An association between renal cell carcinoma and multiple myeloma: a case series and clinical implications

Authors


Mohamad A. Hussein, H. Lee Moffitt Cancer and Research Institute, Division of Hematologic Malignancies, 12902 Magnolia Drive, SRB-4, Tampa, FL 33612, USA.e-mail: mohamad.hussein@moffitt.org

Abstract

OBJECTIVE

To describe an association between renal cell carcinoma (RCC) and multiple myeloma (MM) in patients with both disorders, and suggest possible explanations for the association.

PATIENTS AND METHODS

We retrospectively reviewed the records of patients with MM and RCC at the Cleveland Clinic between 1990 and 2005, and identified 1100 with MM, 2704 with RCC and eight with concomitant MM and RCC. The medical records of these eight patients were reviewed.

RESULTS

In four of the eight patients, RCC was diagnosed after the MM at 3, 8, 23 and 46 months, respectively; in the remaining four, the RCC was diagnosed before MM by 108, 35, 13 and 1 months, respectively. The number of cases of RCC expected in the present 1100 patients with MM over 15 years was lower than the four recorded (P < 0.001, Fisher’s exact test). Similarly, the number of cases of MM expected in the 2704 patients with RCC was also lower than the four recorded (P < 0.001, Fisher’s exact test).

CONCLUSIONS

RCC and MM can occur in the same patient at an incidence higher than the expected rate. Possible explanations include genetic abnormalities, environmental exposures or immune-related mechanisms predisposing to the second malignancy. These findings are particularly relevant in the management of patients with known RCC and lytic bone lesions, or those with known MM and subsequent or concomitant renal masses, especially those involving the right kidney.

Abbreviations
MM

multiple myeloma

DVd

pegylated liposomal doxorubicin, vincristine and dexamethasone.

INTRODUCTION

RCC and multiple myeloma (MM) comprise ≈ 3% and 1% of all adult malignancies, respectively [1]; >36 000 new cases of RCC and 16 000 cases of MM will be diagnosed in the USA in 2006 [1]. Although patients with familial forms of RCC, e.g. with Von Hippel-Lindau disease, are at high risk of developing haemangioblastomas, pancreatic neuroendocrine tumours and phaeochromocytoma [2], sporadic kidney cancer is rarely associated with other malignancies. Specifically, an association between RCC and MM has not been described previously. However, a reported case suggested the possibility of one malignancy producing a tumour-stimulating substance that enhances the carcinogenic potential of the second malignancy [3].

Our institution is a tertiary-care centre with dedicated multidisciplinary programmes for both RCC and MM, and a major referral centre for these two entities. We attempted to review the incidence of a diagnosis of RCC and MM in the same patient, analysed the presentation and characteristics of this association, and compared the observed incidence to that in the general population.

PATIENTS AND METHODS

Two comprehensive databases of patients with RCC and MM referred to the Cleveland Clinic Foundation, Cleveland, Ohio, USA, between 1 January 1990 and 31 December 2005 were reviewed; 2704 patients with RCC and 1100 with MM were identified in this period, with eight identified as having a concomitant diagnosis of MM and RCC. The medical records of these eight patients were obtained and all relevant data relating to each diagnosis was abstracted.

RESULTS

The median (range) age at diagnosis of a second malignancy (RCC or MM) was 63 (47–70) years and six of the patients were men (Table 1). In four of the eight patients the RCC was diagnosed after the MM by 3, 8, 23 and 46 months, respectively. Surgery was the main treatment for RCC and no recurrence was documented at the time of the last follow-up. The four patients with RCC as a second malignancy all had stage I or II kidney tumours, and are still alive after a median (range) follow-up of 33 (4–120) months. The four patients with MM as a second malignancy presented as late-stage lytic bony disease. They were followed for a median of 20 (7–31) months, and three of the four have since died, the remaining patient being lost to follow-up after 20 months.

Table 1.  The characteristics of the eight patients
Patient/genderAge at diagnosis of 2nd malignancy, yearsDate of diagnosis of MMMM typeDate of diagnosis of RCCMonths between diagnosesInterval treatment
  1. chemo, chemotherapy; RT, radiotherapy; (H)(R)(P)N, (hemi) (radical) (partial) nephrectomy.

1/M6612/2003IgGκ 9/2005 23Chemo, Renal cryoablation
2/M47 6/1995κ light chain 9/1995  3Chemo, HN
3/M64 2/2001IgGλ12/2004 46RT, chemo, PN
4/F62 1/2001IgGκ 9/2001  8Chemo, RN
5/M61 5/2002IgGκ 5/1993108N, chemo, biological therapies
6/M56 7/2004λ light chain 3/2003 13Left PN, right RN, chemo
7/M66 2/2003Unknown 1/2003  1Right N, chemo
8/F61 6/1993IgGλ 5/1990 35Right N, chemo

CASE 1

In December 2003, a 64-year-old Caucasian man presented with new back pain and was found to have a compression fracture at the level of T11. Further evaluation and laboratory assessment showed multiple lytic lesions and an IgG monoclonal protein, κ light chain. A bone marrow biopsy confirmed the diagnosis of MM. The patient was treated with 23 cycles of thalidomide and dexamethasone, and had an unconfirmed complete response. In addition, he has received pamidronate for his skeletal complications related to MM. The patient had a ‘known’ kidney mass before the diagnosis of his myeloma. At 23 months after his initial diagnosis and after his MM was under control, CT of the abdomen showed an enlarging 3.2 × 2 cm enhancing right kidney lower-pole solid mass, highly suspicious of malignancy. He had a biopsy of his renal tumour, showing clear cell RCC, stage I, Fuhrman nuclear grade 2 of 4, which was followed by laparoscopic cryoablation. In October 2005 the patient showed signs of disease progression from his MM and was started on therapy with lenalidomide. In December 2006, his MM progressed again and he was started on pegylated liposomal doxorubicin, vincristine and dexamethasone (DVd). At his last follow-up in April 2007, he showed signs of disease progression and will initiate therapy with bortezomib soon, but he remains kidney cancer-free.

CASE 2

A 46-year-old Caucasian man presented in June 1995 with a chief complaint of back pain. Further evaluation with a bone scan showed increased uptake at T8–T10, with compression fractures at that level. A bone marrow biopsy was consistent with MM. He was started on chemotherapy with vincristine, adriamycin and decadron. Three months later, CT of the abdomen showed a 7.5-cm right renal mass and the patient had a right lower-pole heminephrectomy. The final pathology from the surgical specimen showed stage II right clear cell RCC. From December 2005 the patient had several chemotherapy regimens for his MM, including melphalan, cytoxan, arsenic trioxide, thalidomide and bortezomib. He has also received pamidronate for his bony disease and several courses of radiation therapy. His MM is stable on maintenance thalidomide, as of March 2007, and he remains kidney cancer-free.

CASE 3

A 60-year-old African-American man presented to a local emergency room in January 2001 with a sternal mass. A biopsy confirmed plasmacytoma and on laboratory evaluation he was found to have IgGλ MM. After several courses of palliative radiation to the chest to treat the plasmacytoma, he was started on melphalan and prednisone for his MM. MRI in November 2004 for right-sided abdominal pain showed a right renal mass; 1 month later, resection of the kidney mass showed an early-stage RCC with no recurrence, as of April 2007. In October 2006, his sternal mass increased in size and he was started on thalidomide and prednisone. As of April 2007, he is on maintenance prednisone, his MM remains stable and he is kidney cancer-free.

CASE 4

In January 2001, a 61-year-old Caucasian women was seen by her primary-care physician with complaints of neck discomfort. X-rays of the neck showed lytic lesions and further evaluation to the diagnosis of IgGκ MM. She was started on rituximab, melphalan and prednisone as part of a clinical trial. In September of 2001, during an evaluation for persistent low back pain, MRI showed a possible lesion involving the right kidney. The patient had a laparoscopic nephrectomy, revealing a stage II grade I clear-cell RCC, that never recurred. Her MM progressed after her initial therapy and she received further chemotherapy regimens with DVd, lenalidomide, and subsequently with cytoxan and prednisone. The patient was in remission from her MM in December 2005, but progressed in September 2006 and died 1 month later.

CASE 5

A 69-year-old Caucasian man was initially diagnosed with RCC in May 1993 and was treated by surgery with curative intent. In 1999, he had a systemic pulmonary recurrence from his RCC and received cytokine-based therapy, with a durable partial response. In May 2002, after a bone marrow biopsy and serum electrophoresis as a part of an evaluation for anaemia, the patient was diagnosed as having IgGκ MM. He was started 1 month later on melphalan and prednisone for the MM, when no further treatment was given for his RCC, which was still in remission. The patient completed treatment for his MM in July 2003, and appeared to be clinically stable; no further treatment was initiated for either malignancy. The patient was lost to follow-up in February 2004.

CASE 6

In September 2002, a 54-year-old Caucasian man was seen by his local physician to evaluate persistent back pain in addition to abdominal distension. CT showed a 25-cm renal mass on the right. The patient had a right radical nephrectomy that revealed plasmacytoma. He was later diagnosed with λ light chain MM and received therapy for MM (thalidomide and dexamethasone). In March 2003, routine CT showed a left-sided new kidney mass. The patient had a partial left nephrectomy, with pathology from this procedure showing a grade 2, 4-cm clear cell RCC. Although the patient was not followed at our institution, his local oncologist notified us when the patient’s MM progressed, with widespread plasmacytomas requiring chemotherapy, but he died from MM shortly after, in March 2005.

CASE 7

In February 2003, a 66-year-old Caucasian man presented at the emergency room with significant weight loss and renal insufficiency. After an extensive evaluation he was found to have a large renal mass, the biopsy of which confirmed the diagnosis of clear cell RCC. One month later, a bone marrow biopsy to evaluate pancytopenia showed nearly complete infiltration by plasma cells with lytic lesions. In March 2003, the patient was started on therapy with melphalan and prednisone at a local hospital, to treat his MM, and in April 2003 elected to undergo a right kidney nephrectomy. The patient was lost to follow-up in July 2003 and subsequently died in October 2003.

CASE 8

A 63-year-old Caucasian woman had a right nephrectomy for early-stage RCC diagnosed in July 1990. She remained cancer-free until she was diagnosed with lytic bony lesions in June 1993; the evaluation showed IgGλ MM. The patient has since had several different chemotherapy regimens for MM at another institution. Her MM subsequently became refractory and she died in September 1996.

Based on cases diagnosed in 1990–2005, the National Cancer Institute and Surveillance Epidemiology and End Results [1] estimates the incidence of RCC in the general population over the 15-year period to be 10.4–13 persons per 100 000 per year, corresponding to a mean of 11.6 persons per 100 000 per year. Similarly, the mean occurrence of MM in the general population is 5.7 persons per 100 000 per year over the 15-year period (Table 2).

Table 2.  The actual yearly incidence of MM and RCC between 1990 and 2005
YearIncidence per 100 000
MMRCC
19905.610.4
19916.010.6
19925.910.8
19935.610.7
19945.711.3
19955.711.1
19965.811.3
19976.110.9
19985.911.8
19995.511.4
20005.912.4
20015.712.4
20025.712.7
20035.313.0
20045.412.7
20055.712.9

Assuming that the 2704 patients with RCC and 1100 with MM from our institution were all newly diagnosed, two groups of patients can be formed, the first comprising the 180 newly diagnosed with RCC each year. Assuming a homogeneous population, if these patients were followed for 3, 8, 23 and 46 months, MM would be expected to occur in 0.0025, 0.0068, 0.019 and 0.039 patients, respectively, in those periods, compared with the ‘one’ patient actually recorded in each period (P < 0.001, Fisher’s exact test) (Table 3). Likewise, taking the 74 patients seen each year with newly diagnosed MM, the expected numbers of RCC in this group would be 0.00074, 0.0093, 0.025 and 0.077 after 1, 13, 35 and 108 months, respectively, compared with the four actually identified (P < 0.001, Fisher’s exact test, Table 3).

Table 3.  Number of observed vs expected cases of MM in 2704 patients with newly diagnosed RCC, or cases of RCC in those with newly diagnosed MM (1990–2005)
No. of patientsFollow-up, monthsNo. of MM or RCC
observedexpected
RCC
180  310.0025
180  810.0068
180 2310.019
180 4610.039
MM
74  110.00074
74 1310.0093
74 3510.025
7410810.077

DISCUSSION

Taken together, these data suggest, with reasonable certainty, an association between RCC and MM that cannot be explained by random incidence alone. Several assumptions were made in the present analysis that might have affected the results. First, the expected incidence of either MM or RCC was not age-adjusted. If these patients were in an age group with a higher rate of either MM or RCC, we would underestimate the number of expected cases and increase the chance of finding a higher association. Second, the number of newly diagnosed patients in each group was considered as constant and calculated as the mean incidence over 15 years. This might potentially cause an overestimate of the number of expected cases and make the probability of finding an association smaller. Biologically, the two diseases share cytokines, e.g. interleukin-6, that support the growth and metastasis of the disease [4]. Of interest is that seven of the eight cases of RCC were early-stage disease, with no recurrence after local therapy. When RCC was diagnosed first, the findings of lytic bone lesions could have raised the possibility of advanced RCC, especially that the incidence of bone metastases is reported to be 26–31% in the metastatic setting [5,6]. That those patients presented with early-stage kidney cancer initially, and had no pulmonary or visceral metastases when lytic lesions were found, made the diagnosis of recurrent RCC unlikely. However, all the cases of MM were associated with advanced-stage features, e.g. as lytic bone lesions as the initial presentation. The presentation with advanced-stage MM, especially with advanced skeletal disease, suggests probable significantly high levels of interleukin-6 that might have been generated from the renal tumour, as was reported previously. All patients, except the one presenting with a large plasmacytoma of the right kidney, presented with right renal involvement, suggesting a favouring of the right side. The findings in case 6, who presented initially with a large right kidney mass and was found to have a plasmacytoma, emphasizes that newly diagnosed plasmacytoma/MM do not have to be confined to the upper respiratory tract or the skeletal system.

An explanation for the association between RCC and treatment-related malignancy, like MM, is unclear. A treatment-related second malignancy is unlikely. In the case where RCC was the initial malignancy, patients mostly had early-stage disease and had no systemic treatment. In the other cases where MM was the primary cancer, patients nos 2 and 4 had their RCC diagnosed after 3 and 8 months only, which is too early for a treatment-related RCC. The two remaining patients (nos 1 and 3) were diagnosed after 23 and 46 months, respectively. Patient 1 received thalidomide, which is not known to have tumorigenic effects in animal models [7]. Patient 3 received several rounds of melphalan, an alkylating agent, before developing RCC. Alkylating agents were rarely reported to induce secondary treatment-related RCC. One report describes a case of RCC developing in a patient treated for 5 years with cyclophosphamide for vasculitis [8].

A common genetic abnormality explaining the occurrence of this dual malignancy is possible. Abnormalities in chromosome 3p are present in the vast majority of patients with RCC [9,10]. However, 3p abnormalities have not been described in MM.

An immune-mediated process predisposing to both malignancies is also possible. Sakai et al.[3] described a dual case of MM and RCC where interleukin-6 produced by the renal malignancy might have stimulated the proliferation of MM cells. This hypothesis was supported by the fact that the patient who had nephrectomy had a significant decrease in serum interleukin-6 levels and a marked spontaneous reduction in the marrow plasma cell percentage (from 20.5% to <5%). In the present series, most of the patients were diagnosed at >1 year after they had their first malignancy, making the possibility of one tumour producing a cancer-stimulating cytokine unlikely.

In summary, we describe eight patients with dual RCC and MM; the probability of this association was much higher than that expected in the general population. No clear treatment-related, environmental, genetic or immune-mediated common factors can fully explain this association. Clinicians should consider that these two malignancies can coexist and an evaluation for MM is indicated when patients with early-stage resected RCC present with bony lytic lesions as their only ‘recurrence’ site. Similarly, patients with known MM who present with a renal mass (especially the right kidney) should not be assumed to have plasmacytoma, and a renal biopsy is prudent to achieve the correct diagnosis and thus appropriate therapy.

CONFLICT OF INTEREST

None declared.

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