Diffuse Large B-Cell Lymphoma with Cutaneous Manifestations in a Young Patient Using Clozapine for Schizophrenia: A Case Report

Background

Non-Hodgkin lymphoma is the most common hematological malignancy in the world, comprising 2.8% of worldwide diagnosed cancers in 2020 [1]. The most common type is diffuse large B-cell lymphoma (DLBCL), which accounts for 31% of lymphoid malignancies among adults, with an average age at diagnosis of 67 years, with over half of the diagnoses occurring after the age of 65 [1,2].

There are well established known risk factors for DLBCL, such as exposure to radiation and smoking [2]. In the last decade, there has been growing discussion surrounding the potential link between clozapine and hematological malignancies. However, definitive evidence from studies remains elusive. A recent nationwide Finnish study indicated that the use of clozapine was related to a 3-fold increase in the risk of developing hematological malignancies. These findings have heightened awareness regarding this possible association [3].

Clozapine is the criterion standard treatment for refractory schizophrenia, which is a chronic psychiatric disorder characterized by chronic and recurrent psychotic symptoms with impairment of occupational and social functions, with a prevalence of 0.3–0.7% of the general population [4,5].

This case report highlights the possibility of this recently described association, through the description of a diffuse large B-cell lymphoma diagnosed from an atypical cutaneous manifestation in a patient without other risk factors for the development of hematological malignancies and with long-term use of clozapine, with few similar case reports in the literature.

Case Report

A 44-year-old female patient diagnosed with schizophrenia 31 years ago has been taking a clozapine regimen since 2009 to manage her treatment-resistant condition. The dose was titrated up to 600 mg daily within the first year of administration. Despite the complex nature of her illness, characterized by hallucinations and compulsive behaviors that led to neglect in self-care, the patient responded positively to a combined treatment plan of clozapine, sertraline, and valproic acid.

The patient sought consultation at our outpatient clinic for cutaneous nodules that had manifested over 6 months. Initially, the lesions were small, erythematous, infiltrative, and painless, but they evolved to display a widespread, centrifugal distribution, affecting her chest, dorsum, arms, and legs. Four months into this dermatological condition, she began to experience respiratory and gastrointestinal issues, including cough, hoarseness, dysphagia, and a significant weight loss of 12 kilograms, which led her to seek immediate medical attention.

At her initial evaluation, she had diffusely distributed nodular and infiltrative lesions of variable dimensions, with the largest lesion measuring 6 cm. She also presented with painless subcutaneous masses of hard consistency in the right infra-axillary and gluteal regions (Figure 1A–1C). During her initial visit, laboratory evaluation revealed anemia (hemoglobin level of 9.3 g/dL) and low serum iron levels. Her white blood cell count and platelet levels were within the normal range. A hemogram was conducted 5 months prior and did not indicate any hematological abnormalities.

Computed tomography revealed multiple enlarged lymph nodes on both sides of the diaphragm, in addition to multiple large subcutaneous masses located the right flank and on the right upper lateral chest wall (infra-axillary), homogeneous splenomegaly, and heterogeneous nodular areas of hypoenhancement, poorly delimited, in both kidneys (Figures 2, 3). PET-CT showed similar findings. A skin biopsy was performed, which showed diffuse large B-Cell lymphoma, non-germinal center subtype. The patient was classified as stage IVX because she had extra-nodal involvement (cutaneous and renal) and bulky subcutaneous masses. HIV, HTLV, and hepatitis C infections were excluded.

The patient did not present with any additional risk factors commonly associated with the onset of hematological malignancies. Specifically, she had no history of exposure to radiation or toxic substances, nor did she engage in smoking or alcohol consumption. Furthermore, her family medical history was devoid of any neoplastic diseases.

Although a monthly blood count was advised for her clozapine regime, the patient generally underwent these evaluations every 3 months due to logistical constraints and limited healthcare accessibility within the Brazilian public system. Intriguingly, she developed anemia during the 5-month interval between these tests, while her white blood cell count remained consistently within the normal range throughout her medical follow-up.

After the initial diagnosis, chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days) was initiated, with the patient presenting regression of the cutaneous lesions after the first cycle.

New PET-CT was performed after 5 cycles of chemotherapy, showing regression of hypermetabolic lymph nodes, only identifying discrete residual activity in the interaortocaval lymph nodes, clear reduction in the volume and metabolic activity of the subcutaneous nodules, and an increase in glycolytic metabolism in the spleen was no longer evident.

After consultations with the psychiatric and hematology teams, an exhaustive review of the relevant scientific literature was conducted. This research did not yield a consensus regarding the discontinuation of clozapine under the given circumstances. Considering expert opinions and the complexity of the patient’s psychiatric symptoms – specifically, the highly challenging management of both positive and negative symptoms of her schizophrenia – the team arrived at the decision to continue the administration of clozapine.

This decision was motivated by the understanding that ceasing clozapine treatment could exacerbate the patient’s condition by causing a relapse, further endangering treatment adherence. Given the historical difficulties in effectively controlling the patient’s schizophrenia, the collective clinical judgment was to maintain the current psychiatric treatment regimen without conclusive evidence implicating clozapine in the patient’s emergent hematological issues.

One and a half year after the initial diagnostic, during the patient’s follow-up, a new PET-CT was performed and relapse of the disease was evidenced. The new image revealed multiple enlarged and with hyperenhancement lymph nodes (cervical, axillary, mediastinal, para-tracheal, para-aortic and in the pulmonary hila, costophrenic, multiple abdominal, retroperitoneal); homogeneous splenomegaly, and bone marrow of the axial and proximal appendicular skeletons widely affected. Multiple small subcutaneous nodules sparsely distributed in the posterior cervical region, gluteal region, and upper and lower limbs were also observed, but there was no recurrence of visually detectable cutaneous nodules upon physical examination.

A rescue chemotherapy was initiated with rituximab plus gemcitabine and oxaliplatin (R-GemOx) and the patient is currently during her first treatment cycle.

Discussion

In this case report, we describe a case of advanced DLBCL in a young patient with long-term clozapine use.

Diffuse large B-cell lymphomas (DLBCL) can have primary or secondary skin involvement. Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL) is defined when, at the time of diagnosis, there is only skin involvement without the involvement of other sites, while DLBCL can have skin involvement as a sign of dissemination of the disease [6]. In a South Korean cohort, secondary cutaneous manifestations were found in 1.4% of the patients, of whom 56% had other sites of extranodal involvement at the diagnosis of the skin lesions, presenting more commonly with extensive cutaneous involvement in several non-contiguous anatomical sites when compared to PCDLBCL, which is compatible with our patient’s features [6].

The known modifiable risk factors for NHL are exposure to radiation, chemical occupational exposure, tobacco smoking and alcohol consumption, obesity, breast implants, and some infections such as HIV, EBV, and hepatitis C1 [2]. None of these risk factors were identified in our patient.

Recently, an association between clozapine use and a higher risk of hematological malignancies has been suggested. The hypothesis for the development of lymphomas and leukemias associated with clozapine is related to the same etiology as agranulocytosis, which involves the formation of N-arylnitrenium ions involved in chemical carcinogenesis [3].

In a retrospective pharmacovigilance cohort study in Vigibase, clozapine was significantly associated with a higher reporting of lymphoma (adjusted odds ratio 9.13, 95% CI 7.75–10.77) and leukemia (adjusted odds ratio 3.54, 95% CI 2.97–4.22) compared to other antipsychotics. This association is directly proportional to the daily dose of clozapine, with doses higher than 425 mg/day associated with a 5.25 adjusted odds ratio for the development of lymphoma [7]. Our patient used a daily dose of 600 mg of clozapine, which increased the risk of hematological malignancies. The median age at diagnosis was 49.5±11.7 years, significantly younger than that in the general population, where the diagnosis of DLGBCL presents with an average age at diagnosis of 67 years, with over half of the diagnoses occurring after the age of 65, consistent with our patient’s age [2,7].

These findings were reinforced by a recently published nationwide case-control and cohort study using prospectively gathered data from the Finnish national registers. This study showed that compared with non-use of clozapine, clozapine use was associated with higher odds of hematological malignancies in a dose-response manner, having an adjusted odds ratio of 3.35, (95% CI 2.22–5.05) for a cumulative defined daily dose higher than 5000 (which is a concept defined by World Health Organization and represents the assumed average maintenance dose per day for a drug used for its main indication in adults, and clozapine is represented by 0.3 g per day), representing an effect of cumulative response [3,8,9]. The risk of lymphoma was higher than that of other hematological malignancies, with an adjusted odds ratio of 4.066. Exposure to other antipsychotic drugs is not associated with increased risk [3].

Despite the higher relative risk of lymphoma in the use of clozapine when compared to other antipsychotics, the benefits of this drug might be higher than the risks, once there is a reduction of all-cause mortality in patients with schizophrenia due to the use of this medication, with an estimated relative risk of 0.43, with a protective effect for external and natural causes of death [10].

Monitoring blood cell counts and identifying abnormalities that may indicate the early stages of hematological malignancies are essential for the proper management of these patients. This is particularly important because individuals with refractory schizophrenia might struggle with adhering to medical treatments and may have difficulty reporting their symptoms accurately [10]. These specific factors underscore the necessity for clinicians to maintain a heightened level of clinical suspicion in such cases. In our case, the patient had difficult performing monthly blood count and developed anemia during the interval in-between, emphasizing the need to carry out strict control.

The risk-benefit profile of long-term clozapine therapy remains ambiguously defined. While the drug demonstrates marked efficacy in the management of schizophrenia symptoms – thereby contributing to decreased overall mortality rates and enhanced quality of life – its use is not without concern. Notably, risks such as agranulocytosis and a potential association with hematologic malignancies have been cited in case reports and pharmacovigilance studies.

What sets our case apart is the relatively young age of the patient and her positive response to initial chemotherapy with relapse after 1.5 years, while continuing clozapine treatment. It is not clear whether the decision to maintain the clozapine treatment had an impact on promoting the disease relapse. This dual positive and negative profile underscores the need for further research to elucidate the complexities of long-term clozapine use. The aim is to better understand its potential implications for hematologic malignancies and other adverse events, thereby informing future clinical decisions on its safe and effective utilization.

In summary, while clozapine offers significant therapeutic benefits for a challenging patient population, the potential risks cannot be disregarded. Additional research is imperative to refine our understanding of these risks, as well as to provide comprehensive clinical guidelines for the medication’s safe and effective long-term use.

Conclusions

This case report emphasizes a potential link between clozapine use and an increased risk of lymphoma, a hypothesis partially corroborated by emerging epidemiological studies and some case reports. Remarkably, our young patient, diagnosed with diffuse large B-cell lymphoma, initially responded favorably to chemotherapy while continuing her clozapine regimen and experienced no relapse in her schizophrenia symptoms. At 1.5 years after the diagnosis, she presented with relapse of the disease while continuously using clozapine. This intricate clinical picture calls for further investigation.