Case 28

Male 35. Common variable immunodeficiency. Six

month history of slowly growing nodules right arm and

left lower leg (biopsied). Ziehl-Neelsen, PAS, Grocott

and Gram stains all negative. The best diagnosis is:

A. Necrobiosis lipoidica

B. Granulomas of immunodeficiency

C. Deep granuloma annulare

D. Atypical mycobacterial infection

E. Necrobiotic xanthogranuloma

HISTORY

Diagnosed in adulthood with common variable immunodeficiency as found to be panhypoglobulinaemic

Prior to diagnosis he had problems with recurrent ear, sinus and chest infections

HISTORY

6 month history of “insect bite” that had not healed on left lower leg and slowly become more crusty

HISTORY

• lesion on right arm had become red, raised and itchy

Case 28: Clinical differential diagnosis

Infection – bacterial such as ecthyma, leishmaniasis, TB, deep

fungus

But, multiple courses of various antibiotics for his chest had made

no difference to his skin lesions

Sarcoid

Lymphoma or other skin cancers (BCC)

So - biopsies taken from right arm and left shin for histology and

multiple cultures.

Punch biopsy skin left shin

Punch biopsy skin left shin

Punch biopsy skin right arm

Some granulomas more

well circumscribed,

“sarcoidal”

Some granulomas have central necrosis,

“necrotising granuloma”

Punch biopsy skin right arm

mixed granulomatous inflammation in both biopsies

necrotising, tuberculoid, sarcoidal and necrobiotic

granulomas present to varying degrees

No evidence of infection on special stains (Ziehl-Neelsen,

Gram, PAS and Grocott)

No evidence of infection on cultures including mycobacteria

Case 28: FINAL DIAGNOSIS Granulomas of immunodeficiency (Cutaneous non infectious granulomas in common variable immunodeficiency)

Management: Prednisolone 20mg daily for 2 weeks weaned

by 5mg every 2 weeks

Topical dermovate

Within 1 month

significantly better

After 1 month

of treatment Before

treatment

Management

Prednisolone 20mg daily for 2 weeks weaned by 5mg every 2

weeks

Topical dermovate

Within 1 month

Significantly better After 1 month of

treatment rbBefore

treatment

bbbbb

Follow up

Stopped steroid after 8 weeks and has had no further skin

issues to date

Lesions completely healed with scarring.

Repeat CT chest/abdo/pelvis has excluded internal

granulomas

No further skin lesions since (1 year later)

Case 28 differential diagnosis

necrobiosis lipoidica:

also shins,

full thickness dermis mainly with only

extension into subcutis;

also plasma cells, lymphocytes

Case 28 differential diagnosis

necrobiosis lipoidica: also shins, full thickness dermis mainly

with only extension into subcutis; also plasma cells, lymphocytes

necrobiosis lipoidica

Case 28 Differential diagnosis:

deep (subcutaneous) granuloma annulare

Case 28 Differential diagnosis:

deep (subcutaneous) granuloma annulare

10 year old girl.

Firm subcutaneous nodules on scalp.

necrobiotic granuloma

necrobiotic granuloma

Necrobiotic granuloma: loss of collagen and elastic fibres (elastic van Gieson)

deep (subcutaneous) granuloma annulare:

clinical features

• Children mainly, 1-6yrs especially, mean 4.7years.

• Present with sometimes tender nodule(s) 10-35mm on lower legs (shins) > scalp (occiput) > feet, buttocks, fingers, hands, forehead.

• Mobile (less so on scalp).

• Often misdiagnosed as tumour and 6 month average to diagnosis – get frozen sections from orthopaedics.

• A few have typical GA lesions.

• No rheumatoid arthritis or other A/I disease.

• Mostly regress within months to few yrs so don’t

need to treat but up to19% recur (same site).

• ?trauma related in some:

6/14 just started shoes/new shoes (Aberdeen study1).

• CT/MRI:confined to subcutis.

deep (subcutaneous) granuloma annulare:

histological features

• Multiple well circumscribed nodules of necrobiosis in subcutaneous tissue with

palisading macrophages around the nodules, mucin in centre, normal between.

• Loss of elastin. Little other inflammation.

• Often vascular spaces at edge of nodule

• Central mucin – grey/blue not eosinophilic like rheumatoid nodule

• Usually not recognized before biopsy unless paediatric

dermatologist, diagnosis often doubted especially if recurs.

• Unusual sites for necobiotic disorders a clue

Evans MJ, Blessing K, Gray ES.

Pseudorheumatoid nodule (deep granuloma annulare) of

childhood: clinicopathologic features of twenty patients.

Pediatr Dermatol. 1994 Mar;11(1):6-9

Differential diagnosis – infective granulomas e.g.

Atypical mycobacterial infection (such as M. chelonae infection)

also shows necrotising granulomas (and suppurative granulomas)

Differential diagnosis –

Necrobiotic xanthogranuloma

Br J Dermatol. 1994 Jan;130(1):118-20.

Cutaneous sarcoid-like granulomas in primary immunodeficiency disorders.

Levine TS(1), Price AB, Boyle S, Webster AD.

Author information:

(1)Department of Cellular Pathology, Northwick Park Hospital and Clinical Research

Centre, Harrow, Middlesex, U.K.

We report the occurrence of cutaneous sarcoid-like granulomas in one patient with

common variable immunodeficiency and another with 'thymoma and

hypogammaglobulinaemia'. To our knowledge, this is the first time that such skin

lesions have been described in patients with primary immunodeficiency. These

granulomas may be attributed to a combination of interleukin-2 deficiency and a

profound CD4 lymphopenia. The lesions are similar to the non-infectious 'papular

eruption' associated with human immunodeficiency virus infection, and might

reflect a common pathogenic mechanism.

COMMON VARIABLE IMMUNODEFICIENCY

X-LINKED AGAMMAGLONULINEMIA

ISOLATED IgA DEFICIENCY

HYPER IgM SYNDROME

Di GEORGE SYNDROME

SEVERE COMBINED IMMUNODEFICIENCY

IMMUNODEFICIENCY WITH THROMBOCYTOPENIA

AND ECZEMA

GENETIC DEFICIENCIES OF COMPLEMENT,

IMMUNODEFICIENCY SYNDROMES

Common variable Immunodeficiency

(CVID)

Low levels of most or all Ig classes

Lack of B lymphocytes or plasma cells that are capable of

antibody production

Frequent bacterial infections

Signs and symptoms of CVID

Recurrent bacterial infections The most common are sinusitis, pneumonia, bronchitis, otitis, conjunctivitis and

gastrointestinal infection.

Streptococcus and haemophilus most common

Autoimmune phenomena in 20-50% Rheumatoid arthritis/haemolytic anaemia/neutropaenia/thrombocytopaenia

Malignancy – B cell lymphomas

Granulomatous disease – skin and internal organs

Dermatologic manifestations of CVID

Alopecia areata.

Vitiligo

Skin granulomas - both sarcoid-like

(non-necrotising) and tuberculoid (necrotising)

Increased risk of actinic keratosis,

squamous cell carcinomas and melanoma.

Increased risk of polymorphic light eruption and atopic

dermatitis.

MANAGEMENT

All skin lesions suggestive of infection need biopsy

Imaging. This is likely to be required and may have to be

extensive, including different modalities (CT scanning, MRI)

according to the clinical manifestations of disease.

Management of granulomas

Exclude infection

Oral steroids

Other immunosuppressant's

TNF alpha antagonists

Take home message:

Non-infectious granulomas are not uncommonly seen in the

skin of patients with immunodeficiency disorders

Infection must be ruled out first

Treatment is with immunosuppressive agents eg steroids

Investigation for possible immunodeficiency should be

considered especially in children and young adults with

unusual granulomatous skin pathology.

Case 28

Male 35. Common variable immunodeficiency. Six

month history of slowly growing nodules right arm and

left lower leg (biopsied). Ziehl-Neelsen, PAS, Grocott

and Gram stains all negative. The best diagnosis is:

A. Necrobiosis lipoidica

B. Granulomas of immunodeficiency

C. Deep granuloma annulare

D. Atypical mycobacterial infection

E. Necrobiotic xanthogranuloma