Incidental Finding of Cryptococcus on Prostate Biopsy for Prostate Adenocarcinoma Following Cardiac Transplant: Case Report and Review of the Literature

Background

Atypical invasive fungal infections in patients following transplantation have been found to vary depending on multiple factors, including the type of organ transplanted, the degree of immunosuppression, and the post-transplant period [1].

Cryptococcus has been found to be one of the more common causative organisms of fungal infections in immunosuppressed patients [1]. The median time to the presentation is approximately 18-months post-transplant [2]. In the cardiac transplant population specifically, the median time to atypical fungal infection is 25 months post-transplant [3].

Cryptococcal fungal infection most commonly involves the central nervous system and respiratory system [1–3]. The prostate gland has been found to act as a possible reservoir for systemic infections and has rarely been found to be the primary site of infection [4]. Prostatic involvement by Cryptococcus infection post-transplant is very rare. We report the case of a 62-year-old man with an incidental finding of Cryptococcus on prostate biopsy for prostate adenocarcinoma, four months following cardiac transplant, and review the published literature of similar cases.

Case Report

A 62-year-old male African-American underwent prostate biopsy, four months following cardiac transplant. He had a history of transthyretin-related amyloidosis presenting as restrictive cardiomyopathy with subsequent congestive heart failure and cardiogenic shock, requiring cardiac transplantation. There was no history of meningitis or pneumonia.

The patient had initially been found to have slightly elevated prostate-specific antigen (PSA) level two years prior to cardiac transplant, with the PSA increasing from 4.95 ng/mL in October 2014, to 5.64 ng/mL in October 2015. In April 2015, a pelvic computed tomography (CT) scan was performed, which showed two nodules in the prostate gland that were highly suspicious for malignancy.

Cardiac transplant occurred in May 2016. In July and August 2016, PSA levels were found to be above 12.0 ng/mL. Furthermore, he complained of recent non-specific urinary symptoms. These PSA results, symptoms, imaging findings, and an abnormal finding on digital rectal examination prompted a prostate biopsy.

A six-core prostate biopsy showed prostate adenocarcinoma, Gleason grade 4+4=8, with areas containing foamy cells (Figure 1). These foamy cells had the appearance of histiocytes (tissue macrophages) associated with areas of fibrosis. The foamy cells contained round and oval encapsulated structures, suggestive of fungal elements (Figure 2). The differential diagnoses at this time included the following fungal organisms: Histoplasma capsulatum, Pneumocystis jirovecii, Cryptococcus neoformans, Coccidioides immitis, and Blastomyces dermatitidis, among others.

Histochemical special stains were performed on the prostate biopsy tissue sections. Grocott methenamine silver (GMS), and periodic acid-Schiff (PAS) staining showed abundant round and oval 5–7 µm diameter intracellular fungal elements (Figure 3). On GMS staining, the fungal structures were of various sizes with narrow-based buds, and no spherules with smaller endospores (suggestive of Coccidiomycosis), or broad-based budding (suggestive of Blastomycosis), or characteristic ‘crushed ping-pong ball’-like structures (suggestive of Pneumocystis) were seen. Mucicarmine staining highlighted the fungal polysaccharide capsule, diagnostic for Cryptococcus (Figure 4). Cryptococcal antigen detection was made by the latex agglutination test and cultures, confirming the diagnosis.

The patient was treated with fluconazole (Diflucan) 400 mg daily following the prostate biopsy results. Subsequent prostatectomy showed diffuse infiltration by Cryptococcus with Gleason grade 4+3=7 adenocarcinoma. Patient urological follow-up has shown PSA levels of <0.01 ng/mL since prostatectomy.

Imaging performed one-month following surgery revealed new bilateral pulmonary nodules, and lung biopsy showed Cryptococcal organisms and an absence of malignant cells. Fluconazole treatment was extended for a total duration of one year. The patient continues to have urological, infectious disease, and cardiac transplant follow-up.

Discussion

Fungal infections occur in immunocompromised patients, including patients who have had solid organ transplants [1]. The risks of atypical infection have been found to vary, depending on the organ transplanted, which may be a factor that is secondary to the level of immunosuppression used post-surgery [1]. Also, the causative organism has been found to vary based on both the original organ transplanted and the period from transplantation to infection [1].

Cryptococcus neoformans is a small encapsulated yeast that causes infection secondary to inhalation [5]. Cryptococcus infection results is a mild, non-specific pulmonary tract infection that, depending on the host immune system and the infective dose and virulence of the organism, causes a latent infection or disseminated infection [6]. Occasionally, patients can have asymptomatic Cryptococcus infection and/or incidental discovery of a lung nodule on X-ray [5,6]. While respiratory tract infection is common, due to an inhalational spread of the organism, the most common site of disease in transplant recipients is the central nervous system, with resultant meningitis. Skin is another commonly affected organ [5,6].

Infection with Cryptococcus is relatively common [7]. Cryptococcus infection leads to a latent stage in most patients who have inhaled cryptococcal spores, which usually reside in granulomas, with no clinical evidence of disease [7]. In patients with underlying immunosuppression, an increase in the fungal burden leads to the transition from latency to disease [8]. Reactivation is also a major cause of Cryptococcus infection, especially in the immunosuppressed host; however, a primary disease can also be seen [1,6,7].

Cryptococcus infection was previously found to predominate in HIV-infected patients. However, the patient population now thought to be at greatest risk of Cryptococcus infection are organ transplant recipients [3]. Cryptococcus is the third most common invasive fungal organism in solid organ transplant recipients, responsible for approximately 8% of invasive fungal infections [2]. Cryptococcus infection occurs relatively late in the post-transplant period, with the literature suggesting a median time to development of 1.6 years [2,3]. This pattern of infection differs from other post-transplant fungal infections, which predominantly occur within 90 days of transplantation [2].

When looking specifically at heart transplant recipients, invasive fungal infections have been found to occur in less than 10% of recipients, with Candida and Aspergillus most commonly implicated [3]. In this patient population, 15% of cases had an onset of Cryptococcus infection within three months of transplantation and the median time to onset was found to be 25 months [3]. Additionally, prostate cancer was found to be the most common urologic malignancy associated with cardiac transplant patients [9].

Given the rapidly increasing PSA level following cardiac transplant that was seen in this case, a literature search was performed. However, no studies or reports were found to report accelerated cancer growth following induction of immunosuppression treatment. Of interest is the possible etiological link between prostate cancer and fungal infections. From this case report, it cannot be determined with certainty whether the rapidly increasing PSA was due to a new, incidental fungal infection occurring concurrently with a pre-existing high-grade cancer, or accelerated growth of a previously indolent cancer, following high-level immunosuppression, with incidental fungal infection, or a new-onset post-transplant cancer occurring in the presence of previous fungal infection.

There has been growing evidence suggesting an association between prostate carcinogenesis and intra-prostatic inflammation [10–12]. A literature search showed limited information regarding a possible link between prostate cancer and fungal infection, possibly due to the low prevalence of prostatitis cases caused by these organisms. Further studies need to be performed to determine the impact of fungal infections, and corresponding intra-prostatic inflammation, on carcinogenesis.

While fungal organisms are not a common cause of prostatitis in the immunocompetent population, prostatic involvement by Cryptococcus is a not-uncommon finding in the immunosuppressed population [10–15]. The prostate gland is thought to be a possible sanctuary for the organism in patients receiving systemic treatment for cryptococcal meningitis, allowing the organism to be cultured in the urine or even causing reinfection at a later period of immunosuppression. However, prostatic involvement by Cryptococcus in post-transplant patients has rarely been reported, with such presentation in post-cardiac transplant patients being even rarer [10–15].

Review of the literature has shown 70 reported cases of Cryptococcus infection in the prostate gland (Table 1) [13–57]. Of these reported cases, only one case (1.4%) was seen in a cardiac transplant recipient, with onset occurring five years post-transplant [13]. An additional case (1.4%) was reported in a patient who had previously had a renal transplant [14]. Commonly seen immunosuppressive factors include steroid therapy, HIV/AIDS, leukemia/lymphoma, and diabetes; rare reports present patients listed as having no significant predisposing factors or immunosuppression (Table 1).

Among the 44 patients (63%) presenting without definite symptoms suggestive of Cryptococcus infection involving the prostate gland, 16 cases (36%) were patients with incidental findings of prostatic involvement found on autopsy; one patient (2%) was found to have Cryptococcus on a biopsy done for a prostatic nodule noted on physical examination. The remaining cases were diagnosed predominantly by urine or semen cultures; 27 (61%) of these 44 cases were in patients that had a previous diagnosis of Cryptococcus infection, 25 (93%) of which had previous diagnoses of cryptococcal meningitis. Only 10 of the 70 cases (14%) were diagnosed by prostate biopsy, with one biopsy performed secondary to the presence of a prostatic nodule, and the remaining nine biopsies (90%) done secondary to presenting symptoms of prostatism (Table 1).

A case of Cryptococcus infection of the prostate, diagnosed on prostate biopsy, in the setting of prior renal transplant was the sole case (1%) where prostatic adenocarcinoma was concurrently diagnosed [14]. One additional case involved a patient initially diagnosed with prostate cancer on biopsy, with the examination of the prostate gland at autopsy showing Cryptococcus infection with no identifiable prostatic adenocarcinoma [15].

Conclusions

Fungal infections of the prostate are rare and occur mainly in immunocompromised patients. We have reported a unique case of prostatic Cryptococcus found incidentally at four months following cardiac transplantation. This case report highlights the need to consider atypical fungal infection as a differential diagnosis for prostatitis in immunosuppressed patients, including transplant patients. A literature review has shown this case to be the second case of post-cardiac transplant prostatic Cryptococcus infection and the second case of concurrent prostatic adenocarcinoma and Cryptococcus infection, and is the first case to combine all three of these factors. Additionally, this case had an unusually rapid onset of post-transplant Cryptococcus infection. This case may help to raise awareness of the possibility of latent infection combined with carcinoma. While in our case, we cannot definitely determine whether it was the cancer or the infection that led to the recent onset of urinary symptoms or the spike in PSA levels, this case raises the necessity to rule out infectious etiologies in transplant recipients with urinary symptoms.