Patozone

Emboli

Deep Vein Thrombosis (DVT)

Hypertension-induced changes

Varicose Veins

Aortic dissection

Aneurysm of AV fistula

Antiphospholipid syndrome

Large vessels

Temporal (giant cell) aortitis / arteritis

Takayasu's arteritis

Medium Vessels

Kawasaki disease

PAN

Thrombangitis obliterans (Buerger's disease)

Small vessels

Henoch-Schonlein purpura

Cryglobulinemia

Lupus vasculopathy

Goodpasture

ANCA vasculitides

• Granulomatosis with polyangiitis (Wegener's granulomatosis)

• Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

• Microscopic polyangiitis

Hypocomplementemic Urticarial Vasculitis

Sturge-Weber disease

Hypersensitivity vasculitis

Raynaud's disease

Telangiectasia

Segmental mediolytic arteriopathy

Hemangiomas

• Infantile Hemangioma
• Cherry angioma
• Cavernous hemangioma
• Epithelioid hemangioma
• Microvenular hemangioma
• Spingle cell hemangioma

Pyogenic granuloma

Lymphatic Malformations

Hemangioendothelioma

Epithelioid / histiocytic hemangiogenothelioma

Kaposiform Hemangioendothelioma

Epithelioid Sarcoma-like Hemangioendothelioma

Glomus tumor

Perivascular Epithelioid Tumor (PEComa)

Bacillary angiomatosis - Infectious Dermatopathology

Angiokeratoma

Atypical Vascular Lesion (AVL)

Angiosarcoma

Kaposi sarcoma

Lymphangiosarcoma

Venous lake

Aortic Dissection

MC risk factor is HTN

- may be assoc c trauma, surgery, or inherited CT dz

- atherosclerosis and diabetes are also risk factors, but not as much as HTN

PolyArteritis Nodosa (PAN)

Immune complex-mediated transmural vasculitis c fibrinoid necrosis of small and medium muscular arteries

- not present in arterioles, capillaries or venules

- lungs are spared

Sx: abd pain, myalgia, HTN, neurologic dysfunction, cutaneous eruptions

- involves renal vessels, nerves (monomeuritis multiplex), skin and visceral (kidneys, mesentery) vessels, though not pulmonary arteries (lungs are spared)

*** PAN = Pulmonary Arteries Normal ***

- lesions are different ages

Micro: bx shows segmental fibrinoid necrosis of inflamed arterial walls, c a predilection for branch points

- characteristic feature is segmental nature of involvement, c active and healing lesions next to normal segments of bv's

Labs: 30% have hep B seropositivity

- multiple aneurysms and constrictions on arteriogram

- No assoc c ANCAs

Tx: corticosteroids, cyclophosphamide

- same tx as Wegener's; cures 90%; fatal if untx'd

Granulomatosis with polyangiitis (GPA)

- formely (Wegener's granulomatosis)

Triad of upper respiratory tract, lung, kidney

- focal necrotizing vasculitis, necrotizing granulomas in the lung and upper airway, necrotizing glomerulonephritis

Sx: hemoptysis, nasal septum perforation, chronic sinusitis

*** the C's: Cavitary lesions, Crescentic GN, C-nose, C-anca, Cyclophosphamide, Corticosteroids ***

Micro: Fibrinoid necrosis c early neutrophils followed by macros and granuloma c giant cells

- see focal segmental necrotizing glomerulonephritis, pauci-immune type, in kidneys

- palisading necrotizing granuloma with neutrophils (stellate abscesses)

- epidermis necrotic or ulcerated

- necrosis is blue bc comes from neutrophilic microabscesses

Triad: 1) mixed inflam c GCs; 2) geographic necrosis, 3) vasculitis

Labs: (+) Anti-proteinase 3 (PR3-ANCA) by ELISA [formerly C-ANCA]

*** 3 = W ***

cANCA (+) in >90% of cases [5-20% pANCA (+)]

- Confirm Wegener's c ELISA for anti-proteinase 3 !!!

- urinalysis: hematuria and red cell casts

Imaging: large nodular densities

Tx: Cyclophosphamide, Corticosteroids

Eosinophilic granulomatosis with polyangiitis (EGPA)

- formerly Churg Strauss

- Look for vasculitis in a young asthmatic !!!

- used to be considered a variant of polyarteritis nodosa, distinguished by presence of granulomas and abundance of eosinophils

Dx criteria:

1) Asthma

2) Eosinophilia

3) Mono- / polyarthropathy

4) Migratory lung infiltrates on xray

5) Paranasal sinusitis

6) extravascular eosinophilic accumulation

Micro: neutrophilic LCV c palisading granulomas

Lab: (+) p-ANCA (anti MPO)

Complications: pts can die from coronary arteritis or myocarditis

- neurologic involvement can be debilitating

Microscopic polyangiitis (MPA)

- similar to Wegener's, but without the granulomas; lesions are of the same age (like HS purpura)

- involves lungs and kidneys and other organs, tending to affect small arterioles and venules

Sx:

1) Constitutional sx

2) inflamed kidneys

3) skin lesions (palpable purpura)

4) Peripheral nerve damage

5) lung involvement (alveolar hemorrhage from pulmonary capillitis)

Lab: (+) pANCA (aka anti MPO; similar to Churg-Strauss)

Micro: alveolar hemorrhage, hemosiderin-laden macrophages in alveolar spaces, and neutrophilic capillaritis

Epithelioid Hemangioma

- aka angiolymphoid hyperplasia with eosinophilia, or histiocytoid hemangioma

3 subtypes:

1. typical

2. cellular

3. angiolymphoid hyperplasia with eosinophilia (ALHE)

Clinically is a multinodular red / purple plaque

- often on temple (craniofacial region)

- may be secondary to trauma

- usually will see the damaged vessels in the specimen somewhere

Micro: multinodular / nodular, large component of round blue cells in background which are lymphs

- clustered vessels with plump eosinophilic endothelial cells

- also lots of eos inbackground

-- can be difficult to recognize vessel spaces on small bx

- endothelial cells hobnail into vessel lumen

Usually easy H&E dx, but can cause possible confusion with angiosarcoma if:

- small bx

- hypercellular or mitatically active

- minimal inflam or few / absent eosinophils

- non-classic clinical setting

- "penile-type" notoriously confused with angiosarcoma (cellular and atypical in appearance) - may result in terrible irreversible surgery - so should be extra cautious with penile lesions

IHC: (+) vascular markers, CD31, ERG, CD34 (to a lesser extent)

Gene: 1/3 with FOS gene abnormalities by FISH

- ALHE lacks FOS rearrangements suggesting different pathogenesis

Px: b9, no mets

Glomeruloid Hemangioma

Rare cutaneous hemangioma assoc c POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M protein/Myeloma, Skin (hemangiomas) and Sclerotic bone lesions)

Microvenular Hemangioma

Slit like vascular channels that can mimic Kaposi sarcoma

- infiltrative-looking lesion that has vascular spaces growing between colagen bundles

Mciro: vascular spaces that infiltrate bwt collagen and go into the deep dermis (looks like Kaposis bc of infiltration)

- spindle lesion with compressed vascular channels

- no atypia, very few mits, blood is usually confined to the vascular spaces

Tto distinguish from Kaposi sarcoma:

- channels intercalate bwt dermal collagen but do not dissect / encompass collagen bundles

- no infiltrative proliferation of spindled endothelial cells

- minimal atypia or mitotic activity

- minimal extravasation of RBCs

- minimal inflam (few plasma cells)

- clinical history and appearance also helpful

IHC:

- neg: HHV-8

Px: B9

Spindle cell hemangioma

- formerly spindle cell hemangioendothelioma (but reclassified bc of its b9 nature)

- theory of why they are multifocal is bc they grow inside large BV

Assoc c Maffucci syndrome

Micro: has 2 zones - 1 zone that looks like a cavernous hemangioma (or a cavernous malformation) and another that is more cellular (similar to Kaposi sarcoma)

- tumor grows inside large blood vessels

- despite name, can have very epithelioid cells

- has complressed slit-like spaces

- unique finding is little groups of cells that look like compressed fat cells, which is actually a group of endothelial vacuoles

- phlebolith - calcified thrombus that can be seen on imaging

Genes: IDH1 mutation in many cases

- seen in both sporadic and Maffucci assoc

- evidence that this is a true neoplasm and not a malformation

IHC:

- neg: HHV-8

Pyogenic granuloma

aka lobular capillary hemangioma or granula gravidarum (pregnancy tumor; in 1% of pregnant women, regresses after delivery), or eruptive hemangioma

Mucosal or skin lesion that grows fast, exophytic red nodule attached by stalk to skin or gingival mucosa that bleeds easily and ulcerates

- 1/3 are due to trauma, can also be from irritation or homones

- often found in gums, skin, nasal septum, possibly the thigh

- may be painful

- can be assoc c Bortonella seropositivity

- often assoc c peripheral giant cell granuloma (PGCG) and peripheral ossifying fibroma

- the name "pyogenic granuloma" misleading bc is not a true granuloma, but is actually a capillary hemangioma of lobular subtype (which is why the lesion is more prone to bleed)

Micro: lobular prolif of capillaries, epidermal "collarette", edema in stroma, acute / chronic inflam and ulceration, epidermal atrophy

- resembles granulation tissue

Epithelioid / histiocytic hemangioendothelioma

Intermediate grade vascular malig in extremities of older adults derived from a vein (in 50%) ; arise from a small to medium-sized vessel

- most aggressive form of hemangioendothelioma (significant morbidity and mortality)

- MC in lung and liver, with a minority in ST, bone

-- sometimes more indolent when occurs in skin / ST

- can be multicentric, but no real specific clinical appearance

Gross: up to 18 cm

Micro: cords / small nests of round endothelial cells c lots of reddish cytoplasm that expand the vessels as they extend centrifugally from the lumen to the soft tissue in myxoid / mucinous sclerotic background

- blister cells c red cell fragments, which are tumor cells trying to form vascular lumens (similar to what may be seen in lobular breast ca)

-- can have vacuoles in lots of vascular tumors (blister cells are NOT specific for EHE) with plump endothelial cells

- usually does not make well-formed infiltrating vascular channels (like angiosarcoma does); good to distinguish from angiosarc

- lumen filled c necrotic debris, tumor and dense collagen

- round and possibly indented nuclei c intracytoplasmic vacuoles

- minimal mits, atypia or necrosis; though can be significant in small subset

IHC: (+) ERG, FLI1, CD34, CD31; many are keratin positive (CK+)

Genes: t(1;3)(p36;q25) WWTR1-CAMTA1 fusion (in nearly all cases)

- small subset have YAP-TFE3

- can test for FISH in difficult cases

YAP1::TFE3 fused hemangioendothelioma

•Clinical features

•F> M 17:7

•Median age 44 years (range20-78 years)

•Soft tissue (including skin) 50%, bone 29%, lung 13%, liver 8%

•Two-thirds multifocal on presentation; Distant metastasis: 7

•Follow-up, median 36 months

•35% ANED

•47% long term survival despite multifocal or metastatic disease

•88% 5 year disease specific survival

•Multinodular and infiltrative

•Patterns

•Sheets and nests separated by collagenous stroma

•Pseudoalveolar

•Pseudo or true vasoformation

•Cords and nests in myxoidstroma

Tx: low-grade - exicision c wide margins

- high grade - radical excision c dissection

Px: unpredictable (?), but not as bad as angiosarcoma

- 15% die from dz, 15% recur, up to 1/3 mets

- if has inc mits, 5 yr survival is 60%, vs low mets 100%

Kaposiform hemangioendothelioma

- also Acquired Tufted Angioma

Rare, locally aggressive neoplasm of infants / kiddos in skin retroperitoneum and bone

- death from extensive dz and severe coagulopathy (Kasabach-Merritt syndrome)

- no mets

Micro: infiltrating nodules (cannon-balls) and sheets of compact spindle cells c slit-like lumina

- platelets get stuck in whorled nodular vascular channels

- has dilated lymphatic channels at periphery

IHC: (+) VEGFR-3

- GLUT-1 negative (unlike infantile hemangioma)

DDx: Acquired tufted angioma (looks identical microscopically, BUT just a small skin lesion in adults and is not assoc c KM syndrome)

Tx: may be a difficult decision to remove tumor bc of low platelets in pts

Px: 10% mortality; usually when assoc c bleeding from low platelets in KM syndrome

Epithelioid Sarcoma-like Hemangioendothelioma

- aka pseudomyogenic hemangioendothelioma

Presents as multifocal skin / subcutis / deep mscule / bone nodules on extremities

- multiple lesions in multiple tissue planes

- clinically is very worrisome for metastatic disease

•Originally described as ESH in 2003

•Subsequently re-described as PH in 2011

•M:F 3-5:1

•Multifocal disease involving multiple tissue compartments in 2/3 patients

•Relatively indolent

•High risk of local recurrence

•Rare lymph node and distant metastasis

Micro: looks a lots like epithelioid sarcoma or rhabdomyosarcoma

•Ill-defined nodules, sheets or fascicles

•Spindled to epithelioid tumor cells, often with admixed neutrophils (50%)

•Abundant, dense eosinophilic cytoplasm

•No overt vascular channels

•Positive for AE1/3, CD31 (50-70%), ERG,SMARCB1 (INI-1) retained

•Negative for CD34

IHC: (+) CK (nearly 100%), CD31, ERG, FLI-1

- neg: CD34, desmin

- nuclear INI-1 is retained (which is lost in epithelioid sarcoma)

•Cytogenetics: t(17;19)(q22;q13)SERPINE1-FOSB

•Subsets with ACTB-FOSB, WWTR1-FOSB, CLTC-FOSB fusions

•Immunostain for FOSB (nuclear positivity) effective surrogate

•Caveat: Some epithelioid hemangiomas have FOSBfusions and are positive for FOSB by immunohistochemistry

DDx: Differences from epithelioid sarcoma

•Lacks central necrosis of sometimes seen in epithelioid sarcoma

•Cells have denser eosinophilic cytoplasm

•Stromal neutrophils (when present)

•Epithelioid sarcoma has more nuclear atypia

•Epithelioid sarcoma negative for CD31, Fli-1, FOSB, and INI-1 (negative nuclei); (?ERG)

•Epithelioid sarcoma CD34+ ~50-60%

Px: may be locally aggressive but is rarely fatal (vs epithelioid sarcoma)

Glomus tumor

B9, wide age range, comes from modified sm muscle of glomus body (specialized AV anastamosis dealing c thermoregulation)

- usually under fingernails (normal glomus cells are modified sm muscle cells and are normally found on sides of digits and coccyx

- should have at least some focus of typical glomus tumor (usually at periphery)

- usually are extremely painful

- abundantly produces type IV collagen

Similar entities:

- Glomangioma: glomus tumor that looks like a cavernous hemangioma c thicker vessels; usually multiple

- Glomangiomatosis: diffuse angiomatosis that looks like angiomatosis c excess glomus cells; assoc c lots of fat)

- Glomangiomyoma: glomus tumor and angioleiomyoma

- Glomus tumor of uncertain malignant potential: lots of mits, or >2cm or if found deep

- Glomangiosarcoma: Deep + >2cm or atypical mits or high nuclear grade; can met

Micro: branching vascular channels separated by stroma c glomus cells that are small, regular, round c no nucleoli seen in nests / aggregates ("string of black pearls"); glomus cells found around vessels (vessels can be HPC-like)

- more infiltrative in kiddos, but no mits

Cyto: cohesive clusters of uniform round cells c scanty cytoplasm

- background of scattered amorphous magent material, blood and occasional inflam cells

IHC: (+) SMA, MSA, type IV collage (pericellular), vimentin, CD34 (1/5), variable h-caldesmin / calponin

- negative cytokeratin, desmin, S100 and chromogranin

Tx: Excision

Perivascular Epithelioid Cell Tumor (PEComa)

Perivascular clear cell and epithelial-like tumor that has melanocytic and muscle markers, 7F>>1M

- in the family of angiomyolipoma, clear cell "sugar" tumor of lung, clear cell myomelanocytic tumor of the falciform ligament,  lymphangiomyomatosis (all assoc c tuberous sclerosis)

- deregulation of mTOR pathway (can tx c sirolimus or mTOR inhibitor)

Micro: perivascular tumor cells in nests and fascicles in radial shape around lumen, epithelial cells close to vessel, spindle cells farther away

- may not have perivascular pattern and look more clear cell-like in more undifferentiated cancers

IHC: (+) Melanoma and sm muscle markers, c-kit, cathepsin K, TFE3 (some, also seen in alveolar soft parts sarcoma), SMA, Desmin, S100

- neg CK, CD117, CD34

Genes:TSC1 (9q34), TSC2 (16p13.3)

- obvious abnormalities in most cases, some have rearrangement or amplification of TFE3

Atypical vascular lesion (AVL)

Is a specific dx, not just a description

- b9 vascular prolif post-rads

- clinically looks like flesh-colored papules arising in radiation site

- may be confused with well-diff angiosarc, and sometimes may occur adjacent to angiosarcoma

Micro: looks like lymphangioma, dermal prolif of infiltrating vascular channels that dissect bwt the collagen bundles

- can have some hyperchromasia

- does not have multilayering, does not have mits or pleomorphism/ atypia

- should be fairly superficial lesions, do not go deep

Genes: Negative for c-myc amplification (vs a post-radiation angiosarcoma)

Tx: controversial; but may be surgically excised although sometimes not feasible if there are many lesions

- ensuring adequate sampling of lesion is the most important issue (must avoid underdiagnosis of angiosarcoma)

- should be closely followed clinically (make sure that no new vascular lesions are developing)

Px: Usually b9 and does not progress to angiosarc (though exceptions do occur)

Angiosarcoma

Rare tumor in adults, (<1% of sarcomas), ~7th decade (very rare in kiddos) derived from endothelial cells of blood vessels that can occur in multiple sites depending on type of risk factor exposure

- skin>> breast > ST > solid organs > bone

- well differentiated (hemangiosarcoma) to anaplastic tumor that can look like melanoma or carcinoma

- risk factors: chronic lymphedema, PVC, radiation (esp breast), sun exposure, Thorotrast

- mets to node in 14%

- tumors do not arise in assoc c b9 hemangioma (though rarely epithelioid angiosarcoma arises in assoc c schwannoma)

Subtypes:

MC variant is cutaneous (40%, affecting sun-exposed areas of head and neck)

- radioation assoc angiosarcoma: in abdominal wall/cavity, Mullerian malignancy, >10 yrs after radiation; also in the skin of breast c breast cancer 3-5 years after radiation, incidence ~0.1%, can see irreg papules / plaques that are multicentric

- lymphedema assoc angiosarcoma - Stewart-Treves syndrome, chronic lymphedema, obesity assoc lymphedema (localized massive lymphedema, lymphangiomatosis is less likely precursor

- Primary breast angiosarcoma - women in 3rd or 4th decades; mass in breast parenchyma, overlying skin changes, ill-defined, destructive growth

- Soft tissue / Solid organ angiosarcoma - any age, ~1/3 syndromic (NF, Maffucci syndrome, Klippel-Trenaunay syndrome); predisposed by thoratrast, polyvinyl chloride, arsenic, foreign material (AV fistulas, shrapnel, plastics), epithelioid morphology, very poor px

-- Mass in Right Atrium = Angiosarcoma (until proven otherwise)

Gross: early on is sharply defined, asymptomatic multiple red nodules

- later is fleshy gray white c hemorrhage, necrosis and deeply invasive

Micro: atypical vascular spaced lined by endothelial cells c atypia and multilayering that involves subQ and has RBCs in intracytoplasmic lumina in more solid areas

- lots of mits and necrosis

IHC: (+) Factor 8 related peptide, CD31, Ki-67, FLI-1, thrombomodulin, CD34, c-kit, VEGFR-3, ERG, INI-1 (is lost in epithelioid sarcoma)

- occasionally stains for cytokeratins (CK18/7/8 in ~1/2)

- no loss of INI-1 (excludes epithelioid sarcoma)

Genes: high level MYC amplifications, esp in secondary tumors (post-radiation and in chronic lymphedema; not usually positive in primary sun damaged skin in elderly)

DDx: May mimic ecchymosis or solar purpura

- Kaposi can mimic angiosarc (and vice versa), they have totally different tx and px (Kaposi is usually not a surgical disease and is not fatal), should get HHV8 if there is any confusion

- epithelioid angiosarcoma can mimic other cancers (carcinoma, epithelioid sarcoma, melanoma) - epithelioid angiosarcoma often expreses keratins just like carcinoma and epithelioid sarcoma

- small biopsies may not be representative; if there is high suspicion, should repeat the biopsy!! Must communicate with clinician, and have higher index of suspicion if hx of lymphedema or radiation history

Tx: early aggressive surgery

- recurrence and progression still common since is a vascular lesion

- chemo and rads also used

- Sorafenib has a dramatic, although not a long-term effect

Px: poor survive past 5 years (<30%); most die in <12 mo after dx

- mets to lung and bone

Kaposi sarcoma

Low grade endothelial malignancy that can be classic or AIDS assoc

- hyperhcromatic spindle cells c vascular slit pattern and extravasated RBCs

- HHV-8 plays role in all subtypes

Classic

Not assoc c HIV, old Mediteranean dudes, rare in US

Endemic

more rapid clinical course than classic disease

10% of all malig tumor central Africa, usually in young adults and kids;

- poor px if over 50 yo

HIV-assoc (epidemic)

derived from vasoformative mesenchymal multipotential cells

- can be mistaken for bacillary angiomatosis

- 75% involve the viscera in AIDS pts;

Iatrogenic

Transplants, immunosuppression

Micro: spindle cells forming slits c extravasated RBCs, hemosiderin laden macrophages, lymphs and fibrosis

- minimal atypia

- can have lots of PAS+ hyaline bodies, which are heme breakdown products

- moderate mits

Stages: Early-patch, later-plaque tumor, and nodular

- also a lymphanioma-like variant with thin, angulated vessels with no RBCs

Early-patch - bizarre staghorn vessels and plasma cells

Later-plaque - busy dermis surrounding adnexal structures and vessels

- Promontory sign - protrusion of pre-existing structues into lake-like ectatic space, leaves vessels looking like they are floating in space

Nodular - fascicles of spindle cells, separated by slit-like vascular spaces containing erythrocytes, PAS positive diastase resistant hyaline globules, extravasated RBCs, scattered plasma cells, and hemosiderin deposits

IHC: (+) CD34>CD31, factor VIII related antigen, podoplanin (D2-40), LANA (very sensitive and specific for HHV-8 infx)

- negative keratin and desmin

Genes: diploid and clonal

- HHV8 present in all types

Tx: radio chemo