Disseminated Mycobacterium haemophilum causing granulomatous mastitis

Highlights

• •Mycobacterium haemophilum causes disseminated disease in immunocompromised hosts but is rare in immunocompetent individuals.
• •Mycobacterium haemophilum infection disseminating to the breast tissue and causing granulomatous mastitis has not been previously described.
• •Timely diagnosis requires including mycobacterial infection in the differential diagnosis, particularly when granulomatous inflammation is seen in pathology.
• •Multidrug therapy is recommended, and treatment is usually prolonged, depending on the patient's immune status and clinical response.

Abstract

We present the case of a 58-year-old female with celiac disease, obesity, and recently diagnosed type 2 diabetes mellitus who developed a rash on her left thigh which spread and progressed to her arms, face, and abdomen. A biopsy of the left forearm grew Mycobacterium haemophilum. Weeks after the diagnosis of the M. haemophilum skin infection, the patient underwent a screening mammogram which showed new masses in both breasts. A biopsy of a left breast mass revealed cystic granulomatous inflammation with scattered neutrophils and lymphocytes within fibroadipose tissue. PCR and sequencing from breast tissue and AFB culture confirmed M. haemophilum. The patient was also later diagnosed with sinonasal involvement. No underlying immunodeficiency has been identified. This case highlights dissemination of M. haemophilum to multiple sites including skin, breast, and sinonasal tissues in a diabetic patient who was not otherwise immunocompromised. To our knowledge, it is the first reported case of granulomatous mastitis caused by M. haemophilum.

1. Case presentation

A 58-year-old woman with a history of celiac disease previously complicated by dermatitis herpetiformis, obesity, gout, hepatic steatosis, and recently diagnosed type 2 diabetes mellitus, was seen for a rash by her primary care physician. The rash started as a single lesion on her left lateral thigh with a bruise-like appearance and eventually ulcerated. She then noticed firm subcutaneous nodules that began to spread diffusely on her legs, arms, and face, as well as erythematous and violaceous papules and plaques (Fig. 1, Panel A). The patient was seen by dermatology and a punch biopsy of a thigh lesion was performed. She was started on topical steroids. The biopsy of the left upper thigh lesion showed granulomatous dermatitis. Tissue culture grew Corynebacterium propinquum. She was started on doxycycline with initial improvement, but the rash progressed with new lesions (including lesions on her abdomen). Some of the lesions were painful. A repeat left leg skin punch biopsy again showed granulomatous dermatitis, and a left forearm skin punch biopsy revealed superficial and deep dermal mixed inflammation. Acid-fast bacillus (AFB) and fungal stains were negative. Routine tissue and fungal cultures of the left forearm biopsy did not grow any organisms. There was concern for sarcoid versus a granulomatous drug reaction. The patient was started on prednisone and hydroxychloroquine.

Fig. 1.

Panel A shows representative violaceous nodules on her anterior thighs. Panel B is a core breast biopsy with predominantly non-necrotizing granulomas with admixed acute and chronic inflammation and rare cystic spaces (H&E, 20× magnification). Panel C is an AFB (Ziehl Neelsen) special stain highlighting numerous rod-shaped organisms throughout the breast tissue sample (40× magnification).

Four weeks later, mycobacterial (AFB) culture of the left forearm tissue grew Mycobacterium haemophilum, identified by Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS). Doxycycline was discontinued, and she was tapered off prednisone and hydroxychloroquine. The isolate was susceptible to clarithromycin, rifampin, trimethoprim/sulfamethoxazole, linezolid, and ciprofloxacin; the isolate was resistant to amikacin, doxycycline, and minocycline by the agar disk elution method performed at a reference laboratory. She was seen at the Infectious Disease outpatient clinic, and was treated with azithromycin, ciprofloxacin, and rifampin.

Six weeks after the diagnosis of M. haemophilum skin infection, the patient underwent a screening mammogram which showed new masses in both the right and left breasts. An ultrasound-guided biopsy of one of the left breast masses revealed a confluent granulomatous inflammation admixed with scattered neutrophils and lymphocytes within fibroadipose tissue (Fig. 1, Panel B). The Grocott methenamine silver (GMS) and AFB/Ziehl-Neelsen stains were positive, highlighting numerous organisms (AFB/Ziehl-Neelsen stain, Fig. 1, Panel C). Due to her skin infection, culture optimized for M. haemophilum was requested. Broad range PCR and sequencing from formalin-fixed paraffin embedded breast tissue was positive for M. haemophilum and AFB culture grew M. haemophilum. Susceptibilities were sent and were similar to the initial isolate, except that this isolate was also reported susceptible to amikacin, doxycycline, and minocycline. Computed tomography (CT) chest, abdomen and pelvis was performed and did not show any other evidence of dissemination, and the patient did not have any other symptoms. Blood culture for AFB did not grow mycobacteria.

Approximately 18 months into treatment, she was seen by otolaryngology (ENT) for a 6-month history of sinus pressure, congestion, and purulent nasal drainage that did not significantly improve with antibiotics and nasal sprays. Examination revealed nasal septal perforation with an irregular posterior border. Sinus CT showed a 15 × 10 mm anterior cartilaginous perforation and mild soft tissue fullness in the anterior and right posterior aspects of the perforation. A biopsy of the nasal septal tissue showed ulcerated and inflamed granulation tissue with granulomatous inflammation and AFB on AFB/Fite and AFB/Ziehl-Neelsen stains. AFB culture grew M. haemophilum which now showed resistance to rifampin and minocycline, but remained susceptible to the other antibiotics tested. Rifampin was discontinued, and linezolid was added to azithromycin and ciprofloxacin.

She was referred to Immunology for evaluation of a possible underlying immunodeficiency. Initial studies were unrevealing including neutrophil oxidative burst, cytokine panel, complement deficiency assay, and tests for humoral immunity. She was referred to the immunogenetics clinic and a primary immunodeficiency panel was sent but did not find any significant or conclusive genetic changes. Further testing was done for Mendelian susceptibility to mycobacterial diseases (MSMD) and results did not support this diagnosis. Testing for anti-interferon gamma autoantibody was also negative.

Her most recent mammogram showed resolution of previously seen mammographic findings in both breasts. Her skin lesions were resolving, and no new skin lesions have developed. Her sinonasal disease was improving on follow-up ENT evaluation, and surgery has been deferred for now. She remains on azithromycin, ciprofloxacin, and linezolid with plans to continue treatment for M. haemophilum until her sinonasal disease has also resolved.

2. Discussion

Mycobacterium haemophilum has been shown to cause both localized and disseminated disease in immunocompromised individuals, and less commonly has caused disease in immunocompetent hosts. The most common presentation is cutaneous disease [1], with a predilection for the extremities, particularly over joints, which may be explained by the organism’s preference for growth in cooler temperatures [1], [2]. Various cutaneous lesions have been described, including papules, nodules, plaques, abscesses, or ulcers [3]. Lesions can initially present as papules that progress to pustules then to deeper lesions such as abscesses or ulcers [1], [3], [4]. Lesions in a sporotrichoid pattern have been reported in an IgA-deficient patient [5]. Multifocal cutaneous lesions are a well-documented manifestation of disease in the immunocompromised population, including patients with AIDS, solid organ and bone marrow transplant recipients, and patients on steroids or other immunosuppressive drugs. In this population, disseminated infection involving skin, lungs, and joints has been described, with M. haemophilum cultured from blood [3]. Other reported clinical presentations include pyomyositis, osteomyelitis, septic arthritis, and ocular infections [3].

Pediatric patients who are otherwise healthy typically develop cervicofacial lymphadenitis [3], although this presentation has also been reported in adult patients [1]. Reported cutaneous manifestations in immunocompetent adults include eyebrow lesions (nodules, cysts, papules, pustules, and plaques), with multiple cases associated with tattooing and a case associated with the use of a contaminated eyebrow pencil [6]; subcutaneous nodules involving the right forearm following coral injury [7]; papular rash on the right forearm following coronary artery bypass surgery [8]; purulent superficial ulceration of the scrotum/inguinal folds in a patient with diabetes [9]; and three patients with unilateral plaques with focal erosions on the forearm [10]. Ocular infections in immunocompetent hosts include postoperative endophthalmitis in a patient with uncontrolled diabetes [11], and nodular scleritis and keratouveitis in a healthy male patient [12].

Our patient’s clinical presentation was notable for three reasons. First, other than recently diagnosed type 2 diabetes mellitus, she was not known to be immunosuppressed but presented with disseminated cutaneous lesions, breast masses, and sinonasal disease. She did receive iatrogenic immunosuppression prior to the diagnosis of granulomatous mastitis; however, she had multiple skin lesions at the time steroids were initiated. A recent case report described a patient with multiple subcutaneous nodules and abscesses in the shoulders and upper back, but the patient had a history of multiple subcutaneous lipolysis injections [13]. Our patient underwent evaluation by Immunology and Immunogenetics and no underlying immunodeficiency has been identified, including testing for MSMD and anti-interferon gamma autoantibody. Secondly, sinonasal involvement is rare. One reported case was a renal transplant recipient with several months of epistaxis and left nasal fullness; tissue histology showed AFB, and M. haemophilum was identified by PCR [14]. Another case was in an immunosuppressed patient with M. haemophilum disseminated skin lesions who developed symptoms of nasal congestion, hyposmia, and nasal crusting approximately 6 months into treatment [15]. The patient had an anterior septal perforation on examination, and extensive crusting throughout the nasal cavity. Histopathology showed non-necrotizing granulomatous inflammation with negative AFB stains, and AFB cultures were negative. The patient underwent surgical debridement [15]. Thirdly, to our knowledge, no case reports have detailed breast involvement by M. haemophilum presenting as granulomatous mastitis (GM).

Granulomatous mastitis is a benign inflammatory disease of the breast, with infectious (tuberculous mastitis, most commonly from Mycobacterium tuberculosis) or non-infectious (idiopathic granulomatous mastitis) etiology [16], [17]. Typically, the clinical presentation of GM is a painful mass, with up to 50% of patients reporting erythema and swelling of the breast involved [16]. Common findings on mammogram and ultrasound are increased asymmetric, diffuse density, hypoechoic mass lesions, or nodular structures [17]. Histopathology often reveals non-caseating granulomas, multi-nucleated giant cells, and histiocytes [16]. In idiopathic, non-infectious GM, granulomas can occur around the lobules and ducts in the breast with no specific infectious agents. In infectious GM, microbiological special stains (e.g., Ziehl-Neelsen) may also be negative. In our patient, her previous left arm and left leg skin biopsies revealed negative GMS, periodic acid-Schiff, AFB/Ziehl-Neelsen and AFB/Fite stains.

In a GM presenting with cystic spaces as in our case, the immediate differential is cystic neutrophilic granulomatous mastitis (CNGM), which is presumed to manifest in response to a bacterial infection, most commonly Corynebacterium species, which can be identified as small gram-positive bacilli within the cystic spaces. Rarely, non-tuberculous mycobacteria, including M. abscessus, have been associated with CNGM [18]. The morphologic hallmark of CNGM is cystic spaces lined by varying degrees of neutrophils and histiocytic/granulomatous inflammation. Our case is interesting because although all the histomorphologic components of CNGM are present, the neutrophils do not line the cystic spaces. Instead, they are found infiltrating amongst the granulomatous areas. This is an important distinction, as Gram stain will not highlight Mycobacterium spp. such as in this case. In cases where the histomorphology does not fit with the classic, distinct CNGM appearance, additional stains, such as the AFB/Ziehl-Neelsen stain to rule out alternate infectious microorganisms, should be considered.

Timely diagnosis of this infection requires that the clinician consider mycobacterial infection, especially when initial bacterial cultures fail to elucidate a pathogen or histopathology reveals granulomatous inflammation. Due to the unique growth characteristics of some clinically important species, mycobacterial culture of skin and soft tissue specimens and other specimens from the extremities are routinely incubated at 28-32°C. Recovery of M. haemophilum also requires supplementation of media with a source of iron, such as hemin, hemoglobin, or ferric ammonium citrate [19]. Tissue from the present case was incubated at 30°C in the mycobacteria growth indicator tube (MGIT) liquid culture medium (Becton Dickinson), supplemented with an X factor (hemin) strip. Had the patient not been diagnosed with M. haemophilum infection prior to the breast and sinus biopsies, AFB culture might not have been requested. The clinical team communicated the scheduled biopsies to the Mycobacteriology Laboratory prior to collection. Without this awareness, AFB culture of breast and sinus tissues might not have included appropriate culture and incubation conditions. Diagnosis would have relied on PCR from formalin-fixed paraffin-embedded tissue and susceptibility testing of the subsequent isolates would have been unavailable. These aspects of the case highlight the need for communication among teams and awareness of appropriate culture conditions to optimize the chance for recovering this species. Without susceptibility testing, development of rifampin resistance would have been missed. Some discrepancies with susceptibility results were noted. These may reflect the difficult nature of performing this test for mycobacteria, particularly for fastidious species such as M. haemophilum. Our patient’s strain was probably truly susceptible to amikacin and resistant to minocycline since these results were reproducible. There is no standardized susceptibility testing for M. haemophilum (although CLSI recommends using disk agar elution methods) and there are no standardized antimicrobial guidelines for treatment [3], [19]. In-vitro susceptibility testing may not correlate with clinical response [2]. Treatment regimens usually include a combination of clarithromycin, ciprofloxacin, and rifamycins [1]. However, a single mutation in the 23S gene can lead to macrolide resistance, and a mutation in the rpoB gene can lead to rifampin resistance [3]. As in our case, development of rifampin resistance while on treatment has been reported [20], emphasizing the need to use multidrug therapy. Treatment duration is usually prolonged (may take 12–24 months), and ultimately depends on the patient’s clinical response and immune status [3].

In summary, this case report of M. haemophilum with dissemination causing granulomatous mastitis is unusual and notable. Dissemination possibly started from her cutaneous lesions but remains uncertain. Other than a recent diagnosis of diabetes mellitus and a brief course of steroids, no other immunosuppressing condition has been discerned, as might be expected in disseminated disease.

Ethical statement

The privacy rights of the human subject have been observed and consent for the case study was obtained and documented.

CRediT authorship contribution statement

Jacob Rattin: Writing – review & editing, Writing – original draft, Conceptualization. Cyndee Miranda: Writing – review & editing. Susan Harrington: Writing – review & editing. Lauren A. Duckworth: Writing – review & editing. Raza Hoda: Writing – review & editing. Patrick J. McIntire: Writing – review & editing.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.