Non-infectious granulomas

Question 1

What age groups are most affected by granuloma annulare and what is the sex preponderance?

Answer 1

66% of cases arise before the age of 30. F>M (2:1)

Question 2

What is the hypothesized pathophysiology of granuloma annulare?

Answer 2

Likely a Th1-type delayed hypersensitivity reaction to a trigger (trauma/isomorphic koebner, insect bites, TBST, mycobacterial/viral infxn, or UV radiation)

This Th1 rxn leads to monocyte accumulation in the derms–> release of lysosomal enzymes –> degradation of elastic fibers

Question 3

What is localized granuloma annulare associated with? Generalized?

Answer 3

Most cases of localized GA occur in healthy pts. Generalized may be associated with hyperlipidemia (45%), type I diabetes, HIV, thyroid disease, and malignancy

Question 4

What is the clinical presentation of granuloma annulare?

Answer 4

Benign and self-resolving

• Usually, asymptomatic annular/arciform plaques comprised of multiple small non-scaly, flesh-colored to pink or violaceous papules

Question 5

What is a common presentation of GA on the fingers?

Answer 5

Solitary, umbilicated papules

Question 6

What are the most common distributions of GA?

Answer 6

Isolated hands/arms are the most common, especially the dorsal hands/fingers and elbows (60%) [makes sense w/ trauma hypothesis], isolated legs/feet, again especially the dorsal feet/ankles (20%), combined upper and lower extremities (7%).

• Less common: isolated trunk (7%), or trunk and other sites (7%)

Question 7

What are the 5 different variants of GA?

Answer 7

Patch, subcutaneous/deep dermal, generalized, perforating, GA-like eruptions

Question 8

What is the clinical appearance of patch GA?

Answer 8

Symmetrical erythematous patches, usually bilateral dorsal feet vs trunk vs extremities. Doesn’t always have the annular configuration

Question 9

What is the histology most commonly of patch-type GA?

Answer 9

Interstitial GA

Question 10

What is the clinical appearance of subcutaneous/deep GA and what can it be confused with?

Answer 10

Most common in children <6 y/o

• Large, asymptomatic rheumatoid-like nodule on the dorsal foot (most common), palms, shins, buttocks, and scalp. Often a/w trauma, 50% also have classic GA lesions

Question 11

What is the age distribution of generalized GA?

Answer 11

Generally older (40s-50s)

Question 12

Clinical characteristics of generalized GA?

Answer 12

Innumerable small red-violaceous papules coalescing into small annular plaques, especially on the upper trunk/proximal upper extremities.

Generally poorly responsive to treatments

Question 13

Disease associations with generalized GA?

Answer 13

Lipid abnormalities (45%), diabetes in 21% (vs only 10% in localized GA), increased prevalence of HLA-Bw35

Question 14

What is the disease course of generalized GA?

Answer 14

Self-resolves over 3-4 years

Question 15

Clinical characteristics of perforating GA?

Answer 15

Most commonly on the dorsal hands and fingers

• Small papules w/ central keratotic plug, umbilication, or ulceration.

Histologically characterized by GA w/ transepidermal elimination of degenerated collagen

Question 16

In what diseases can GA-like eruptions be associated with?

Answer 16

B- and T-cell lymphomas, HIV (more generalized GA>localized), or at sites of prior herpes zoster scars

Question 17

What are the 3 most common types of GA histologically?

Answer 17

1. Interstitial (most common, 75% of cases)
2. Palisaded granulomas (25% of cases)
3. Sarcoidal pattern (5%)

Deep GA: palisaded granulomas w/ central blue-colored mucin in deep dermis/SQ (this is in comparison to pink fibrin in RA nodules)

Perforating GA: typical GA + transepidermal elimination of degenerated collagen and granulomatous debris

Question 18

Treatment for GA?

Answer 18

Localized/asymptomatic reassurance, high potency topical and intralesional steroids, TCIs, lasers and light cryotherapy

Question 19

What is the prognosis/clinical course in patients with GA?

Answer 19

Most spontaneously resolve in 2 years (50%), however there is a 40% recurrence rate, but these episodes tend to remit sooner

Question 20

What is the treatment of severe GA disease?

Answer 20

phototherapy, antimalarials, nicotinamide, isotretinoin, dapsone, pentoxifylline, PDT, triple antibiotic regimens, (mino, ofloxacin and rifampin) and TNF-a inhibitors

Question 21

What is the annular elastolytic giant cell granuloma (AEGCG, actinic granuloma of O’Brien, and atypical facial NLD)?

Answer 21

It is a GA-variant that affects chronically sun-exposed/damaged skin.

Question 22

What is the clinical course of annular elastolytic giant cell granuloma (AEGCG, actinic granuloma of O’Brien, and atypical facial NLD)

Answer 22

Starts as flesh-colored to pink papules that progress to annular plaques 1-10cm in diameter. Usually less than ten lesions

Question 23

What are the characteristic histopathologic findings of annular elastolytic giant cell granuloma (AEGCG, actinic granuloma of O’Brien, and atypical facial NLD)

Answer 23

Interstitial >well-formed palisaded. there are more multinucleated foreign body giant cells than usually seen in GA. Phagocytosed elastic fibers within histocytes and giant cells “elastophagocytosis”; no collagen alteration or lipid deposition lacks mucin: VVG stain shows the absence of elastic fibers and loss of solar elastosis in affected areas

Question 24

What is interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?

Answer 24

These two diseases exist on a spectrum. These have different clinical, distributive, and associated diseases.

Question 25

What are the clinical differences between interstitial granulomatous dermatitis and arthritis; and palisaded neutrophilic granulomatous dermatitis?

Answer 25

IGDA: annular plaques or linear red to skin-colored cords (rope sign, usually in the axilla) PNGD: umbilicated skin-colored to violaceous papules with or without perforation/ulceration

Question 26

What are the clinical distributions between interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?

Answer 26

IGDA: Trunk, buttocks, and intertriginous areas (symmetric) PNGD: Symmetric involvement of extensor digits, elbows, and other extensors

Question 27

What are the most common disease associations between interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?

Answer 27

IGDA: RA (most common), seronegative arthritis, autoimmune thyroiditis, SLE PNGD: RA, SLE and ANCA vasculitides (Wegener's/Churg-Strauss)

Question 28

Histology differences between interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?

Answer 28

IGDA: Small **rosettes of palisading histiocytes** in mid/deep reticular dermis (bottom-heavy), around small foci (smaller than GA) of degenerated collagen; no mucin +/- neutrophils; **no obvious vasculitis** PNGD: small vessel LCV w/ basophilic collagen degeneration (early) --\> palisaded granulomas with basophilic collagen degeneration +/- perforating collagen (late)

Question 29

What is the pathogenesis of interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?

Answer 29

Autoimmune condition --\> immune complex deposition in/around dermal vessel walls --\> chronic, low-intensity vasculitis (more brisk and neutrophil-rich in PNGD) --\>gradual impairment of blood flow to dermal collagen --\> collagne degeration --\> palisaded granulomaotous inflammation in reaction to degernated collagen

Question 30

How often is ANA + in interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?

Answer 30

50%

Question 31

What can interstitial granulomatous drug eruptions look like?

Answer 31

Can look like GA, IGDA, PNGD ## Footnote *Annular, red, non-scaly papules and plaques w/ indurated border; favors creases and often photodistributed; spares mucous membranes*

Question 32

What drugs most commonly cause interstitial granulomatous drug eruption?

Answer 32

CCBs and ACE inhibitors (**usually months to years after drug initiation**) -TNF-a inhibitors in RA patients, statins, furosemide, beta-blockers, antihistamines, HCTZ, anakinra, and thalidomide

Question 33

Histology of interstitial drug eruption?

Answer 33

May resemble GA, IGDA, PNGD, but is frequently deeper, (bottom to 2/3 of the dermis), interface dermatitis, atypical lymphs, and lacks mucin.

Question 34

Epidemiology of necrobiosis lipoidca (NLD)

Answer 34

F>M (3:1) **0.03% of diabetics have NLD**, but 22% of patients with NLD have or will develop diabetes/glucose intolerance ## Footnote *May be associated w/ smoking*

Question 35

What are diabetics w/ NLD have increased risk of having?

Answer 35

Peripheral neuropathy, retinopathy, and joint immobility

Question 36

What is the pathogenesis of necrobiosis lipoidica?

Answer 36

Vascular compromise from immune deposition vs diabetes-related microangiopathic changes leads to subacute dermal ischemia. The dermal collagen degeneration that results leads to secondary granulomatous inflammatory response

Question 37

Clinical features of necrobiosis lipoidica?

Answer 37

Early: firm, reddish papules --\> expand into atrophic plaques on b/l shins w/ a peripheral violaceous to the erythematous rim and atrophic central yellow-brown discoloration w/ telangiectasias. - Minor trauma leads to ulceration ## Footnote *Adnexae and neural elements frequently lost within the lesions/plaques --\> decreased pinprick/fine touch sensation, hypohidrosis, and localized alopecia*

Question 38

Histology of necrobiosis lipoidica?

Answer 38

Mirrors the pathophysiology: square bx, horizontally arranged (cake layers) palisaded granulomatous inflammation w/ horizontal tiers of degenerated collagen fibers and dermal sclerosis. - A diffuse process that affects the **entire dermis** and subQ fat (vs GA that is patchy). - Lacks mucin, **plasma cells and multinucleated giant cells are abundant**

Question 39

What is the treatment for necrobiosis lipoidica?

Answer 39

First line: potent topical and/or intralesional steroids (place the injection into the inflammatory rim); TCI for early lesions Systemic: steroids, colchicine, cyclosporine, TNF-a inhibitors, CO2 laser, stanozolol, and pentoxifylline in chronic/recalcitrant cases ## Footnote *Surgical excision to fascia w/ skin grafting amy be necessary in severe ulcerative cases*

Question 40

What is the prognosis/clinical progression of necrobiosis lipoidica?

Answer 40

Rarely undergoes spontaneous remission (17% at 8-12 years) - control of blood glucose levels **does not** affect dz course - No treatment has shown effective ## Footnote ***SCC can arise in chronic ulcerative lesions***

Question 41

What is necrobiotic xanthogranuloma and what is the clinical presentation?

Answer 41

A multisystem histiocytic disease that presents with firm **yellow xanthomatous plaques and nodules**, most often in the **periorbital area** (more than the trunk, proximal extremities)

Question 42

What secondary features are often seen in necrobiotic xanthogranuloma?

Answer 42

Often ulcerates and leads to scarring

Question 43

What other organ systems can be affected by necrobiotic xanthogranuloma?

Answer 43

Strongly associated with IgGkappa monoclonal gammopathy (plasma cell dyscrasia or multiple myeloma) Other associations: 50% have ophthalmic manifestations (ectropion, proptosis, uveitis, and keratitis); majority also have endocardial involvement; hepatosplenomegaly as well ## Footnote *skin findings precede the diagnosis of malignancy by 2-20 years!*

Question 44

Histology of necrobiotic xanthogranuloma?

Answer 44

Diffuse (all of the dermis into subcutis) palisading xanthogranulomas w/ necrobiotic collagen, foamy histiocytes, scattered inflammatory cell debris, abundant cholesterol clefts and LARGE multinucleated cells with the "horseshoe-like" appearance. These are more unique to this entity and are not present in GA and NLD

Question 45

Treatment of necrobiotic xanthogranuloma?

Answer 45

No effective treatment, tx the underlying malignancy or paraproteinemia

Question 46

What percent of patients with Crohn's get skin or mucosal findings?

Answer 46

20-45%

Question 47

What is more common, Crohn's specific skin findings or non-specific reactive findings?

Answer 47

Non-specific reactive findings (erythema nodusum, pyoderma gangrenosum, etc are more common)

Question 48

What type of Crohn's dz is more commonly associated with cutaneous findings?

Answer 48

Cutaneous Crohn's is more frequently a/w colorectal cancer rather than dz in the small intestine. ## Footnote *skin findings may occur before dx of IBD in ~20% of cases*

Question 49

What are the most common reactive/non-specific cutaneous findings in IBD?

Answer 49

Erythema nodosum, pyoderma gangrenosum (UC\>Crohn's), pyostomatitis vegetans (UC\>Crohn's), Pathergy (pustular response to trauma), EB acquista (IBD is most common cause of EBA), and acrodermatitis

Question 50

What is the pathogenesis of the granulomatous dz seen in Crohn's?

Answer 50

Genetic predisposition + defective microbial clearance, mucosal compromise or altered gut flora balance which leads to an exaggerated Th1 and Th17 response to gut flora --\> granulomatous dz in gut and skin

Question 51

Clinical features of genital Crohn's?

Answer 51

Labial or scrotal edema +erythema/ulceration and fissures. Often violaceous hue. In women look for thick swollen labia majora, almost resembling "a life vest"

Question 52

Clinical features of perianal Crohn's?

Answer 52

Ulcers, sinus tracts, fissures, or eroded vegetating plaques; lesions often extend to perineum, buttocks, and abdominal surgical ostomy sites. ## Footnote *Look for the fissures and fitulae around the site of the ostomy*

Question 53

Clinical features of oral Crohns?

Answer 53

Key feature is "cobblestoning" of the buccal mucosa, can also see pyostomatitis vegetans, cheilitis granulomatosa, gingival hyperplasia, diffuse oral swelling, fissures, apthous-like ulcers, linear ulcers, and small gingival nodules

Question 54

Clinical appearence of extragenital "metastatic" Chrons?

Answer 54

Dusky red papules/plaques --\> ulcerations with undermined edges, fistulas, draining sinuses and scarring ## Footnote *most common sites: **lower extremities/soles** (38%), abdomen/trunk (24%), upper extremities (15%), face/lips (11%), flexures (8%), generlized (4%)*

Question 55

What is an important differential that must be considered for hidradenitis suppurativa?

Answer 55

Cutaneous Crohns can appear similarly and can occur in flexural sites

Question 56

Histopathology of cutaneous Crohn's?

Answer 56

Non-caseating tuberculoid granulomas w/ inflammatory rim of lymphocytes in the superficial and deep dermis; frequent Langerhans giant cells

Question 57

What is the treatment of cutaneous Crohn's disease?

Answer 57

First line: oral metronidazole, topical/intralesional steroids and TCI Severe cases: oral steroids, sulfasalazine, MTX, MME, cyclosporine, thalidomide, azathioprine, 6-MP, and TNF-a inhibitors

Question 58

What is the correlation between cutaneous Crohns and the severity of the GI disease?

Answer 58

They are not correlated, disease ends to be chronic

Question 59

What is the epidemiology of sarcoidosis?

Answer 59

- Bimodal incidence peaks: 35-35 yo and 45-65 yo - African Americans have the highest incidence and disease tends to be more severe/progressive - Increased incidence of cases in spring and winter (there is an infection/environmental trigger hypothesis)

Question 60

What is the pathogenesis of sarcoid?

Answer 60

The multisystem granulomatous disease caused by the upregulation of CD4+ cells. - Genetic predisposition + unknown antigens presented by monocytes with MHC class II molecules --\> activation of CD4+ Th1 cells--\> IL-2, IFN-gamma, TNF-a, and monocyte chemotactic factors --\> monocytes leave the circulation and enter peripheral tissues, including skin, where they form granuloma --\> granulomas have potential to result in end-organ dysfunction

Question 61

Drugs associated with sarcoidosis?

Answer 61

- Hepatitis C pts on treatment (IFN-a, ribavirin) - HIV pts on HAART - Other meds: TNF-a inhibitors, vemurafenib, ipilimumab, and alemtuzumab

Question 62

What percent of patients with sarcoidosis end up with cutaneous lesions?

Answer 62

35%

Question 63

What initial workup is needed for a patient with cutaneous sarcoidosis?

Answer 63

CXR, PFTs, and regular eye exams

Question 64

Clinical features of cutaneous sarcoid?

Answer 64

Red-brown or erythematous papules and plaques w/ "apple jelly" color on diascopy Less common presentations include hypopigmented, ichthyosiform, angiolupoid (prominent telangiectasias), psoriasiform, annular, verrucous, cicatricial alopecia and erythrodermic

Question 65

What is the most common distribution of lesions in cutaneous sarcoid?

Answer 65

Lesions tend to occur on the face (especially lips and nose), neck, and the upper half of the body ## Footnote *Lesions also tend to occur in areas with preexisting scars, piercings or tattoos*

Question 66

If you see erythema w/ underlying nodules on the shins of a patient with sarcoidosis what is this and what does it mean for the prognosis/clinical course?

Answer 66

Erythema nodosum: most important non-specific manifestation of sarcoidosis since it predicts a benign self-limited course

Question 67

What are the most common areas of involvement in sarcoidosis outside of the skin?

Answer 67

- Lung disease (90%): alveolitis, bronchiolitis, and pleuritis may culminate in "honeycombing" of lung w/ fibrosis and bronchiectasis - Lymphadenopathy (90%): Hilar and/or paratracheal typically asymptomatic - Ocular involvement (20-50%): anterior uveitis (most common), retinitis, lacrimal inflammation, and conjunctivitis which can lead to blindness - Hypercalcemia (10%): due to calcitriol synthesis by sarcoidal granulomas (converts 25-hydroxyvitamin D to more active 1,25-dihydroxyvitamin D which leads to hypercalcemia, hypercalciuria, and nephrocalcinosis (this can lead to renal failure) - Other: clubbing, onycholysis, subungual hyperkeratosis, oral involvement (salivary gland, gingiva, hard/soft palate and tongue), liver, and heart

Question 68

What is the histopathology of sarcoid?

Answer 68

- Superficial and deep dermis packed w/ nodules of well-formed, non-caseating, "naked epithelioid granulomas," (lack of inflammatory rim around granulomas) - asteroid bodies (star-shaped eosinophilic inclusions of collagen) and Schaumann bodies (basophilic calcium and protein inclusions) are commonly seen within histiocytic giant cells

Question 69

What is the Kveim-Siltzbach test?

Answer 69

Not routinely performed: injecting a suspension of sarcoidal spleen into the skin of a patient w/ sarcoidosis --\> sarcoidal granuloma at the injection site constitutes a + test

Question 70

What is lupus pernio?

Answer 70

Violaceous (vs red-brown) papules coalescing into infiltrative plaques. Occurs on the nose, earlobes, cheeks. It has a beaded appearance around the nasal rim.

Question 71

What is the prognosis/clinical course of sarcoid in lupus pernio?

Answer 71

Strongly associated with **chronic sarcoid lung dz** (75%) and upper respiratory tract (50%) of dz, cystic degeneration of bones of distal phalanges, ocular involvement, and reticuloendothelial involvement ## Footnote *is associated with **bad prognosis**

Question 72

What is it called when patients have subcutaneous nodules that are found to be sarcoid?

Answer 72

Darier-Roussy - presents with painless, firm, deep-seated, mobile nodules, 90% have hilar adenopathy and multiple lesions but it is associated with good prognosis

Question 73

What lab/dx tests could be done for sarcoid?

Answer 73

CXR or CT scan (most sensitive): hilar/paratracheal lymphadenopathy and +/- pulmonary infiltrates - PFT: restrictive pattern of lung disease. You see decreased total lung capacity, decreased diffusing capacity, and decreased vital capacity - Increased ACE level (in 60% of cases, generally more useful for monitoring responses than for diagnosis) - Elevated ESR, hypercalcemia, lymphopenia

Question 74

What is Löfgren's syndrome?

Answer 74

The acute form of sarcoidosis: presents with erythema nodosum + hilar adenopathy + fever + migrating polyarthritis + acute iritis; most common in Scandanavian whites, rare in blacks, **associated with good prognosis**

Question 75

What is Heerfordt's syndrome (uveoparotid fever)?

Answer 75

Uveitis + parotid gland enlargement + fever + cranial nerve palsy (usually cranial nerve)

Question 76

What is it called when you have enlarged salivary, lacrimal or parotid glands in the setting of granulomatous disease? - What diseases are most commonly associated with this entity?

Answer 76

Mikulicz's syndrome - Can be seen in **TB, sarcoid, Sjogren's syndrome, lymphoma**

Question 77

What is it called if sarcoid is seen in a 5 y/o child?

Answer 77

Early-onset (\<5 y/o) sarcoid-like disease; triad of skin, eye, and joint dz

Question 78

What is the genetic mutation of Blau syndrome?

Answer 78

NOD2 mutation

Question 79

What is the treatment for sarcoid?

Answer 79

First line: oral prednisone for systemic involvement +/- topical or IL-steroids fo skin involvement; the degree of lung, eye and other internal involvement determins how quickly the prednisone can be tapered ## Footnote *For chronic skin-predominant disease hydroxychloroquine and chloroquine can be used* *other: TNF-a inhibitors, MME, azathioprine, minocycline, and leflunomide*

Question 80

What treatment can be used for chronic skin-predominant sarcoid?

Answer 80

Hydroxychloroquine and chloroquine

Question 81

What is the presentation of foreign body reactions?

Answer 81

Presents with inducrated red or red-brown papules coalescing into plaques +/- ulceration ## Footnote *basically any material that is resistant to being broken down by biologic processes*