Malakoplakia in Thoracic Transplant Recipients

Abstract

Malakoplakia is a rare granulomatous disease characterized by the presence of Michaelis-Gutmann bodies on histopathologic analysis. Lesions manifest in a wide range of organs with cutaneous, gastrointestinal and genitourinary systems being most common and often result in significant co-morbidities owing largely to misdiagnoses and the similar appearance to malignancy or granulomatous processes. Most patients are immunocompromised, including the solid organ transplant population. Amongst organ recipients, malakoplakia is most commonly seen in renal transplantation, and only rarely reported in thoracic organ recipients. Here, we report two cases of malakoplakia in thoracic transplant patients that highlight the critical need for tissue diagnosis to avoid delay in management.

Introduction

Malakoplakia is a rare pathological diagnosis secured by the presence of Michaelis-Gutmann bodies on histology and can manifest as inflammatory plaques, nodules and/or ulcers in multiple organs. Diagnosis is often delayed secondary to lesions mimicking other conditions, particularly malignancy. The pathogenesis is linked to abnormal innate immune responses towards bacterial pathogens, most frequently gram-negative bacteria. It is most common in immunocompromised individuals, including solid organ transplant patients. Malakoplakia has been described in renal transplant recipients, but rarely seen in thoracic transplantation. Here, we report two cases in thoracic transplant recipients and review the literature.

Case One:

A 67-year-old man, who underwent bilateral lung transplant for idiopathic pulmonary fibrosis, presented with perianal ulceration 17 months later. Pre-transplantation he required bridging therapy with veno-venous extracorporeal membrane oxygenation (VV-ECMO). Initial posttransplant medications included tacrolimus, mycophenolate mofetil, prednisone, atovaquone and valganciclovir (CMV D+/R−).

Nine months post-transplant, he received three doses of methylprednisone in the context of a new pleural effusion which was originally thought to represent rejection but was subsequently identified as a Candida empyema requiring decortication and prolonged fluconazole. Steroids were rapidly tapered to baseline and mycophenolate mofetil was discontinued secondary to his fungal infection. Ten months after transplantation, perianal lesions developed, thought to be hemorrhoids. In response to an increase in size of the lesions, he was empirically treated for Herpes simplex infection without improvement.

The lack of resolution prompted collection of anal biopsies that revealed dermal histiocytic infiltrate with chronic inflammation and fibrosis. Grocott methenamine silver (GMS) stain suggested blastomycosis based on morphology of yeast forms, an unexpected result given negative chest CT, sputum cultures and serum fungal markers. Histoplasma urinary antigen, serum cryptococcal antigen and blastomyces serum antibody returned negative. Repeat biopsies revealed dense macrophage infiltration with cytoplasmic calcific inclusions in keeping with Michaelis-Gutmann bodies with a similar appearance to fungal organisms, consistent with malakoplakia (Figure 1, panels A-D). Wound cultures grew E. coli, K. pneumoniae and rare alpha hemolytic Streptococcus, with no evidence for fungal pathogens. Immunosuppression was tapered with subsequent resolution of lesions.

Figure 1:

Gross photo, histology and ultrastructural appearance of malakoplakia lesions. Sheets of epithelioid macrophages, many of which contain small intracytoplasmic inclusions (Michaelis-Gutman bodies) (panel A), Von Kossa histochemical stain highlights the calcified cytoplasmic inclusions (panel B), ultrastructure demonstrating bacillary forms consistent with the E. coli (panel C), ultrastructure shows a calcified lysosomal structure consistent with a Michaelis-Gutman body (panel D), gross photos of malakoplakia lesions from right upper thigh (panel E), penis (panel F) and scrotum (panel G).

Case Two:

A 56-year-old diabetic man underwent an orthotopic cardiac transplant for ischemic cardiomyopathy. The pre-transplant course was complicated by lower extremity ischemia requiring bilateral transmetatarsal amputations secondary to bridging therapy with a left ventricular assist device. Post-transplant complications included a sacral decubitus ulcer and allograft rejection noted on right ventricle biopsy requiring treatment with anti-thymocyte globulin, plasmapheresis and rituximab. Medications included tacrolimus, mycophenolate mofetil, prednisone, atovaquone and valganciclovir (CMV D+/R+). Persistent low grade (1A/1R) rejection led to a delayed taper of steroid therapy.

Four months after transplant, multiple painless ulcers involving thighs, scrotum and penis evolved (Figure 1, panels E-G). At this time, he was continuing to taper prednisone as per our institutional protocol. Work-up included negative urine Chlamydia trachomatis and Neisseria gonorrhea nucleic acid detection, HIV antibody/antigen, treponemal antibody, cryptococcal antigen and swabs for HSV antigen. Skin cultures revealed E. coli, Enterococcus faecalis, Staphylococcus haemolyticus, moderate Proteus mirabilis and rare Klebsiella pneumoniae. Fungal and mycobacterial cultures were negative. Biopsies revealed acute and chronic dermal inflammation with necrosis, with Brown-Hopps stain positive for bacterial aggregates. Additional studies including GMS, Giemsa, Fite special stain and spirochete immunostains were negative. Despite prolonged antimicrobial courses of amoxicillin-clavulanate and doxycycline, the genitourinary lesions remained unchanged over two months.

The patient presented again with acute right groin pain six months after transplant. Physical exam, ultrasound and CT imaging confirmed a 3.2 cm inguinal lymph node. Blood cultures were positive for E. coli and S. epidermidis. Amoxicillin-clavulanate was changed to vancomycin and piperacillin-tazobactam, with continued doxycycline. Lymph node excision and skin biopsies revealed sheets of histocytes with acute abscess formation. Von Kossa special stain for calcium confirmed Michaelis-Gutmann bodies, consistent with malakoplakia. Treatment was narrowed to ceftriaxone with initial improvement but worsened in the context of treatment for subsequent cardiac rejection and intensification of his immunosuppressive regimen. Twelve months post-transplant, lesions had resolved with the formation of keloid scars.

Literature review

We performed a PubMed literature search using the mapped term ‘malakoplakia’ in addition to the stems ‘malakoplak’ and ‘malacoplak’ limited to thoracic organ transplantation. Cases were limited to those published in English. Of 966 cases reviewed, two additional (1, 2) thoracic transplant cases were found (Table 1).

Table 1.

Review of known cases with malakoplakia in thoracic transplant recipients

Reference	Case (years)	Underlying transplanted Organ	Location	Organism	Comment	Treatment	Outcome	Differential diagnosis
Case 1	55 male	Heart	Perineal ulcer with regional lymph nodes	E. coli, Staphylococcus epidermidis		Ceftriaxone 1g IV for 21 days Doxycycline 100mg orally BID for 21 days Vancomycin IV for 14 days	Cure	Sexually transmitted genitourinary ulcers
Case 2	67 male	Lung	Perirectal ulcers and rectal mass	E. coli		Reduction in immunosuppression	Cure	Invasive Blastomycosis
Colby et al. (1)	42 male	Heart	Pulmonary nodule	Unclear- Possible organisms include- Corynebacterium spp, Acinetobacter spp, Cryptococcus or Staphylococcus spp.	Lost to follow-up while on treatment, Final admission also presented with possible cerebral lymphoma	Ampicillin for 3 months, Erythromycin for unclear duration (loss to followup), Amphotericin B and 5FC for 14 days until death	Death	Not documented
Teeters et al. (2)	55 female	Heart	Perineal ulcers and rectal mass with regional lymph nodes	E. coli	Diabetes	Ciprofloxacin IV then oral for 10 weeks	Cure	Rectal cancer

These four cases show an age range from 42–67 years with a male predominance of 75%. None of these thoracic transplant cases had classic involvement of the urinary tract, instead perineal and gastrointestinal involvement with regional lymphadenopathy were most typical. E. coli was identified as the most frequent organism though in some cases the causative organism was not always clear. Despite literature reporting frequent surgical debridement as primary management, it was not required in these cases. Targeted antibiotic therapy ranged from three to 12 weeks. One case resolved with reduction in immunosuppression alone.

Discussion

Malakoplakia, derived from the Greek malakos (soft) and plakos (plaque), is a histological diagnosis seen commonly, but not exclusively, with the pathognomonic Michaelis-Gutmann bodies. Michaelis-Gutmann bodies consist of foamy macrophages showing “targetoid” basophilic intracytoplasmic inclusions, which have undergone progressive mineralization likely related to calcification of the lysosome. Macroscopically it presents as yellow-tan plaques or nodules (3). Microscopic features are progressive with early lesions showing plaque like induration followed by ulceration, granulomatous inflammation with sheets of epithelioid histocytes, which may later calcify and fibrose (3).

As in these cases, the major risk factors include immune dysregulation such HIV infection, diabetes mellitus, alcohol and use of immunosuppression, although presentations in apparently immunocompetent individuals are reported (4, 5).

Both of our cases highlight a critical difficulty, namely the delay and misdiagnosis of malakoplakia for indolent infections or malignancy. Complicating the diagnosis is the association of malakoplakia with co-existent malignancy particularly adenocarcinoma of the colon and rectum (6), primary lymphomas of the bladder (7), squamous cell and papillary urothelial cancers of the renal tract and prostate (8, 9). Unlike this series in thoracic recipients, the genitourinary tract is the most common presenting location, though other sites of involvement include the tongue, colon, stomach, lung, trachea, liver, bone, thyroid and uterus (3). In genitourinary tract disease, 40% occurs within the bladder with a female preponderance (ratio of 4:1) reported (3). These cases demonstrate the critical need for considering malakoplakia on the differential diagnosis, especially in immunocompromised patients.

The pathogenesis of malakoplakia is thought to involve a defect in innate immune catabolic responses following ingestion or phagocytosis of bacteria within phagolysosomes. Many mediators have been implicated such as low intracellular cyclic-guanosine monophosphate (cGMP) levels, particularly in ratio to cyclic-adenosine monophosphate (c-AMP), which result in defective microtubule function.

Similar to our cases, the association of malakoplakia with particular organisms suggests a pathogen-specific abnormal innate immune response. E. coli is the most common agent, although other gram-negative and positive organisms have been implicated. Rhodococcus equi, a gram-positive cocci-bacillus, has been associated with pulmonary malakoplakia in particular with those with HIV infection, as well as transplant recipients (10). Other associated pathogens include mycobacteria, Staphylococcus aureus, Pasturella multocida, Stenotrophomonas maltophilia, Whipple’s disease and syphilis (3, 11–15). In addition, concomitant infections with non-bacterial agents including Candida albicans, Paracoccidioides brasiliensis, parasites such as Taenia species and viruses including Herpes simplex and Human papilloma virus have been described (3, 12, 15–18). Given that phagocytosis appears to be central to the pathogenesis, both host and microbial factors warrant further investigation for the identification of specific molecular mechanisms linking innate immune responses and pathogen recognition in malakoplakia.

While classical pathological changes are seen within tissue macrophages, abnormal inclusions have also been seen within circulating monocytes (19, 20). These observations imply a more systemic immune dysfunction beyond variables localized directly to tissue infection. There are no clear associations with particular immunosuppressant medications to explain the phagocytic defect in malakoplakia, though it has been postulated that rates have decreased in the modern era of targeted T-cell therapies in transplant such as tacrolimus and mycophenolate, rather than prednisone (21). Interestingly, although one of our cases was on a delayed taper of steroids due to persistent low-grade rejection, and the other had received a pulse dose prior to presumed rejection, neither were on high doses at the time of lesion onset and were being tapered as per our institutional protocol. In a recent review of 40 cases of malakoplakia in kidney transplant recipients, events occurred at a median of 24 months post-transplant (16). The thoracic cases described here occurred with a similar duration post-transplant, ranging from 4 to 17 months post-thoracic organ transplantation.

Management involves the combination of prolonged antibacterial treatment targeting causative organisms, reduction in immunosuppression, and surgery. Protracted courses can result from cases where ongoing immunosuppression is required, particularly in cases of allograft rejection requiring higher intensity immune suppression. Use of bethanechol, a cholinergic agonist, and ascorbic acid have been utilized to alter the cGMP/cAMP ratios, improve microtubule function and promote phagocytosis, with some success in healing malakoplakia lesions (17, 20, 22).

These cases highlight malakoplakia as a diagnosis in the context of thoracic transplantation, though this observation may represent reporting bias. Despite thoracic transplant procedures occurring less frequently as compared to liver or renal transplantation, thoracic recipients likely carry a higher risk of infection owing to complex mechanical and anatomical defects. In addition, unlike abdominal transplantation where blood biomarkers indicate the need for invasive biopsy (liver tests and creatinine), thoracic organ recipients often follow routine biopsy schedules that may reveal low level rejection well before clinical symptomatology. This clinical approach may tend to place thoracic allograft recipients on more intensified immunosuppression, in turn resulting in more complex clinical manifestations of malakoplakia. Overall, further investigations of malakoplakia in the thoracic transplant population are warranted, especially as the numbers of thoracic recipients increase.

In conclusion, malakoplakia appears to be a rare, systemic disorder typically seen in immunocompromised patients, including thoracic transplant recipients. The chronicity of the lesions and resemblance to other critical processes such as fungal infection or malignancy emphasize the need for rapid biopsy diagnosis, in order to avoid unnecessary diagnostics and delay to appropriate therapy.

Highlights:

1. Malakoplakia is a rare pathological diagnosis secured by the presence of Michaelis Gutmann bodies on histology and can manifest in multiple organs.

2. Diagnosis is often delayed secondary to lesions mimicking other conditions, particularly malignancy.

3. The pathogenesis is linked to abnormal innate immune responses towards bacterial pathogens, most frequently gram-negative bacteria.

4. It is most common in immunocompromised individuals, including solid organ transplant patients.

5. Malakoplakia has been described in renal transplant recipients, but rarely seen in thoracic transplantation.