Incidence and prognostic significance of hypercalcaemia in B-cell non-Hodgkin's lymphoma

Hypercalcaemia is considered to be rare in B-cell non-Hodgkin's lymphoma (B-NHL).¹ In this letter I report eight cases with this complication among 112 patients (7.1%) diagnosed with B-NHL over a period of five years. The diagnosis of B-NHL was established by morphology and immunohistochemistry of biopsy specimens, and staging was done by computed tomography scan of the chest and abdomen, together with bone marrow aspirate and trephine biopsy. There were 70 patients with high grade B-NHL, 52 of whom had advanced disease (stage III/IV). The remaining 42 had low grade B-NHL.

Five patients with high grade B-NHL presented with hypercalcaemia and another patient developed hypercalcaemia at the time of relapse. One patient with low grade B-NHL developed hypercalcaemia at the time of transformation to Richter's syndrome. One other patient with low grade B-NHL developed hypercalcaemia at the time of relapse. All patients had advanced disease. Table 1 shows the details of the patients.

Table 1.

Details of the clinical and laboratory findings of the patients with hypercalcaemia and non-Hodgkin's lymphoma (NHL)

Case	Age/ Sex	Type of NHL and stage at diagnosis	Time (months) from diagnosis to hypercalcaemia	Highest calcium value (mmol/l)	Recurrence of hypercalcaemia	Treatment	Response	Survival (months) from developing hypercalcaemia
1	51/M	DLB	At diagnosis	3.08	Recurred terminally	CIDEBOM	NR	11
		IIIB				DXR	NR
2	23/M	DLBC	At diagnosis	4.05	No recurrence	CHOP	PR, early relapse	10
		IVB
3	71/F	HGGM	At diagnosis	4.16	Recurrent	CHOP	PR	10
		IVB				DXR	NR
4	70/F	DLBC	At diagnosis	2.96	No recurrence	CIOP	NR	9
		IIIB				Mini-BEAM	PR
5	61/F	HGGM	At diagnosis	2.92	No recurrence	CIOP	PR	9
		IVB
6	57/M	DLBC	24, at relapse	3.16	Recurred terminally	CIOP	CR	5
		IIIB				Mini-BEAM	PR
		IVB at relapse
7	65/F	FCC	49, at the time of transformation	3.02	No response to treatment	Chlorambucil	PR	2
		IVB				Mini-BEAM	NR
		DLBC at transformation
8	74/M	FCC	15, at relapse	3.27	Recurred terminally	Chlorambucil	PR	9
		IVA				CHOP	PR

Normal calcium range, 2.2–2.6 mmol/l. Type of B-NHL: DLBC, diffuse large B cell; HGGM, high grade gastric maltoma; FCC, follicular centre cell. Chemotherapy protocols: C, cyclophosphamide; I, idarubicin; D, dexamethasone, E, etoposide; B, bleomycine; O, vincristine; M, methotrexate in BOM, melphalan in mini-BEAM; H, doxorubicin; P, prednisolone; A, ARA-C; DXR, radiotherapy. Response: CR, complete response; NR, no response; PR, partial response.

Median survival of the five patients with high grade B-NHL presenting with hypercalcaemia was 10 months. This was significantly shorter than the 47 other patients with advanced disease (21 months; p < 0.05) who did not present with hypercalcaemia. The median survival of all eight patients from the time of developing hypercalcaemia was only nine months.

All five patients (cases 1–5) presenting with hypercalcaemia initially responded to rehydration and pamidronate 90 mg intravenously, with normalisation of the serum calcium concentration. Parathyroid hormone was undetectable in one patient and low normal in the other four. None of the patients had a paraprotein in the serum or urine or had bone marrow plasmacytosis. No lytic bone lesions were seen on skeletal survey. Once the diagnosis of B-NHL was established they were treated with standard chemotherapy protocols. None of these five patients achieved complete remission with the standard protocol or with further intensive chemotherapy and/or radiotherapy. During the course of the disease one patient had recurrent hypercalcaemia and required intravenous infusion of pamidronate on four occasions.

One patient (case 6) with high grade B-NHL presented in stage IIIB and achieved complete remission with standard chemotherapy. He relapsed after 24 months in stage IVB with bone marrow involvement and hypercalcaemia. There was no plasmacytosis in the bone marrow and no paraprotein was detected. He was treated with intravenous pamidronate infusion with normalisation of serum calcium concentration. He showed only a partial response to intensive chemotherapy. Hypercalcaemia recurred terminally.

None of the 42 patients with low grade B-NHL presented with hypercalcaemia. One of these patients (case 7) transformed to high grade lymphoma (Richter's syndrome) after 49 months. She presented initially with generalised lymphadenopathy and bone marrow involvement and achieved partial remission with chlorambucil. Her disease relapsed after 24 months but she again achieved partial remission with the same drug. She developed hypercalcaemia at the time of transformation. Hypercalcaemia did not respond to repeated intravenous infusion of pamidronate. Her disease showed no response to intensive chemotherapy and she died within two months.

The last patient (case 8) of this series presented with low grade B-NHL in stage IVA with bone marrow involvement. He was initially treated with chlorambucil and achieved partial remission. His disease relapsed after 15 months with hypercalcaemia. Repeat biopsy showed no change of the histological type and serum parathyroid hormone was low normal. Hypercalcaemia responded to intravenous pamidronate 90 mg and he achieved partial remission with CHOP. However, the remission lasted for only three months and both lymphadenopathy and hypercalcaemia recurred. He died of chest infection shortly afterwards. None of the eight patients had renal failure at the time of developing hypercalcaemia, although three of them developed renal impairment in the terminal stages of their disease.

Hypercalcaemia is supposed to be rare in B-NHL but several individual case reports have appeared over the years.^2–5 No systematic study of hypercalcaemia in B-NHL has been published. Firkin and co-workers² reported an 8.5% incidence of hypercalcaemia in newly diagnosed patients with high grade B-NHL. This incidence was similar to the present study (7%). Some patients in other reports^4,6 showed radiological evidence of bone destruction but none of the patients in the present series had this feature.

Transformation of low grade lymphoma into high grade (Richter's syndrome) is a rare and usually terminal complication. Hypercalcaemia has been reported previously in only one patient with Richter's syndrome.⁶ The patient reported here showed total resistance to bisphosphonate treatment for hypercalcaemia, in addition to no response to intensive chemotherapy. This is not unusual for Richter's syndrome and this patient died within a short period.

Hypercalcaemia appears to be rare in low grade B-NHL. None of the patients in the present series presented with this complication and only one patient with follicular centre cell lymphoma developed hypercalcaemia during the course of the disease. There appear to be no other reported cases of hypercalcaemia in patients with follicular centre cell lymphoma, although it has been reported in some patients with Waldenstrom's macroglobulinaemia (lymphoplasmacytic lymphoma), another subtype of low grade B-NHL.⁴

The cause of hypercalcaemia in B-NHL appears to be humoral. A raised concentration of parathyroid hormone related protein was found in some patients but not in all.³ A close correlation between the concentration of this protein and hypercalcaemia was also found in some patients, which strongly suggests a causal role.² The importance of the other humoral mediators of bone resorption, such as tumour necrosis factor α and interleukin 6, is conjectural.⁶

Hypercalcaemia is usually associated with a poor prognosis in malignant diseases.¹ B-NHL appears to be no exception. It is concluded that hypercalcaemia is not rare in B-NHL, particularly in the high grade type, and carries a poor prognosis.