After participating in this activity, physicians should be better able to:
- Describe the diagnostic challenge of granulomatous skin lesions and the role of histopathology in this field;
- Distinguish the various types of granulomas from an histological point of view;
- Identify the main diseases associated with each type of granuloma;
- Explain the influence of geographical location on the distribution of the main granulomatous skin diseases.
A granuloma is usually defined as an organized collection of mature mononuclear phagocytes, admixed with variable numbers of multinucleated giant cells, inflammatory cells, and, in some cases, additional features such as necrosis.1 Granulomatous skin lesions represent a distinctive pattern of chronic inflammatory response of the skin, characterized by the presence of granulomas in reaction against various organic or inorganic antigens.2,3 Several types of granulomas are identified, according to their cellular constituents and associated changes. It is difficult to present a completely satisfactory classification of granulomatous reactions, but common types of granulomas include tuberculoid, sarcoidal, necrobiotic, suppurative, foreign body, and xanthogranulomas.4 Granulomatous skin lesions often present a diagnostic challenge to dermatopathologists because of the multiple possible diagnoses with an identical histological picture. The frequency and types of different granulomatous lesions vary according to geographical locations.4 This study aimed to determine the frequency and pattern of different granulomatous skin lesions in our hospital. Our secondary goals were to compare our results with similar studies and to evaluate the grade of clinicopathological concordance in the most frequent pathologies.
MATERIALS AND METHODS
This was a retrospective study of all skin biopsies with granulomatous lesions received in the Dermatopathology Department of Hospital de Santa Maria, Lisboa, Portugal, over a period of 10 years (from January 2008 to December 2017). Clinical information and relevant data were recorded from medical records. All sections were stained with hematoxylin and eosin. Special stains (periodic acid–Schiff, Ziehl–Neelsen stain, Grocott, Gram, Giemsa, etc.) were applied as required. Sections were observed under light microscope using scanner (×40), low-power (×100), and high-power (×400) lenses. Foreign-body granulomas secondary to ruptured cyst, folliculitis, or suture material were excluded.
In the 10 years encompassed in our study, a total of 48,253 skin biopsies were evaluated in our Dermatopathology Department. Granulomatous skin lesions were identified in 905 cases, comprising 1% of the total. From these, 444 cases were excluded (424 foreign-body granulomas secondary to ruptured cyst, folliculitis, or suture material and 20 cases in which the final diagnosis was not known), leaving a total of 461 biopsies, corresponding to 411 patients.
Among these 411 patients, 253 (62%) were women and 158 (38%) were men, with a female-to-male ratio of 1.6:1. Ages ranged from 4 to 98 years, with a mean age of 54.1 years and a median of 55 years. Maximum numbers of cases were found among the age group of 51–60 years (20%; N = 83). Age and sex distributions of the included patients are shown in Table 1.
Of our 411 patients, 330 (80.3%) had noninfectious granulomatous skin diseases. Distribution according to the different types of granulomas is shown in Table 2. Necrobiotic granulomas were the most frequent (N = 111; 27.0%), followed by sarcoidal (N = 72; 17.5%), tuberculoid (N = 51; 12.4%), suppurative (N = 45; 10.9%), foreign body (N = 40; 9.7%), and xanthogranulomas (N = 26; 6.3%). The remaining 16.1% corresponded to miscellaneous granulomas. Distribution of the various types of granulomas is shown in Table 2.
Among necrobiotic granulomas, the most frequent etiology was granuloma annulares (N = 98; 88.3%), followed by necrobiosis lipoidica (N = 9; 8.1%), pseudorheumatoid nodules (N = 2; 1.8%), rheumatoid nodules (N = 1; 0.9%), and superficial pyoderma gangrenosum (N = 1; 0.9%). In the case of sarcoid granulomas, sarcoidosis was the most frequent pathology (N = 47; 65.3%), followed by granulomatous cheilitis (N = 9; 12.5%), Crohn disease (N = 8; 11.1%), and syphilis (N = 8; 11.1%). In the group of tuberculoid granulomas, granulomatous rosacea was the most frequent diagnosis (N = 24; 47.1%), followed by erythema induratum of Bazin (N = 12; 23.5%), cutaneous tuberculosis (N = 7; 13.7%), Hansen disease (N = 5; 9.8%), and cutaneous leishmaniasis (N = 3; 5.9%).
During these 10 years, the most frequent noninfectious granulomatous skin diseases were granuloma annulare (N = 98; 23.8%) and sarcoidosis (N = 47; 11.4%). Both diagnoses were more frequent in women (74%). The mean age of patients presenting with granuloma anulare was 56.7 years, and the most frequent location was the upper limb, namely the hand (N = 49; 50%). Clinicopathological concordance for this entity was 54%. Patients with sarcoidosis had a mean age of 54.8 years, and the most frequent locations were the face and lower limbs. Clinicopathological concordance for sarcoidosis was 57%.
Infectious pathology was observed in 19.5% of all cases, corresponding to 80 patients. The mean age of this group was 55.6 years, and the most frequent location was the lower limb. In infectious diseases, clinicopathological concordance was 63%. In this group, we had 19 cases of cutaneous tuberculosis, 8 cases of deep fungal infections, 7 cases of Hansen disease, 5 cases of atypical mycobacterial infections, and 3 cases of Leishmania infection.
Granulomatous inflammation was recognized as a distinct entity early in the 19th century since then has been of increasing interest.5 Traditionally, granulomatous inflammation is defined as a distinctive form of chronic inflammation that occurs in response to a variety of stimulus including infection, autoimmunity, toxic, allergic, drug, and neoplastic conditions.6 Characteristically, it is defined by the presence of granulomas, which are organized collections of mature mononuclear phagocytes, admixed with variable numbers of multinucleated giant cells, inflammatory cells, and, in some cases, additional features such as necrosis.1 Granulomatous inflammation occurs in all age groups, and within all tissues, the skin being one of the most accessible ones. Thus, it is of paramount importance for a dermatologist to recognize subtle changes and characteristic features of granulomatous skin diseases to help with differential diagnosis.
There are several classifications of granulomas in the literature.7–9 In our article, we considered 7 histological types of granulomas, namely tuberculoid, sarcoidal, necrobiotic, suppurative, foreign body, xanthogranulomas, and miscellaneous granulomas. Sarcoidal granulomas are discrete, round to oval, composed of epithelioid histiocytes and multinucleated giant cells. They are usually surrounded by a sparse rim of lymphocytes and plasma cells, hence their denomination as “naked granulomas” (Figs. 1A, B). Sarcoidal granulomas are characteristic of sarcoidosis, although this should be a diagnosis of exclusion. They also appear in reaction to some foreign materials (such as silica) and in some cases of granulomatous cheilitis, Crohn disease, and secondary syphilis. Tuberculoid granulomas tend to be less circumscribed than sarcoidal ones and are characterized by the presence of a substantial rim of lymphocytes and plasma cells (Figs. 2A, B). Langhans giant cells are common, and in the case of tuberculosis, there may be areas of caseation. Tuberculoid granulomas are observed not only in tuberculosis but also in cases of tuberculids, granulomatous rosacea, Hansen disease, and leishmaniasis, among others. Necrobiotic granulomas are characterized by the presence of collagenolysis, which refers to areas of altered dermal connective tissue where there is loss of definition of collagen bundles (Figs. 3A, B). There is usually a surrounding histiocytic rim that may include multinucleate giant cells, and in some cases, there is also a palisade. Necrobiotic granulomas are seen for example in granuloma annulare, necrobiosis lipoidica, and rheumatoid nodules. Suppurative granulomas are collections of epithelioid histiocytes, which may include multinucleated giant cells, and in the center of which are collections of neutrophils (Figs. 4A, B). They are associated with infectious conditions, namely deep fungal and mycobacterial infections. Foreign-body granulomas occur in response to foreign material, either exogenous (eg, suture material) or endogenous (eg, keratin). This foreign material becomes surrounded by histiocytes, multinucleated giant cells, and various inflammatory cells (Figs. 5A, B). Xanthogranulomas are composed of histiocytes with foamy cytoplasm, a variable amount of inflammatory cells, and Touton giant cells (Figs. 6A, B). The most common condition in this group is juvenile xanthogranuloma, but it also includes other non-Langerhans cell histiocytoses. In the group of miscellaneous granulomas are included conditions that do not fit into any of the previously mentioned categories.10
Histopathology is the gold standard tool for the diagnosis of the various granulomatous skin diseases.3 However, this is frequently a challenge because many granulomatous skin lesions have identical histopathological aspects, and conversely, a single histopathological pattern can be associated with a variety of clinical diagnosis.11 In the case of infectious diseases, histopathology should always be complemented by adequate microbiological examinations.
The frequency and types of different granulomatous skin lesions vary according to geographical locations.2–5 In our study, necrobiotic granulomas were the most frequent ones, followed by sarcoidal and only then by tuberculoid granulomas. This is in contrast with previous studies, where tuberculoid granulomas were by far the most frequent (Table 3). In fact, all these studies were undertaken in Southern Asia, notably around India and Pakistan. It is known that the prevalence of tuberculosis and Hansen disease is still high in this part of the world, these 2 countries being some of the ones with more reported cases.12,13
In our study, granuloma annulare and sarcoidosis were the most common diagnosis. Both conditions were seen predominantly in women, which is in concordance with the available literature.14,15 Granuloma annulare is a relatively common benign inflammatory dermatosis whose cause remains unknown. It is rare in infancy and clinically is characterized by the presence of dermal papules and annular plaques. Histological examination usually shows foci of degenerative collagen associated with necrobiotic granulomas.16 Sarcoidosis is a multisystem inflammatory disease of unknown etiology that is characterized by the presence of sarcoidal granulomas mainly in the lungs and intrathoracic lymph nodes. Cutaneous manifestations occur in 25% of patients with sarcoidosis and are usually accompanied by systemic involvement.17
We found that noninfectious granulomatous skin diseases were 4 times more frequent than infectious ones in our population. In fact, only 20% of our patients had infectious pathology, which included some cases of cutaneous tuberculosis, deep fungal infections, Hansen disease, atypical mycobacterial infections, and leishmaniasis. It is also important to note that these infections occurred mostly in patients coming from other continents, namely Africa and South America.
The overall grade of concordance between clinical and histopathological diagnosis in our study was 54%. The highest level of concordance was observed in infectious pathology (63%). This highlights the importance of histopathology in the diagnosis of granulomatous skin diseases, potentially influencing also treatment and prognosis of these patients. In this way, it is essential that clinicians provide detailed clinical information, which should include age, sex, and phototype of the patient, the precise location of the biopsy, a concise history including recent or past trips, and an accurate description of the lesion. A list of differential diagnosis should also be given, so that the pathologist can be able to rule out certain ones in favor of others. As Pinkus wrote in 1981, “cooperation between clinician and pathologist is more important in the field of skin disease than in almost any other field.”18
Granulomatous skin diseases are a heterogeneous group of conditions occurring mainly in women and with diverse clinical and histopathological presentations. Necrobiotic granulomas were the most prevalent in our population, followed by sarcoidal ones. Granuloma annulare and sarcoidosis were the 2 more frequent diagnoses. In our population, noninfectious granulomatous skin diseases are 4 times more frequent than infectious ones. This is in contrast with previous studies performed in Southern Asia, where the prevalence of infections such as tuberculosis and Hansen disease is still high. More studies with larger sample sizes are needed to confirm our findings. Clinicopathological correlation is essential in the diagnosis of this group of diseases, but represents a frequent challenge in daily practice, with additional stains and complementary tests being frequently required.
1. Adams DO. The granulomatous inflammatory response. A review. Am J Pathol. 1976;84:164–192.
2. Gautam K, Pai RR, Bhat S. Granulomatous lesions of the skin. J Pathol Nepal. 2011;1:81–86.
3. Chakrabarti S, Pal S, Biswas BK, et al. Clinico-pathological study of cutaneous granulomatous lesions- a 5 yr experience in a tertiary care hospital in India. Iranian J Pathol. 2016;11:54–60.
4. Zafar MNU, Sadiq S, Memon MA. Morphological study of different granulomatous lesions of the skin. J Pak Assoc Derma. 2008;18:21–28.
5. Dhar S, Dhar S. Histopathological features of granulomatous skin diseases
: an analysis of 22 skin biopsies. Indian J Dermatol. 2002;47:88–90.
6. Shah KK, Pritt BS, Alexander MP. Histopathologic review of granulomatous inflammation. J Clin Tuberc Mycobact Dis. 2017;7:1–12.
7. Tronnier M, Mitteldorf C. Histologic features of granulomatous skin diseases
. Part 1: non-infectious granulomatous disorders. J Dtsch Dermatol Ges. 2015;13:211–216.
8. Mitteldorf C, Tronnier M. Histologic features of granulomatous skin diseases
. J Dtsch Dermatol Ges. 2016;14:378–388.
9. Gru AA. Introduction to inflammatory dermatoses: histological clues for the practicing pathologist. Semin Diagn Pathol. 2017;34:210–219.
10. Patterson JW. Weedon's Skin Pathology. London, United Kingdom: Elsevier Health Sciences; 2015.
11. Singh R, Bharathi K, Bhat R, et al. The histopathological profile of non-neoplastic dermatological disorders with special reference to granulomatous lesions—study at a tertiary care centre in pondicherry. Internet J Pathol. 2012;13:14240.
12. Scollard DM, Adams LB, Gillis TP, et al. The continuing challenges of leprosy. Clin Microbiol Rev. 2006;19:338–381.
13. WHO. Global Tuberulosis Report 2018. World Health Organization. Available at: http://www.who.int/topics/tuberculosis/en/
. Assessed December 30, 2018.
14. Krell W, Bourbonnais JM, Kapoor R, et al. Effect of smoking and gender on pulmonary function and clinical features in sarcoidosis. Lung. 2012;190:529–536.
15. Piette EW, Rosenbach M. Granuloma
annulare: clinical and histologic variants, epidemiology, and genetics. J Am Acad Dermatol. 2016;75:457–465.
16. Piette EW, Rosenbach M. Granuloma
annulare: pathogenesis, disease associations and triggers, and therapeutic options. J Am Acad Dermatol. 2016;75:467–479.
17. Tchernev G. Cutaneous sarcoidosis: the “great imitator”: etiopathogenesis, morphology, differential diagnosis, and clinical management. Am J Clin Dermatol. 2006;7:375–382.
18. Pinkus H, Mehregan A. A Guide to Dermatopathology. New York, NY: Appleton-Century-Crofts; 1981.
19. Mohan H, Bal A, Dhami GP. Non-infectious granulomatous dermatitis: a clinicopathological study. J Cutan Pathol. 2006;33:767–771.
20. Pawale J, Purank R, Kulkarni M. A histopathological study of granulomatous inflammations with an attempt to find the aetiology. J Clin Diagn Res. 2011;5:301–306.
CME EXAM INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITSTM
The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational needs of its readers.
An annual total of 12 AMA PRA Category 1 Credits™ is available through the twelve 2020 issues of The American Journal of Dermatopathology. This activity is available for credit through February 28, 2022.
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- Credit Designation Statement
Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of one (1) AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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CME EXAMINATION March 2020
Please mark your answers on the ANSWER SHEET.
After participating in this activity, physicians should be better able to 1. Describe the diagnostic challenge of granulomatous skin lesions and the role of histopathology in this field, 2. Distinguish the various types of granulomas from an histological point of view, 3. Identify the main diseases associated with each type of granuloma, and 4. Explain the influence of geographical location on the distribution of the main granulomatous skin diseases.
- Which of the following are the main cells comprising a granuloma?
Which of the following characteristics is most commonly seen in sarcoidal granulomas?
- a. Foamy cells;
- b. Neutrophils;
- c. Mononuclear phagocytes;
- d. Eosinophils;
- e. Multinucleate giant cells.
Which of the following conditions are more commonly associated with tuberculoid granulomas?
- a. Central necrosis;
- b. Substantial rim of lymphocytes and plasma cells;
- c. Central collection of neutrophils;
- d. Sparse rim of lymphocytes and plasma cells;
- e. Presence of collagenolysis and surrounding histiocytic rim with palisade.
A 42-year-old European women presents with several pruritic erythematous and skin-colored papules distributed over the limbs and trunk. Cutaneous biopsy of one of the lesions shows collagenolysis surrounded by a histiocytic rim forming a palisade. Which of the following is the most probable diagnosis?
- a. Tuberculosis and foreign body reaction to silica;
- b. Granuloma annulare and Leishmaniasis;
- c. Granulomatous rosacea and tuberculids;
- d. Necrobiosis lipoidica and tuberculosis;
- e. Deep fungal infection and sarcoidosis.
Which of the following is not true about granulomatous skin lesions?
- a. Sarcoidosis;
- b. Leishmaniasis;
- c. Foreign body reaction;
- d. Secondary syphilis;
- e. Granuloma annulare.
- a. Granulomatous inflammation may occur in response to a variety of stimulus including infection, autoimmunity, toxic, allergic, drug, and neoplastic conditions;
- b. When performing a skin biopsy, the clinician should provide a list of possible differential diagnosis;
- c. In developed countries, non-infectious diseases are responsible for the majority of granulomatous skin lesions;
- d. The overall grade of concordance between clinical and histopathological diagnosis is usually high, making skin biopsy unnecessary in the majority of granulomatous skin lesions;
- e. The frequency and types of different granulomatous skin lesions vary according to geographical location.