Problems of differential diagnosis in dermatology using the example of polyangiitis of a single organ and papulonecrotic tuberculosis of the skin

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BACKGROUND

Cutaneous tuberculosis, as one of the manifestations of tuberculosis, is caused by Mycobacterium tuberculosis (human type) or Mycobacterium bovis (bovine type) and may, in some cases, represent one of the complex mechanisms of infectious allergy. The diagnosis of cutaneous tuberculosis is rare, accounting for less than 0.1% of all tuberculosis cases [1].

According to the reports, there is no universally accepted classification of cutaneous tuberculosis. In the National Guideline on Phthisiopulmonology, cutaneous tuberculosis is divided into two main groups: true cutaneous tuberculosis (localized, granulomatous, or bacterial) and skin lesions resulting from allergic immune (pseudospecific) inflammation, predominantly in the form of allergic vasculitis, referred to as disseminated hyperergic cutaneous tuberculosis and classified by J. Darier under the term tuberculids. The National Guideline on Dermatovenereology classifies miliary tuberculosis and lichenoid tuberculid as disseminated forms [2].

Historically, classifications of cutaneous tuberculosis were based on clinical manifestations, but modern diagnostic criteria take into account the histopathologic, immunologic, and molecular characteristics of the disease, which enables more accurate differentiation of various forms of cutaneous tuberculosis [1]. However, difficulties in diagnosing rare and atypical forms persist, highlighting the need to improve existing classifications or develop a new international classification that would integrate all aspects of the disease—from clinical forms to genetic mutations.

An important factor that plays a key role in the development of cutaneous tuberculosis is the presence of a primary tuberculosis focus in the body. The primary focus serves as a source of mycobacteria, most commonly located in the lungs or lymph nodes. Spreading predominantly by endogenous routes—hematogenous or lymphatic—from other tuberculous foci in the body (lungs, lymph nodes), the migrating mycobacteria infect the skin and cause secondary cutaneous lesions [3].

Histologically, cutaneous tuberculosis is characterized by granulomas composed of epithelioid cells surrounded by lymphocytes. Typical features include Langhans giant cells, caseous necrosis in the center of the tubercle, and the presence of mycobacteria in forms such as primary, miliary, colliquative (scrofuloderma), papulonecrotic tuberculosis of the skin, and ulcerative tuberculosis of the mucous membranes. In lupus vulgaris and verrucous cutaneous tuberculosis, mycobacteria are difficult or nearly impossible to detect [2].

Cutaneous forms of tuberculosis include a wide range of pathological processes that vary in their clinical presentation—from isolated nodules and plaques to more extensive and infiltrative skin lesions. The clinical picture is diverse and often requires differential diagnosis with other dermatologic diseases.

The diagnosis of all forms of cutaneous tuberculosis is based on a comprehensive approach. Clinical findings play an important role; however, accurate diagnosis requires chest radiography, histologic examination of a skin biopsy specimen, and specific tuberculin-based tests, including polymerase chain reaction (PCR) of serum, T-SPOT.TB, and Diaskintest.

Papulonecrotic tuberculosis of the skin is a rare form of cutaneous tuberculosis that can present in two clinical forms: superficial and deep [3]. In the superficial form, small firm inflammatory papules appear on the skin. These lesions protrude above the skin surface as flat or hemispherical nodules and may vary in color from reddish to bluish or brown. The surface of the lesions may exhibit a crust, under which a crater-like, slightly bleeding depression or a small round ulcer with smooth edges can be observed. During healing, a characteristic whitish scar remains, commonly referred to in clinical practice as a “stamped” atrophic scar, often surrounded by pigmentation. In some cases, the lesions regress and disappear within 6–8 weeks, and if necrosis does not develop, only a faint atrophic scar remains. The papules are arranged irregularly, sometimes in a serpiginous or circular pattern.

Typical locations of the superficial form include the extremities, the extensor surfaces of the lower legs, thighs, shoulders, forearms, knees, elbows, dorsal surfaces of the hands, soles, and buttocks. Less frequently, other areas such as the face, ears, genitalia, and trunk may be affected.

The disease course may vary. The general condition of the patient is usually not impaired, although cases with a protracted course over several years have been observed, featuring periods of exacerbation and remission, pronounced seasonality, and dependence on menstrual cycles [4]. In some instances, atypical forms with pronounced necrotic processes occur [4].

The deep form of papulonecrotic tuberculosis begins as small, firm elements located in the subcutaneous tissue, not adherent to surrounding tissues, with central necrosis developing beneath a yellow-brown crust. Within a few days, the crust is shed, and the infiltration resolves, leaving a scar with a brownish rim.

Diagnosis of this disease can be challenging. The superficial form of cutaneous tuberculosis must be differentiated from secondary syphilis, whereas the deep form should be distinguished from tertiary syphilis. Papulonecrotic tuberculosis of the skin also requires differentiation from the papulonecrotic form of dermal vasculitis.

Cutaneous vasculitides (skin angiitis) represent a group of dermatoses in which the primary pathological feature is nonspecific inflammation of blood vessel walls of various calibers in the dermis and hypodermis. Currently, approximately 50 nosological forms of cutaneous vasculitis are recognized. Many of these forms share significant clinical and histopathological similarities, which must be considered when establishing a diagnosis.

No universally accepted classification of cutaneous vasculitides exists. In practice, the nomenclature of the American College of Rheumatology and the criteria of the Chapel Hill Consensus Conference (North Carolina, USA, 2012) are often applied; however, their use in dermatologic practice is limited because many nosological forms are not included, clinical manifestations may not correspond, and accurate descriptions of characteristic cutaneous signs are sometimes lacking. Dermal vasculitis may involve small blood vessels and, according to the Chapel Hill nomenclature (2012), is referred to as single-organ vasculitis, hypersensitivity vasculitis, or microscopic polyangiitis.

Necrotizing cutaneous vasculitis may develop in the context of chronic infections of bacterial or viral origin (Staphylococcus, Streptococcus, Enterococcus, Yersinia, mycobacteria, Epstein–Barr virus, hepatitis B and C viruses, HIV, parvovirus, cytomegalovirus, herpes simplex virus, influenza virus). There is also evidence for the role of fungal infections in the development of cutaneous vasculitis [1].

The development of vasculitis is also influenced by medication use, including antibacterial drugs (penicillins, tetracyclines, sulfonamides, cephalosporins), diuretics (furosemide, hydrochlorothiazide), anticonvulsants (phenytoin), antigout agents (allopurinol), nonsteroidal anti-inflammatory drugs (ibuprofen, aspirin), antihypertensives (hydralazine), and biologics (rituximab, infliximab) [1]. Studies on genetic mutations causing thrombophilia, which alter the coagulation system, are of particular interest [1].

For practicing dermatologists, the most practical tool is the clinical working classification of angiitis proposed by O.L. Ivanov (1997), which is based primarily on the evaluation of morphological elements of the rash, general findings, laboratory results, and histological data. In this group, papulonecrotic vasculitis occupies a special place, characterized by lesions on the lower legs with a tendency to necrosis and the formation of atrophic, “stamped” scars.

CASE DESCRIPTION

Patient Information

Patient M., a 60-year-old woman from the Tambov region, was admitted on February 10, 2023, to the Rakhmanov Clinic of Skin and Venereal Diseases, Sechenov First Moscow State Medical University, with complaints of ulcerative skin lesions on the lower extremities accompanied by subjective discomfort.

Comorbidities: varicose veins of the lower extremities; chronic venous insufficiency, class C2 on the right and C6 on the left; grade III hypertension; grade III cardiovascular risk; chronic pancreatitis; class III obesity; deforming osteoarthrosis of the hip; grade I osteoarthritis of the right knee; and type 2 diabetes mellitus.

History of allergy: skin reaction in the form of an itchy rash after consuming citrus fruits and taking ampicillin.

Anamnesis morbi: The patient considered herself ill since spring 2016, when she first noticed a pink spot on the distal third of the left lower leg, which turned violet within a month and subsequently ulcerated and developed purulent discharge. She sought medical attention from a surgeon at her local clinic. Based on consultation and diagnostic findings (ultrasound of the lower extremities), a presumptive diagnosis of varicose vein disease of the lower extremities was made. In November 2016, the patient underwent combined phlebectomy of the left lower extremity in the great saphenous vein basin and received treatment with diclofenac, ceftriaxone, acetylsalicylic acid, pentoxifylline, and heparin, along with topical dressings containing chloramphenicol and methyluracil. After therapy, improvement was noted with complete scarring of the ulcerative defect.

In subsequent years, the patient reported recurrent lesions in the same area and repeatedly consulted various specialists (surgeons, phlebologists, oncologists). Diagnoses included varicose vein disease of the lower extremities and trophic ulcers of the lower extremities.

Routine laboratory findings (complete blood count, urinalysis, coagulation profile, and clinical chemistry panel) showed no significant abnormalities. She received repeated courses of venoactive drugs, antibiotics, and antiseptic dressings.

In March 2022, the patient consulted a dermatologist because of suspected vasculitis. Testing for antibodies to neutrophil cytoplasmic antigens (ANCA Combi 7) and cyclic citrullinated peptide was negative. Complete blood count, clinical chemistry parameters, coagulation profile, and C-reactive protein levels were within reference ranges. Elevated values were observed for creatine phosphokinase (187 U/L; reference 0–167), mean platelet volume (MPV, 12.8 fL; reference 9.4–12.4), and platelet large cell ratio (48.0%; reference 13.0–43.0). Increased lymphocyte count (LY, 44.9%; reference 19.0–37.0), monocyte count (MO, 12.7%; reference 3.0–12.0), and decreased neutrophil count (NE, 41.0%; reference 47.0–72.0) were also noted. Antinuclear antibody testing using HEp-2 cells revealed IgG positivity (640 g/L) with a positive (160) nuclear granular fluorescence pattern (AC-2,4), indicating the presence of antinuclear antibodies, which are typically observed in systemic autoimmune disorders.

According to the pathology report based on diagnostic skin biopsy, histopathological examination revealed an epidermal cyst, marked inflammatory infiltration throughout all layers of the dermis, and venulitis.

During dermatologic observation, the patient received treatment with levocetirizine (Suprastinex) 5 mg once daily for 5 days, topical Akriderm (betamethasone) ointment twice daily (long-term), and emollients. No remission of the skin process was achieved.

Because of joint pain, the patient was referred to a rheumatologist, who diagnosed polyosteoarthrosis with predominant involvement of the knee joints and prescribed topical therapy with nonsteroidal anti-inflammatory and chondroitin-based ointments.

Phlebologic examination, including ultrasound of the lower extremities, revealed normal findings; vasculitis was excluded. The patient was prescribed nonsteroidal anti-inflammatory drugs for 14 days, omeprazole 20 mg at bedtime, tolperisone hydrochloride 150 mg three times daily for 3 weeks, intramuscular chondroitin sulfate 100 mg (20 injections) followed by oral chondroitin sulfate 500 mg plus glucosamine hydrochloride 500 mg twice daily for 3 months, and diacerein 50 mg twice daily for 2 months. No clinical improvement was achieved, and further examination was continued at the local outpatient clinic.

Doppler ultrasound: the right lower limb was of normal color and temperature; pulsation of the femoral, popliteal, anterior, and posterior tibial arteries was distinct; no edema was observed. Reticular veins and telangiectasias were present on the thigh and leg; a varicose perforating vein was noted at the mid-third of the leg. The left lower limb was hyperemic, with areas of lipodermatosclerosis in the mid and lower third, scar deformities, and up to two superficial ulcers measuring 1.2 cm. Reticular veins and telangiectasias were also detected on the thigh and leg.

Ultrasound angioscanning: the trunks of the great saphenous veins in both lower limbs were patent, not dilated, and without reflux.

Based on the examination results, the diagnosis was post-thrombotic disease of the left lower limb (C1, 4b, 5, 6, Ep, As, Pr, 1, 6, LII) and varicose veins of both lower extremities (C2s, Ep, As, Pr, 1, 8, LII). Treatment included class II compression stockings, Phlebodia (diosmin) 600 mg once daily for 2 months, Xarelto 20 mg once daily for 2 months, and topical Akriderm GK ointment twice daily. Despite therapy, no marked clinical improvement was noted.

Given the refractory nature of the skin process to standard therapy, the patient was examined by a phthisiatrician at her local clinic in the Tambov region. Tuberculin skin testing (Diaskintest) revealed a papule of 30 mm in diameter. Chest radiography showed clear lung fields without focal or infiltrative shadows; hilar structures and the cardiac silhouette were normal. Preventive specific therapy with isoniazid 0.75 mg and rifampicin for 20 days produced no positive effect.

On February 1, 2023, at the Rakhmanov Clinic of Skin and Venereal Diseases, the provisional diagnosis of tuberculosis of the skin, papulonecrotic type, was established.

Diagnostic assessment

Physical examination: the skin lesions were chronic and inflammatory in nature. On the anterior and lateral surfaces of the lower legs, polymorphic eruptions with a bluish–violet hue were observed, consisting of plaques and ulcers with sharply demarcated borders measuring up to 12–13 cm, irregular in shape, without a tendency to coalesce. The lesions were tender on palpation. Varicose veins were noted adjacent to the affected areas. Skin outside the lesions was pale pink (Fig. 1).

 

Fig. 1. Clinical picture of skin tuberculosis on admission: on the anterior and lateral surfaces of the skin of the lower legs there are polymorphic rashes, of a livid purple colour, represented by plaques and ulcers with sharp borders, up to 12–13 cm in size, irregularly shaped, without tendency to merge. [Photo from the archive of the I.M. Sechenov First Moscow State Medical University. Published for the first time with the permission of the administration of the institution].

 

Laboratory tests. Blood tests revealed elevated relative lymphocyte count (LY%, 51.4%; reference, 18.0–44.0), uric acid (420.50 µmol/L; reference, 154–357), total cholesterol (5.42 mmol/L; reference, 0–5.2), lactate dehydrogenase (254 U/L; reference, <248), and creatine phosphokinase (153 U/L; reference, 0–145), with decreased relative neutrophil count (NE%, 40.0%; reference, 45.0–72.0). Urinalysis and coagulation studies were within reference limits.

Computed tomography (CT) of the chest and abdomen. Interstitial changes were noted in the lower lobes of both lungs, likely post-inflammatory in nature. Calcified foci in both lungs suggested prior infectious processes with subsequent calcification. Bronchiectasis was observed in the upper lung fields. Solitary calculi were identified in the calyces of both kidneys. Colonic diverticula were present without signs of inflammation; appendicolithiasis was noted. Atherosclerotic changes were observed in the aorta and coronary arteries.

Renal ultrasound. Heterogeneous echotexture of the left kidney, with an anechoic lesion measuring 16 mm and exhibiting posterior acoustic enhancement. An anechoic lesion in the renal sinus measured 12.5 mm. Overall echogenicity was uniformly increased. The pelvicalyceal system was deformed. The right kidney showed altered sinus echotexture due to a rounded anechoic lesion with posterior acoustic enhancement measuring 15.6 mm. Overall echogenicity was uniformly increased. The report concluded that the changes identified on CT could correspond to sequelae of prior pulmonary tuberculosis and may affect respiratory function, potentially causing dyspnea, reduced exercise tolerance, and an increased risk of infections. Pulmonology consultation is recommended to clarify the nature of the interstitial changes and bronchiectasis, and to perform pulmonary function tests to assess their impact on respiratory function.

Diagnostic skin biopsy with immunohistochemistry. The biopsy specimen included epidermis with mild hyperkeratosis and acanthosis. In the dermis and partially in the subcutaneous adipose tissue, there was a chronic granulomatous inflammatory process, with granulomas composed of lymphocytes, epithelioid cells, and Langhans giant cells with areas of caseous necrosis. Focal lymphoplasmacytic infiltration with pseudo-follicle formation was observed, mainly surrounding microvascular structures in the dermis (Fig. 2). Immunohistochemical Kinyoun staining did not reveal acid-fast bacilli. Conclusion: findings were consistent with the papulonecrotic tuberculosis of the skin.

 

Fig. 2. Histological examination. Epidermis with phenomena of moderately pronounced hyperkeratosis and acanthosis, in the dermis and partly in the subcutaneous fatty tissue morphological picture of chronic granulomatous inflammatory process, granulomas consisting of lymphocytes, epithelioid and Pirogov-Langhans cells with zones of caseous necrosis, also in the dermis mainly along the periphery of microcirculatory vessels focal lymphoplasmocytic inflammatory infiltration with formation of pseudofollicles. Haematoxylin-eosin staining, ×10. [Photo from the archive of the I.M. Sechenov First Moscow State Medical University. Published for the first time with the permission of the administration of the institution].

 

Differential diagnosis

Differential diagnosis with vasculitis is based on the results of biopsy and comprehensive patient evaluation. Initial testing is recommended for tuberculosis DNA and the Mycobacterium complex (M. tuberculosis, M. bovis, M. bovis BCG, M. microti, M. africanum) in serum using real-time PCR. Only after these results can T-SPOT.TB (gamma-interferon release assay) or Diaskintest be performed, along with a skin biopsy to detect a typical granulomatous infiltrate in the tissue specimen.

Treatment

During evaluation, the patient received azithromycin 500 mg, omeprazole 20 mg, Nise (nimesulide) 100 mg, antifungal therapy (fluconazole 150 mg every 3 days); antihypertensive therapy with torasemide 10 mg in the morning and losartan 50 mg in the evening; type 2 diabetes therapy with gliclazide 60 mg and metformin 1000 mg; topical therapy with Akriderm Genta ointment twice daily at night and Lioton (sodium heparin) gel applied in a thin layer to the lower legs 15 minutes after Akriderm Genta; and a physiotherapy course including systemic oxygen–ozone therapy (intravenous ozonized saline solution 400 mL, O₃ 2 mg/L) every other day, 10 sessions. Based on cutaneous tuberculin testing, CT findings, and histopathological data, consultation with a phthisiatrician was recommended, and a comprehensive specific anti-tuberculosis therapy was initiated: isoniazid, rifampicin, pyrazinamide, and ethambutol for 3 months.

Follow-up and outcomes

During therapy, the patient showed a positive clinical response with complete healing of the ulcerative lesions on the lower legs, formation of “stamped” scars, and residual peripheral hyperpigmentation (see Fig. 3).

 

Fig. 3. Clinical picture after treatment. Positive dynamics in the form of complete scarring of ulcer defects on the skin of the lower extremities with formation of stamped scars and residual hyperpigmentation around the periphery is observed. [Photo from the archive of the I.M. Sechenov First Moscow State Medical University. Published for the first time with the permission of the administration of the institution].

 

DISCUSSION

Differential diagnosis between papulonecrotic tuberculosis of the skin and the papulonecrotic form of dermal vasculitis is a complex, multifaceted task that requires a comprehensive approach. Key aspects that allow differentiation between these two conditions include clinical manifestations, laboratory findings, and histopathological examination. Clinical features of papulonecrotic tuberculosis of the skin include firm papules with central necrosis, varying in color from red to bluish-brown, with a crusted surface under which a crater-like, slightly bleeding depression or a small round ulcer with smooth edges may be observed. Following resolution, atrophic “stamped” scars remain. Papulonecrotic dermal vasculitis on the lower legs presents with clinically similar features.

Laboratory diagnostics play an important role in differential diagnosis. In papulonecrotic tuberculosis of the skin, tuberculin tests are often positive, and skin biopsy reveals a granulomatous infiltrate composed of lymphocytes, epithelioid cells, and Langhans giant cells with areas of caseous necrosis, along with characteristic changes in lymph nodes, lungs, kidneys, and other organs and tissues. The presence of a primary tuberculous focus in the lungs or lymph nodes is an important diagnostic and pathogenic factor, serving as the source of mycobacteria that cause secondary cutaneous lesions.

In papulonecrotic forms of vasculitis, elevated levels of inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, cryoglobulins), and the presence of antineutrophil cytoplasmic antibodies (ANCA) may be observed.

Histopathological examination is a key step in differentiating cutaneous tuberculosis from vasculitis. Papulonecrotic tuberculosis of the skin is characterized by granulomatous inflammation with central caseous necrosis within the granulomas. In contrast, the histology of papulonecrotic vasculitis demonstrates necrotizing vasculitis with fibrinoid necrosis of vessel walls, perivascular inflammatory infiltration, leukocytoclasia, and erythrocyte extravasation.

CONCLUSION

Thus, differential diagnosis between papulonecrotic tuberculosis of the skin and the papulonecrotic form of vasculitis is based on a combination of clinical, laboratory, and histopathological findings. Comprehensive use of these methods, along with timely identification of the primary infection focus, allows prevention of disease spread, accurate diagnosis, and selection of the optimal treatment strategy for each individual patient.

ADDITIONAL INFORMATION

Author contributions. O.V. Grabovskaya ― consultation of the patient, determination of the diagnosis and tactics of management, correction of the text of the article, approval of the submission of the article to the press; N.P. Teplyuk ― consultation of the patient, determination of the diagnosis and tactics of management, making significant changes to the manuscript in order to increase the scientific value of the article; S.A. Mishin ― consultation of the patient, determination of the diagnosis and tactics of management, direct management and observation of the patient, collection of literature data, drafting the text of the article, sending the manuscript to the editorial office of the journal; A.R. Tavitova ― patient consultation, determination of diagnosis and management tactics, correction of the text of the article. Thereby, all authors provided approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Consent for publication. The authors received written informed voluntary consent from the patient to publish personal data, including photographs (with the face covered), in a scientific journal, including its electronic version (date of signing: 11/14/2024). The volume of published data was agreed upon with the patient.

Funding sources. The work was carried out in accordance with the scientific research plan of the First Moscow State Medical University named after I.M. Sechenov of the Ministry of Health of the Russian Federation (Sechenov University). The authors did not receive sponsorship support.

Disclosure of interests. The authors have no relationships, activities or interests for the last three years related with for-profit or not-for-profit third parties whose interests may be affected by the content of the article.

Statement of originality. In creating this work, the authors did not use previously published information (text, illustrations, data).

Data availability statement. The editorial policy regarding data sharing does not apply to this work, and no new data was collected or created.

Generative AI. Generative AI technologies were not used for this article creation.

Provenance and peer-review. The present paper was submitted to the journal on a proactive basis and reviewed according to the usual procedure. Two external reviewers, a member of the editorial board and the scientific editor of the publication participated in the review.

About the authors

Olga V. Grabovskaya

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: olgadoctor2013@yandex.ru
ORCID iD: 0000-0002-5259-7481
SPIN-code: 1843-1090

MD, Cand. Sci. (Medicine), Professor

Russian Federation, 4/1 Bolshaya Pirogovskaya st, Moscow, 119991

Natalia P. Teplyuk

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: Teplyukn@gmail.com
ORCID iD: 0000-0002-5800-4800
SPIN-code: 8013-3256

MD, Dr. Sci. (Medicine), Professor

Russian Federation, 4/1 Bolshaya Pirogovskaya st, Moscow, 119991

Sergey A. Mishin

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: sergey.mischin1995@gmail.com
ORCID iD: 0000-0002-4387-3085
SPIN-code: 4644-2560
Russian Federation, 4/1 Bolshaya Pirogovskaya st, Moscow, 119991

Alana R. Tavitova

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Email: alatavitova@mail.ru
ORCID iD: 0000-0003-1930-0073
SPIN-code: 2113-9091

MD, Cand. Sci. (Medicine)

Russian Federation, 4/1 Bolshaya Pirogovskaya st, Moscow, 119991

References

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