Abstract

We describe the case of a patient diagnosed to have Mantle cell lymphoma (MCL), who underwent spontaneous tumor lysis syndrome, with overwhelming metabolic acidosis and acute kidney injury, was managed conservatively without the need for hemodialysis and went on to receive cytotoxic chemotherapy. ATLS is rare in patients with MCL, and spontaneous ATLS is even rare.

Keywords: Mantle cell lymphoma, spontaneous, tumor lysis syndrome, acute kidney injury, CD20, cyclin-D1.

Introduction

Acute tumor lysis syndrome (ATLS) results from a sudden and rapid release of cellular breakdown products after the treatment of cancer. The extra-cellular release of intracellular contents could lead to alterations in metabolic profile. Renal function may be severely impaired and a high anion gap metabolic acidosis ensues, leading even to death [1]. ATLS occurring spontaneously, i.e. without antecedent cytotoxic therapy, is rare. We report the case of a patient diagnosed with Mantle Cell Lymphoma (MCL), who developed ATLS spontaneously while undergoing staging investigations.

CASE REPORT

A 65-year-old gentleman was admitted through the emergency room with a 2-month history of cervical and axillary lymphadenopathy, weight loss, and low-grade fever. There was no history of drenching sweats. On examination, the gentleman appeared cachectic and had generalized lymphadenopathy. Examination of the chest was unremarkable; however, examination of the abdomen revealed a palpable spleen 5 cm below the subcostal margin and an epigastric mass, nodular in surface, measuring 6.5 x 5 cm.

10.1gm/dl; WBC 13.5 x 109/l; ANC 2.5 x 109/l; absolute lymphocyte count 9.8 x 109/l; platelets 350 x 109/l; urea 5.0 mmol/L; creatinine 126 μmol/L; Na 133 mmol/L; K 4.1 mmol/L; Cl 105 mmol/L; HCO3 23 mmol/L; LDH 390 IU/L; Uric acid 0.26 mmol/L; bilirubin 16 mmol/L; ALT 9 IU/L; AST 25 IU/L ; ALP 76 IU/L; Albumin 23 gm/L; Ca 2.61 mmol/L; PO4 1.13 mmol/L. A chest x-ray revealed bilateral pleural effusion and mediastinal lymphadenopathy. The peripheral blood smear showed

large atypical lymphocytes and a few smudge cells. The diagnosis of a lymphoproliferative disorder was suspected and the patient was started on allopurinol. Peripheral blood flow cytometry revealed the lymphocyte population to be positive for CD5 and CD20, and negative for CD10 and CD23, consistent with a diagnosis of MCL.

Staging CT investigations revealed mediastinal and hilar lymphadenopathy, bulky retroperitoneal, para-aortic, para-iliac, and inguinal nodes, and splenomegaly. The liver was not enlarged, and there were focal lesions within the spleen. The patient was staged to have stage IIIBSX disease.

On the 3rd day of admission and before the treatment could be instituted, the patient developed hypotension, tachycardia, and desaturated, necessitating transfer to ICU for monitoring and institution of supportive management. The ECG was unremarkable, and an urgent CT angiogram of the chest did not show evidence of pulmonary embolism. However, serum urea and electrolytes revealed the following: urea 10.5 mmol/L; creatinine 196 μmol/L; Na 133 mmol/L; K 5.1 mmol/L; Cl 110 mmol/L; HCO3 16 mmol/L; Urate 0.36 mmol/L Ca 2.46 mmol/L; PO4 2.07 mmol/L. A diagnosis of ATLS with normal anion gap metabolic acidosis was made and the patient was treated with normal saline at 200 ml/hour, along with loop diuretics, to maintain a urine output of 120-150 ml/hour. The baseline and subsequent serum creatinine and electrolytes are shown in Fig. (1). The patient became clinically stable by around the third day of the treatment and was started on combination chemotherapy, consisting of non-cross resistant alternating weekly cycles of prednisolone, mitoxantrone, cyclophosphamide, etoposide, and bleomycin and vincristine (PMitCEBO). Biochemical features of tumor lysis syndrome were monitored. No further rise in K, PO4, or urate was observed.

Meanwhile, the cervical lymph node biopsy was reported to reveal large irregular nodular areas, within which

Fig (1): Graph showing serial measurements of Creatinine and other markers of acute tumor lysis syndrome. Calcium levels are corrected for albumin. The X-axis shows time, 0 hours being the time when the patient became acutely unwell and electrolytes and creatinine were measured. The Y- axis shows Potassium, urate, phosphate, and calcium (mmol/L), and the Y- axis on the right side shows serum creatinine (μmol/L).

was the diffuse proliferation of monomorphic lymphoid cells, moderately large, and showing increased mitotic activity. Immunohistochemistry revealed the cells to be positive for CD20 antigen. CD5 and CD3 positivity was seen around the nodular region of CD20-positive cells. Although the cyclin D1 stain remained negative, the morphological and immunohistochemical features were consistent with the diagnosis of MCL and corresponded to the immunophenotypic pattern of the peripheral blood. Bone marrow flow cytometry also revealed features similar to the peripheral blood; the bone trephine revealed a population of small lymphocytes staining positively for the CD5 and CD20 antigens and negative for the cyclin D1 stain.

The patient continued to receive the weekly chemotherapy for 4 weeks and was returned to the ward. Subsequently, he developed sepsis secondary to candidemia and passed away.

DISCUSSION

ATLS occurs due to the rapid destruction of tumor cells and a subsequent release of cellular breakdown products. The cardinal features of ATLS are hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia. The constellation of these biochemical features may result in acute kidney injury and high anion-gap metabolic acidosis [1]. Factors that predispose to ATLS include a chemo-sensitive tumor, bulky disease, a large number of ischemic areas within the tumor, high lactate levels, high LDH levels, and impaired renal function [2]. ATLS has been known to occur most frequently

following induction chemotherapy for Burkitt’s lymphoma [3] but has also been reported to occur following the treatment of aggressive lymphoproliferative disorders and occasionally after treatment of solid tumors [1, 4]. More recently, ATLS has been described in patients with chronic lymphocytic leukemia using novel targeted agents [5].

Spontaneous ATLS is a rare condition. It occurs due to the rapid cell destruction in patients who present with bulky widespread or metastatic disease. Only a few cases of spontaneous ATLS have been reported. Spontaneous ATLS has been described in acute leukemias, high-grade NHL, and myelofibrosis [6-10]. ATLS has also been reported in some solid tumor malignancies, such as cancers of the lung, breast, and colon [11-15]. Acute kidney injury (AKI) as a result of spontaneous ATLS has been reported in patients diagnosed to have Burkitt’s lymphoma and acute myeloid leukemia [6, 8]. Our patient with Mantle cell lymphoma developed spontaneous ATLS leading to AKI and metabolic acidosis. Only a few cases of spontaneous ATLS have been reported, mostly in the blastoid variants [16-18].

MCL is a discrete clinicopathological sub-type of NHL. The clinical, immunophenotypic, and molecular characteristics are distinc [19]. Clinically, MCL has a failure-free survival rate of only around 10% at 5 years, and an overall survival rate of 15-20% at 5 years. However, several histologic subtypes of MCL have been described, such as nodular, diffuse, and blastoid variants and the clinical behavior is known to be variable [20]. The nodular and the diffuse variants follow an intermediate course, and the blastoid variant is clinically the most aggressive sub-type, exhibits a higher mitotic index, a higher proliferative rate, frequently over-expresses p53, and is more often tetraploid. Our patient had the blastoid variant, as suggested by the peripheral blood flow cytometry results.

The most important immunophenotypic characteristics of MCL are the expression of CD5 and a lack of expression of CD10 or CD23. In contrast to B-cell CLL, CD23 is absent, and in distinction from follicular lymphoma, CD5 is expressed. The tumor shows rearrangement of the BCL-1 oncogene caused by (11;14) translocation [21]. This gene rearrangement leads to the over-expression of the cyclin D1 protein. Although cyclin D1 expression has a diagnostic value in MCL, occasionally, this expression may be absent [22]. For example, even using multiple breakpoint probes for BCL-1 (MTC, p94PS) and cyclin D1, approximately 70% of MCL only, have a rearrangement consistent with a t (11;14) (q13; q32). Additionally, when using paraffin sections, as was the case here, occasionally fixation or other technical factors may lead to satisfactory staining. However, the morphologic, and immunophenotypic pattern in our case established the diagnosis of MCL, even in the absence of cyclin D1 expression.

CONCLUSION

MCL is a relatively rare type of non-Hodgkin lymphoma. Different sub-types have been recognized. The Blastoid variant is the most aggressive sub-type. ATLS is most often reported in Burkitt lymphoma, aggressive leukemias, and other chemo-sensitive tumors, presenting with bulky disease. Although spontaneous ATLS is rare, it can develop in patients with MC, as shown in this case. Cases like these need to be reported to the literature, so that rare manifestations of the disease and its treatment could be disseminated and recorded.

CONSENT FOR PUBLICATION

Verbal consent was taken from the patient.

CONFLICT OF INTEREST

None.

ACKNOWLEDGEMENTS

None.

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