Clinically suspected granulomatous skin lesions on the face: A prospective clinico-pathological correlation study of 77 cases

Introduction

Granulomatous skin lesions affect the face frequently, usually presenting as inflammatory plaques and nodules. However, these clinical features are non-specific and may be shared by a variety of non-granulomatous dermatoses as well, making the clinical diagnosis challenging. Though histopathology is widely regarded as the gold standard for diagnosis, histological patterns are often overlapping, adding to diagnostic uncertainty.^1–4

We conducted this study to describe the clinical and histopathological features of facial granulomatous skin lesions and their non-granulomatous clinical mimics, and to evaluate the utility of clinico-pathological correlation in making the final diagnosis.

Methods

This was a prospectively conducted cross-sectional study from April 2023 to November 2024 at All India Institute of Medical Sciences, New Delhi, India, after approval from the Institutional Ethics Committee (IECPG-76/07.03.2023, RT-08/23.03.2023). After informed consent, 77 patients with clinically suspected granulomatous skin lesions on the face were included. A 4 mm punch biopsy was performed from a representative facial skin lesion and stained with haematoxylin and eosin (H & E) in all cases and special stains as required. The histopathological features were independently evaluated by three dermatopathologists (MR¹, VG¹, SKA²/SA²) blinded to clinical information, and findings were recorded in a pre-designed proforma. A granuloma was defined as a collection of activated or epithelioid histiocytes with/without lymphocytes, giant cells, and other inflammatory cells and/or necrosis.^5,6 All the proformas were reviewed at the end of the study (by VG¹ and SA¹) and any discrepancies between the investigators, including those related to histopathological findings, were resolved through discussion and mutual agreement.

Final diagnosis was based on clinico-pathological correlation and supplemented, where necessary, by ancillary investigations like imaging, Mantoux test, relevant serologies, slit-skin smears, cultures, nucleic acid amplification tests, and biopsies from extracutaneous sites, and/or a therapeutic trial. Final diagnosis was categorised as confirmed, probable, or undiagnosed [Supplementary Table 1], based on consensus among three dermatology experts (VG¹, MR¹, SK¹). The diagnosed cases were classified as granulomatous or non-granulomatous based on the overall clinico-investigative profile. Clinico-pathological correlation was classified as concordant (histopathology consistent with any of the clinical diagnoses), discordant (histopathology diagnostic of a disease not suspected clinically), or non-contributory (histopathology not suggestive of a particular diagnosis).

Continuous variables were presented as mean (±standard deviation, range) and categorical variables as frequency (%). For statistical analysis, ‘confirmed’ and ‘probable’ diagnoses were grouped into a single category. Categorical variables were compared using the chi-square test or the Fisher’s exact test as applicable. A p-value <0.05 was considered statistically significant.

Results

Of the 77 patients, 40 were males and 37 were females with a mean age of 38±16.20 (range 8-74) years. Most patients had Fitzpatrick skin type V (n=41, 53%) or VI (n=29, 38%).

A single clinical diagnosis was considered in 42 (55%) patients, while 35 (45%) patients had two or more differential diagnoses: 12 (16%), 15 (19%), 7 (9%), and 1 (1%) patient had two, three, four, and five clinical differential diagnoses, respectively. The clinical differential diagnoses included only granulomatous conditions in 54 (70%) cases, while both granulomatous and non-granulomatous conditions were considered in 23 (30%) cases.

Overall, a final diagnosis was established in 70 (91%) out of 77 patients: 58 (75%) based on clinico-pathological correlation and 12 (16%) through ancillary investigations (n=3) and/or therapeutic trial (n=9). Seven patients (9%) remained undiagnosed at the end of the study; orofacial granulomatosis (OFG) was the most common clinical differential diagnoses in these cases [Supplementary Table 2]. Figure 1 shows the flowchart illustrating the stepwise classification of cases based on the presence or absence of granulomas and the final diagnosis.

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Figure 1:

Study flowchart illustrating the stepwise classification of cases.

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Of the 70 diagnosed cases, 58 (83%) were categorised as ‘confirmed’ and 12 (17%) as ‘probable’ diagnosis.’ These included 60 (49 confirmed, 11 probable) classified as granulomatous and 10 (9 confirmed, 1 probable) as non-granulomatous cases. Non-infectious granulomatous cases (39, 65%) were more than infections (21, 35%). The most common granulomatous diagnoses were OFG (n=25), leprosy (n=15), and sarcoidosis (n=10), while non-granulomatous diagnoses were chronic cutaneous lupus erythematosus (CCLE, n=4) and pseudolymphoma (n=4) [Figure 2].

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Figure 2:

Final diagnosis of 77 cases with level of certainty in diagnosis (confirmed, probable, or undiagnosed).

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Clinical features

The common clinical morphologies included plaques (42, 55%), swellings (29, 38%), papules (17, 22%), nodules (4, 5%), and macules (4, 5%) [Figure 3]. Forty-four (57%) patients had more than one facial skin lesion, of whom 29 had facial lesions with different clinical morphologies.

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Figure 3a:

Lip and chin swelling (orofacial granulomatosis).

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Figure 3b:

Hypopigmented macule (Borderline tuberculoid leprosy).

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Figure 3c:

Large plaque with scaling (Borderline tuberculoid leprosy in Type 1 reaction).

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Figure 3d:

Subcutaneous frim nodules (sarcoidosis).

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Figure 3e:

Multiple papules with varioliform scarring (Lupus miliaris disseminatus faciei).

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Figure 3f:

Hyperpigmented plaque with scaling and crusting (phaeohyphomycosis).

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Figure 3g:

Erythematous succulent plaque (neutrophilic dermatosis).

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Figure 3h:

Erythematous-to-violaceous plaques (discoid lupus erythematosus).

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Histopathological patterns

Overall, 54 (70%) of 77 cases showed a granulomatous histopathology. Of these, a final diagnosis could be established in 51 (94%) cases, 43 (80%) on clinico-pathological correlation, and eight (15%) on ancillary investigations and/or therapeutic trial. Similarly, 19 out of 23 cases (83%) with a non-granulomatous histopathology could be diagnosed, 15 through clinico-pathological correlation, and four using ancillary investigations/therapeutic trial.

Among the 60 cases finally classified as granulomatous conditions, 51 (85%) showed a granulomatous histopathology. Histopathology did not show granulomas in 9 granulomatous cases seven OFG, one histoplasmosis, and one granulomatosis with polyangiitis [Figure 1]. Among the granulomatous histological patterns, the most common type was tuberculoid granulomas (30, 59%), followed by sarcoidal (12, 24%), suppurative (3, 6%), and foreign body type (1, 2%) [Figure 4]. In nine (18%) cases, no specific type of granuloma could be identified. Four cases showed more than one type of granuloma in the same slide: sarcoidal and tuberculoid (n=2, OFG and borderline tuberculoid (BT) leprosy), sarcoidal and suppurative (n=1, pheohyphomycosis), and tuberculoid and foreign body (n=1, lupus miliaris disseminatus faciei). The histopathology patterns corresponding to individual groups of granulomatous diseases are shown in Table 1.

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Figure 4a:

Tuberculoid granulomas in ‘leprosy pattern’ (Borderline tuberculoid leprosy, Haematoxylin & eosin, 100x).

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Figure 4b:

Lymphocyte-poor sarcoidal granulomas (Borderline borderline leprosy in type 1 reaction, Haematoxylin & eosin, 100x).

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Figure 4c:

Lymphocyte-rich sarcoidal granuloma (sarcoidosis, Haematoxylin & eosin, 100x).

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Figure 4d:

Perifollicular tuberculoid and foreign body granuloma (lupus miliaris disseminatus faciei, Haematoxylin & eosin, 200x).

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Figure 4e:

Dense dermal lymphocytic infiltrates with ‘lymphoid follicle’ formation (pseudolymphoma, Haematoxylin & eosin, 200x).

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Figure 4f:

Lichenoid tissue reaction (discoid lupus erythematosus, Haematoxylin & eosin, 200x).

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Table 1: Histopathological patterns corresponding to individual groups of granulomatous disorders (n=60)

Histopathology pattern	Diagnosis (n=60)							p-value
	OFG (n=25)	Sarcoidosis (n=10)	Leprosy (n=15)	Other infections* (n=6)	LMDF (n=2)	POGD (n=1)	GPA (n=1)
Tuberculoid granulomas, leprosy pattern (n=13)	1 (4%)	0	12 (80%)	0	0	0	0	<0.001
Tuberculoid granulomas, lichenoid (n=1)	0	0	0	1 (17%)	0	0	0	0.167
Tuberculoid granulomas, perifollicular (n=2)	0	0	0	0	1 (50%)	1 (100%)		0.003
Tuberculoid granulomas, no specific pattern (n=14)	12 (48%)	0	1 (7%)	1 (17%)	0	0	0	0.011
Sarcoidal granulomas, lymphocyte poor (n=10)	0	8 (80%)	1 (7%)	1 (17%)	0	0	0	<0.001
Sarcoidal granulomas, lymphocyte rich (n=4)	1 (4%)	2 (20%)	1 (7%)	0	0	0	0	0.533
Suppurative granulomas (n=3)	0	0	0	3 (50%)	0	0	0	0.005
Foreign body- perifollicular (n=1)	0	0	0	0	1 (50%)	0	0	0.067
Granulomas, not otherwise specified (n=9)	5 (20%)	2 (20%)	1 (7%)	0	1 (50%)	0	0	0.518
Non-granulomatous (n=9)	7 (28%)	0	0	1 (17%)	0	0	1 (100%)	0.033

OFG: Orofacial granulomatosis; LMDF, Lupus miliaris disseminates faciei; POGD: Peri-orificial granulomatous dermatitis; GPA: Granulomatosis with polyangiitis. *Included histoplasmosis (n=2), phaeohyphomycosis (n=1), lupus vulgaris (n=1), atypical mycobacterial infection (n=1), cutaneous leishmaniasis (n=1), Bold values means they are statistically significant

The histopathological patterns of non-granulomatous cases included pseudolymphomatous (n=4), lichenoid (n=4), neutrophil-rich dermal infiltrate (n=1), and non-specific (n=1) [Figure 4].

Clinico-pathological correlation

The histological diagnosis was concordant with the clinical diagnosis in 57 (74%) cases, discordant in eight (10%) cases, and non-contributory in 12 (16%) cases. All 57 concordant cases received a final diagnosis, based on clinico-pathological correlation alone (n=50) or ancillary investigations/therapeutic trial (n=7). All 8 discordant cases also received a final diagnosis, 7 cases through clinico-pathological correlation and 1 requiring confirmation by ancillary investigation. Among the 12 non-contributory cases, only 5 received a final diagnosis - 1 through clinico-pathological correlation and 4 through other means. Histopathology changed the final diagnosis in eight cases (discordant): leprosy (n=2), pseudolymphoma (n=2), sarcoidosis (n=1), histoplasmosis (n=1), neutrophilic dermatosis (n=1), and CCLE (n=1).

The clinico-pathological concordance was higher for granulomatous cases as compared to non-granulomatous (87% vs. 50%) and for cases with a single clinical diagnosis as compared to those with two or more clinical differential diagnoses (83% vs. 63%). Among the most frequent clinically suspected conditions, the clinico-pathological concordance rates were 77% for OFG, 65% for leprosy, 33% for sarcoidosis, and 20% for pseudolymphoma. Figure 5 shows the clinico-pathological correlation of individual clinically suspected diagnoses.

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Figure 5:

Correlation of histological diagnosis with clinical differential diagnoses: concordant, discordant, or non-contributory.

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In the 35 cases with two or more clinical differential diagnoses, histopathology aided the diagnostic process in 20 (57%) cases by providing a single diagnosis in 18 (51%) cases (confirmed one of the clinical diagnoses in 13 cases, changing the clinical diagnosis in 5 cases) and by narrowing down the differential diagnoses in another two (6%) cases. The most common final diagnoses among this subgroup were OFG (n=7), sarcoidosis (n=6), and CCLE (n=4).

Discussion

Our study highlights the wide clinical spectrum of facial granulomatous skin lesions and their clinical mimics. OFG, leprosy, and sarcoidosis were the most common facial granulomatous dermatoses, constituting 83% (n=50/60) of the cases. Interestingly, non-infectious granulomas (39, 65%) were more common than infections in our study, in contrast to previous studies from Southeast Asia (3-11%).^1,2 Studies by Mathur et al¹ (n=30, Nepal) and Bansal et al² (n=18, India) reported leprosy (55-83%) and lupus vulgaris (13-22%) as the most common, while the study by Aryanian et al⁷ (n=150, Iran) reported granulomatous rosacea (32%) and sarcoidosis (14%) to be the commonest. This difference in the case profile could be partly due to previous studies being retrospective reviews of skin biopsy forms and/or histopathology records, which limited the data to routinely biopsied facial lesions. In contrast, ours is a prospective study that included consecutive cases of clinically suspected facial granulomatous skin lesions, providing a profile that more accurately mirrors the true clinical spectrum.

We found pseudolymphoma and chronic cutaneous lupus erythematosus to be common clinical mimics of granulomatous facial skin lesions in our cohort, and these have been confused with granulomatous lesions by others as well.^1,7 In the study by Aryanian et al, mimics of facial granulomatous lesions also included inclusion cyst, basal cell carcinoma, and xanthogranuloma.⁷ Despite the largely overlapping clinical features, some soft clues to differentiate granulomatous facial skin lesions from their clinical mimics may be discerned from our results. For example, a lip swelling or a large plaque (> 5cm) is more likely to be a granulomatous disease, while the presence of a plaque with follicular plugging may indicate a non-granulomatous skin lesion. These findings, though potentially useful, may have been influenced by the more common conditions in our study, OFG and borderline tuberculoid (BT) leprosy in the granulomatous group and CCLE in the non-granulomatous group.

The overall clinico-pathological concordance rate (74%) in our study was similar to earlier studies (77-80%).^1,2 However, the concordance rates for specific diagnoses, such as leprosy (n=13/20, 65%), lupus vulgaris (n=1/3, 33%), sarcoidosis (n=9/27, 33%), and leishmaniasis (n=1/4, 25%) were lower than previous studies (50-100%).^1,2 This discrepancy is attributable to differences in study design. Unlike previous studies that included only histologically confirmed granulomatous dermatoses, our study included clinically suspected cases. This broader inclusion likely contributed to the lower concordance rates in our cohort, but provides a more realistic reflection of diagnostic uncertainty in facial granulomatous skin lesions.

Our findings put into perspective the value of histopathology, and ancillary investigations and/or therapeutic trial in diagnosing clinically suspected facial granulomatous skin lesions. Overall, we could establish a final diagnosis through clinico-pathological correlation in 75% (n=58/77) cases. Histopathology was particularly valuable in clinically challenging cases (n=35), where it helped in over half the cases (n = 20, 57%). Yet, histopathology was not helpful in the remaining 25% cases, being either concordant with all the clinical possibilities or being non-specific, highlighting the importance of incorporating ancillary investigations and/or therapeutic trial which increased our diagnostic yield from 75% to 91%. We assigned a level of certainty to the diagnosis as ‘confirmed,’ ‘probable,’ or ‘undiagnosed,’ that simulates real-life. Such a methodology has been employed previously, reflecting that absolute diagnostic certainty is not always possible when dealing with challenging diagnoses.⁸ For example, we could not diagnose seven (9%) cases despite a comprehensive evaluation, while 12 cases received a ‘probable’ diagnosis.

In our study, tuberculoid granulomas comprised the most common type of granuloma (n=30/60, 50%), consistent with other studies from the Indian subcontinent, including both facial and extra-facial lesions (58-93%).^3,9,10 However, necrobiotic granulomas, seen in 27% cases in a Portuguese study (n=461),⁴ were not seen in our cohort and other facial granuloma studies from the Indian subcontinent. However, the study by Aryanian et al. had a small proportion (n=3, 2.1%) of necrobiotic granulomas.⁷ Other granuloma types in our study included sarcoidal (12, 20%), suppurative (3, 5%), and foreign body type (1, 2%). We were not able to classify granulomas into a particular type in nine (15%) cases, similar to the Portuguese study (16%).⁴

Not only clinically, granulomatous diseases can be challenging to diagnose on histopathology as well, due to frequently overlapping patterns. Still, the diagnostic value of some granuloma patterns is supported by our findings, such as tuberculoid granulomas in a ‘leprosy’ pattern (leprosy), perifollicular tuberculoid granulomas (rosacea variants), ‘naked’ sarcoidal granulomas (sarcoidosis), and suppurative granulomas (mycobacterial and deep fungal infections). Notably, a variety of histological patterns were noted in OFG- tuberculoid granulomas in no specific pattern (12, 48%), granulomas not otherwise specified (5, 20%), and a non-granulomatous non-specific pattern (7, 28%), consistent with the literature.¹¹ From a pathologist’s perspective, different granulomatous patterns were diagnostically helpful in 80% (n=43/54) cases based on correlation with clinical findings.

The strengths of our study are its prospective design, including consecutive cases with clinically suspected granulomatous skin lesions on the face, histopathological evaluation by a panel of dermatopathologists blinded to clinical information, use of ancillary investigations and therapeutic trial as adjunct diagnostic tools, and assigning a level of certainty to the diagnosis.

Limitations

As we included only patients with a clinical suspicion of granulomatous disease, non-granulomatous mimics may have been underrepresented, limiting the comparative power of the study. Further, some individual granulomatous conditions were disproportionately less common, likely representing their inherently low prevalence.

Conclusion

Facial granulomatous lesions exhibit diverse clinical morphologies and histopathological patterns with few distinguishing features, making diagnosis challenging. Though not conclusive in all cases, histopathology remains a valuable diagnostic tool, especially in clinically challenging cases. A strong clinico-pathological correlation is essential and often needs to be supplemented by ancillary investigations or a therapeutic trial. A small proportion of cases remain undiagnosed despite comprehensive evaluation.