosis)

CYTOLOGY• Noncaseating granulomas• Composed of aggregates of epithelioid histiocytes

– Nuclei are round, oval, curved (boomerang-shaped), or spindled– Cytoplasm is abundant– Cell border is indistinct

• Forming pseudo-syncytial aggregates• Also giant cells and lymphocytes

– Isolated multinucleated giant cells should prompta thorough search for granulomas

• Hypocellular or acellular In long standing cases– Due to extensive fibrosis

SPECIAL STUDIESLaboratory tests

• Elevated serum and urine calcium– Due to activation of vitamin D precursor by macrophages– Leading to metastatic calcification, dystrophic calcification, or stone

formation

• Elevated serum immunoglobulins (polyclonal)– Due to activation of B cells by hyperactive helper T cells

• Elevated serum angiotensin converting enzyme– Thought to be produced by epithelioid macrophages itself or by influencing

endothelial cells in the lung (the normal source of ACE) to produce more amount

SPECIAL STUDIESSkin Tests

• Kveim skin test– Inject skin with spleen extract from a known sarcoidosis patient– Positive test granuloma formation (4 – 6 weeks later)– Not commonly used

• due to lack of extract and longer duration to obtain results

• Anergy to other skin tests– such as Candida or tuberculosis purified protein derivative (PPD)

SPECIAL STUDIESMicrobiological tests

• Culture:– No organism

• Special stains:– Ziehl-Neelsen stain no mycobacteria– PAS and GMS stains no fungi

Do not misinterpret Hamazaki-Wesenberg bodies with TB of fungi

• Culture is negative

DIFFERENTIAL DIAGNOSISGenera l Categor ies o f

Granu lomas

Classic(Non-

necrotizing)Necrotizing(Caseating)

Necrobiotic

Suppurative Non-classic

DIFFERENTIAL DIAGNOSIS1. Classic (non-necrotizing):• Round aggregate of histiocytes

– Abundant cytoplasm (epithelioid)– Indistinct cell borders (syncytial growth)

• Giant cells are usually (but not always) present• Examples:

– Foreign body or particles (suture, beryllium)– Sarcoidosis– Infection (some cases are non-necrotizing)– Autoimmune (Crohn’s, hypersensitivity pneumonitis, primary biliary cirrhosis)– Drug reactions– Chronic granulomatous disease (rare)

Better to called it granulomatous inflammation (rather than granuloma) if syncytial aggregates of histiocytes/giant cells are in sheets (rather than in a discreet nodule)

DIFFERENTIAL DIAGNOSIS2. Necrotizing (caseating) granuloma:• Caseating:

– Cheese-like appearance– Macroscopic term only

• Necrotizing:– Microscopic counterpart to “caseating”

• Examples:– Infection (TB, fungus)– Sarcoidosis (minimal necrosis is allowed)– Necrobiotic granulomas (see later)

DIFFERENTIAL DIAGNOSIS3. Suppurative granuloma:• Granulomas with central collections of neutrophils• Examples:

– Cat scratch disease (Bartonella henselae)– Lymphogranuloma venereum (Chlamydia trachomatis)– Tularemia– Yersinia

• You should rule out Mycobacteria, Fungi at first

Coalescent abscesses in granulomas have been termed “stellate microabscesses”

DIFFERENTIAL DIAGNOSIS4. Necrobiotic granuloma:• Nuclear (karyorrhectic) debris

– Resulted from degenerated neutrophils and/or degenerated collagen– Appear as Blue-red granular necrosis– In dermatopathology cases, it may appear bluish “degenerated” collagen,

without prominence of nuclear debris• Surrounded by epithelioid histiocytes• Examples:

– Post-transurethral resection granuloma (prostate, bladder)– Granuloma annulare (central mucin)– Rheumatoid nodule– Wegener’s granulomatosis– Necrobiosis lipoidica diabeticorum (shins; cake-like horizontal layers)

DIFFERENTIAL DIAGNOSIS5. Non-classic granulomas:• Either a “misnomer”

– E.g. clinical term of “nodule/mass”, applied by non-pathologists• Or Not strictly follow the “classic definition” of granulomas

– E.g. lesions where histiocytes are present but are not prominent• Examples:

– Plasma cell granuloma (lung) = Inflammatory myofibroblastic tumor– Eosinophilic granuloma (lung) = Langerhans cell histiocytosis– Pulmonary hyalinizing granuloma = sclerosing lesion analogous to

sclerosing mediastinitis– Pyogenic granuloma = Lobular capillary hemangioma– Lethal midline granuloma = NK/T lymphoma nasal type

DIFFERENTIAL DIAGNOSISOther Granulomatous Lung Diseases• Infectious diseases (e.g. TB, fungi) organisms detected by special

stains• Foreign bodies (e.g. Beryllium, talc, aluminum) clinical history• Hypersensitivity pneumonitis clinical history, poorly formed

granulomas (interstitial chronic inflammation > well-formed granulomas)• Granulomatous reaction to 1ry / metastatic tumors (e.g.

lymphomas, lung cancer, seminoma) clinical history• Drug reactions clinical history• Wegener's granulomatosis poorly formed granulomas, vasculitis,

necrosis, c-ANCA

DIFFERENTIAL DIAGNOSISOther Granulomatous Lymphadenopathies• Infectious diseases (e.g. TB, fungi, toxoplasmosis)• Infectious mononucleosis• Foreign bodies (e.g. Beryllium, talc, aluminum)• Lymphomas (e.g. Hodgkin lymphoma and T-cell lymphoma)• Lymph node draining malignancies (e.g. lung cancer and

seminoma)• Drug reactions

DIFFERENTIAL DIAGNOSISO t h e r C a u s e s o f G r a n u l o m a s i n O t h e r O r g a n s

O t h e r C a u s e s o f   H i l a r / M e d i a s t i n a l Ly m p h a d e n o p a t h y

O t h e r C a u s e s o f D r y E y e

O t h e r C a u s e s o f U v e i t i s

O t h e r C a u s e s o f E r y t h e m a N o d o s u m

O t h e r C a u s e s o f H e p a t o - s p l e n o m e g a l y

O t h e r C a u s e s o f M y o c a r d i t i s

O t h e r C a u s e s o f M y o s i t i s

O t h e r C a u s e s o f Tu b u l o i n t e r s t i t i a l N e p h r i t i s

O t h e r C a u s e s o f E n d o c r i n e h y p o f u n c t i o n

O t h e r C a u s e s o f A s e p t i c M e n i n g i t i s

Always suspect sarcoidosis in any case showing noncaseating granulomas

DIFFERENTIAL DIAGNOSISOther Causes o f  Hyperca lcemia• Hyperparathyroidism

– Parathyroid tumors– Parathyroid hyperplasia– Paraneoplastic syndrome

• Vitamin D–related disorders– Vitamin D intoxication– Vitamin D activation (e.g. sarcoidosis)

• Bone diseases– Tumors

• 1ry• Metastasis

– Accelerated bone turnover (e.g., Paget disease)• Renal failure• Thiazide diuretics• Familial hypocalciuric hypercalcemia

FINAL REPORTAn unequivocal diagnosis of sarcoidosis cannot be made histologically• Needs correlation with available clinical, radiological, and laboratory data

Appropriate terminology for a report could be:• Noncaseating granulomas “see comment“

• The comment may state that the findings are consistent with sarcoidosis– But that infection, hypersensitivity pneumonitis, reaction to inhaled minerals and metals

(beryllium, aluminum, talc) or drugs must be ruled out

• Results of stains and cultures should be given (usually negative for microorganisms)

– With the warning that they are not 100% sensitive

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