Renal cell carcinoma and plasma cell myeloma: Unique association and clinical implications.

Several case series, in the recent past, have postulated an association between plasma cell myeloma (MM) and renal cell carcinoma (RCC). Population-based data have revealed a bi-directional association between these two malignancies, which points to shared risk factors, similar cytokine (Interleukin-6, IL-6) requirements for growth and survival, and overlapping clinical presentation. The presence of lytic lesions in a patient with prior RCC may simulate bone metastasis; thus, leading to a diagnostic pitfall with potentially adverse clinical implications. Besides these, therapeutic strategies employed for MM have been tried for RCCs with partial success. We aimed to describe two patients, aged 64 and 54 years, with RCC-MM association, with review of relevant literature; and create awareness among pathologists/hematologists, and oncologists. Elucidating a common genetic basis might throw some light in understanding the pathobiology of these tumors and development of newer targeted therapies.

INTRODUCTION

Survivors of a primary malignancy have an increased risk of developing a second primary malignancy (SPM), which is attributed more commonly to antecedent chemotherapeutic agents (alkylators) as well as genetic, life style, or environmental factors.[1] Although patients of syndromic renal cell carcinomas (RCCs) are at increased risk of second primary tumors, sporadic RCCs are rarely associated with other malignancies.[2] Specifically, an association between RCC and plasma cell myeloma (MM) is extremely rare, and only sporadically reported in the literature. Recent epidemiological data have shown that RCC-MM link is bi-directional with shared risk factors. The risk of development of one with a prior history of the other is more than expected in the general population, for which further in-depth studies are necessary.[3456789]

We aimed to describe two patients with RCC and MM for the first time from India, with a review of existing literature and create awareness among clinicians regarding such association.

CASE REPORT

The clinical presentation (both past and present), lab investigations, radiological characteristics, management, and follow-up data of two patients are presented in Table 1.

Table 1

Clinical presentation, laboratory findings, and management of two patients of plasma cell myeloma with prior history of renal cell carcinoma

Contrast-enhanced computerized scan of abdomen from case two showing a heterogeneously enhancing mass with central necrosis in the right kidney, highly suggestive of renal cell carcinoma

Bone marrow aspirate smears (case 1) (a) showing immature myeloma cells (plasmablasts) with polylobated nuclei and conspicuous nucleoli (Wright Giemsa, ×400), which on trephine biopsy, showed diffuse sheets of myeloma cells with intense cytoplasmic positivity for kappa (b), and negativity for lambda (c) monoclonal antibody (Peroxidase-anti-peroxidase method, ×400)

T2W (a) and T1W (b) mid sagital magnetic resonance imaging (MRI) of spine from case 1 showing wedge compression fracture with altered signal at L1-L3 vertebral bodies, suggestive of osteoporosis or metastasis

DISCUSSION

Renal cell carcinoma and MM are more frequently diagnosed among older adults, constituting 3% and 1% of malignancies, respectively.[10] A recent population-based study (1973-2006) analyzed data from 57,190 primary RCCs (62.2% males; mean age = 61.2 years; SD = 16.4) and 34,156 primary MMs (52.6% males; mean age = 67.9 years; SD 12.3).[3] Patients with RCCs had a higher overall relative risk (51%) of secondary MMs (n = 88) than in the general population (median follow-up = 2.5 years), whereas that of RCCs was 89% higher among MM patients compared to the general population (n = 69, median follow-up = 1.83 years). Thirty five percent (31/88) of secondary MMs and 55% (38/69) of secondary RCCs were observed within the first year of diagnosis of primary malignancy. Women had a remarkably higher relative risk of MM incidence within one year after RCC diagnosis compared to men. A bimodal age distribution (50-59 and >80 years) of increased risk was observed for MMs following RCC diagnosis, whereas age-specific relative risk of secondary RCCs followed a constant pattern across the age groups. Throughout the whole study period (33 years), only two patients were found to have MM associated with metastatic RCCs. As majority of SPMs occurred within first year of the diagnosis of first malignancy, the authors postulated a complex interplay between genetic, environmental, or lifestyle factors rather than treatment-related consequences, which is consistent with other reported SPMs among patients with RCC. Furthermore, surgery rather than chemoradiotherapy is the treatment of choice of RCC, which also decreases the potential of therapy-induced carcinogenesis in MM.[2]

A systematic review of 21 patients with RCC and MM, including those reported by Cooper et al.,[8](1991-2008), and their comparison with our cases is presented in Table 2. As described by Ojha et al.[3] and others, majority of cases were observed in males (M:F = 13:8) with a predilection for the whites (11/21) as opposed to the Afro-Americans in whom MM is known to be more common.[10] The mean age at diagnosis of RCCs and MMs was 61 years (38-70) and 63 years (49-78), respectively. In 13/21 (52%), MM occurred as a SPM after a time gap ranging from 11 months to 26 years, comparatively longer than RCC as SPM (9/21, 42.8%, 20-24 months). Synchronous RCC and MM were reported in three patients (two by Ozturk et al., one by Sakai et al.).[49] Of interest is the fact that right-sided RCCs outnumbered the left [11 (52%) vs. 8 (38%)]; bilateral in one, and majority were of clear cell phenotype. Baring three patients (two pulmonary, one para-aortic lymph node metastases), all presented at early stage (I/II) (stage III in our cases) and were managed by curative resection without any evidence of local recurrence or distant metastases on follow-up. In contrast, patients with MM presented at an advanced stage with multiple lytic bone lesions; three had plasmacytoma (rib/sternum/right kidney), and one had monoclonal gammopathy of undetermined significance (MGUS).[67] Sixteen of 21 (76%) (including case one, present series) had a kappa (κ) chain phenotype. When RCC was diagnosed first, the finding of lytic bone lesions could have raised the possibility of metastatic RCC especially that the incidence of bone metastases is reported to be 26-31% in the metastatic setting.[6] However, in the absence of visceral or pulmonary metastases, these lytic lesions were unlikely to be from an early stage RCC. The morbidity and mortality of patients were due, mostly, to MMs (4/13 expired), whereas none of the patients had RCC-related mortalities.

Table 2

Association between renal cell carcinoma and plasma cell myeloma: Comparison between present two cases with those published in literature (1991-2008)

Interleukin-6 is one of the most important proliferation and survival factors in myeloma.[10] Sakai et al.,[9] for the first time, described a case of synchronous RCC and MM in an elderly female where serum levels of IL-6 decreased from 240 ng/L to 19 ng/L following nephrectomy which, in turn, had a dramatic impact on therapy for MM. On the other hand, when stimulated with recombinant IL-6 in vitro, cultured myeloma cells started proliferating. Based on this, the authors hypothesized that IL-6 produced by RCC cells acted in a paracrine fashion for the survival, proliferation, and progression of MM.

Though both MM and RCC are dependent upon on the same cytokines such as IL-6, tumor necrosis factor- α (TNF- α) etc., this seems highly unlikely in our cases as the second malignancy occurred years after the first. On the other hand, the cumulative effect of IL-6, produced by prior RCC, caused osteoclast activation, which possibly led to advanced lytic bone lesions in our second patient (very high IL-6, Table 1). A high proportion of patients with MM had a ‘κ’ phenotype rather than lambda (λ) (16κ, 5λ, including our series). This probably explained the lack of renal insufficiency (more common with ‘λ’) as a dominant presentation and the overall favorable prognosis seen in all MMs (2/4 deaths were of λ phenotype).

C-met oncogene mutation, seen more commonly in hereditary papillary RCCs, has recently been implicated in IL-6-induced myeloma cell proliferations.[11] However, majority of RCCs reported till date with MMs have been of clear cell phenotype, which commonly harbors Chromosome 3p abnormality. However, this abnormality has not been described in MMs. Besides this, a probable genetic basis for the ‘κ’ light chain preponderance needs to be explored.

CONCLUSION

RCC-MM association has certain unique characteristics such as; (i) shared risk factors like obesity (increased IL-6 production by adipose tissue),[3] hypertension, smoking; (ii) similar cytokine requirements; and (iii) lytic bone lesions. Both myeloma and RCC appear to benefit from therapies such as those directed against cytokines (TNF-α receptor blocker), immunomodulators drugs like thalidomide/lenalidomide, proteosome inhibitor (bortezomib), and autologous stem cell transplantation, although results have been more satisfying for MMs than metastatic RCCs.[6] Therefore, any new lytic bone lesions in a patient with prior RCC should be carefully evaluated for possible myeloma, especially in the absence of pulmonary or visceral metastases. Similarly, all patients of MM should be carefully evaluated for complex mass lesion in the kidneys, more specifically in the right side.