INTRODUCTION
Although some workers use the term granuloma to denote a focal collection of histiocytes, we believe the term is more meaningful if it is restricted to denote a focal collection of epithelioid cells [Figure 1]. By this definition, every granuloma is an epithelioid cell granuloma. However, when the term is used without qualification, epithelioid cell granuloma refers to those granulomas that do not show any additional findings such as acute inflammatory cells in suppurative granulomas, altered collagen in necrobiotic granulomas, and foreign material in foreign body granulomas.
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Figure 1: Epithelioid cell granuloma with multiple epithelioid cells (cells with abundant cytoplasm with indistinct margins and a vesicular nucleus) and giant cells (H and E, Ă—400) (Courtesy: Dr Navjeevan Singh)
Epithelioid cells are transformed or activated macrophages or histiocytes, formed in response to various inflammatory mediators.[1] Histologically, they appear as cells with abundant eosinophilic cytoplasm with indistinct cell margins and elongated or slipper-shaped vesicular nuclei with prominent nucleoli [Figure 1]. They have increased functional activity but decreased phagocytic activity evidenced by an increase in the number of endoplasmic reticulum and fewer lysosomes.[2]
Apart from epithelioid histiocytes, other cells may be part of a granuloma. Giant cells are formed by the fusion of macrophages and are typically large and multinucleate. Nuclei are arranged in a complete or partial wreath at the periphery in Langhans giant cells and are arranged haphazardly toward the center of the cell in foreign body giant cells.[3]
Lymphocytes are commonly seen in granulomas and may be arranged in a cuff or mantle around a core of epithelioid cells [Figure 2]. This cuff of lymphocytes is typically absent in sarcoidosis [Figure 3]. In addition, other cells such as histiocytes and plasma cells may be noted. Less frequently, small numbers of neutrophils and eosinophils may be seen though they are more prominent in mixed cell or suppurative granulomas.
Figure 2: Epithelioid cell granuloma with a central core of epithelioid cells and a cuff of lymphocytes in the periphery (H and E, Ă—400)
Figure 3: Sarcoidal granuloma composed predominantly of epithelioid cells with paucity of lymphocytes (H and E, Ă—400)
The presence or absence of necrosis is an important finding that helps to categorize epithelioid cell granulomas. Necrosis is a prominent finding in lupus miliaris disseminatus faciei (LMDF), intraneural granulomas of leprosy, and some cases of lupus vulgaris, while it is usually absent in tuberculoid (TT) leprosy, sarcoidosis, and most cases of cutaneous tuberculosis. The type of necrosis is also used as a clue, for example, caseation necrosis in LMDF and fibrinoid necrosis in sarcoidosis, but this is a more difficult and less reproducible differentiating feature.
Cytoplasmic inclusion bodies, usually within giant cells, are a feature of some granulomas. Asteroid bodies are eosinophilic stellate bodies. They have a red-brown center with blue radiating spikes on staining with phosphotungstic acid hematoxylin and are composed of either cytoplasmic filaments or microtubular elements, though their exact composition is not known. Schaumann bodies are round, laminated, bluish bodies formed of calcium deposits.[4] Rarely, small brown Hamazaki–Wesenberg bodies, periodic acid-Schiff (PAS)-positive large lysosomes containing hemolipofuscin, have been reported. Initially thought to be specific for certain types of epithelioid cell granulomas, it is now recognized that these inclusions are more common in some conditions than others but not diagnostic of any particular disease.[5]
The tendency of epithelioid cell granulomas to coalesce or stay discrete is also a helpful morphological feature in differentiating the causes of this reaction pattern. Granulomas are discrete in sarcoidosis and coalescent in leprosy, tuberculosis, and leishmaniasis.
Apart from the findings in individual granulomas, their arrangement within the dermis provides clue to specific disorders, for example, the branched granulomas of leprosy, the lichenoid granulomatous pattern of lupus vulgaris, and the huddled but discrete granulomas of sarcoidosis.
Epithelioid granulomas may be due to both infectious and noninfectious causes. In general, epithelioid cell granulomas are associated with good host immunity and it is difficult to find organisms in infective granulomas. However, a search for organisms should be undertaken to ensure that an infective cause is not missed. Organisms can be seen within histiocytes and giant cells or in extracellular locations using hematoxylin and eosin or special stains such as Ziehl–Neelsen staining for mycobacteria, Giemsa stain for leishmaniasis, and PAS and Gomori's silver methenamine for fungi. Immunohistochemical stains are also available for some organisms such as Treponema pallidum. Nucleic acid amplification tests may aid in the identification of some pathogens.
Clinically, granulomatous disorders show some common features. They are usually chronic, long-standing, gradually progressive plaques that are only mildly symptomatic. The plaques tend to be annular or arciform with central healing and peripheral activity [Figure 4]. The central area shows fibrosis and scarring in some diseases such as lupus vulgaris and cutaneous leishmaniasis, while there is only slight flattening and reduced inflammation in other diseases such as leprosy and sarcoidosis [Figure 5]. The active area shows deep-seated, erythematous papules that have a persistent yellow-brown color when they are blanched with a glass slide, an appearance referred to as apple jelly nodules. (This finding can be seen in many granulomatous disorders and is not confined to lupus vulgaris.) Papules tend to coalesce into plaques, but in sarcoidosis, they may remain discrete, especially on the upper trunk. The degree of erythema varies and tends to be more prominent in cutaneous leishmaniasis [Figure 6]. The degree of verrucosity is also variable, being most prominent in tuberculosis verrucosa cutis [Figure 7], less prominent in lupus vulgaris and cutaneous leishmaniasis, and absent in leprosy and sarcoidosis.
Figure 4: Plaque of lupus vulgaris with peripheral activity and a trailing scar
Figure 5: Erythematous plaques of mid-borderline (BB) leprosy, with two of them showing classical inverted saucer appearance (sharp punched out inner edge and slopping outer edge) with normal appearing skin at the center
Figure 6: Cutaneous leishmaniasis presenting as solitary bright erythematous plaque with central yellowish crusting on exposed skin (courtesy: Dr. Mahesh Kumawat)
Figure 7: Tuberculosis verrucosa cutis presenting as a solitary verrucous plaque over the foot
Other findings that are seen in individual diseases and point to the diagnosis include sensory loss, nerve thickening, and peripheral neuropathy in leprosy; plaques on the skin of exposed areas in cutaneous leishmaniasis; condyloma lata and generalized lymphadenopathy in granulomatous syphilis; hilar lymphadenopathy, pulmonary parenchymal involvement, and ocular lesions in sarcoidosis; pulmonary tuberculosis or tuberculosis elsewhere in cutaneous tuberculosis and tuberculids; multiple papules, papulo-nodules, and some pustules on the face and neck with eyelid involvement in LMDF; background erythema and telangiectasias in granulomatous rosacea; remittent edema of the lip and face with geographic tongue and facial nerve palsy in Melkersson–Rosenthal syndrome (orofacial granulomatosis) [Figure 8]; knife-cut fissures and gastrointestinal involvement in cutaneous Crohn's disease [Figure 9]; tiny, skin-colored papules on the tips of fingers and penis in lichen nitidus; similar, tiny papules in a blaschkoid distribution in lichen striatus; and crusted and smooth, tiny papules on the trunk in small groups or discretely, in lichen scrofulosorum [Figure 10], among other granulomatous diseases.
Figure 8: Granulomatous cheilitis with prominent swelling of the upper and lower lips
Figure 9: Metastatic Crohn's disease showing asymmetrical vulvar swelling
Figure 10: Multiple skin-colored follicular papules over the trunk in lichen scrofulosorum
A large number of conditions show epithelioid granulomas [Table 1]. A description of those conditions in which the histomorphological appearance of the granulomas is distinctive or diagnostic appears below.
Table 1: List of conditions showing granulomatous infiltrate
LEPROSY
In leprosy, epithelioid cell granulomas are a characteristic feature of TT leprosy (both TT and borderline TT [BT] leprosy). They are also a constant feature of mid-borderline (BB) leprosy, often associated with foamy histiocytes. Borderline lepromatous (BL) leprosy is dominated by foamy histiocytes and lymphocytes but may occasionally show small epithelioid cell granulomas.
Although the nature and composition of granulomas varies across the leprosy spectrum, the arrangement of infiltrates in a characteristic, “leprosy pattern” is a helpful clue to the diagnosis [Figure 11]. There are superficial and deep, well-circumscribed, oval, oblong, or curvilinear infiltrates in a perivascular and peri-appendageal distribution with minimal extension into the interstitial dermis. The overlying epidermis is normal. This is a distinctive and easily recognizable pattern that can be identified under low power. The oblong appearance of leprosy infiltrates is believed to be due to involvement along the neurovascular bundles.
Figure 11: Well-circumscribed, oval, oblong, and curvilinear epithelioid cell granulomas in a perivascular and peri-appendageal location involving superficial and deep dermis with minimal interstitial spill (leprosy pattern) (H and E, Ă—40)
When present, infiltrates around and within nerve twigs and arrectores pilorum are useful additional clues [Figure 12].
Figure 12: Perineural infiltrate composed of lymphocytes, histiocytes, and epithelioid cells (H and E, Ă—200)
TT leprosy is characterized by compact granulomas with a central core of epithelioid cells and a dense cuff of lymphocytes. Langhans giant cells are often seen. Necrosis is not a feature except in large intraneural granulomas which are seen only rarely. Granulomatous infiltrates in the upper dermis may abut on the overlying epidermis with damage to basal cells. BT leprosy is reported to show fewer lymphocytes and fewer and smaller giant cells, but this is a blurry line and it may be easier to make the distinction between TT and BT on clinical grounds. Rarely, sarcoidal and necrobiotic granulomas may be seen in addition to the typical epithelioid granulomas of TT leprosy.
BB leprosy shows two patterns: the first pattern is a diffuse, loose infiltrate composed almost exclusively of epithelioid cells with a paucity of lymphocytes and other cells. It is difficult to identify the leprosy pattern in these cases. The second, and more common pattern in our experience, shows an about equal admixture of epithelioid cell granulomas and foamy histiocytes in the typical leprosy distribution [Figure 13].
Figure 13: Mid-borderline leprosy showing epithelioid cells and foamy histiocytes in an about equal proportion along with giant cells (H and E, Ă—400)
BL leprosy does not usually show epithelioid granulomas and infiltrates are composed of foamy histiocytes and many lymphocytes are arranged in the leprosy pattern. Occasionally, small collections of epithelioid cells may be noted.[6]
Epithelioid granulomas are absent in lepromatous (LL) and indeterminate leprosy.
A similar histopathological spectrum is seen in nerve biopsies, though they tend to show more advanced disease than skin biopsies from the same patient.[7]
Stains for acid-fast bacilli are usually negative in TT and BT and positive in BB and BL leprosy.
The histopathological appearance of granulomas in leprosy is altered in type 1 reaction. A striking change is the development of edema both within the granuloma and in the adjacent dermis. The circumscription of infiltrates is lost and they spill into the interstitial dermis. This is accompanied by an increase in the number of lymphocytes, epithelioid cells, and giant cells, which may be more difficult to discern unless a baseline biopsy is available for comparison. Rarely, granulomas may erode the overlying epidermis, and caseous necrosis may occur within nerves.
Granulomas resolve following treatment, but resolution may be incomplete even several months after effective treatment. Jain et al. studied 44 biopsies taken immediately following the end of 6 months of paucibacillary-multidrug therapy (PB-MDT) and found disease activity in 27 (61%) cases. Following treatment, there was a predominance of lymphocytes and loose granulomas.[8] In another study, 33% (8/24) of cases of BT leprosy showed histological activity after 6 months of multidrug therapy.[9] When biopsies were taken 12 months after single-dose rifampicin-ofloxacin-minocycline therapy for PB leprosy, persistent granulomas were noted in 15% of cases.[10] Joshi has described several changes in treated leprosy including the presence of noncohesive epithelioid cell granulomas with edema.[11]
In one series, 13% (4/30) of biopsies showed an increase in disease activity after treatment, including half that had not shown granulomas at baseline. Dermal fibrosis was noted in about half (54.5%) of biopsies that showed granulomas at baseline.[12]
CUTANEOUS TUBERCULOSIS
Epithelioid granulomas are seen in many biopsies from cutaneous tuberculosis. The granulomas are often accompanied by a dense cuff of lymphocytes along with Langhans giant cells. Eosinophils and neutrophils are not seen in significant numbers, but a few may occasionally be noted. Occasionally, plasma cells may be present. Necrosis within granulomas is not as frequent as in tuberculosis of the lung and other sites, but may be seen. Epidermal hyperplasia is frequent and dermal fibrosis is common. The subtypes of cutaneous tuberculosis are described below. Scrofuloderma typically shows suppurative granulomas and is not discussed in this article.
Biopsies of lupus vulgaris show granulomas in about 70% of cases.[1314] There is a characteristic distribution of granulomas with a broad, confluent granulomatous infiltrate in the upper dermis abutting on the overlying epidermis with lichenoid basal cell damage. This is referred to as the lichenoid-granulomatous pattern or the lupus vulgaris pattern. The mid-dermis is relatively spared, while the lower dermis shows smaller, discrete, nodular granulomas that may be arranged around sweat glands or hair follicles [Figure 14]. The overlying epidermis is acanthotic with follicular plugs that are often parakeratotic. The degree of epidermal hyperplasia is variable but is often quite significant, noted in 41.2%–77.3%.[131415] Uncommonly, the epidermis may be atrophic. This prototypical presentation is seen in about 20% of biopsies, while other biopsies show epithelioid granulomas and epidermal and dermal changes but lack any particular distribution.
Figure 14: Lichenoid granulomatous pattern in lupus vulgaris: Broad, confluent granulomatous infiltrate in the upper dermis abutting on the overlying acanthotic epidermis with a deep, discrete granuloma (H and E, Ă—40)
Necrosis within granulomas is not usual and was seen in 11%–59% of cases in different series.[13141516] Dermal fibrosis is commonly seen and was found in 29.4% and 72.7% of cases in two studies of 165 and 103 cases, respectively.[1516] In some cases, depending on the type of lesion and site of biopsy, fibrosis may dominate the picture with a few granulomas within the fibrosis. Acid-fast bacilli are hardly ever seen. Other findings that have been reported include transfollicular elimination of granulomas seen as granulomas engulfed by hyperplastic follicular infundibulum in a case of lupus vulgaris.[17]
In a series of 14 cases of lupus vulgaris, Pai et al. found epithelioid granulomas in all cases, epidermal hyperplasia in 11 (78.5%), caseous necrosis in 3 (21%), dermal fibrosis in 3 (21%), and foreign body giant cells and calcific nodules in giant cells in 2 (14%). Acid-fast bacilli were not seen in any case.[18]
Tuberculosis verrucosa cutis shows findings similar to lupus vulgaris with prominent epidermal features such as hyperkeratosis, acanthosis, papillomatosis, and pseudoepitheliomatous hyperplasia [Figure 15].[19] Neutrophilic microabscesses are noted in the epidermis and neutrophils may be seen in the upper dermal infiltrate. Deep biopsies are required for a diagnosis as characteristic granulomas may be seen only in the deep dermis. Acid-fast bacilli are usually not seen.
Figure 15: Hyperkeratosis, acanthosis, papillomatosis, and pseudoepitheliomatous hyperplasia along with a lichenoid granulomatous infiltrate in tuberculosis verrucosa cutis (H and E, Ă—40)
By definition, tuberculids show epithelioid cell granulomas. In lichen scrofulosorum, there are focal granulomas centered on and replacing hair follicles and also around sweat glands [Figure 16]. They may be accompanied by papillary dermal granulomas resembling lichen nitidus.[20] Papulonecrotic tuberculid (PNT) shows focal, wedge-shaped necrosis of the epidermis and dermis with leukocytoclastic vasculitis. In addition, loose epithelioid cell granulomas are seen adjacent to the necrosis.[21] PNTs of the penis show focal, epithelioid cell granulomas with lymphocytes accompanied by fibrosis in long-standing lesions. Erythema induratum is a granulomatous lobular panniculitis with vasculitis. There are nodular, epithelioid cell granulomas within lobules that are often, but not invariably, accompanied by vasculitis of small and/or medium vessels [Figure 17]. In a series of 12 cases of erythema induratum, diffuse, lobular granulomatous panniculitis was seen in 75%, focal septolobular in 25%, vasculitis in 75%, caseous necrosis in 83.3%, and eosinophils in 83.3%.[22]
Figure 16: Epithelioid cell granuloma replacing the hair follicle in lichen scrofulosorum (H and E, Ă—100)
Figure 17: Lobular granulomatous panniculitis in erythema induratum (H and E, Ă—400)
CUTANEOUS LEISHMANIASIS AND POST KALA AZAR DERMAL LEISHMANIASIS
Epithelioid granulomas are a feature of chronic cutaneous leishmaniasis and leishmania recidivans though they have also been described in around 30% of cases of acute leishmaniasis.[23] Although most cases of nodular post kala azar dermal leishmaniasis are non-granulomatous, epithelioid granulomas are seen in some cases. Presence of epithelioid cells in leishmaniasis has been found to be associated with a lower requirement of drug for treatment.[2425] They are also more frequent in diseases caused by Leishmania braziliensis and in recurrent cutaneous leishmaniasis.[2526]
Leishmania–Donovan bodies (LD bodies) are amastigotes appearing as blue-gray bodies of size 2–4 μm with a nucleus and a kinetoplast on higher magnification. Seen within or outside macrophages, these can sometimes be confused with nuclear debris or other fungal elements such as histoplasma. This diagnostic finding is seen only in 15%–30% of biopsies, showing a granulomatous infiltrate.[2728] However, one group noted that epithelioid cells were as frequent in biopsies with Leishmania amastigotes as in those without them.[29] Plasma cells are frequent in biopsies of cutaneous leishmaniasis but are less common when there are epithelioid cell granulomas [Figure 18].
Figure 18: Plasma cells (left side), epithelioid cells (center), and Leishmania–Donovani bodies (arrow) in cutaneous leishmaniasis (H and E, ×400)
Epidermal changes ranging from atrophy to ulceration to hyperplasia can be seen depending on the clinical manifestation. Some authors have reported amastigotes within the epidermis representing transepithelial elimination.[23] The granulomas are loose involving the upper and mid-dermis, though compact granulomas can be found. Andrade-Narvaez et al. and Quintella et al. observed granulomas in 6.8% and 39.7% of cases, respectively.[2430] Necrosis is usually absent, but was noted in about a quarter of biopsies in two different series.[2431]
Recently, Fernandez-Flores and Rodriguez-Peralto described a “messy granuloma” in cutaneous leishmaniasis. They found granulomas in 82% of biopsies (14/17); out of which, 8 showed discrete and 6 showed confluent granulomas. According to them, messy granulomas are loose epithelioid cell granulomas with low cellularity. Granulomas are composed of elongated histiocytes with glassy cytoplasm arranged haphazardly, with an intervening hyaline dense substance, likely degenerated collagen (as stained green by Masson trichrome stain). There were few lymphocytes, no giant cells, or necrosis.[32]
Epithelioid granulomas are not usually seen in nodular post kala azar dermal leishmaniasis but may be observed in a minority of patients. They were seen in 4 (4.5%) of a large series of 88 cases reported by Singh et al. Biopsies showed nodular aggregates of epithelioid cells and macrophages surrounded by lymphocytes and plasma cells along with epidermal atrophy [Figure 19].[33]
Figure 19: Nodular epithelioid cell granulomas within a dense, diffuse dermal infiltrate with follicular plugging of the overlying epidermis in post kala azar dermal leishmaniasis (H and E, Ă—40)
Special stains such as Giemsa stain, immunohistochemistry for leishmanial antigens such as G2D10, culture, and polymerase chain reaction studies may aid in the diagnosis of leishmaniasis.[34]
SARCOIDOSIS
The prototypical sarcoidal granuloma is the so-called naked granuloma, composed almost exclusively of epithelioid cells accompanied by a sprinkling of lymphocytes. The granulomas tend to be round and of small to moderate size. An important histological clue is the lack of confluence of individual granulomas even when they are huddled close to each other [Figure 20]. Giant cells in granulomas may contain Schaumann bodies, lamellar inclusions of calcium or asteroid bodies, star-like structures composed of degenerated collagen or elastin. Necrosis is typically absent and fibrosis is not a feature of sarcoidosis.
Figure 20: Compact, closely placed yet discrete granulomas in sarcoidosis (reticulin stain, Ă—200)
However, there are several variations on this theme. While naked granulomas formed the majority, significant lymphocytic infiltrates accompanied the granulomas in 14%–29% of biopsies in three series of 28, 31, and 32 cases.[43536] Coalescent granulomas were seen in most biopsies in one study (29/42, 69%) and was a striking finding in five biopsies.[4] Similarly, Cardoso et al. noted coalescent granulomas in 65% (20/31) of cases.[35]
Giant cells were seen in nearly all biopsies (30 of 31, 97%) in one series, but other cells such as neutrophils and plasma cells were hardly ever noted (1 case each, 3%).[35]
Schaumann and asteroid bodies were found within giant cells in four (9.5%) cases and ten (32%) cases in two series.[435] However, we have seen Schaumann bodies in leprosy and cutaneous tuberculosis on rare occasions and asteroid bodies were seen in 33% (8/24) of cases of necrobiotic xanthogranuloma, with paraproteinemia in one series.[5]
Another important finding in cutaneous sarcoidosis is the presence of polarizable foreign bodies. It was initially believed that the demonstration of foreign bodies in a sarcoidal granuloma refuted the diagnosis of sarcoidosis. However, it is now recognized that authentic sarcoidosis often shows these inclusions within giant cells. Mangas et al. found foreign material in 26%, Cardoso et al. in 13%, and Ball et al. in 50% of biopsies.[43536]
Although necrosis and fibrosis are typically absent in sarcoidal granulomas, these findings have been reported in different studies. Focal necrosis was seen in 6%–43% in various studies though it was not seen in any case in one study.[43536] We have frequently noted small foci of fibrinoid necrosis at the center of sarcoidal granulomas and use this finding as a diagnostic clue to differentiate sarcoidosis from other granulomatous disorders [Figure 21].
Figure 21: Epithelioid cell granuloma with fibrinoid necrosis in sarcoidosis (H and E, Ă—400)
Fibrosis is a constant finding in scar sarcoidosis where, by definition, sarcoidal granulomas are seen in the context of dermal fibrosis. However, mild fibrosis can be seen in other variants of sarcoidosis and was noted in 10% of cases in one study.[35] Fibrosis or sclerosis is the predominant feature along with epithelioid cell granulomas in morpheaform sarcoidosis which presents with indurated, morphea-like plaques. Fibrosis and obliteration of fat along with granulomas has been reported in this variant.[37] Other rare features noted in sarcoidosis include elastophagocytosis (39%) and increased dermal mucin (18%) in a series by Ball et al.[36]
The density of the infiltrate also varies from mild infiltrates seen in 19% (6/31) to moderate in 45% (14/31) and severe in 36% (11/31). In this series, the infiltrate was oriented horizontally most commonly (61%) followed by vertical (23%) and mixed horizontal and vertical (13%) orientation, while one biopsy showed infiltrates in the adventitial dermis.[35]
In relation to dermal structures, the granulomatous infiltrate was frequently noted around appendages, vessels, and nerves, and linear peri-neural granulomas were seen in 25% of cases in one study.[36] We have noted a strong resemblance to tuberculoid leprosy in some biopsies of sarcoidosis, both in the composition and distribution of the granulomas. Granulomas were also noted in the interstitial dermis, and a lichenoid granulomatous pattern was described in 4 of 28 biopsies.[36]
LUPUS MILIARIS DISSEMINATUS FACIEI and GRANULOMATOUS ROSACEA
In well-developed lesions of LMDF, there are large, nodular aggregates of epithelioid cells with prominent central necrosis, often adjacent to a hair follicle. Among cutaneous granulomatous disorders, LMDF shows the most impressive caseation necrosis even though it is a non-infective condition [Figure 22]. Caseous necrosis was seen in 12.5%–69% of cases in different series.[38394041] The combination of caseating granulomas in a patient with multiple facial papules and papulo-pustules is pathognomonic of the condition. However, necrosis is not invariable and non-necrotizing granulomas may also be seen.[1342] Non-caseating sarcoidal and tuberculoid granulomas were noted in 16%–37.5% of cases.[383942] Early and late lesions are non-granulomatous and show peri-appendageal (mainly perifollicular) lympho-histiocytic infiltrates and fibrosis, respectively. Neutrophils may be noted if the biopsied lesion showed pustulation. Neutrophilic infiltrates and microabscesses were seen in 12.5%–24% of cases.[384142]
Figure 22: Epithelioid cell granulomas with prominent central necrosis in lupus miliaris disseminatus faciei (H and E, Ă—100)
Some workers believe that lupus miliaris disseminates faciei is a variant of granulomatous rosacea.
Granulomatous rosacea presents with small, epithelioid cell granulomas centered on pilosebaceous units and vessels in the upper and mid-dermis, respectively. Vascular dilatation is a clue when differentiating it from other granulomatous conditions.
In a study on histological features of 53 cases of granulomatous rosacea, epithelioid cell granulomas were seen in 11%, granulomas with caseation in another 11%, histiocytic infiltrates with a few giant cells in 34%, and lympho-histiocytic infiltrates in 40%.[43]
In another study on 24 biopsies of granulomatous rosacea, 4 distinct patterns were noted: nodular (33%), perifollicular (12.5%), diffuse (8.3%), and combined perifollicular and nodular (54%). Other histological features seen were solar elastosis (100%), fibroplasia (100%), telangiectasia (67%), demodex mite (29%), and spongiosis (13%).[44]
MISCELLANEOUS CAUSES
There are a number of other granulomatous conditions that show some features that may be helpful in diagnosis.
Epithelioid cell granulomas are classically seen in tertiary syphilis (gummas), and occasionally in secondary syphilis. Gummas, rarely encountered now, show necrotizing granulomas.[45] In secondary syphilis, granulomas appear to be more frequent in long-standing disease that presents with a nodular eruption.[46] These granulomas are arranged in a band-like manner around the superficial papillary dermal vasculature with deeper extension into the reticular dermis along the appendages.[47] Rysgaard et al. have described this finding as T-shaped or candelabra-shaped pattern.[48] Besides this, a perivascular and peri-appendageal distribution and perineural distribution resembling the leprosy pattern have also been reported.[4950] Plasma cells are a clue to the diagnosis of secondary syphilis but their numbers may vary in biopsies from granulomatous lesions. When present, they may be seen around appendages, away from the epithelioid granuloma. Endothelial cell swelling is usually not a feature.[4651] Sarcoidal granulomas and interstitial granulomas also have been described in secondary syphilis.[4952]
T. pallidum can be identified with the help of special stains such as Warthin–Starry stain, direct immunofluorescence, or immunohistochemistry. However, in granulomatous syphilis, the chances of finding Treponema are low.
Orofacial granulomatosis or Melkersson–Rosenthal syndrome presents with granulomatous inflammation. In a study on recurrent facial swelling in 104 cases, granulomatous inflammation was seen in 47% (40/85). Among these, there were 68% (27/40) cases of orofacial granulomatosis and 43% (3/7) cases of solid facial edema.[53]
In an unpublished study conducted in our department, 10 (52.6%) of 19 cases of clinically diagnosed granulomatous cheilitis showed granulomas. In three of them, granulomas were seen between the skeletal muscle bundles at the deep aspect of the lip biopsy, in addition to dermal granulomas [Figure 23]. Granulomas were noted more frequently in those who had more severe lip swelling and for a longer duration.[41]
Figure 23: Epithelioid cell granulomas in superficial and deep dermis extending up to muscle in granulomatous cheilitis (H and E, Ă—40)
Granulomatous peri-orificial dermatitis shows a histopathological resemblance to granulomatous rosacea. There are peri-appendageal lympho-plasmacytic infiltrates with non-caseating epithelioid cell granulomas and many multinucleated giant cells.[54]
Peri-oral dermatitis is another condition that resembles granulomatous rosacea on histology. It shows perivascular and perifollicular lymphocytic infiltrates with giant cells and dermal edema.[55]
Facial aseptic granuloma presents as an asymptomatic erythematous nodule over the cheeks in children. Histopathology shows peri-folliculitis, granulomatous follicular inflammation with surrounding lympho-plasmacytic infiltrate. Some consider it to be a variant of granulomatous rosacea.[56] Mixed inflammatory infiltrates can also be seen.[57]
Cutaneous Crohn's disease, also known as metastatic Crohn's disease, shows the presence of non-suppurative, sarcoidal, epithelioid cell granulomas in dermis and subcutis with many Langhans and foreign body giant cells and a mild-to-moderate perivascular mixed inflammatory infiltrate. Rarely, granulomatous vasculitis, necrobiosis, and eosinophils in the infiltrate have been reported.[5859] Emanuel and Phelps found non-caseating epithelioid cell granulomas with a slight cuff of lymphocytes in a nodular or diffuse manner with perivascular mixed inflammatory infiltrate as the predominant finding in 12 cases of metastatic Crohn's disease. The infiltrate was both superficial and deep in the majority (75%) of cases. Other findings noted were epidermal infiltration (25%), lichenoid infiltrate (16.7%), ulceration (41.7%), presence of eosinophils (66.7%), granulomatous vasculitis (16.7%), and dermal edema (16.7%).[60]
CONCLUSION
A large number of conditions present with granulomas on biopsy. The histopathological appearance is quite suggestive of the diagnosis in some diseases such as leprosy, sarcoidosis, and lupus vulgaris. In other conditions, the histopathological appearance is not enough by itself but when taken with the clinical appearance can lead to the diagnosis as in LMDF, penile tuberculid, granulomatous cheilitis, or Crohn's disease. In all these diseases, additional clinical information and laboratory tests are helpful to provide further evidence for the diagnosis. This may include information about residence in an endemic area for cutaneous leishmaniasis or kala-azar, risky sexual behavior in syphilis, and co-existence of pulmonary sarcoidosis. Although organisms are usually difficult to find or grow from epithelioid granulomas, positive cultures and nucleic acid amplification tests for fungi, mycobacteria, and leishmania may be of help in diagnosis. In some cases, the answer comes from a therapeutic trial and prolonged follow-up, while in some, the diagnosis cannot be established. Histological salient features of various granulomatous conditions are mentioned in Table 2. An approach to biopsies showing epithelioid granulomas is outlined in Figure 24.
Table 2: Salient histological features of various granulomatous conditions
Figure 24: Diagnostic approach to epithelioid cell granulomas
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Conflicts of interest
There are no conflicts of interest.
REFERENCES
1. James DG. A clinicopathological classification of granulomatous disorders Postgrad Med J. 2000;76:457–65
2. de Brito T, Franco MF. Granulomatous inflammation Rev Inst Med Trop Sao Paulo. 1994;36:185–92
3. Okamoto H, Mizuno K, Horio T. Langhans-type and foreign-body-type multinucleated giant cells in cutaneous lesions of sarcoidosis Acta Derm Venereol. 2003;83:171–4
4. Mangas C, Fernández-Figueras MT, Fité E, Fernández-Chico N, Sà bat M, Ferrándiz C, et al Clinical spectrum and histological analysis of 32 cases of specific cutaneous sarcoidosis J Cutan Pathol. 2006;33:772–7
5. Winkelmann RK, Dahl PR, Perniciaro C. Asteroid bodies and other cytoplasmic inclusions in necrobiotic xanthogranuloma with paraproteinemia J Am Acad Dermatol. 1998;38:967–70
6. Jayalakshmi. . Histopathology of skin lesions in leprosy Malays J Pathol. 1980;3:39–45
7. Khan A, Koranne RV, Bajaj P, Ravi B. Clinico-histopathological correlation of skin and nerve in leprosy J Dermatol. 2004;31:632–6
8. Jain S, Ramesh V, Singh A, Yadav A, Ramam M, Khandpur S, et al Clinical and histopathological features of paucibacillary leprosy before and after multidrug therapy: A prospective study Trans R Soc Trop Med Hyg. 2016;110:350–8
9. Ebenezer GJ, Suneetha S, Arunthathi S. Clinical and histopathological activity in paucibacillary leprosy patients after fixed-duration multidrug therapy Lepr Rev. 1997;68:218–24
10. Ebenezer GJ, Job CK. Histopathological activity in paucibacillary leprosy patients after ROM therapy Int J Lepr Other Mycobact Dis. 1999;67:409–13
11. Joshi R. Clues to histopathological diagnosis of treated leprosy Indian J Dermatol. 2011;56:505–9
12. Sasidharanpillai S, Govindan A, Riyaz N, Binitha MP, Parambath SP, Khader A, et al Histopathology of skin lesions of leprosy before and after fixed duration treatment Lepr Rev. 2017;88:142–53
13. Sehgal VN, Srivastava G, Khurana VK, Sharma VK, Bhalla P, Beohar PC, et al An appraisal of epidemiologic, clinical, bacteriologic, histopathologic, and immunologic parameters in cutaneous tuberculosis Int J Dermatol. 1987;26:521–6
14. Thakur BK, Verma S, Hazarika D. A clinicopathological study of cutaneous tuberculosis at Dibrugarh district, Assam Indian J Dermatol. 2012;57:63–5
15. Sharma S, Sehgal VN, Bhattacharya SN, Mahajan G, Gupta R. Clinicopathologic spectrum of cutaneous tuberculosis: A retrospective analysis of 165 Indians Am J Dermatopathol. 2015;37:444–50
16. Vashisht P, Sahoo B, Khurana N, Reddy BS. Cutaneous tuberculosis in children and adolescents: A clinicohistological study J Eur Acad Dermatol Venereol. 2007;21:40–7
17. Desai CA, Khopkar U. Cutaneous tuberculosis with a difference: Documenting transfollicular elimination of granulomas Indian Dermatol Online J. 2016;7:297–9
18. Pai VV, Naveen KN, Athanikar SB, Dinesh US, Divyashree A, Gupta G, et al Aclinico-histopathological study of lupus vulgaris: A 3 year experience at a tertiary care centre Indian Dermatol Online J. 2014;5:461–5
19. Santos JB, Figueiredo AR, Ferraz CE, Oliveira MH, Silva PG, Medeiros VL, et al Cutaneous tuberculosis: Diagnosis, histopathology and treatment - Part II An Bras Dermatol. 2014;89:545–55
20. Singhal P, Patel PH, Marfatia YS. Lichen scrofulosorum: A diagnosis overlooked Indian Dermatol Online J. 2012;3:190–2
21. Tirumalae R, Yeliur IK, Antony M, George G, Kenneth J. Papulonecrotic tuberculid-clinicopathologic and molecular features of 12 Indian patients Dermatol Pract Concept. 2014;4:17–22
22. Chen YH, Yan JJ, Chao SC, Lee JY. Erythema induratum: A clinicopathologic and polymerase chain reaction study J Formos Med Assoc. 2001;100:244–9
23. Handler MZ, Patel PA, Kapila R, Al-Qubati Y, Schwartz RA. Cutaneous and mucocutaneous leishmaniasis: Differential diagnosis, diagnosis, histopathology, and management J Am Acad Dermatol. 2015;73:911–26
24. Andrade-Narvaez FJ, Medina-Peralta S, Vargas-Gonzalez A, Canto-Lara SB, Estrada-Parra S. The histopathology of cutaneous leishmaniasis due to leishmania (Leishmania) mexicana in the Yucatan peninsula, Mexico Rev Inst Med Trop Sao Paulo. 2005;47:191–4
25. Gutierrez Y, Salinas GH, Palma G, Valderrama LB, Santrich CV, Saravia NG, et al Correlation between histopathology, immune response, clinical presentation, and evolution in
Leishmania braziliensis infection Am J Trop Med Hyg. 1991;45:281–9
26. Souza LW, Souza SV, Botelho AC. Comparative analysis of the geographic distribution of the histopathological spectrum and
Leishmania species of American cutaneous leishmaniasis in Brazil An Bras Dermatol. 2012;87:369–74
27. Venkataram M, Moosa M, Devi L. Histopathological spectrum in cutaneous leishmaniasis: A study in Oman Indian J Dermatol Venereol Leprol. 2001;67:294–8
28. Sharquie KE, Hassen AS, Hassan SA, Al-Hamami IA. Evaluation of diagnosis of cutaneous leishmaniasis by direct smear, culture and histopathology Saudi Med J. 2002;23:925–8
29. Dias-Polak D, Geffen Y, Ben-Izhak O, Bergman R. The role of histopathology and immunohistochemistry in the diagnosis of cutaneous leishmaniasis without “Discernible” Leishmania-Donovan bodies Am J Dermatopathol. 2017;39:890–5
30. Quintella LP, Passos SR, de Miranda LH, Cuzzi T, Barros MB, Francesconi-do-Vale AC, et al Proposal of a histopathological predictive rule for the differential diagnosis between American tegumentary leishmaniasis and sporotrichosis skin lesions Br J Dermatol. 2012;167:837–46
31. Andrade RV, Massone C, Lucena MN, Talhari AC, Talhari S, Guerra JA, et al The use of polymerase chain reaction to confirm diagnosis in skin biopsies consistent with American tegumentary leishmaniasis at histopathology: A study of 90 cases An Bras Dermatol. 2011;86:892–6
32. Fernandez-Flores A, Rodriguez-Peralto JL. Messy granuloma: An additional pattern of granulomatous reaction Rom J Morphol Embryol. 2016;57:51–7
33. Singh A, Ramesh V, Ramam M. Histopathological characteristics of post kala-azar dermal leishmaniasis: A series of 88 patients Indian J Dermatol Venereol Leprol. 2015;81:29–34
34. Beena KR, Ramesh V, Mukherjee A. Identification of parasite antigen, correlation of parasite density and inflammation in skin lesions of post kala-azar dermal leishmaniasis J Cutan Pathol. 2003;30:616–20
35. Cardoso JC, Cravo M, Reis JP, Tellechea O. Cutaneous sarcoidosis: A histopathological study J Eur Acad Dermatol Venereol. 2009;23:678–82
36. Ball NJ, Kho GT, Martinka M. The histologic spectrum of cutaneous sarcoidosis: A study of twenty-eight cases J Cutan Pathol. 2004;31:160–8
37. Burov EA, Kantor GR, Isaac M. Morpheaform sarcoidosis: Report of three cases J Am Acad Dermatol. 1998;39:345–8
38. Sehgal VN, Srivastava G, Aggarwal AK, Belum VR, Sharma S. Lupus miliaris disseminatus faciei Part I: Significance of histopathologic undertones in diagnosis. Skinmed. 2005;4:151–6
39. Al-Mutairi N. Nosology and therapeutic options for lupus miliaris disseminatus faciei J Dermatol. 2011;38:864–73
40. Shitara A. Clinicopathological and immunological studies of lupus miliaris disseminatus faciei J Dermatol. 1982;9:383–95
41. Rai M, Rai A, Ramam M, Khandpur S, Singh MK, Arava S. Clinical and Histopathological Study of Lupus Miliaris Disseminatus Faciei and Granulomatous Cheilitis Submitted as MD Thesis, Department of Dermatology and Venereology, AIIMS, New Delhi; November,. 2014:52–66
42. el Darouti M, Zaher H. Lupus miliaris disseminatus faciei - Pathologic study of early, fully developed, and late lesions Int J Dermatol. 1993;32:508–11
43. Helm KF, Menz J, Gibson LE, Dicken CH. A clinical and histopathologic study of granulomatous rosacea J Am Acad Dermatol. 1991;25:1038–43
44. Sánchez JL, Berlingeri-Ramos AC, Dueño DV. Granulomatous rosacea Am J Dermatopathol. 2008;30:6–9
45. Tanabe JL, Huntley AC. Granulomatous tertiary syphilis J Am Acad Dermatol. 1986;15:341–4
46. Abell E, Marks R, Jones EW. Secondary syphilis: A clinico-pathological review Br J Dermatol. 1975;93:53–61
47. Pandhi RK, Singh N, Ramam M. Secondary syphilis: A clinicopathologic study Int J Dermatol. 1995;34:240–3
48. Rysgaard C, Alexander E, Swick BL. Nodular secondary syphilis with associated granulomatous inflammation: Case report and literature review J Cutan Pathol. 2014;41:370–9
49. Wu SJ, Nguyen EQ, Nielsen TA, Pellegrini AE. Nodular tertiary syphilis mimicking granuloma annulare J Am Acad Dermatol. 2000;42:378–80
50. Pandhi D, Reddy BS, Khurana N, Agarwal S. Nodular syphilis mimicking histoid leprosy J Eur Acad Dermatol Venereol. 2005;19:256–7
51. Alessi E, Innocenti M, Ragusa G. Secondary syphilis Clinical morphology and histopathology. Am J Dermatopathol. 1983;5:11–7
52. Kahn LB, Gordon W. Sarcoid-like granulomas in secondary syphilis A clinical and histopathologic study of five cases. Arch Pathol. 1971;92:334–7
53. Miest RY, Bruce AJ, Comfere NI, Hadjicharalambous E, Endly D, Lohse CM, et al Adiagnostic approach to recurrent orofacial swelling: A retrospective study of 104 patients Mayo Clin Proc. 2017;92:1053–60
54. Lucas CR, Korman NJ, Gilliam AC. Granulomatous periorificial dermatitis: A variant of granulomatous rosacea in children? J Cutan Med Surg. 2009;13:115–8
55. Lipozencic J, Ljubojevic S. Perioral dermatitis Clin Dermatol. 2011;29:157–61
56. Neri I, Raone B, Dondi A, Misciali C, Patrizi A. Should idiopathic facial aseptic granuloma be considered granulomatous rosacea? Report of three pediatric cases Pediatr Dermatol. 2013;30:109–11
57. González RodrĂguez AJ, Jordá Cuevas E. Idiopathic facial aseptic granuloma Clin Exp Dermatol. 2015;40:298–300
58. Burns AM, Walsh N, Green PJ. Granulomatous vasculitis in Crohn's disease: A clinicopathologic correlate of two unusual cases J Cutan Pathol. 2010;37:1077–83
59. Siroy A, Wasman J. Metastatic Crohn's disease: A rare cutaneous entity Arch Pathol Lab Med. 2012;136:329–32
60. Emanuel PO, Phelps RG. Metastatic Crohn's disease: A histopathologic study of 12 cases J Cutan Pathol. 2008;35:457–61
