Non-infectious granulomatousdermatitis: a clinicopathological study

Background: Granulomatous dermatitis frequently presents a diag-nostic challenge to dermatopathologists because an identical histologicpicture is produced by several causes, and conversely, a single causemay produce varied histologic patterns.Methods: A retrospective analysis of skin biopsies received over aperiod of 7 years was performed, and cases of non-infectiousgranulomatous dermatitis diagnosed on histopathological examinationwere retrieved.Results: Out of a total of 586 cases of granulomatous dermatitis, 71cases (12.11%) were categorized as non-infectious granulomatousdermatitis on the basis of clinicopathological findings. Furthersubcategorization was done based on morphology of granulomas asepithelioid granulomas; 15 cases of sarcoidosis, 21.1%, one case ofCrohn’s vulvitis, 1.4%, necrobiotic granulomas; 11 cases of granulomaannulare, 15.4%, two cases of rheumatoid nodule, 2.8%, 10 cases offoreign body granulomas, 14.0%; 32 cases of miscellaneous group, 45%.Conclusions: Morphology alone is seldom specific and cannot beused as a diagnostic tool for identification of specific diseases. Adequateclinical data and work up in combination of pathological resources canhelp in elucidation of specific etiology of granulomatous dermatitis.

Mohan H, Bal A, Dhami GP. Non-infectious granulomatous dermatitis:a clinicopathological study.J Cutan Pathol 2006; 33: 767–771. # Blackwell Munksgaard 2006.

Harsh Mohan1, Amanjit Bal2

and G. P. Dhami3

1Department of Pathology,2Department of Pathology, and3Department of Dermatology, GovernmentMedical College & Hospital, Chandigarh, India

Dr Harsh Mohan, Professor and Head, Departmentof Pathology, Government Medical College,Sector-32-A, Chandigarh 160030, IndiaTel: þ91 172 2665253x1050e-mail: drharshmohan@yahoo.com

Accepted for publication January 17, 2006

Introduction

Granulomatous dermatitis is a pattern of reaction tovarious organic and inorganic antigens. Accordingto the current concept, ‘granuloma’ is defined as ‘afocal chronic inflammatory response to tissue injurycharacterized by collection of activated histiocytes,epithelioid cells, and multinucleate giant cells thatmay or may not be rimmed by lymphocytes and/orshow central necrosis.1

Granulomatous dermatitis frequently presents adiagnostic challenge to dermatopathologists becausean identical histologic picture is produced by severalcauses, and conversely, a single cause may producevaried histologic patterns.2,3 Moreover, it is difficultto present a completely satisfactory classification ofgranulomatous dermatitis. This study aims at classi-fying non-infectious granulomatous dermatitis basedon etiology and morphology of granulomas and tohighlight significance of clinical correlation in mak-ing a specific diagnosis.

Materials and methods

A retrospective analysis of skin biopsies received inthe department of Pathology, Government MedicalCollege, Chandigarh, over a period of 7 years wasperformed, and cases of non-infectious granuloma-tous dermatitis diagnosed on histopathologicalexamination were retrieved.Clinical information like appearance and dura-

tion of lesion and clinical diagnosis were recorded.In each case haematoxylin and eosin stained paraffinsections along with special stains, like periodic-acidSchiff (PAS), alcian blue, reticulin, phosphotungsticacid hematoxylin (PTAH), Ziehl Neelsen stain, andso on, were studied.

Observations

A total of 586 cases of granulomatous dermatitiswere retrieved. Out of these, on the basis of clinico-pathological findings, 71 cases (12.11%) were

J Cutan Pathol 2006: 33: 767–771doi: 10.1111/j.1600-0560.2006.00566.xBlackwell Munksgaard. Printed in Singapore

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categorized as non-infectious granulomatous derma-titis. The age of the patients ranged from 2 to 85years with a male to female ratio of 1.9:1. Casesincluded in non-infectious granulomatous dermatitisare summarized in Table 1.This group was further subcategorized based on

morphology of granulomas as under (i) Epithelioid/sarcoid granulomas, characterized by circumscribedcollections of epithelioid histiocytes without necrosisand scant mononuclear cell infiltrate (15 cases ofsarcoidosis, 21.1%; Fig. 1, one case of Crohn’s vul-vitis, 1.4%). (ii) Necrobiotic granulomas, havingareas of collagen degeneration which appeared aspale staining areas or central fibrinoid necrosisappearing bright pink on routine hematoxylin andeosin stained sections. This degeneration wasaccompanied by granulomatous reaction in theform of palisading histiocytes and multinucleategiant cells (11 cases of granuloma annulare, 15.4%;Fig. 2, two cases of rheumatoid nodule, 2.8%;Fig. 3, one case of interstitial granulomatous derma-titis, 1.4%; Fig. 4). (iii) Foreign body granulomashaving epithelioid granulomas and foreign body ingiant cells (10 cases, 14.0%; Fig. 5). (iv)Miscellaneous group included three cases of xantho-granuloma, 11 cases of granulomatous rosaceaincluding cases of lupus miliaris disseminatus faciale(Fig. 6), one case of Langerhans’ histiocytosis, threecases of granulomatous cheilitis, and 13 cases ofnon-specific granulomas. Xanthogranuloma showedcollections of foamy histiocytes with touton giant

cells. Granulomatous rosacea was chracterized byvascular dilatation and perivascular and perifollicu-lar lymphoplasmacytic infiltrate admixed with gran-ulomas. Lupus miliaris disseminatus faciei, a variantof granulomatous rosacea showed areas of caseationnecrosis. One such case with extensive areas ofcaseation necrosis was wrongly diagnosed as cuta-neous tuberculosis. Langerhans’ histiocytosis showedclassical Langerhans’ histiocytes with cereberiformnuclei in a polymorphic background. In granuloma-tous chelitis, classical location, presence of oedema,and dilated lymphatics in addition to granulomaswas diagnostic. Thirteen cases could not be placedin any specific category even after clinicopathologi-cal correlation.

Discussion

Granulomatous inflammation is a chronic inflam-matory process in response to an antigen. There isconsiderable variation in the microscopic appear-ance of granulomas producing different morpholo-gic pictures within the same biopsy or from onelesion to another.It is difficult to present a completely satisfactory

classification of granulomatous dermatitis. It hasbeen previously classified on the basis of pathophy-siology, etiology, immunology, and morphology.2 Inthis study, granulomatous dermatitis was classifiedusing combination of etiology and morphology ofgranuloma.

Table 1. Clinicohistopathological categorization of non-infectious granulomatous dermatitis

S.No. Age range (Years) Sex ratio (M : F)Clinical diagnosis(number of cases) Histopathological diagnosis

Number of cases(n ¼ 71)

1. Epithelioid/sarcoid granulomas 16 (22.5%)11–66 6:9 Sarcoidosis (12)

Lymphocytoma cutis (1)Foreign body granuloma (1)Dermatofibroma (1)

Sarcoidosis 15

48 0:1 Granulomatous vulvitis(known case of Crohn’s)

Crohn’s vulvitis 1

2. Necrobiotic granulomas 14 (19.7%)5–65 7:4 Granuloma annulare (10)

Pyoderma gangrenosum (1)Granuloma annulare 11

18–53 2:0 Rheumatoid nodule (2) Rheumatoid nodule 254 0:1 Churg–Strauss syndrome (1) Interstitial granulomatous dermatitis 1

3. 21–65 3:7 Discharging sinus (4), non-healingulcer (2), keloid (1), swelling (3)

Foreign body granuloma 10 (14%)

4. Miscellaneous group 31 (43.6%)21–52 4:2 Granulomatous rosacea (6) Granulomatous rosacea 622–46 3:2 Lupus miliaris disseminatus faciei (4)

Lymphocytoma cutis (1)Lupus miliaris disseminatus faciei 5

2–50 2:1 Xanthogranuloma (2)Fibroma (1)

Xanthogranuloma 3

35–45 2:1 Granulomatous chelitis (3) Granulomatous chelitis 318 1:0 Lipoma (1) Langerhans’ histiocytosis 114–70 4:9 Non-healing ulcer (4), tuberculosis (4),

sarcoidosis (2), discoid lupus erythematosis (1),granuloma annulare (1), folliculitis (1)

Non-specific granulomas 13

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Non-infectious granulomatous dermatitis hasbeen categorized on the basis of granulomatousreaction pattern into four distinct types; (i) epithe-lioid granulomas (tuberculoid and sarcoidal), (ii)necrobiotic/palisading granulomas, (iii) foreignbody granulomas, and (iv) histiocytic granulomas.Sarcoidosis, a multisystem disease, has cutaneous

lesions in 20–35% cases and is the prototype ofsarcoidal granulomas.4,5 Morphologically, it is char-acterized by compact non-caseating, lymphocytepoor, naked epithelioid cell granulomas with a for-eign body and Langhans’ type of giant cells. Giantcells may contain star-shaped eosinophilic structures(asteroid body) and laminated calcified bodies (con-choid/Schaumann bodies). Sarcoid granulomas arereticulin rich with reticulin fibers surrounding andpermeating the epithelioid granulomas (Fig. 1B). Inthe present series, two cases were associated withprevious history of trauma, thus representing clinicalvariant scar sarcoidosis.6 Cutaneous tuberculosisforms an important differential diagnosis of epithe-lioid cell granulomas as absence of caseation

necrosis does not rule out tuberculosis. In suchcases, clinical investigations like X-ray chest andserum calcium levels are required for confirmation.7

Similar epithelioid granulomas may be seen inmetastatic Crohn’s disease. Skin involvement inCrohn’s disease occurs in 10–20% of patients andcommonly involves perianal skin, vulva, and in rareinstances distant sites.8 One case in our series waslabeled as Crohn’s vulvitis because of location andhistopathological documentation of Crohn’s diseasein intestine.‘Necrobiosis’ refers to focal alteration or degen-

eration of collagen and is surrounded by palisadinghistiocytes forming necrobiotic granulomas. Thisgroup is further divided into two categories.

Fig. 1. (A) Photomicrograph showing circumscribed collections

of epithelioid histiocytes without necrosis and scant mononuclear

cell infiltrate in sarcoidosis (hematoxylin and eosin, �100).

(B)Reticulin-rich granulomas (reticulin stain).

Fig. 2. Photomicrograph of granuloma annulare with characteristic

central necrobiotic areas containing basophilic stringy mucin

surrounded by palisading inflammatory cells (hematoxylin and

eosin, �40).

Fig. 3. Photomicrograph of rheumatoid nodule showing character-

istic central area of fibrinoid degeneration surrounded by palisading

histiocytes (hematoxylin and eosin, �100).

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769

1. ‘Blue collegenolytic granulomas’9 which havecentral basophilic area either due to deposi-tion of mucin or nuclear dust and includes,granuloma annulare (GA), rheumatoid vascu-litis, and Wegener’s granulomatosis.

2. ‘Red collegenolytic granulomas’10 which havecentral eosinophilic area due to hyalinizedcollagen, fibrin, or degranulated eosinophilsand includes, necrobiosis lipoidica, necrobioticxanthogranuloma, rheumatoid nodule, Churg–Strauss syndrome, and eosinophilic cellulitis.

In the present series, there were 11 cases of GA.Granuloma annulare has characteristic centralnecrobiotic areas containing basophilic stringymucin surrounded by palisading inflammatory cellsin the superficial and mid-dermis. Alcian blue andcolloidal iron stains aid in highlighting themucin.11,12 GA has to be differentiated from rheu-matoid nodule which occurs in 20% of patients withrheumatoid arthritis as an extra-articular cutaneousmanifestation.13 Microscopic examination showscharacteristic central irregular large areas of fibri-noid degeneration which has homogeneous, brighteosinophilic appearance surrounded by palisadinghistiocytes. Fibrinoid necrosis can be highlightedby PTAH stain.The present series included one case of interstitial

granulomatous dermatitis, a rare type of reactionpattern seen in systemic disorders like systemiclupus erythematosus, rheumatoid, Wegener’s gran-ulomatosis, and so on.14,15 This case was clinicallydiagnosed as Churg–Straus syndrome; there wasdense neutrophilic infiltrate and collagen degenera-tion with leukocytoclastic vasculitis and palisadedextravascular granulomas.

Foreign body granulomas also resemble epithe-lioid granulomas with relative abundance of giantcells. For diagnosis, identification of polarizing/non-polarizing foreign body within giant cells is must.16

Foreign body was demonstrated in all 10 cases ofpresent series which included one case showing for-eign body granulomas in response to steroidsinjected in keloid.17

Miscellaneous group was constituted by lesionsthat may sometimes show granulomatous reactionpattern. Of these, granulomatous rosacea and itsvariant lupus miliaris disseminatus faciei formedthe major group. One case of lupus miliaris disse-minatus faciei with classical flesh-colored papules onface was wrongly diagnosed as cutaneous tubercu-losis because of extensive areas of caseationnecrosis.18

Fig. 4. Photomicrograph of interstitial granulomatous dermatitis

showing dense collagen degeneration with leukocytoclastic vasculitis

and palisaded extravascular granulomas (hematoxylin and

eosin, �100).

Fig. 5. Photomicrograph showing foreign body granulomas in

response to steroids injected in keloid (hematoxylin and

eosin, �100).

Fig. 6. Photomicrograph of lupus miliaris disseminatus faciei show-

ing extensive areas of caseation necrosis, resembling tuberculous

granulomas (hematoxylin and eosin, �100).

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Conclusions

There is a significant overlap in histolopathologicpicture of different granulomatous reactions. Thus,morphology alone is seldom specific and cannot beused as diagnostic tool for identification of specificdiseases. In this study, combination of clinicalimpression and morphology was useful for makingdefinite diagnosis in most of the cases while in 17cases morphology alone helped in making definitediagnosis where clinical impression was wrong.Thus, adequate clinical data and work up in combi-nation of pathological resources can help in elucida-tion of specific etiology and good clinicopathologiccorrelation.

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