|Year : 2017 | Volume
| Issue : 1 | Page : 37-42
Noninfectious granulomatous dermatoses: A puzzle for dermatologists and histopathologists
Sumit Grover1, Shubangi Vinayak Agale2, Grace D'Costa2, Arvind G Valand3
1 Department of Pathology, Dayanand Medical College and Hospital, Ludhiana, Punjab, India
2 Department of Pathology, Grant Government Medical College, Mumbai, India
3 Department of Pathology, Swami Ramanand Tirth Rural Government Medical College, Ambajogai, Maharashtra, India
|Date of Web Publication||17-Jan-2017|
Department of Pathology, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana - 141 001, Punjab
Source of Support: None, Conflict of Interest: None
Background: Noninfectious granulomatous dermatoses (NGDSs) are a broad group of distinct reactive inflammatory conditions that share clinical as well as histological similarities. Because of these similarities, these lesions pose a diagnostic difficulty to naοve and even expert dermatologists and pathologists and need a clinicopathological correlation. Aims and Objectives: We aimed at determining the histopathological profile of NGDS in Western Indian population correlating it with morphology, age, and anatomic distribution with an attempt to find the etiology. Materials and Methods: In a prospective study conducted over 2 years in a tertiary care referral center in Mumbai, out of 1872 skin biopsies received, 29 histopathologically diagnosed cases of NGDS were selected and studied for histopathological features of granuloma. A clinico-histopathological correlation was attempted. Results: Out of the total 1872 skin biopsies received in our department in 2 year period, 29 biopsies were histopathologically diagnosed as NGDS of which necrobiotic granulomas (n = 14) were the most common diagnosis which included granuloma annulare (78.57%), necrobiosis lipoidica (14.29%), and rheumatoid nodule (7.14%). Other frequently diagnosed lesions were sarcoidosis (13.79%), actinic granuloma (10.34%), erythema nodosum (6.89%), and erythema induratum (3.44%). Conclusions: Various NGDS exhibit histopathological features with considerable overlap. However, their knowledge is must to understand the clinical behavior. Similarly, detailed clinical history and examination of early and mature lesions help in differentiating between lesions sharing similar histological features.
Keywords: Erythema nodosum, granuloma annulare, granulomatous dermatosis, necrobiosis lipoidica, noninfectious, sarcoidosis
|How to cite this article:|
Grover S, Agale SV, D'Costa G, Valand AG. Noninfectious granulomatous dermatoses: A puzzle for dermatologists and histopathologists. J Med Soc 2017;31:37-42
|How to cite this URL:|
Grover S, Agale SV, D'Costa G, Valand AG. Noninfectious granulomatous dermatoses: A puzzle for dermatologists and histopathologists. J Med Soc [serial online] 2017 [cited 2022 Jan 25];31:37-42. Available from: https://www.jmedsoc.org/text.asp?2017/31/1/37/198444
| Introduction|| |
Granulomatous dermatoses develop as a response of immune system to an external or internal antigen, leading to congregation of epithelioid histiocytes, various inflammatory and immune cells often surrounded by fibrosis or lymphocyte cuff.  Noninfectious granulomatous dermatoses (NGDSs) are a large spectrum of distinct reactive inflammatory conditions with varied etiologies and pathogenesis, but they share certain clinical as well as histological features. , Because of overlapping features and still a diverse histopathological spectrum, these lesions pose a diagnostic difficulty to naïve and even expert dermatologists and pathologists and need a clinicopathological correlation.
| Materials And Methods|| |
In this present prospective study, all the skin biopsies submitted in the Pathology Department of Grant Government Medical College, Mumbai, Maharashtra for 2 years were considered. The cases which were histopathologically diagnosed as NGDS were selected. Ethical committee permission was sought even if no patient was directly involved. Only clinical history and treatment details mentioned on the requisition forms were taken into account. The cases were studied for histopathological features of granuloma, predominant cell, location of granuloma in the dermis and epidermal changes if any. All these data were carefully tabulated, and a clinico-histopathological correlation was attempted. Skin biopsies were fixed, processed, stained with H and E stain, Gomori's methenamine silver stain, reticulin stain, Giemsa stain and studied.
The study being more descriptive, only percentages were calculated for categorical variables.
| Results|| |
Out of the total 1872 skin biopsies received in our department in 2 year period, 29 cases were found to be of NGDS, of which necrobiotic granulomas (n = 14) were the most common diagnosis which included granuloma annulare (GA) 78.57%, necrobiosis lipoidica (NL) 14.29%, and rheumatoid nodule (7.14%). Other frequently diagnosed lesions were epidermal cyst with foreign body giant cell reaction (EC), sarcoidosis, elastolytic granuloma including actinic granuloma (AG) and granulomatous panniculitis including erythema nodosum (EN) and erythema induratum (EI) [Table 1].
|Table 1: Distribution of histopathologically diagnosed granulomatous lesions with noninfectious etiology |
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In our study, 14 biopsies were histopatholoically diagnosed as necrobiotic granulomas out of which nine cases were categorized into GA. Five biopsies out of these nine showed characteristics blue necrobiosis with mucin and collagen degeneration and four biopsies showed palisading of histiocytes [Figure 1]a. Two cases were labeled as incomplete GA because of the "busy dermis" appearance with partial collagen degeneration and perivascular lymphocytes [Figure 1]b. On analyzing the clinical features, GA (11 cases) showed a female preponderance with an M:F ratio of 1:1.2. GA was found to be almost equally distributed in all age groups with maximum three cases in 31-40 years [Table 2]. GA lesions were widely distributed on arms, forearms, hands, and legs. The lesions appeared as flesh-colored papules and nodules arranged in a ring or semicircle fashion on feet and serpiginous fashion on hands [Figure 1]c.
|Figure 1: (a) Photomicrograph of granuloma annulare showing a palisade of elongated epithelioid histiocytes surrounding degenerated collagen in the upper dermis. (H and E, ×100). (b) Photomicrograph of granuloma annulare showing scattered epithelioid histiocytes, partial degeneration of collagen, and perivascular inflammatory infiltrate in the dermis (H and E, ×200). (c) Clinical photograph of granuloma annulare showing papules or nodules arranged in a serpiginous fashion on hands|
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|Table 2: Distribution of cases of noninfectious granulomatous dermatoses according to age |
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Two out of the 14 cases of necrobiotic granulomas showed histopathological features of NL. Histologically one case showed a conspicuous granulomatous component as palisading of histiocytes around fragmented paler collagen with Langhans and foreign body type giant cells on biopsy [Figure 2] and second case on biopsy showed scattered epithelioid cells with slight sclerosis. NL was seen as chronic shiny, yellowish sclerotic lesion on the leg of a 36-year-old male and as a recurrent sclerotic plaque with depressed scaly center on shin of a 65-year-old diabetic female patient.
|Figure 2: Photomicrograph of necrobiosis lipoidica: Dermis showed fragmented paler collagen with a palisade of histiocytes, Langhans, and foreign body type giant cells (H and E, ×200)|
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A biopsy from a nodule on the leg of a 20 years female was sent with a clinical suspicion of malignancy. The nodule was firm on palpation, located close to feet and was fixed to underlying tendon. On histopathology, it showed necrobiosis as a well-circumscribed area of fibrinoid degeneration of collagen in subcutaneous tissue surrounded by a palisade of histiocytes and foreign body giant cells. The surrounding stroma showed a neutrophilic infiltrate. It was diagnosed as rheumatoid nodule.
Three biopsies were diagnosed as AG and showed altered elastic fibers, thick elastotic material in surrounding dermis, interstitial histiocytes, and multinucleated giant cells [Figure 3]. AG was seen more commonly in 51-60 years (2/3 cases) and lesions were common on arms, forearms and hands. The lesions appeared as annular lesions on sun-exposed areas.
|Figure 3: Photomicrograph of actinic granuloma showing horizontally oriented collagen fibers with altered elastic fibers, intervening zone of histiocytes, and multinucleated giant cells in the dermis (H and E, ×400)|
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Sarcoidal granulomas (n = 4) were seen as discrete naked epithelioid cell nodules with focal confluence and without central caseation and multinucleated giant cells containing an asteroid body [Figure 4]. Special stains did not highlight any organism or foreign body. Sarcoidosis showed M: F ratio of 3:1, was common in 11-20 years age group (3/4 cases). The lesions were equally distributed on body seen as multiple brownish lichenoid papules and few soft psoriasiform nodules. In one of the patient clinical differential of GA was kept. Three patients showed hypercalcemia and elevated angiotensin converting enzyme level.
|Figure 4: Photomicrograph of sarcoidosis showing confluent epithelioid cell granulomas with multinucleated giant cell containing asteroid body (H and E, ×400)|
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Granulomatous panniculitis included EN (6.89% of cases) which histopathologically showed the involvement of subcutaneous tissue septae with widening; histiocytic infiltrate, and dense neutrophilic infiltrate extending into lobule [Figure 5]a. The lesions were found in 3 rd decade and showed female preponderance. Clinically, EN presented as painful erythematous nodules and plaques on anteromedial aspect of lower extremity [Figure 5]b.
|Figure 5: (a) Clinical photograph of erythema nodosum showing erythematous plaques and subcutaneous nodules on lower extremity. (b) Photomicrograph of erythema nodosum: Subcutaneous tissue septa showed edema with dense neutrophilic infiltrate extending into lobule (H and E, ×100)|
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Skin biopsy from painless, circumscribed nodule and plaques on the posterior calves in a 42-year-old female showed coagulative fat necrosis of subcutaneous adipose tissue lobules, with surrounding dense granulomatous reaction comprised foreign body giant cells and epithelioid histiocytes [Figure 6]. It was diagnosed as EI.
|Figure 6: Photomicrograph of erythema induratum ell-formed giant cells surrounding ischemic necrosis of the fat lobule (H and E, ×100)|
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Out of 11 histopathologically proven cases of GA, only 6 (54.55%) were received with a clinical suspicion of GA. One case which clinically appeared to be GA was histopathologically found to be NL.
| Discussion|| |
NGDS include a challenging group of diseases both in terms of their diagnosis and in counseling patients regarding their prognosis, in addition to the possible systemic comorbidities, they may subsequently encounter. An important source of this challenge is the clinical and histologic overlap among these conditions (along with the potential for misdiagnosis due to this overlap).  Most of the studies published in literature discuss the infectious skin granulomas or noninfectious granulomas as an individual entity with emphasis on either clinical or histological features. We have made an attempt to study the whole histopathological spectrum of NGDS and present important histopathological and clinical features with review from literature.
A collagenolytic or necrobiotic granuloma is noninfectious granuloma in which a granulomatous infiltrate develops around a central area of altered collagen and elastic fibers. The altered collagen fibers lose their distinct boundaries and exhibit new staining patterns, becoming more basophilic or eosinophilic. There may be deposition of mucin (blue) which include GA, Wegener's granulomatosis, and rheumatoid vasculitis or deposition of fibrin (red), which includes NL, necrobiotic xanthogranuloma, rheumatoid nodules, and Churg-Strauss syndrome. 
The skin lesions of GA may be single or multiple with flat center and a well-delineated edge. It commonly affects extremities and young females under 40 years of age. The generalized form is more typical among older patients and involves trunk.  In our study, seven cases were under 40 years of age with a female predilection. GA may clinically resemble tinea corporis, lichen planus, erythema annulare centrifugum, and erythema elevatum diutinum. It histologically resembles cutaneous sarcoidosis, NL, and annular elastolytic giant cell granuloma.  The histology is of a necrobiotic area with palisading granulomas in giant cells.  GA was histopathologically diagnosed in 11 cases out of 276 skin biopsies studied for granulomatous lesions making an incidence of 3.98% similar to Gautam et al. (3.7% incidence out of 106 biopsies studied).  In our study, the incidence is 11 out of 29 cases of noninfectious dermatosis (37.93%) while Mohan et al. found an incidence of 11 cases (15.4%), out of 71 cases of noninfectious dermatosis. 
NL is said to be associated with diabetes mellitus. The nondiabetic type of NL has its greatest incidence in people 20-40-year-old while NL diabeticorum peaks after 50 years. The lesion begins as an erythematous nodule in the pretibial area. As the lesion extends, it becomes a shiny, waxy, yellowish-red sclerotic plaque, a violet-red margin and superficial telangiectatic vessels coursing over its surface.  Enhanced glycosylation of dermal collagen with increased collagen cross-linking and microvascular changes leading to degenerative process have been proposed as its etiopathogenesis.  NL was histopathologically diagnosed in two cases, out of 29 cases of NGDS making an incidence of 6.89%. In both the biopsies dermis showed collagen degeneration in the form of fragmented paler collagen.
In our study, we found a single case of rheumatoid nodule out of 29 NGDS (incidence = 3.4%). Mohan et al. found two cases (2.8% incidence), out of 71 cases, which correlate with our study. 
We found three cases of AG in our study. It is characterized by annular plaques on neck, face, chest, and arms. The initial lesions are skin colored or erythematous papules on sun-exposed areas that coalesce to form centrifugally enlarging annular lesions with slight central atrophy.  It has been suggested that sun-damaged elastic tissue plays a major role in AG and annular elastolytic giant cell granuloma. , There is debate whether it is a distinct clinicopathological entity or a variant of GA or multiforme and NL.  In our study, light microscopy showed altered elastic fibers, surrounding increased thick elastotic material, an intervening zone of interstitial arrangement of histiocytes and multinucleated giant cells in the dermis. Al-Hoqail et al. found multinucleated giant cells, sarcoidal, and palisading granulomas confined to the superficial dermis with interstitial pattern of granulomatous inflammation; however, no elastophagocytosis or loss of elastic fibers was observed. 
Sarcoidosis on histopathology showed discrete well circumscribed epithelioid cell nodules without central caseation and sparse lymphocytic infiltrate at margins in upper dermis in the two biopsies. In study by Ball NJ on sarcoidosis, findings were classic naked sarcoidal granulomas in 25 biopsies (89%), tuberculoid granulomas (four biopsies), and interstitial granulomas (five biopsies). Additional histologic findings included birefringent foreign material in 14 biopsies (50%), focal necrosis (43%), elastophagocytosis (39%), increased dermal mucin (18%), and lichenoid inflammation (14%).  Similarly, Cardoso et al. reported naked granuloma (71% cases), necrosis (two cases), periadnexal distribution (32% cases), interstitial distribution (16% cases), and foreign material (13% cases).  Hence, due to variable histological presentations, sarcoidosis lesions could be misdiagnosed as leprosy, syphilis, GA, NL, and foreign body reaction. In our study, clinical history and investigations supported the diagnosis of sarcoidosis in three cases.
The incidence of sarcoidosis in our study was 4 out of 31 cases (12.9%) similar to the studies by Mohan et al. (21.1%) and Dhar and Dhar (13.7%). , While Gautam et al. and Zafar et al. found an incidence of 1.6% and 1.9%, respectively. , We found a male preponderance (M: F-3:1) with three patients in the second decades. In the study conducted by Mahajan et al., most patients presented between age group of 20-40 years with a male to female ratio of 8:15. 
Two biopsies showed dense neutrophilic infiltration of subcutaneous tissue septae extending into lobule and infiltration by histiocytes and multinucleated giant cells and were diagnosed as EN (granulomatous panniculitis). Yi et al. found predominantly septal panniculitis in 72% cases while lobular panniculitis and mixed septal-lobular panniculitis in 4.2% and 23% cases, respectively.  Thurber and Kohler observed neutrophilic lobular panniculitis with suppuration in two cases and lobular panniculitis associated with septal-lobular panniculitis with vasculitis in other two cases. 
EI on histopathology showed granulomatous lobular panniculitis with features of vasculitis. Niemi et al., while studying EI, observed lobular panniculitis with vasculitis in four cases (36%) and lobular panniculitis with epithelioid cell or palisading granulomas without vasculitis in the remaining seven (64%) cases.  Maharaja et al. in their study histologically proved EN in 14 (32.6%) cases and EI in four cases (9.3%) out of 43 cases.  The lesions predominantly involved the anterior aspect of legs in EN in 85.7% cases and posterior aspect in EI similar to our study.
Out of 29 cases of NGDS, the incidence of foreign body granulomas in our study was 19.35% similar to the studies by Mohan et al. (14%) and Gautam et al. (18.9%). , Majority of the cases were of the epidermal cyst with wide age distribution occurring predominantly on the head and neck area, and the trunk.
The strengths of this study are analysis of whole spectrum of histopathological features of various NGDS. The considerable overlap in histopathology and pathogenesis in early, as well as well- developed lesions, lead to similarity in the clinical features too, which pose a significant diagnostic dilemma in the front of dermatologists. The limited incidence and prevalence of NGDS have precluded the researchers from providing more varied spectrum and not many wholesome studies are available in the literature to compare the incidence and demographic factors and histomorpholgical variations in different patients and regions of country and world. We share the same limitation of less number of cases (only 29 cases out of 1872 biopsies studied.
| Conclusions|| |
The knowledge of histomorphological variations in NGDS is must to understand the clinical behavior. Similarly, the clinical history and examination, including age, sex, anatomic location and type of lesion help in differentiating between lesions sharing similar histological features. Histopathology also helps in guiding the treatment also as early stages of granuloma development are more responsive to the conventional therapeutic approaches as compared to older lesions. We recommend more such studies to be conducted on larger populations in larger referral centers to elucidate the variations in NGDS to guide better diagnosis and treatment of these rare dermatological lesions.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]