Granulomatous dermatitis
Philip E. LeBoit, M.D.
Depts. of Pathology and Dermatology
Univeristy of California, San Francisco
Granulomatous dermatitis refers to inflammatory skin diaseases in which histiocytes
predominate, at least in some foci. In sarcoidal granulomatous dermatitis, histiocytes are present
in compact collections, with some lymphocytes, but with only a few lymphocytes around them.
In tuberculoid granulomatous dermatitis, infiltrates of lymphocytes are present around the
aggregates of histiocytes. In palisaded granulomatous dermatitis, histiocytes surround less
cellular areas. In suppurative and granulomatous dermatitis, histiocytes surround neutrophils,
both intact and degenerating. The differential diagnosis of that pattern is large, and contains
many infections. In diffuse histiocytic infiltrates, histiocytes are present throughout the reticular
dermis; some of these cases are examples of “histiocytoses”, poorly understood proliferations of
histiocytes or histiocyte-like cells, and others are infections, with parasitized histiocytes.
The key features in distinguishing among the palisaded granulomatous dermatitides are:
-the location of the infiltrates within the dermis/subcutis
-the material that the histiocytes are surrounding
-the presence of other types of inflammatory cells
Sarcoidal granulomatous dermatitis
Some important sarcoidal granulomatous dermatides are:
•
•
•
•
•
•
Lichen nitidus
Lichen striatus
Sarcoidosis
Crohn’s disease
Tuberculoid leprosy
Rosacea
Lichen striatus
Lichen striatus is a condition that presents as papules along Blaschko’s lines in children and in
adolescents, being rare in adults. It does not become widespread, and the importance of
recognizing it is largely to avoid the diagnosis of the many conditions it can mimic.
Histopathologic features:

Sarcoidal granulomas can occur, but usually do so in the company of a patchy
lymphocytic infiltrate in the papillary dermis and psoriasiform epidermal hyperplasia
1



Spongiosis can also be present
One can see many lymphocytes within the epidermis, simulating mycosis fungoides
The finding of lymphocytes around eccrine coils can be very helpful in confirming the
diagnosis
Gianotti R, Restano L, Grimalt R, Berti E, Alessi E, Caputo R.
Lichen striatus--a chameleon: an histopathological and immunohistological
study
of forty-one cases.
J Cutan Pathol. 1995 Feb;22(1):18-22.
Lichen nitidus
Lichen nitidus is a condition that is relatively common in dark skinned peoples, resulting in tiny
shiny flat topped papules, often on the dorsal hands or genitalia. Its small papules can be
confused with those of lichen planus, but are unrelated.
Histopathologic findings:



Small compact collections of histiocytes with variable numbers of lymphocytes in
widened dermal papillae
Slight epidermal hyperplasia
Vacuolar change, but not necrotic keratinocytes or colloid bodies in number
Be alert to this pattern, with lymphocytes and plasma cells in sun exposed skin- there is a variant
of polymorphous light eruption sometimes termed lichen nitidus actinicus or “pinpoint papular”
polymorphous light eruption that can cause these changes.
Bansal I, Kerr H, Janiga JJ, Qureshi HS, Chaffins M, Lim HW, Ormsby A.
Pinpoint papular variant of polymorphous light eruption: clinical and
pathological correlation.
J Eur Acad Dermatol Venereol. 2006 Apr;20(4):406-10.
Al-Mutairi N, Hassanein A, Nour-Eldin O, Arun J.
Generalized lichen nitidus.
Pediatr Dermatol. 2005 Mar-Apr;22(2):158-60.
Yanez S, Val-Bernal JF.
Purpuric generalized lichen nitidus: an unusual eruption simulating pigmented
purpuric dermatosis.
Dermatology. 2004;208(2):167-70.
Sarcoidosis
Sarcoidosis often presents in the skin before internal involvement is noted, and sometimes
remains confined to the skin. Its lesions are usually papules, nodules or plaques. A variant with
small papules is called “micropapular sarcoidosis”. Annular lesions are more common in dark
skinned patients. Subcutaneous lesions without dermal involvement can occur. Lesions on the
2
nose are termed lupus pernio, a confusing state of affairs, as pernosis (chilblains) can occur in
lupus erythematosus. A critical fact to be aware of is that foreign material can form the nidus for
the formation of granulomata in patients who are developing systemic sarcoidosis, and that the
finding of foreign material in a sarcoidal granulomatous dermatitis does not rule out sarcoidosis.
Histopathologic features:







“Naked” granulomas, in which histiocytes abut the collagen bundles of the reticular
dermis are typical, but are not always present
Lymphocytes are present in number in some cases, resulting ain a tuberculoid pattern
Necrosis, neutrophils, plasma cells, granulomas along nerves are variable features
Ichthyosiform sarcoidosis features lamellar hyperkeratosis above the epidermal surface
Granulomas can be present around follicles, eliciting a differential diagnosis of
granulomatous rosacea
There are endogenous refractile crystals in the granulomata of sarcoidosis, but the finding
of authentic foreign material does not rule out sarcoidosis!!!!
Subcutaneous sarcoidosis is often accompanied by fibrosis in between the granulomatous
foci, to a greater extent than its mimic, erythema nodosum
Mangas C, Fernandez-Figueras MT, Fite E, Fernandez-Chico N, Sabat M, Ferrandiz
C.
Clinical spectrum and histological analysis of 32 cases of specific cutaneous
sarcoidosis.
J Cutan Pathol. 2006 Dec;33(12):772-7.
Ball NJ, Kho GT, Martinka M.
The histologic spectrum of cutaneous sarcoidosis: a study of twenty-eight
cases.
J Cutan Pathol. 2004 Feb;31(2):160-8.
Callen JP.
The presence of foreign bodies does not exclude the diagnosis of sarcoidosis.
Arch Dermatol. 2001 Apr;137(4):485-6.
Marcoval J, Mana J, Moreno A, Peyri J.
Subcutaneous sarcoidosis--clinicopathological study of 10 cases.
Br J Dermatol. 2005 Oct;153(4):790-4.
Ahmed I, Harshad SR.
Subcutaneous sarcoidosis: is it a specific subset of cutaneous sarcoidosis
frequently associated with systemic disease?
J Am Acad Dermatol. 2006 Jan;54(1):55-60.
Resnik KS.
The findings do not conform precisely: fibrosing sarcoidal expressions of
panniculitis as example.
Am J Dermatopathol. 2004 Apr;26(2):156-61.
3
Tuberculoid leprosy
Tubercuoloid leprosy occurs in patients with a high degree of immunity to M. Leprae. There are
usually only a few lesion, often asymmetrically distributed. Sharply bordered plaques are
characteristic, often with atrophic centers. Pigmentation may be lost in long standing lesions.
There is often hypoesthesia in affected skin.
Histopathologic features:




Sarcoidal granulomas
Some granulomas can abut the the undersurface of the epidermis (loss of the Grenz zone)
Either histiocytes or lymphocytes around nerves, with destruction of nerves
Few bacilli or none on special stains
TUBERCULOID GRANULOMATOUS DERMATITIS
Tuberculosis
The lesions of cutaneous tuberculosis pose much less of a problem for clinicians and
histopathologists than they did in past years. The main clinical challenge in the developed world
is recognizing that a patient might have cutaneous TB.
The clinical manifestations range from tuberculous chancres in children, to warty lesions of
tuberculosis verrucosa cutis in immunocompetent adults, to lesions caused by direct extension
from lymph nodes (scrofuloderma) to a lesion of hematogenous origin, lupus vulgaris.
The histopathologic findings in cutaneous TB vary depending on the type of lesion biopsied.




Irregular hyperplasia and hyperkeratosis of the dermis overlying granulomata in
tuberculosis verrucosa
Epidermal hyperplasia or atrophy overlying granulomata in lupus vulgaris
Atropy or ulceration in scrofuloderma
Acid fast organisms are often not demonnstrable in tissue sections, and may be
impossible to find, esp. in lupus vulgaris
The role of polymerase chain reaction (PCR) is debatable, with some labs reporting good and
others bad results.
K. C. Umapathy, R. Begum, G. Ravichandran, F. Rahman, C. N. Paramasivan, V. D.
Ramanathan
Comprehensive findings on clinical, bacteriological, histopathological and
therapeutic aspects of cutaneous tuberculosis
Tropical Medicine & International Health 2006
11 (10), 1521–1528.
4
Lichen nitidus was discussed in the section on sarcoidal granulomatous dermatitis. Sometimes it
presents with a tuberculoid pattern.
Lichen striatus was also discussed in the section on sarcoidal granulomatous dermatitis.
Sometimes it too presents with a tuberculoid pattern.
Rosacea
Rosacea is a common condition usually involving the central face, with papules, telangiectases or
both. The papular form is the one that is usually biopsied, often to rule out other conditions.
Extrafacial rosacea can affect the hair bearing skin at other sites.
Histopathologic features:



Perifollicular lymphocytes, histiocytes, histiocytic giant cells and plasma cells
Slight spongiosis of follicular infundibula
Neutrophils can be present in early lesions (pustules)
Rosacea and the perifollicular variant of sarcoidosis can be difficult to distinguish. The presence
of plasma cells is more common in rosacea, but they are present in a small number of lesions of
sarcoidosis. Histiocytes palisade around small foci containing degenerated collagen and fibrin in
both conditions, and this finding is a consistent one in the form of rosacea-like dermatitis termed
lupus miliaris disseminatus faciei .
el Darouti M, Zaher H.
Lupus miliaris disseminatus faciei--pathologic study of early, fully
developed,
and late lesions.
Int J Dermatol. 1993 Jul;32(7):508-11.
Deep fungal infections can result in a pattern of tuberculoid granulomatous dermatitis. As they
more often are suppurative and granulomatous, they will be considered later.
PALISADED GRANULOMATOUS DERMATITIS
Granuloma annulare (GA)
GA is one of the protean diseases in dermatology- a condition with many clinical variants.
Because it is one of the most common inflammatory skin diseases, and one of the most
commonly biopsied ones, it is particularly important that pathologists be able to recognize it
microscopically.
Clinical features

Patients are usually well (rarely, GA is associated with systemic diseases)
Localized disease is the most common form
5




-annular plaques made up of white, tan or pink papules
-resolution in most cases after a few years, even without treatment
Generalized papules (often umbillicated), associated in some cases with diabetes
Deep GA
-subcutaneous nodules, often in children
-misdiagnosis as rheumatoid nodule common
Macular GA
-dusky, erythematous patches
-misdiagnosis as morphea, mycosis fungoides, erythema multiforme
Actinic GA (actinic granuloma of O’Brien, annular elastolytic granuloma)
-Annular lesions in sun damaged skin
-Controversy: entity sui generis, or variant of GA
Histopathologic features

“Interstitial GA”
-May be early changes in other types of GA
-Lymphocytes around small vessles, histiocytes between collagen bundles
-Interstitial mucin (Alcian blue, colloidal iron positive, pH 2.5) in areas of histiocytes
`Differential diagnoses: Morphea, reticular erythematous mucinosis (REM), interstitial pattern of
mycosis fungoides

Palisaded GA
-Superficial and deep perivascular lymphocytic infiltrates
-Interstitial histiocytes
-Rings of histiocytes surrounding degenerating (and regenerating collagen) and mucin
-A few neutrophils and some dust around necrotic venules in the centers of granulomas (rare)
Differential diagnosis: Necrobiosis lipoidica, rheumatoid nodule, palisaded neutrophilic and
granulomatous dermatitis, others

Deep GA
-Large oval mass of histiocytes surrounding less cellular area
-Degenerating collagen and mucin in the center, but more brightly eosinophlic than in
conventional palisaded granuloma annulare
Differential diagnosis: Rheumatoid nodule, phaeohyphomycotic cyst

Actinic GA
-Palisaded histiocytes around fibrosis
-Giant cells commonly present
-Elastotic material in cytoplasm of giant cells
-Elastic tissue absent from centers of granulomatous foci
Al-Hoqail IA, Al-Ghamdi AM, Martinka M, Crawford RI.
Actinic granuloma is a unique and distinct entity: a comparative study with
granuloma annulare.
Am J Dermatopathol. 2002 Jun;24(3):209-12.
6
Patterson JW.
Rheumatoid nodule and subcutaneous granuloma annulare. A comparative
histologic
study.
Am J Dermatopathol. 1988 Feb;10(1):1-8.
Necrobiosis lipoidica
Necrobiosis lipoidica, formerly or more fully called necrobiosis lipoidica diabeticorum is mostly
but not exclusively found in patients with diabetes mellitus.
Clinical features Most lesions bilaterally on shins
 Early lesions are red papules with sharp borders
 Later, yellow, hard atrophic plaques
 60% have frank diabetes, another 20% abnormal glucose tolerance or +FH
Histopathologic features (fully developed lesions)
 Palisaded granulomatous inflammation involving whole dermis (top to bottom and side to
side, with layered appearance)
 Degenerated collagen early, fibrosis in established lesions
 Superficial and deep infiltrates of lymphocytes and plasma cells around vessels
 Secondary necrosis of follicles (rupture leads to suppurative foci in rare cases)
 Neutrophlic dust in centers of some lesions, no mucin
 Extension of process into septa of subcutis if biopsy is deep enough
Differential diagnosis: GA, necrobiotic xanthogranuloma
Histopathologic features (late lesions)
 Rings of histiocytes become less cellular
 Fibrosis>degenerated collagen, with thick collagen bundles
 Lymphocytes and plasma cells less notable
 Elastic tissue lost (unlike morphea)
Differential diagnosis: Morphea, late stage of palisaded neutrophilic and granulomatous
dermatitis
Comment: I did not list the features of early lesions of NLD as they are seldom biopsied. NLD
may begin as a small vessel leukocytoclastic vascuilitis, and even older lesions can have
neutrophils or histiocytes in the walls of damaged vessels.
Peyri J, Moreno A, Marcoval J.
Necrobiosis lipoidica.
Semin Cutan Med Surg. 2007 Jun;26(2):87-9.
7
Rheumatoid nodule
Rheumatoid nodule (RN) is a condition usually found in patients with rheumatoid arthritis or
other collagen vascular diseases. They are particularly common among patients with rheumatoid
arthritis (20-30%) and lupus (upto 7%). They usually occur in patients with established disease,
so the diagnosis of RN should be made with caution if there is no known collagen vascular
disease.
Clinical features
 Symmetrical papules and nodules
 Usually subcutaneous, sometimes fixed to tendons
 Skin color unchanged, sometimes yellow (simulating xanthomas)
 Extensive disease with joint destruction (rheumatoid nodulosis)
Histopathologic features
 Large oval mass in deep dermis/subcutis
 Palisaded histiocytes surrounding degenerated collagen, large amounts of fibrin, neutrophils
and nuclear dust
 Mucin scant or absent
 Vasculitis in adjacent vessels rarely
Comment: As noted above, RN is seldom a surprise. Most rheumatologists taking care of
patients with rheumatoid arthritis or lupus make this diagnosis clinically. The vast majority of
diagnoses of RN in well children are misdiagnoses of deep GA!
Garcia-Patos V.
Rheumatoid nodule.
Semin Cutan Med Surg. 2007 Jun;26(2):100-7.
8
Palisaded neutrophilic and granulomatous dermatitis
Palisaded neutrophilic and granulomatous dermatitis (PNGD) is my attempt to define a disease
spectrum described in patients with systemic diseases of various kinds. Terms such as
rheumatoid papules, Churg-Strauss granuloma, extravascular necrotizing granuloma and
Winkelmann granuloma also refer to this condition.
The range of systemic diseases in patients with PNGD includes patients with:






Sytemic lupus erythematosus
Rheumatoid arthritis (incl. seronegative cases)
Wegener’s granulomatosis
Lymphoma/leukemia
Inflammatory bowel disease
Systemic vaculitis (incl. Takayasu arterititis, Chrug Strauss disease)
In one study, 21/22 patients with the condition on biopsy had evidence of a systemic disease.
The main clinical presentation is of small, umbillicated papules on the dorsal aspects of joints,
esp. those of the fingers, elbows and knees.
The salient histopathologic features differ for each stage of PNGD:
Early:


Fibrin around vessel walls
Neutrophils and abundant nuclear debris around vessels around fibrin
Fully developed:



Palisaded histiocytes around neutrophils and their debris
Thick, but discolored collagen bundles
Evidence of vasculitis, sometimes
Late:


Palisaded histiocytes around zones of fibrosis with few neutrophils
No vasculitis
Comment: There are several other unusual clinical and histopathologic patterns that may overlap
with the stereotypic picture noted herein.
“Interstitial granulomatous dermatitis with arthritis” (IGDA) was described by Bernard
Ackerman, with several detailed report by Long et al.. and Verneuil and colleagues. The clinical
9
presentations included subcutaneous cords and erythematous plaques, in contrast to those noted
above. There are interstitially distributed histiocytes, with or without a palisaded pattern, but in
the reported cases, no evidence of vasculitis. Interstitial neutrophils and eosinophils are also
present. However, the diseases associated with this pattern overlap considerably with those seen
in PNGD.
“Interstitial granulomatous drug eruption” has large interstitial histiocytes, and a more subtle
palisaded pattern than does PNGD. It presents with dusky eythema in flexural areas. There are
small foci in which degenerated neutrophils and/or eosinophils are present. The reported causes
include non-steroidal anti-inflammatory medications. An unusual drug eruption manifesting as
papules in patients receiving methotrexate also has many interstitial histiocytes, but presents with
erythematous papules. Palisaded foci surrounding degenerated neutrophils and eosinophils are
not yet reported, but histiocytes form rosettes that surround and adhere to thick collagen bundles,
demarcated from the rest of the dermis by clefts. A similar arrangement can occur in PNGD and
in IGDA.
Finan MC, Winkelmann RK. The cutaneous extravascular necrotizing granuloma (Churg-Strauss granuloma) and
systemic disease: a review of 27 cases. Medicine (Baltimore) 1983 May;62(3):142-58
Chu P, Connolly MK, LeBoit PE. The histopathologic spectrum of palisaded neutrophilic and granulomatous
dermatitis in patients with collagen vascular disease. Arch Dermatol 1994 Oct;130(10):1278-83
Wilmoth GJ, Perniciaro C. Cutaneous extravascular necrotizing granuloma (Winkelmann granuloma): confirmation
of the association with systemic disease. J Am Acad Dermatol 1996 May;34(5 Pt 1):753Ackerman AB, Guo Y, Vitale PA< Vossaert K. Clues to diagnosis in dermatopathology. Vol. 3. ASCP Press, Lea
& Febiger, 1994;34-7.
Long D, Thiboutot DM, Majeski JT, Vasily DB, Helm KF Interstitial granulomatous dermatitis with arthritis. J Am
Acad Dermatol 1996 Jun;34(6):957-61
Verneuil L, Dompmartin A, Comoz F, Pasquier CJ, Leroy D. Interstitial granulomatous dermatitis with cutaneous
cords and arthritis: a disorder associated with autoantibodies. J Am Acad Dermatol 2001 Aug;45(2):286-91
Perrin C, Lacour JP, Castanet J, Michiels JF. Interstitial granulomatous drug reaction with a histological pattern of
interstitial granulomatous dermatitis. Am J Dermatopathol 2001 Aug;23(4):295-8
Goerttler E, Kutzner H, Peter HH, Requena L. Methotrexate-induced papular eruption in patients with rheumatic
diseases: a distinctive adverse cutaneous reaction produced by methotrexate in patients with collagen vascular
diseases. J Am Acad Dermatol 1999 May;40(5 Pt 1):702-7
Necrobiotic xanthogranuloma with paraproteinemia
Necrobiotic xanthogranuloma with paraproteinemia (NXG) is a rare condition, but one that is
important to recognize as it can maim patients, and some patients have died of its complications.
Its name refers to its infiltrates of foamy histiocytes, zones of necrobiosis (degenerating and
regenerating collagen) and frequent paraproteinemia. Despite the paraprotein, and the rare
eventuation of myeloma in patients with NXG, it seems to be an inflammatory and not a
neoplastic condition.
10
Clinical features:
 Yellow plaques on limbs, with perioccular/periorbital lesions in most patients
 Progression of lesions in some patients
 Hyperlipidemia/hypercholesterolemia
 Many patients diabetic
 Serum paraprotein (usually IgG )
 Loss of limbs or eye possible
Histopathologic features
 Infiltrate mid- and deep dermis, and both subcutaneous lobules and septa
 Superficial and deep perivascular infiltrates of lymphocytes and plasma cells, sometimes very
dense
 Lymphoid follicles
 Palisaded foamy histiocytes surrounding homogeneous eosinophilic material
 Foamy histiocytes and Touton giant cells in subcutis (“Touton cell panniculitis”)
 Giant cells with scalloped margins
 Cholesterol clefts surrounded by rings of foamy histiocytes (cholesterol granulomas)
Comment: NXG is often mistaken for NLD, as both can present as yellow plaques on the limbs
of diabetic patients. Cholesterol clefts surrounded by foamy histiocytes are practically
pathognomomonic of the condition. Cholesterol clefts were present in3/331 specimens of NLD
in one study, but not surrounded by foamy macrophages and Touton giant cells. While there are
no magically effective treatments for NXG, the potential loss of an eye, and rare compromised of
vasculature of a limb make a misdiagnosis of NLD a poor show.
Kossard S & Winkelmann RK. Necrobiotic xanthogranuloma
with paraproteinaemia. J Am Acad Dermatol 1980; 3: 257–70.
Gibson LE, Reizner GT, Winkelmann RK. Necrobiosis lipoidica
diabeticorum with cholesterol clefts in the differential diagnosis of
necrobiotic xanthogranuloma. J Cutan Pathol 1988; 15: 18–21.
Chave, T. A. & Hutchinson, P. E.Necrobiotic xanthogranuloma with two
monoclonal paraproteins and no periorbital involvement at presentation.
Clinical & Experimental Dermatology 26 (6), 493-496.
Gout
Clinical features
 White to yellow papules or nodules above joints, rims of helices
 Extrusion of chalky material in some cases
Histopathologic features
 Palisaded histiocytes, foreign body giant cells at periphery
 Needle like crystals in center, some nuclear dust as well
 While alcohol fixation preserves crystals the best, formalin adequate in most cases
11
Differential diagnosis: Eruptive xanthoma, oxalosis
Walsh NM, Murray S, D'Intino Y. Eruptive xanthomata with urate-like crystals.
J Cutan Pathol. 1994 Aug;21(4):350-5.
Spiers EM, Sanders DY, Omura EF. Clinical and histologic features of primary oxalosis.
J Am Acad Dermatol. 1990 May;22(5 Pt 2):952-6.
Palisaded granulomatous reactions to foreign material
Histiocytes can be radially arranged around a variety of foreign substances, including suture
material, beryllium, and injectable (bovine) collagen. The mechanism by which the dermis is
altered in some of these reactions is unclear.
Alguacil-Garcia A. Necrobiotic palisading suture granulomas simulating rheumatoid
nodule. Am J Surg Pathol 1993 Sep;17(9):920-3
Stegman S, Chu S, Armstrong RC. Adverse reactions to bovine collagen implant. Clinical and
histologic features. J. Dermatol. Surg. Oncol. 1988:14(suppl.1: 39-48
SUPPURATIVE AND GRANULOMATOUS DERMATITIS
Suppurative and granulomatous dermatitis is the most common pattern seen in cutaneous
infections, and the specific diagnosis rests on identification of the infectious agent. Conventional
bacteria, mycobacteria, filamentous bacteria, fungi, algae and protozoans can all cause this
pattern, and I will show only a few examples, as a comprehensive exposition would cover most
of infectious skin disease.
This pattern can also be seen in reactions to foreign material (e.g. splinters, cactus spines, etc.)
and to material perceived as foreign (extruded corneocytes from ruptured cysts).
DIFFUSE HISTIOCYTIC INFILTRATES
As noted above, diffuse infiltrates of histiocytes are present in the diverse conditions known as
the “histiocytoses”. Some of these represent proliferations of conventional monocytes-derived
melanophages, while others are proliferations of more specialized but related cells, such as sinus
histiocytes in Rosai-Dorfman disease.
Parasitized histiocytes can cause nodular or diffuse infiltrates of the skin, especially in
lepromatous leprosy and in leishmaniasis.
12