Cryptococcal osteomyelitis and meningitis in a patient with non-hodgkin’s lymphoma treated with PEP-C

Abstract

The authors present the first case report of a patient with lymphoma who developed disseminated cryptococcal osteomyelitis and meningitis while being treated with the PEP-C (prednisone, etoposide, procarbazine and cyclophosphamide) chemotherapy regimen. During investigation of fever and new bony lesions, fungal culture from a rib biopsy revealed that the patient had cryptococcal osteomyelitis. Further evaluation demonstrated concurrent cryptococcal meningitis. The patient’s disseminated cryptococcal infections completely resolved after a full course of antifungal treatment. Cryptococcal osteomyelitis is itself an extremely rare diagnosis, and the unique presentation with concurrent cryptococcal meningitis in our patient with lymphoma was likely due to his PEP-C treatment. It is well recognised that prolonged intensive chemotherapeutic regimens place patients at risk for atypical infections; yet physicians should recognise that even chronic low-dose therapies can put patients at risk for fungal infections. Physicians should consider fungal infections as part of the infectious investigation of a lymphopaenic patient on PEP-C.

Background

Cryptococcus neoformans is an encapsulated yeast found in soil contaminated with avian excreta.^{1 2} Manifestations of cryptococcosis range from asymptomatic pulmonary colonisation to potentially fatal cryptococcal meningitis,³ with meningitis the most common presentation due to the organism’s predilection for the central nervous system.² Rare cases of other presentations such as cryptococcal osteomyelitis have also been noted in the literature.^{2 4–6} We present an unusual case of cryptococcal osteomyelitis diagnosed together with cryptococcal meningitis in a non-HIV, immunocompromised patient. This particular combination of cryptococcal foci has not previously been reported, with the exception of one case of cryptococcal sinusitis and meningitis with subsequent skull base osteomyelitis.⁷

Although cryptococcal disease can occur in immunocompetent hosts, the majority of cases occur in those with underlying conditions such as advanced HIV disease.³

Other conditions such as glucocorticosteroid treatment, solid-organ transplantation, sarcoidosis and hematologic malignancies including lymphoma are also associated with increased risk of cryptococcal infection.^{3 8 9} While it is well documented that patients with haematopoietic diseases treated with prolonged or intensive regimens are susceptible to opportunistic infections, regimens that include chronic low-dose chemotherapy are not generally thought to place patients at risk for fungal infections. PEP-C is a regimen consisting of daily oral doses of prednisone (20 mg), plus low-dose etoposide (50 mg), procarbazine (50 mg) and cyclophosphamide (50 mg) developed for the treatment of lymphoma.^{10 11} To our knowledge, our case provides the first report of a patient with lymphoma who developed concurrent cryptococcal osteomyelitis and cryptococcal meningitis while being treated with the PEP-C regimen.

Case presentation

A 66-year-old man with stage IVA nodal marginal zone B cell lymphoma received first line rituximab, cyclophosphamide, vincristine and prednisone (R-CVP).^12–14 After achieving a partial response, he was changed to a daily oral chemotherapy regimen of prednisone, etoposide, procarbazine and cyclophosphamide (PEP-C).^{10 11} Three months after the initiation of PEP-C treatment, the patient developed atraumatic rightsided rib pain that increased in severity over the next few months and was accompanied by a headache and low-grade fever of 101° Fahrenheit. Physical examination revealed a tender soft tissue prominence over the right eighth rib. Laboratory values showed low total leucocyte (white blood cell (WBC) 2.9×10³/mm³) and absolute lymphocyte (absolute leucocyte count 0.37×10³/mm³) counts, with a normal absolute neutrophil (absolute neutrophil count 2.2×10³/mm³) count. Positron emission tomography scan confirmed decreased activity of nodal disease in response to PEP-C therapy, but did not reveal any abnormal hypermetabolic activity in the area of reported rib pain. MRI of the thorax demonstrated a 2.2×6.0 cm lesion involving the lateral eighth right rib and adjacent subcutaneous tissue (figure 1a) as well as a 2.5×2.7 cm lesion in the posterior aspect of the L3 vertebral body.

Figure 1.

(a) Axial T1-weighted image following gadolinium injection and with fat suppression at the level of the right eighth rib demonstrates a heterogeneous soft tissue mass replacing the normal rib (arrow). The lesion has central non-enhancement, and is again non-specific for infection versus neoplasm, though it would be atypical for a non-HIV associated lymphoma. (b) Axial T1-weighted image following gadolinium injection demonstrates a ring enhancing lesion in the right posteromedial frontal lobe (arrow). The lesion is non-specific for infectious versus neoplastic etiologies, though lymphoma does not generally present as a ring-enhancing lesion except in HIV+ patients. Incidentally noted are changes related to prior scalp surgery for squamous cell carcinoma. (d) Axial T1-weighted image following gadolinium injection and with fat suppression obtained 1 year after ‘figure 1a’ demonstrates no abnormality at the level of the right eighth rib (arrow). (c) Axial T1-weighted image following gadolinium injection acquired 1 year after ‘figure 1b’ demonstrates complete resolution of the previously ring-enhancing lesion. The brain at this level is normal (arrow).

Investigations

The patient underwent biopsy of both bony lesions. Biopsy of the L3 vertebral lesion revealed low-grade B cell lymphoma confined to the marrow, consistent with known bone marrow involvement documented at diagnosis. Biopsy of the right eighth rib and adjacent soft tissue revealed only chronic inflammation without evidence of malignancy. In addition to histopathologic examination, the specimens were also sent for bacterial and fungal stains and cultures. Aerobic and anaerobic bacterial cultures of the biopsied tissue were negative. However, fungal culture of the rib tissue was positive for a single colony of Cryptococcus neoformans. Serum cryptococcal antigen titer was found to be elevated at 1:64. Based upon fungal culture and serology results, the patient was diagnosed with cryptococcal osteomyelitis. A HIV 1/2 antibody screen was negative.

Given the predilection of cryptococcus neoformans for the central nervous system, an evaluation for meningitis was performed. Cerebrospinal fluid (CSF) analysis revealed a high protein concentration (139 mg/dl), a low glucose concentration (40 mg/dl), and a lymphocytic pleocytosis (total WBC 44 cells per µl, 2 polymorphonuclear cells, 76 lymphocytes, 21 monocytes and no erythrocytes). Flow cytometry studies of CSF showed no evidence of lymphoma. MRI of the brain with gadolinium uncovered a 4 mm cortical ring-enhancing lesion in the right posterior paramedian region on postcontrast T1-weighted images (figure 1b). The MRI and CSF findings supported the diagnosis of cryptococcal meningitis.

Treatment

The patient was started on intravenous liposomal amphotericin B (AmBisome; amphotericin B 5 mg/kg, Gilead Sciences, Foster City, California, USA) for treatment of both cryptococcal osteomyelitis and meningitis. However, the patient developed renal insufficiency on this regimen and was switched to fluconazole 800 mg daily.

Outcome and follow-up

After 12 months of antifungal treatment for meningitis,¹⁵ the patient experienced clinical and radiographic resolution of the rib mass (Figure 1c), disappearance of the brain lesion on MRI (Figure 1d), and normalisation of CSF studies and serum cryptococcal antigen titre. Although he has not received lymphoma treatment since the diagnosis of cryptococcal infection, his lymphoma remains stable without progression, now more than 1 year since his diagnosis of disseminated cryptococcal infection.

Discussion

Low-dose metronomic (frequently administered) chemotherapy has gained interest in recent years in the treatment of refractory solid tumors and hematologic malignancies.

These regimens are well tolerated; for example, many studies of cyclophosphamide based metronomic chemotherapy show minimal- or no high-grade toxicities. More than 12 studies describe use of low dose/metronomic regimens in haematopoietic and solid tumours, such as low-dose cyclophosphamide, a metronomic treatment most commonly used in prostate cancer.^16–27 In these studies, when reported, occurrences of systemic infections (primarily pneumonia) ranged from 0% to 7.7%.^16–27 PEP-C is a low-dose, metronomic multi-drug regimen used in cases of recurrent lymphoma when patients are unlikely to tolerate regimens that induce significant neutropenia.^{10 11}

Some subtypes of non-hodgkin’s lymphoma including follicular, mantle cell, and marginal zone histologies can have overall response rates to PEP-C as high as 88%, 82% and 71%, respectively.^{10 11}

Though the chemotherapy components of PEP-C are each individually immunosuppressive,^{10 11} the fact that normal neutrophil counts are maintained in patients receiving PEP-C may lead to an underappreciation of the fact that lymphopaenia and opportunistic infections can occur. Of the three papers that describe use of PEP-C in a total of 122 patients, 30 patients (25%) had infection-related adverse events, 14 of which were grade 1–2 and 16 of which were grade 3–4.^{10 11 28} Of note, one case of grade 2 cytomegalovirus retinitis and one grade 3 Pneumocystis carinii pneumonia were reported with this regimen, demonstrating that PEP-C has been associated with severe infections typically seen in the immunocompromised population.

Our case illustrates that the chronic low-dose chemotherapy regimen, PEP-C, can be associated with disseminated cryptococcal infection. Use of steroids in patients with haematologic disease has been previously implicated in cryptococcal disease. A large case series of cryptococcal infections was a report from Memorial Sloan-Kettering Cancer Center: of the 46 patients who developed cryptococcal disease between 1956 and 1972, 38 were patients with leukaemias and lymphomas and 39 were patients treated with steroids.²⁹ In this historical population of patients, cryptococcal meningitis was much more commonly diagnosed than cryptococcal osteomyelitis. Further, all patients with cryptococcal infection were found to have absolute lymphopaenia. Another case series conducted at M D Anderson Cancer Center from 1989 to 1999 demonstrated that of 31 cancer patients with cryptococcal disease (20 of whom had haematologic malignancies), the majority of patients (61%) had lymphopaenia and more than half (52%) had been treated with steroids.³⁰ Other case reports also demonstrate an association between chemotherapy-induced (for example, COPP/ABVD, BEACOPP, fludarabine) lymphopaenia, including CD4+ T-lymphocytopaenia, and development of cryptococcal infection in patients with hodgkin’s and non-hodgkin’s lymphoma.^31–33 One case report and review of the literature cited 54 case reports of cryptococcosis in patients with hodgkin’s lymphoma, and found absolute lymphopaenia present in 93% of the cases in which lymphocyte counts were reported.³¹ These studies suggest that lymphopaenia is the underlying risk factor for cryptococcal disease in patients with haematologic malignancies.

Our patient’s ALC was normal at the time of initiation of PEP-C, fell below the normal range after 1 month of treatment, and had a nadir of 0.37×10³ cells/mm³ just before the diagnosis of disseminated cryptococcal infection (figure 2). After PEP-C was discontinued, his ALC returned to within normal limits within 40 days. The sequence of events suggests that the PEP-C regimen was responsible for his lymphopenia and subsequent cryptococcal infection. Although the PEP-C combination has not been specifically reported to induce lymphopaenia, both prednisone³⁴ and cyclophosphamide³⁵ (including low dose metronomic cyclophosphamide)^{36 37} can induce absolute lymphopaenia, with the former predominately decreasing the CD4+subset of lymphocytes. Though our patient’s T cell subsets were not obtained at the time of lymphocyte nadir, his CD4+ count was found to be normal (688 cells/mm³) 2 months after cessation of PEP-C. We hypothesise that his CD4+ count may have been low during PEP-C treatment due to the combination of prednisone and cyclophosphamide treatment, but that it rapidly normalised, similar to his ALC, upon discontinuation of the regimen. As supported by a body of literature linking cryptococcosis to CD4+ T-lymphocytopaenia in non-HIV and HIV patients alike,^38–41 lymphopaenia, and specifically CD4+ T-lymphocytopenia, was likely the greatest risk factor for cryptococcal infection in our patient.

Figure 2.

Graph of ALC during patient’s course of PEP-C.

Our case serves as a reminder that active lymphoma can co-exist with atypical infections. Although fever and new bone lesions in a patient with lymphoma may indicate progression of neoplastic disease, physicians should strongly consider biopsy of new symptomatic bony sites. In patients at risk for CD4+ T-lymphocytopaenia due to chronic chemotherapy, physicians may further wish to check T cell subsets and maintain a low threshold to exclude fungal infections as well as other severe infections. Our patient has demonstrated that even chronic low-dose therapies such as PEP-C can put patients at risk for serious toxicities typically seen in the immunocompromised population.

Learning points.

• ▶PEP-C (prednisone, etoposide, procarbazine and cyclophosphamide) is a daily oral chemotherapy regimen that may induce prolonged immunosuppression and lymphopaenia.
• ▶Lymphopaenia is the underlying risk factor for cryptococcal disease in patients with haematologic malignancies.
• ▶Physicians should consider fungal infections as part of the infectious investigation of a lymphopaenic patient on PEP-C.