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ORIGINAL ARTICLE
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An approach toward cutaneous granulomatous lesion: A retrospective analysis in a tertiary care setup


1 Department of Pathology, MGM Medical College, Kishanganj, Bihar, India
2 Department of Dermatology, MGM Medical College, Kishanganj, Bihar, India
3 Department of Pharmacology, MGM Medical College, Kishanganj, Bihar, India
4 Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata, West Bengal, India

Date of Submission26-Jun-2020
Date of Decision13-Oct-2020
Date of Acceptance14-Dec-2020

Correspondence Address:
Shatavisa Mukherjee,
Department of Clinical and Experimental Pharmacology, School of Tropical Medicine, Kolkata - 700 073, West Bengal
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/mjdrdypu.mjdrdypu_350_20

  Abstract 


Background: Granulomatous disorders of the skin are commonly encountered and pose a diagnostic challenge due to its diverse etiology with several histological patterns. Granulomatous diseases of skin comprise a large family sharing the common histological finding as of granuloma formation. The various histological types of granulomas can be identified on the basis of the constituent cells and other changes within the granulomas. However, significant overlap exists in histopathological findings of different granulomatous reactions. Thus, morphology alone is seldom specific and cannot be used as a diagnostic tool for the identification of specific diseases. A keen understanding of the manifestations, workup, and subsequent treatment of both infectious and noninfectious cutaneous granulomatous lesion is essential for every practicing clinician and dermatopathologist. Materials and Methods: A 2-year retrospective study involved all the skin biopsies. Detailed clinical and histopathological features were analyzed and were categorized according to the type of granuloma. Special stains were used in few cases for diagnostic purposes. Cases were reviewed and analyzed. Results: In histopathological subtyping, tuberculoid granuloma was the most common type and the most common etiology was leprosy. Others were cutaneous tuberculosis, foreign body granulomas, fungal lesions, cutaneous leishmaniasis, and granuloma annulare. Conclusion: Histopathology when combined with special stain can serve as a gold standard investigation for diagnosis, categorization, and clinicopathological correlation in such cases.

Keywords: Granuloma, histopathology, special stains



How to cite this URL:
Mukherjee M, Bhunia D, Era N, Mukherjee S. An approach toward cutaneous granulomatous lesion: A retrospective analysis in a tertiary care setup. Med J DY Patil Vidyapeeth [Epub ahead of print] [cited 2021 Jun 12]. Available from: https://www.mjdrdypv.org/preprintarticle.asp?id=316421




  Introduction Top


Cutaneous granulomatosis is a diverse group of skin manifestations whose pathophysiological mechanism is still poorly comprehended. It is a granulomatous inflammatory reaction to a wide variety of stimuli, including infections, systemic inflammations, neoplasia, metabolic disorders, and chemicals, leading to a wide variety of clinical and histological presentations. Granulomatous inflammation is best defined as special variety of focal chronic inflammation in which granuloma is formed in response to tissue injury, characterized by the collection of activated histiocytes, epithelioid cells, and multinucleated giant cells.[1] Granulomas may be confluent or discrete in nature with varied degree of necrosis and cell components differ. The presence or absence of Schumann bodies and calcification is distinctive in these cases. According to cellular constituents and associated changes, mainly six types of granulomatous skin lesions are identified, namely tuberculoid, sarcoidal, necrobiotic, suppurative, mixed inflammatory, foreign body, and histoid type.[2]

Granulomatous dermatosis has identical histopathological patterns and may be attributed to several causes, and on the contrary, a single cause may generate several histopathological patterns too.[3] Thus, rational histopathology involves vivid knowledge of the basic pathophysiology of this inflammatory response and distinct delineating of cell morphology in order to shred off diagnostic dilemma. The present study aimed at classifying granulomatous lesions based on the morphology of granulomas and to highlight the significance of clinic-pathological correlation in such cases so as to provide a holistic care by the treating physician to the patient.


  Materials and Methods Top


A retrospective analysis of skin biopsies was performed in the pathology department of a tertiary care teaching hospital in eastern India over a period of 2 years. All histopathologically diagnosed cases of cutaneous granulomatous lesions were reviewed. The cases of nongranulomatous dermatoses and inadequate samples were excluded from the study. Ethical clearance was obtained from the institutional ethical committee before undertaking the study (IEC Ref: MGM/PRI-615/18 dated 31.12.2018). Written consents were obtained from all patients included in the study.

Detailed history and clinical data were collected from the patient's treatment sheet as well as from the hospital's record section. The biopsy samples were undergone routine tissue processing and section cutting. All cases were stained with H and E stain and special stains (periodic acid Schiff [PAS], ZN stain, Giemsa, Fite-Faraco, and reticulin) were applied as required.

Hematoxylin and eosin-stained paraffin sections were reviewed. The morphological pattern of granuloma was classified into sarcoidal, necrotizing, necrobiotic, and suppurative granulomas, and further etiological evaluation for the granulomatous dermatosis was done using various special stains such as PAS stain, Fite-Faraco stain, Gomori methenamine silver stain, and acid-fast bacilli stain. All cases of granulomatous skin lesions were analyzed with respect to clinical information and histopathological examination of biopsy samples. Data analysis was done using statistical software.


  Results Top


Out of a total of 2400 skin biopsies evaluated during the study period, 12.5% (n = 300) were granulomatous skin lesions. In these 300 cases, gender distribution was assessed to be 3:2 (male: female ratio). Cases were seen among the age group of 8–80 years, with maximum cases being among 11–30 years (66.7%).

Histopathological distribution of granulomas

Among the total granuloma cases, 73.3% were tuberculoid granuloma, followed by 16.66% foreign body granuloma, 4.66% suppurative granuloma, 3% mixed inflammatory, 1.66% palisading, and 0.66% sarcoidal granuloma. On basis of epidermal changes and dermal infiltrate pattern, cases of tuberculoid granuloma were subclassified. Based on this morphology, 63.3% of cases were from the leprosy group, whereas 30 cases were of cutaneous tuberculosis. Leprosy was further subclassified according to Ridley and Jopling classification.[4] The most common form of cutaneous tuberculosis was lupus vulgaris, followed by tuberculosis verrucous cutis, scrofuloderma. The most common foreign body granulomas were epidermal cyst, xanthomas, etc., [Table 1]. Cases of suppurative granuloma were predominately due to fungal infection which was confirmed by PAS. Those cases having hyperplastic epidermis and dermis showing the presence of dense inflammatory infiltrates in form of polymorphs, plasma cells , lymphohistiocytes can be diagnosed as a case of fungal infection only after excluding all other causes. Use of special stain like PAS can support the diagnosis and demonstration of Leishman Donovan body concluded as cutaneous leishmaniasis in the mixed inflammatory pattern. Cases having different patterns in form of central necrosis with palisaded granuloma with peripheral deposits of collagen, lymphoid cells, and histiocytes were confirmed to be granuloma annulare [Table 2], [Figure 1] and [Figure 2].
Table 1: Distribution of granuloma

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Table 2: Diagnostic clues

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Figure 1: Description of (1a and 1b) thinning of the epidermis with the presence of epithelioid granuloma in the dermis with neural involvement in a case of borderline tuberculoid leprosy. (2a and 2b) presence of grenz zone with dense dermal infiltrate of lymphocytes with foamy macrophages, ill-formed granuloma and plasma cells in case of borderline lepromatous leprosy. (3a and 3b) hyperplastic epidermis with epithelioid granuloma , Langhans giant cells and necrosis in a case of lupus vulgaris. (4a and 4b) Acanthotic epidermis with areas of ulceration and dermal infiltrate composed of granuloma, Langhans giant cells, along with necrosis in case of tuberculous verrucous cutis. (5) Unremarkable epidermis with dermal infiltrate of foamy macrophage in case of xanthoma

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Figure 2: Positive Ziehl–Neelsen stain for acid-fast bacilli in a borderline leprosy case

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Photomicrography and clinical images of cases biopsied are represented in [Figure 3] and [Figure 4], respectively.
Figure 3: Photomicrography of some important diagnoses. (1) Lupus Vulgaris. (1a) ×4 showing full thickness epidermis with the dermis and subcutaneous layer where epidermal changes with dermal infiltrates are seen. (1b) ×10 showing hyperplastic acanthotic epidermis with dense dermal inflammatory infiltrate. (1c) ×40 shows dermal inflammatory infiltrate composed of epithelioid cells forming granuloma. (2) Borderline tuberculoid leprosy. (2a) ×4 shows presence of epidermis showing no changes and dermis with dense inflammatory infiltrate. (2b) ×10 showing dense dermal infiltrate with epithelioid granuloma. (2c) ×40 showing wellformed epithelioid granuloma composed of macrophages and lymphoid cells. (3) Lepromatous Leprae. (3a) ×10 showing epidermis separated from dermis by grenz zone. (3b) ×40 showing lymphohistocytes collection with some macrophages having foamy changes

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Figure 4: Clinical images of few biopsied cases. (a) Case of tuberculosis verrucosa cutis showing plaque-like lesion and areas showing ulceration. (b) Case of borderline tuberculoid showing plaque-like lesion. (c) Case of lepromatous leprae showing thickening of the pinna of ear lobes with decreased sensation

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  Discussion Top


Granulomatous inflammation is defined as a special variety of chronic inflammation in which the mononuclear phagocyte system cells take the form of macrophages, epithelioid cells, and multinucleated giant cells admixed with other cells such as lymphocytes, plasma cells, and fibroblasts. Epithelioid cells are the hallmark of delayed hypersensitivity granulomas; they are mononuclear cells with finely granular eosinophilic cytoplasm, vesicular nuclei, and indistinct cell boundaries which are usually found aggregated into clusters within certain granulomas.[5] Multinucleated giant cells are a regular feature of granulomatous inflammation produced by the fusion of macrophages. The granulomas result from an intricate relationship between invading organism or antigens, irritants, chemicals, drug or other irritants, persistent antigenemia, macrophage and B cell overactivity, Th1 cell response, and a vast array of biological mediators. Giant cell production is stimulated by lymphokines which are said to be immunologically mediated. Traditionally, inflammatory giant cells have been divided into the Langhan type (tuberculous), in which up to 20 nuclei are distributed centrally or around the periphery of the cell, and the foreign-body type with often very numerous haphazardly arranged nuclei throughout the cytoplasm.[6] There is no fundamental difference between these two cell types, both types are commonly found to coexist in the same lesion and there is no diagnostic significance. Tissue necrosis is due to autodigestion by macrophages enzymes; necrosis may also be produced by the dried toxic action of the causative agent and the immune complex in the center of the lesion. Fibrosis results from interleukin-1, lymphokines, and fibronectin that are synthesized by lymphocytes, macrophages play important in fibroblast migration, proliferation, and collagen synthesis. Nonimmunological, low turnover foreign body type granulomas appear to stimulate the least amount of collagen production.[7]

It is difficult to present a completely satisfactory classification of granulomatous dermatosis. Based on the pure morphology of granuloma, histopathologists have divided granuloma into “foreign body” and “epithelioid” type depending primarily on the absence or presence of epithelioid cells. An inducing agent is often recognizable in foreign body granuloma, while it is impossible to find in the epithelioid lesion. The present study found majority of the cases being tuberculoid granuloma, of which maximum presentations were leprosy. This is similar to studies in Nepal and other parts of India.[8],[9],[10],[11] Cases with epidermis separated from dermis by the grenz zone showing the dense lymphohistiocytic collection, foamy macrophages with adnexal destruction, and highest acid-fast bacilli load were diagnosed as lepromatous leprosy. On the other hand, infiltrate mostly composed of lymphocytes with ill-formed granuloma and fibrosis around the neural structure was diagnosed as borderline leprosy. While cases with the absence of grenz zone with well-formed epithelioid granuloma in all the layers of dermis involving neurovascular structures were labeled as tuberculoid leprosy, cases with giant cells and less marked granuloma were diagnosed as borderline tuberculoid leprosy.

In the present study, granulomatous dermatosis is classified on the morphology of granuloma and its association with vasculitis.[7] Granuloma with vasculitis contributes a minor group of granulomatous dermatoses. They are characterized by inflammatory cells in the vessel wall, endothelial reaction, thrombus formation, and fibrin deposition. The etiological basis of the granulomatous dermatosis has been tried to evaluate with the help of special stains. The present study observed that majority of the cases had granulomas without vasculitis. The granulomatous dermatosis without vasculitis has been subdivided into sarcoidal, necrobiotic, necrotizing, and suppurative. Cases identified with epithelioid histiocytes forming circumscribed nodule without necrosis, with less mononuclear cells with foreign body/Langhan giant cells are classified as sarcoidal granulomas; On the other hand, in necrobiotic type there is presence of pale staining collagen which is rimmed by epithelioid histiocytes in palisading manner along with lymphocytes and fibroblast. Cases having the presence of granuloma with the evidence of acute inflammation and abscess formation are thought of suppurative type. In necrotising type there is presence of coagulative necrosis without the evidence of suppurative inflammation.[7]

Fungal infections were the most common contributor for suppurative granuloma, which were confirmed by PAS. Those cases showing Leishmania donovani body with mixed inflammatory infiltrate along with granuloma were diagnosed as cutaneous leishmaniasis. Cutaneous tuberculosis such as tuberculous verrucous cutis and scrofuloderma had presentations of necrotizing granuloma. Our study corroborates with studies conducted by Bhutto et al and Sehgal et al,[13],[14] where lupus vulgaris was also the most common form of cutaneous tuberculosis.

As there are systemic diseases that show overlapping clinical features, skin biopsy is potentially crucial to establish the diagnosis. In a small percentage of cases in our study, no definitive diagnosis can be given, other than that of granulomatous inflammation, even with all clinical information being available. Such cases have not been included, which remains as a limitation of this study. Thus, the authors think that detailed clinical history, close histopathological workup, and a vivid clinicopathological correlation are imperative in making a final definite diagnosis as stated in other studies also.[8],[12],[13]

A rational histological diagnostic approach to granulomatous inflammation is also not present devoid of limitations. First, there exists a diversity of macrophage morphologies. Second, the reaction of the host's immune system to offending antigens is very individualized. Special stains, culture for organisms, and molecular techniques may also be required to reach a diagnosis. By combining all the available information, one should be able to arrive at a reasonable differential diagnosis on which to proceed.


  Conclusion Top


Granulomatous dermatosis frequently poses a diagnostic challenge to dermatopathologists due to its varied histological presentation. A thorough knowledge of the basic pathophysiology of this distinctive tissue reaction is therefore of fundamental importance in the understanding of many disease processes and to arrive at a specific etiopathological classification, thereby leading to improved pathological reporting and better patient care.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Rathod GB, Parmar P. Histopathological study of dermal granuloma. Indian J Med Sci 2019;71:35-9.  Back to cited text no. 8
    
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Mathur M, Karki A, Acharya P, Jha A. A clinicopathological study of facial granulomatous dermatoses: A hospital-based study. Indian J Dermatopathol Diagn Dermatol 2019;6:25-9.  Back to cited text no. 9
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Gautam K, Pai RR, Bhat S. Granulomatous lesions of the skin. J Pathol Nepal 2011;1:81-6.  Back to cited text no. 10
    
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Bal A, Mohan H, Dhami GP. Infectious granulomatous dermatitis: A clinico-pathological study. Indian J Dermatol 2006;513:217-20.  Back to cited text no. 11
    
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Bhutto AM, Solangi A, Khaskhely NM, Arakaki H, Nonaka S. Clinical and epidemiological observations of cutaneous tuberculosis in larkana, pakistan. Int J Dermatol 2002;41:159-65.  Back to cited text no. 13
    
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Sehgal VN, Srivastava G, Khurana VK, Sharma VK, Bhalla P, Beohar PC. An appraisal of epidemiologic, clinical, bacteriologic, histopathologic, and immunologic parameters in cutaneous tuberculosis. Int J Dermatol. 1987;26:521-6.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

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