Erythema induratum of Bazin
Victoria Sharon MD, Heidi Goodarzi MD, Cindy J Chambers MPH, Maxwell A Fung MD, April W Armstrong MD
Dermatology Online Journal 16 (4): 1

University of California Davis, Sacramento, California

Abstract

An 81-year-old woman with a history of renal cell carcinoma and years of slowly, progressively enlarging pulmonary nodules of uncertain etiology presented with several weeks of painful lower extremity nodules. A biopsy revealed changes consistent with nodular vasculitis. A purified protein derivative and QuantiFERON test were positive, favoring the diagnosis of erythema induratum of Bazin. Treatment with a standard four-drug antituberculous regimen resulted in radiographic and clinical improvement. This case emphasizes the importance of dermatologic manifestations in the detection of systemic disease.



Case report

An 81-year-old woman with a history of renal cell carcinoma (RCC), status-post left nephrectomy, and splenectomy ten years prior, presented to our dermatology clinic with a three-week history of multiple, firm, deep red subcutaneous nodules on the anterior and posterior aspects of her lower legs. The patient’s primary care physician was concerned that these skin findings could represent cutaneous metastasis of her RCC. She reported no recent changes in medications; a review of systems was negative for fever, cough, shortness of breath, weight loss, night sweats, and other systemic symptoms. She recalled that one of her close friends in elementary school was placed in a sanatorium for tuberculosis. Her Bacille Calmette-Guerin (BCG) vaccination status was unknown.

Prior computed tomography (CT) scans of the chest showed several stable six to twelve millimeter pulmonary and pleural nodules with varying degrees of calcification, enlarged aortopulmonary, and precarinal lymph nodes, ground-glass densities in the left upper lobe, and prominent septal thickening in the right middle lobe; these were presumed secondary to metastatic carcinoma versus old granulomatous disease. The patient had declined further evaluation for these chest CT findings, but agreed to close follow-up with semi-annual CT scans for longitudinal observation.

Physical exam revealed multiple one to two centimeter, tender subcutaneous nodules with overlying poorly defined violaceous erythema on the posterior and anterolateral aspects of the bilateral lower extremities bilaterally (Figures 1A and 1B). No regional lymphadenopathy was identified. The remainder of the exam was unremarkable. Based on the history and clinical presentation, our differential diagnosis included primary nodular vasculitis, erythema induratum of Bazin, erythema nodosum, atypical mycobacterial infection including Mycobacterium kansasii, subcutaneous sarcoid, cutaneous metastases of renal cell carcinoma, and de-novo metastatic disease from a new primary site.

Initial evaluation included an incisional biopsy of a representative lesion on the right posterior calf, basic laboratory studies, and a Mantoux skin test or purified protein derivative (PPD) to detect a potential hidden focus of tuberculosis. The patient declined invasive evaluation of her lung nodules including induced sputum and bronchoscopy.


Figure 1A Figure 1B
Figure 1. Tender subcutaneous nodules with overlying poorly defined violaceous erythema on the posterior (1A) and anterolateral (1B) aspects of the bilateral lower extremities

Laboratory studies including a hemogram and complete metabolic panel were normal with the exception of a slightly increased serum creatinine. The PPD was interpreted as positive, demonstrating 15 mm of erythematous induration at 48 hours. A QuantiFERON-TB Gold (QTB) test was positive, confirming true Mycobacterium tuberculosis (MTB) infection in the setting of unknown BCG vaccination status.

Histologic analysis of an incisional biopsy from the calf revealed a predominantly lobular neutrophilic and granulomatous panniculitis with fibrin deposition within the wall of small vessels, and associated karyorrhexis and hemorrhage. Fite and Gomori methenamine-silver (GMS) stains were negative for mycobacteria and fungi, respectively. Polymerase chain reaction (PCR) studies for Mycobacterium tuberculosis on lesional tissue failed to detect MTB DNA (AMPLICOR MTB, Roche Diagnostics Systems, Inc.).

The combined clinical, histopathologic, and laboratory findings were diagnostic of erythema induratum of Bazin in the setting of presumed latent tuberculosis infection. The patient was started on four-drug antituberculous therapy (ATT) with rifampin, isoniazid, pyrazinamide, and ethambutol (RIPE). Following the development of a drug hypersensitivity rash several weeks into therapy, only isoniazid was continued with the addition of rifampin and ethambutol after one month. Within four weeks of beginning ATT, the nodules on our patient’s lower extremities began to fade and there was an absence of new lesions (Figure 2).


Figure 2
Figure 2. Post-inflammatory hyperpigmentation

Within three months of initiating ATT, there were also notable decrease in the size of the aortopulmonary lymph nodes and sub-centimeter pulmonary nodules. Therapy was discontinued at three months because of severe persistent peripheral neuropathy unimproved by increasing doses of vitamin B6. It was felt at this time that the risk of tuberculosis reactivation was lower than could be justified by the harm the medications were causing, particularly in the setting of absent systemic symptoms, resolved erythema induratum, and a significantly improved chest CT and X-ray. The patient has continued longitudinal observation by infectious disease, primary care, and dermatology physicians every 3-6 months. She is currently 19 months since her diagnosis without clinical or radiographic evidence of disease.


Figure 3
Figure 3. Chest CT demonstrating subpleural nodule at presentation (left), resolved after three months of antituberculosis therapy (right)

Discussion


1. Clinical manifestations

Erythema Induratum of Bazin (EIB) typically presents during early adolescence and peri-menopause as recurrent subcutaneous poorly defined erythematous plaques and tender violaceous nodules on the legs of otherwise healthy, often heavy-set, women [1, 2, 3, 4, 5]. The plaques are generally indurated with an overlying scaly surface and the nodules have a tendency to ulcerate centrally [3, 5, 6, 7]. Ulcerated nodules display overlying crust with a rolled erythematous blue-tinged border [3, 5, 6]. The disease preferentially affects the posterior and anterolateral aspects of the lower legs, and is often precipitated by cold weather or peripheral venous stasis [1, 2, 3, 4, 5]. Individual lesions heal over the course of several months, and frequently leave atrophic hyperpigmented scars [3, 5]. If untreated, the disease is usually chronic with recurrent crops of new lesions arising over the course of many years [2, 3, 4].

Clinically, EIB can mimic a number of conditions presenting as chronic lower extremity nodules, including erythema nodosum, cutaneous polyarteritis nodosa, pancreatic panniculitis, lupus profundus, subcutaneous sarcoid, and cutaneous T-cell lymphoma.


2. Association with tuberculosis

Clinicians have long debated the pathogenesis of EIB and its association with MTB. Erythema Induratum was first described by Bazin in 1861, prior to the identification of the tubercle bacillus. Bazin classified EIB as an erythematous benign scrofulid, using scrofulid to refer very generally to deep violaceous nodules [8]. It was not until after the discovery of MTB in 1882 that the term scrofula became commonly associated with TB [5]. In 1896, Darier coined the term tuberculid to describe the cutaneous lesions temporally associated with tuberculosis that had failed to demonstrate the tubercle bacillus. The title, Darier tuberculid, soon replaced scrofula, thus linking EIB to MTB [8].

Audry in 1898, was the first to question the causal relationship between EIB and TB, citing the lack of tuberculoid granulomas or acid-fast bacilli in lesional biopsies of EIB patients [5]. Shortly thereafter, several authors began to report a similar clinical picture in patients without positive tuberculin skin tests and no history of TB exposure [9, 10, 11].

The debate led to the consideration by Whitfield and colleagues in 1901 that there may be two types of erythema induratum, TB-related and TB-unrelated [10]. To address this divergence, the term nodular vasculitis was introduced in 1945 to differentiate the lesions of erythema induratum of non-tuberculous origin, briefly known as erythema induratum of Whitfield, from those of tuberculous origin, or erythema induratum of Bazin [12]. To date, some authors continue to believe that the phrase erythema induratum of Bazin should be reserved for the true tuberculid related to MTB, while nodular vasculitis should be used to refer to non-TB associated cases [8, 14]. Most authors, however, would agree that the clinicopathologic presentations of the two entities can be difficult, if at times impossible, to distinguish [3, 4, 5]. Many clinicians, therefore, advocate using a clinical response to ATT as an indicator to discern the two entities [5, 13, 14].

Currently, tuberculids are best characterized as a cutaneous hypersensitivity reaction to disseminated MTB or its antigens in patients with strong anti-MTB cell-mediated immunity [2, 7]. Their development and presentation may fluctuate based on the underlying immune status of the host [2, 15]. Tuberculids are diagnosed by absence of MTB from skin biopsy or culture, a positive Mantoux skin test, and swift resolution of the eruption with ATT [5, 15]. Entities currently considered tuberculids include erythema induratum of Bazin, lichen scrofulosorum, and papulonecrotic tuberculid [5].


3. Diagnosis

Clinical evidence that supports an association between tuberculosis and EIB includes a positive PPD in up to 60 percent of patients with EIB, improvement in cutaneous lesions in response to ATT, and the occasional ability to isolate MTB DNA by PCR [6]. The reported rates of MTB DNA recovery from the skin lesions vary from 0 to 77 percent, and the inability to detect MTB DNA does not necessarily exclude the diagnosis of EIB [16–21]. For many clinicians, the diagnosis is confirmed by characteristic clinical morphology and histopathologic findings, a positive PPD or isolation of MTB DNA from lesional skin, and a successful response to ATT [5, 8].

Although rare, cases of active TB infection associated with EIB have been reported [22–31]. As such, it is generally recommended that the physician conduct a thorough investigation to evaluate for subclinical active TB infection when a tuberculid is suspected [23, 28, 32, 33]. In patients with suspected EIB, a complete history and physical examination should be followed by an incisional biopsy including an adequate amount of the subcutaneous fat of an early lesion [5]. The specimen should be submitted for Hematoxylin-Eosin staining as well as special staining for bacterial, fungal, and acid-fast organisms. PCR for MTB DNA from a formalin fixed paraffin-embedded specimen, PPD placement, and chest radiography is additionally recommended [5]. The QuantiFERON-TB Gold [QTB] test may also be employed, as in this case, to interpret PPD results in instances where there is a possible or definite history of BCG vaccination [7]. The QTB test is an in vitro interferon-gamma (IFN-γ) release assay that employs tuberculous mycobacterial antigens not shared with the BCG vaccine or other atypical mycobacteria [7, 34]. T-cells from an individual previously sensitized to MTB will produce IFN-γ upon re-encountering MTB antigens in the assay, whereas T-cells from unsensitized individuals will not. Additional recommended laboratory tests include a complete blood count with differential, erythrocyte sedimentation rate, and liver function tests. In cases with negative TB findings, a work up for hepatitis C and other infections may be recommended [35, 36, 37].


4. Pathology

In technically adequate specimens, i.e., deep punch/trephine biopsy or incisional biopsy, EIB exhibits a predominantly lobular pattern of panniculitis that cannot be distinguished from non-MTB-associated cases that may be classified as nodular vasculitis (NV) (Figure 4A) [2, 4]. Although the primary event in EIB/NV is generally regarded to be vasculitis, it is uncertain whether venules, larger septal veins, or arterioles are primarily or most typically involved, or even if vasculitis is in fact a primary event (Figure 4B) [38]. Vasculitis is absent in a minority of cases, at least partly because of sampling error. Thus, the absence of demonstrable vasculitis does not exclude or mitigate against the diagnosis of EIB/NV in an otherwise appropriate clinical and histologic context. Neutrophils are typically sparse to absent within and around affected vessels, supporting the interpretation that the vasculitis of EIB/NV represents a lymphocytic vasculitis rather than a neutrophilic (leukocytoclastic) vasculitis (LCV).


Figure 4A Figure 4B
Figure 4. 4A) Lobular panniculitis. 4B) Fibrin occluding small vessels, with associated leukocytoclastic nuclear debris. 4C) Extravascular necrosis within the subcutaneous lobular infiltrate.

Figure 4C

Vasculitis in EIB/NV, if present, tends to be a focal feature within a subcutaneous lobular mixed inflammatory infiltrate containing an obvious granulomatous (histiocytic) component, sometimes including the formation of small discrete granulomas, along with small lymphocytes, plasma cells, scattered eosinophils, and foci of extravascular caseous or fibrinoid necrosis (Figure 4C). As a rule, all histochemical stains and cultures for infection are negative and no foreign body is identified.

The histologic differential diagnosis of EIB/NV typically includes polyarteritis. The cutaneous and systemic variants of polyarteritis are characterized by neutrophilic arteriolitis, without granulomatous features or the significant extravascular subcutaneous lobular necrosis and inflammatory infiltrates typical of EIB/NV.


5. Treatment

Antituberculous therapy with rifampin, isoniazid, and pyrazinamide, has been favored in the treatment of EIB [2, 39, 40, 41, 42]. Improved clearance and decreased disease relapse have been demonstrated by several authors employing a longer duration of multi-drug treatments [2, 43].

The current recommended treatment regimen for adults and children with culture-positive tuberculosis consists of either a 6-month four-drug course with two months of RIPE, followed by four months of isoniazid and rifampin, or a 9-month three-drug course with two months of rifampin, isoniazid, and pyrazinamide, followed by seven months of rifampin and isoniazid [44]. In 1995, Schneider and colleagues demonstrated the effectiveness of this regimen even in the absence of proven TB. In a sample of 20 patients, only five of whom had positive PCR results, the authors reported total disease clearance for all patients within one to six months of initiating triple ATT [18].

Despite these findings, the non-trivial risk of adverse reactions to ATT has led several authors to recommend reserving ATT for cases in which the patient demonstrates a strongly positive reaction to the Mantoux skin test, a positive QuantiFERON-TB Gold test, or recovery of MTB DNA by PCR [3, 5, 32]. More basic treatment measures including rest and compression stockings or supportive bandages can result in improvement of lesions and may warrant a trial prior to advancing to systemic treatment [3, 5]. The use of non-steroidal anti-inflammatory agents may alleviate discomfort associated with ulcerated lesions and should also be considered [3].

Though generally less well studied, additional treatments including potassium iodide, dapsone, gold salts, and doxycycline have been reported to be effective in the treatment of erythema induratum [22, 36, 45–48].


Conclusion

EIB often remains undiagnosed or misdiagnosed because it can masquerade as other types of chronic nodules of the lower extremities. The clinical differential diagnosis of EIB includes erythema nodosum, cutaneous polyarteritis nodosa, pancreatic panniculitis, lupus profundus, subcutaneous sarcoid, and cutaneous T-cell lymphoma. Whereas the true prevalence of EIB is unknown, recent reports from South Africa and Hong Kong indicate that EIB is not rare, accounting for 12.7 percent to 86 percent of all cases of cutaneous tuberculosis [22, 49, 50]. A consideration of EIB in the differential diagnosis of nodules of the lower legs may allow earlier detection of an otherwise unsuspected underlying systemic disease.

ACKNOWLEDGEMENTS: We would like to thank Dr. David Guillen for providing the histopathological images for this case.

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Title:

Erythema induratum of Bazin

Journal Issue:

Dermatology Online Journal, 16(4)

Author:

Sharon, Victoria;
Goodarzi, Heidi;
Chambers, Cindy J;
Fung, Maxwell A;
Armstrong, April W

Publication Date:

2010

Publication Info:

Dermatology Online Journal, UC Davis

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