Non-infectious granulomas Flashcards
What age groups are most affected by granuloma annulare and what is the sex preponderance?
66% of cases arise before the age of 30. F>M (2:1)
What is the hypothesized pathophysiology of granuloma annulare?
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
What is localized granuloma annulare associated with? Generalized?
Most cases of localized GA occur in healthy pts. Generalized may be associated with hyperlipidemia (45%), type I diabetes, HIV, thyroid disease, and malignancy
What is the clinical presentation of granuloma annulare?
Benign and self-resolving
- Usually, asymptomatic annular/arciform plaques comprised of multiple small non-scaly, flesh-colored to pink or violaceous papules
What is a common presentation of GA on the fingers?
Solitary, umbilicated papules
What are the most common distributions of GA?
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%)
What are the 5 different variants of GA?
Patch, subcutaneous/deep dermal, generalized, perforating, GA-like eruptions
What is the clinical appearance of patch GA?
Symmetrical erythematous patches, usually bilateral dorsal feet vs trunk vs extremities. Doesn’t always have the annular configuration
What is the histology most commonly of patch-type GA?
Interstitial GA
What is the clinical appearance of subcutaneous/deep GA and what can it be confused with?
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
What is the age distribution of generalized GA?
Generally older (40s-50s)
Clinical characteristics of generalized GA?
Innumerable small red-violaceous papules coalescing into small annular plaques, especially on the upper trunk/proximal upper extremities.
Generally poorly responsive to treatments
Disease associations with generalized GA?
Lipid abnormalities (45%), diabetes in 21% (vs only 10% in localized GA), increased prevalence of HLA-Bw35
What is the disease course of generalized GA?
Self-resolves over 3-4 years
Clinical characteristics of perforating GA?
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
In what diseases can GA-like eruptions be associated with?
B- and T-cell lymphomas, HIV (more generalized GA>localized), or at sites of prior herpes zoster scars
What are the 3 most common types of GA histologically?
- Interstitial (most common, 75% of cases)
- Palisaded granulomas (25% of cases)
- 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
Treatment for GA?
Localized/asymptomatic reassurance, high potency topical and intralesional steroids, TCIs, lasers and light cryotherapy
What is the prognosis/clinical course in patients with GA?
Most spontaneously resolve in 2 years (50%), however there is a 40% recurrence rate, but these episodes tend to remit sooner
What is the treatment of severe GA disease?
phototherapy, antimalarials, nicotinamide, isotretinoin, dapsone, pentoxifylline, PDT, triple antibiotic regimens, (mino, ofloxacin and rifampin) and TNF-a inhibitors
What is the annular elastolytic giant cell granuloma (AEGCG, actinic granuloma of O’Brien, and atypical facial NLD)?
It is a GA-variant that affects chronically sun-exposed/damaged skin.
What is the clinical course of annular elastolytic giant cell granuloma (AEGCG, actinic granuloma of O’Brien, and atypical facial NLD)
Starts as flesh-colored to pink papules that progress to annular plaques 1-10cm in diameter. Usually less than ten lesions
What are the characteristic histopathologic findings of annular elastolytic giant cell granuloma (AEGCG, actinic granuloma of O’Brien, and atypical facial NLD)
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
What is interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?
These two diseases exist on a spectrum. These have different clinical, distributive, and associated diseases.
What are the clinical differences between interstitial granulomatous dermatitis and arthritis; and palisaded neutrophilic granulomatous dermatitis?
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
What are the clinical distributions between interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?
IGDA: Trunk, buttocks, and intertriginous areas (symmetric)
PNGD: Symmetric involvement of extensor digits, elbows, and other extensors
What are the most common disease associations between interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?
IGDA: RA (most common), seronegative arthritis, autoimmune thyroiditis, SLE
PNGD: RA, SLE and ANCA vasculitides (Wegener’s/Churg-Strauss)
Histology differences between interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?
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)
What is the pathogenesis of interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?
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
How often is ANA + in interstitial granulomatous dermatitis and arthritis and palisaded neutrophilic granulomatous dermatitis?
50%
What can interstitial granulomatous drug eruptions look like?
Can look like GA, IGDA, PNGD
Annular, red, non-scaly papules and plaques w/ indurated border; favors creases and often photodistributed; spares mucous membranes
What drugs most commonly cause interstitial granulomatous drug eruption?
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
Histology of interstitial drug eruption?
May resemble GA, IGDA, PNGD, but is frequently deeper, (bottom to 2/3 of the dermis), interface dermatitis, atypical lymphs, and lacks mucin.
Epidemiology of necrobiosis lipoidca (NLD)
F>M (3:1)
0.03% of diabetics have NLD, but 22% of patients with NLD have or will develop diabetes/glucose intolerance
May be associated w/ smoking
What are diabetics w/ NLD have increased risk of having?
Peripheral neuropathy, retinopathy, and joint immobility
What is the pathogenesis of necrobiosis lipoidica?
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
Clinical features of necrobiosis lipoidica?
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
Adnexae and neural elements frequently lost within the lesions/plaques –> decreased pinprick/fine touch sensation, hypohidrosis, and localized alopecia
Histology of necrobiosis lipoidica?
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
What is the treatment for necrobiosis lipoidica?
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
Surgical excision to fascia w/ skin grafting amy be necessary in severe ulcerative cases
What is the prognosis/clinical progression of necrobiosis lipoidica?
Rarely undergoes spontaneous remission (17% at 8-12 years)
- control of blood glucose levels does not affect dz course
- No treatment has shown effective
SCC can arise in chronic ulcerative lesions
What is necrobiotic xanthogranuloma and what is the clinical presentation?
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)
What secondary features are often seen in necrobiotic xanthogranuloma?
Often ulcerates and leads to scarring
What other organ systems can be affected by necrobiotic xanthogranuloma?
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
skin findings precede the diagnosis of malignancy by 2-20 years!
Histology of necrobiotic xanthogranuloma?
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
Treatment of necrobiotic xanthogranuloma?
No effective treatment, tx the underlying malignancy or paraproteinemia
What percent of patients with Crohn’s get skin or mucosal findings?
20-45%
What is more common, Crohn’s specific skin findings or non-specific reactive findings?
Non-specific reactive findings (erythema nodusum, pyoderma gangrenosum, etc are more common)
What type of Crohn’s dz is more commonly associated with cutaneous findings?
Cutaneous Crohn’s is more frequently a/w colorectal cancer rather than dz in the small intestine.
skin findings may occur before dx of IBD in ~20% of cases
What are the most common reactive/non-specific cutaneous findings in IBD?
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
What is the pathogenesis of the granulomatous dz seen in Crohn’s?
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
Clinical features of genital Crohn’s?
Labial or scrotal edema +erythema/ulceration and fissures. Often violaceous hue. In women look for thick swollen labia majora, almost resembling “a life vest”
Clinical features of perianal Crohn’s?
Ulcers, sinus tracts, fissures, or eroded vegetating plaques; lesions often extend to perineum, buttocks, and abdominal surgical ostomy sites.
Look for the fissures and fitulae around the site of the ostomy
Clinical features of oral Crohns?
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
Clinical appearence of extragenital “metastatic” Chrons?
Dusky red papules/plaques –> ulcerations with undermined edges, fistulas, draining sinuses and scarring
most common sites: lower extremities/soles (38%), abdomen/trunk (24%), upper extremities (15%), face/lips (11%), flexures (8%), generlized (4%)
What is an important differential that must be considered for hidradenitis suppurativa?
Cutaneous Crohns can appear similarly and can occur in flexural sites
Histopathology of cutaneous Crohn’s?
Non-caseating tuberculoid granulomas w/ inflammatory rim of lymphocytes in the superficial and deep dermis; frequent Langerhans giant cells
What is the treatment of cutaneous Crohn’s disease?
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
What is the correlation between cutaneous Crohns and the severity of the GI disease?
They are not correlated, disease ends to be chronic
What is the epidemiology of sarcoidosis?
- 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)
What is the pathogenesis of sarcoid?
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
Drugs associated with sarcoidosis?
- Hepatitis C pts on treatment (IFN-a, ribavirin)
- HIV pts on HAART
- Other meds: TNF-a inhibitors, vemurafenib, ipilimumab, and alemtuzumab
What percent of patients with sarcoidosis end up with cutaneous lesions?
35%
What initial workup is needed for a patient with cutaneous sarcoidosis?
CXR, PFTs, and regular eye exams
Clinical features of cutaneous sarcoid?
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
What is the most common distribution of lesions in cutaneous sarcoid?
Lesions tend to occur on the face (especially lips and nose), neck, and the upper half of the body
Lesions also tend to occur in areas with preexisting scars, piercings or tattoos
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?
Erythema nodosum: most important non-specific manifestation of sarcoidosis since it predicts a benign self-limited course
What are the most common areas of involvement in sarcoidosis outside of the skin?
- 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
What is the histopathology of sarcoid?
- 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
What is the Kveim-Siltzbach test?
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
What is lupus pernio?
Violaceous (vs red-brown) papules coalescing into infiltrative plaques. Occurs on the nose, earlobes, cheeks. It has a beaded appearance around the nasal rim.
What is the prognosis/clinical course of sarcoid in lupus pernio?
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
*is associated with bad prognosis
What is it called when patients have subcutaneous nodules that are found to be sarcoid?
Darier-Roussy
- presents with painless, firm, deep-seated, mobile nodules, 90% have hilar adenopathy and multiple lesions but it is associated with good prognosis
What lab/dx tests could be done for sarcoid?
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
What is Löfgren’s syndrome?
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
What is Heerfordt’s syndrome (uveoparotid fever)?
Uveitis + parotid gland enlargement + fever + cranial nerve palsy (usually cranial nerve)
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?
Mikulicz’s syndrome
- Can be seen in TB, sarcoid, Sjogren’s syndrome, lymphoma
What is it called if sarcoid is seen in a 5 y/o child?
Early-onset (<5 y/o) sarcoid-like disease; triad of skin, eye, and joint dz
What is the genetic mutation of Blau syndrome?
NOD2 mutation
What is the treatment for sarcoid?
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
For chronic skin-predominant disease hydroxychloroquine and chloroquine can be used
other: TNF-a inhibitors, MME, azathioprine, minocycline, and leflunomide
What treatment can be used for chronic skin-predominant sarcoid?
Hydroxychloroquine and chloroquine
What is the presentation of foreign body reactions?
Presents with inducrated red or red-brown papules coalescing into plaques +/- ulceration
basically any material that is resistant to being broken down by biologic processes
