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ORIGINAL ARTICLE
Year : 2019  |  Volume : 22  |  Issue : 9  |  Page : 1271-1275

Paraneoplastic syndromes and oncological outcomes in renal cancer


1 Department of Surgery, Division of Urology, Lagos State University Teaching Hospital, Ikeja, Lagos, Nigeria
2 Department of Surgery, Division of Urology, LAUTECH Teaching Hospital, Osogbo, Osun State, Nigeria
3 Department of Surgery, Federal Medical Centre, Abuja, Nigeria
4 Department of Surgery, General Hospital, Gbagada, Lagos, Nigeria

Date of Acceptance22-May-2019
Date of Web Publication6-Sep-2019

Correspondence Address:
Dr. O O Ojewuyi
LAUTECH Teaching Hospital, PO Box 5000, Osogbo, Osun State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njcp.njcp_35_19

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   Abstract 


Background: Paraneoplastic syndromes (PNS) have been defined as a constellation of symptoms and signs seen in patients with malignancy, which cannot be ascribed to the local or distant spread of the tumor. Renal cell carcinoma (RCC) is most commonly associated with PNS among urological malignancies. We describe the incidence of PNS and the association between the syndromes and oncological outcomes in our patients with RCC. Subjects and Methods: A retrospective cohort study done at Lagos State University Teaching Hospital, Ikeja, Lagos. This was a retrospective review of our patients who had RCC over 11-year period (2006 to 2016). The incidence of PNS syndromes were hypercalcemia, Stauffer's syndrome, hypertension, anemia, elevated erythrocyte sedimentation rate (ESR), persistent leukocytosis, and its correlation to outcome of disease were analyzed. In addition, the age, gender, clinical features, and stage of disease were analyzed. Chi square, Fischer exact test, and Kaplan–Meier survival, curve and logistic regression. Results: In total, 101 patients were operated within the period. Age of the patients ranged from 11 to 81 years (mean of 45.17 ± 16.3). There were 46 males and 55 females with M:F ratio of 1:1.2. Majority of the patients, 74 (73%), had clear cell variant of RCC. Twenty-seven patients (26.7%) had triad of flank pain, flank mass, and hematuria. The incidence of PNS were hypercalcaemia 7 (6.9%), Stauffer's syndrome 12 (11.9%), hypertension 16 (15.8%), anemia 61 (60.4%), elevated ESR 56 (55.4%), and persistent leukocytosis 3 (3.0%). At a median follow-up of 6 months, 72 patients (71.3%) were alive, whereas 29 patients (28.7%) were dead. Conclusion: Among the PNS, only Stauffer's syndrome was significantly associated with poor outcome.

Keywords: Oncological outcomes, Paraneoplastic syndromes, renal cell carcinoma


How to cite this article:
Ikuerowo S O, Ojewuyi O O, Omisanjo O A, Abolarinwa A A, Bioku M J, Doherty A F. Paraneoplastic syndromes and oncological outcomes in renal cancer. Niger J Clin Pract 2019;22:1271-5

How to cite this URL:
Ikuerowo S O, Ojewuyi O O, Omisanjo O A, Abolarinwa A A, Bioku M J, Doherty A F. Paraneoplastic syndromes and oncological outcomes in renal cancer. Niger J Clin Pract [serial online] 2019 [cited 2019 Oct 21];22:1271-5. Available from: http://www.njcponline.com/text.asp?2019/22/9/1271/266164




   Introduction Top


Paraneoplastic syndromes (PNS) are defined as constellation of symptoms and signs that cannot be ascribed to local or distant spread of the tumor.[1] They are also unrelated to infection, nutritional deficiencies, or toxicity from cancer therapy.[1] These syndromes vary widely from those manifesting with constitutional symptoms (fever of unknown origin, fatigue, and weight loss) to those manifesting with specific biochemical and metabolic derangements (hypercalcemia, Stauffer's syndrome, hypertension, etc.).[2] The uniqueness of renal cell carcinoma (RCC) among urological cancers lies in the fact that it is the most commonly associated with PNS with about 20% of patients affected.[3]

Many theories have been suggested as the cause of PNS: production of biologically active substances (hormones, hormone precursors, or hormone-like substances) aberrantly by the tumor, modulation of immune system via autoimmunity, immune complexes production, and immune suppression. There are also idiopathic causes.[1]

It is important to recognize the clinical features of PNS in RCC, as it can lead to the diagnosis of previously undetected RCC. It can also dominate the clinical picture and thus lead to errors with respect to the origin and type of primary tumor; thus, the expression of RCC as internist tumor or the great masqueraders of medicine.[4] PNS can also follow the clinical cause of the underlying tumor and therefore can be useful in monitoring its evolution. However, it is worthy of note to state that the presence of PNS does not indicate metastasis or poor prognosis. In most cases, successful treatment of the tumor often leads to improvement or resolution of the PNS.[5]

We describe the incidence of PNS and the association between the syndromes and oncological outcomes in our patients with RCC.


   Subjects and Methods Top


This was a retrospective review of our patients who had diagnosis of RCC. The period under review was 11 years (2006 to 2016). All the patients with RCC within the study period were included in the study. The variables analyzed included the following: hypercalcemia, Stauffer's syndrome, hypertension, anemia, elevated erythrocyte sedimentation rate (ESR), persistent leukocytosis, and its correlation to outcome of disease were analyzed. In addition, the age, gender, clinical features, and stage of disease were analyzed. The data were analyzed using Statistical Package for Social Sciences (SPSS) version 22 and P value < 0.05 was considered significant.


   Results Top


In total, 101 patients with RCC were included in the study. The age of the patients ranged from 11 to 81 years (mean 45.17 ± 16.3 years) and there were 46 males and 55 females with M:F ratio of 1:1.2 [Table 1]. Majority of the patients, 74 (73%), had clear cell variant of RCC.
Table 1: Association between demographics/clinical characteristics and outcomes

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The incidence of PNS was as follows: hypercalcemia 7 (6.9%), Stauffer's syndrome 12 (11.9%), hypertension 15 (15.8%), anemia 61 (60.4%), elevated ESR 56 (55.4%), and persistent leukocytosis 3 (3.0%). Duration of symptoms was significantly associated with poor prognosis, P = 0.02 [Table 1]. The presence of Stauffer's syndrome and the tumour node metastasis (TNM) stage of the disease were significantly associated with mortality from renal cancer [Table 1] and [Table 2].
Table 2: Association between paraneoplastic syndromes and outcomes

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In addition, the cumulative survival curve (Kaplan–Meier curve) showed that the presence of Stauffer's syndrome and the duration of the disease were significantly associated with shorter duration of survival [Figure 1] and [Figure 2]. Stauffer's syndrome was an independent predictor of mortality [Table 3]. There was also significant association between Stauffer's syndrome and TNM stage of the disease [Table 4].
Figure 1: Kaplan–Meier survival curve for those with Stauffer's syndrome, P (0.039)

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Figure 2: Kaplan–Meier survival curve for those RCC based on tumor stage, P (0.001)

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Table 3: Binary logistic regression showing Stauffer's syndrome as an independent predictor of mortality

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Table 4: Table showing association between Stauffer's syndrome and TNM stage

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Twenty-seven (26.7%) of the patients had the triad of flank pain, flank mass, and hematuria and 2% were incidental findings on imaging study. Seven of the cases were inoperable at presentation. At median follow-up of 6 months, 72 patients (71.3%) are alive, whereas 29 patients (28.7%) are dead.


   Discussion Top


Previous studies reported estimated that about 20% of patients with RCC will develop PNS.[1],[2] These were done among predominantly Caucasians. However, not much has been said about the incidence of PNS in our environment with a few of the studies putting the incidence of PNS as <5%.[6],[7]

Hypercalcemia has been previously reported to be the most common PNS, affecting between 13% and 20% of patients;[8] this is in sharp contrast to our findings, where it was the fifth most common PNS. Though hypercalcemia has been said to be associated with high-stage lesions in about 75% of cases, this has been shown not to have a significant correlation with tumor grade and survival.[9] This is corroborated by findings from this study where the presence of hypercalcemia was not significantly associated with poor prognosis. The cause of hypercalcemia in RCC is not known; some have attributed it to the production of parathyroid hormone-related peptide (PTHrP) by the tumor.[10] The PTHrP causes increased bone resorption, decrease renal clearance of calcium, and increased phosphorus excretion. This mechanism is also described as nonmetastatic hypercalcemia.

Hypertension is another relatively common PNS. Increased renin secretion, arteriovenous fistula, and polycythemia are some of the underlying mechanisms responsible.[11] We could not find any clear association between presence of hypertension and poor prognosis in our study. This is similar to previously reported findings in the literature.[12] In most cases, the hypertension resolves following nephrectomy.

Nonmetastatic hepatic dysfunction (Stauffer's syndrome) is characterized by elevation of the liver enzymes and hepatic synthetic products. It was the only PNS significantly associated with poor outcome from our findings. In addition, presence of Stauffer's syndrome was significantly associated with shorter cumulative survival. The etiology is poorly understood; evidence shows that abnormal production of interleukin-6 (IL-6) plays a significant role in its etiopathogenesis.[13]

The presence of anemia, elevated ESR, and duration of symptoms >1 year were also associated with shorter cumulative survival, but this did not reach statistical significance.

Paraneoplastic leukocytosis reported in some solid tumors is rarely seen in RCC. Few studies have reported persistent leukocytosis and were mostly animal studies. It has been said to be due to elevation of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF).[14],[15]

In our study, we had three patients who had persistent leukocytosis with predominant neutrophilia (mature neutrophils). There were no focus of infection; urine and blood culture were negative; and review by hematologist ruled out possible leukemia. However; following nephrectomy, there was significant drop in the level of the leucocytes and neutrophills.

The incidence rate of RCC from our study is higher than that reported in previous studies in our environment;[16],[17] this could be attributed to increased awareness about renal cancer and increased accessibility and affordability of imaging studies and surgery.

In addition, we found higher incidence of RCC in females compared with males; this is in sharp contrast to what is reported in the developed world.[18] This is also similar to the findings from other studies in our environment and other part of Africa.[17],[19] Some authors have suggested that estrogen have a role to play in the etiopathogenesis of RCC and this may explain the higher preponderance in females.[20]

Furthermore, expectedly the T-stage of the disease was significantly associated with the overall outcome and the cumulative survival. Those with T1 and T2 disease had longer cumulative survival compared with the T3 and T4 stage of disease.


   Conclusion Top


PNS are important because they could be the first symptom the patient present with and be a pointer to the presence of an occult malignancy. Only Stauffer's syndrome was significantly associated with poor outcome in RCC patients. Persistent leukocytosis though rare is a feature of PNS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Sacco E, Pinto F, Sasso F, Racioppi M, Gulino G, Volpe A, et al. Paraneoplastic syndromes in patients with urological malignancies. Urol Int 2009;83:1-11.  Back to cited text no. 1
    
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Palapattu GS, Kristo B, Rajfer J. Paraneoplastic syndromes in urologic malignancy: The many faces of renal cell carcinoma. Rev Urol 2002;4:163-70.  Back to cited text no. 2
    
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Gold PJ, Fefer A, Thompson JA. Paraneoplastic manifestations of renal cell carcinoma. Semin Urol Oncol 1996;14:216-22.  Back to cited text no. 3
    
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Aldaabil R, Peereboom D. Paraneoplastic Syndromes in Renal Cell Carcinoma. Renal Cell Carcinoma: Springer; 2000. p. 135-45.  Back to cited text no. 5
    
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Takure AO, Shittu OB, Adebayo SA, Okolo CA, Sotunmbi PT. Renal cell carcinoma in Ibadan: A 5-year clinicopathologic review. Afr J Med Med Sci 2013;42:239-43.  Back to cited text no. 6
    
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Salako A, Badmus T, Badmos K, David R, Laoye A, Akinbola I, et al. Renal cell carcinoma in a semi-urban population of south-western Nigeria. East Afr Med J 2017;94:37-43.  Back to cited text no. 7
    
8.
Muggia FM. Overview of cancer-related hypercalcemia: Epidemiology and etiology. Semin Oncol 1990;17 (2 Suppl 5):3-9.  Back to cited text no. 8
    
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Gellhorn A, Plimpton CH. Hypercalcemia in malignant disease without evidence of bone destruction. Am J Med 1956;21:750-9.  Back to cited text no. 9
    
10.
Mangin M, Webb AC, Dreyer BE, Posillico JT, Ikeda K, Weir EC, et al. Identification of a cDNA encoding a parathyroid hormone-like peptide from a human tumor associated with humoral hypercalcemia of malignancy. Proc Nat Acad Sci United States Am 1988;85:597-601.  Back to cited text no. 10
    
11.
Dahl T, Eide I, Fryjordet A. Hypernephroma and hypertension. Two case reports. Acta Med Scand 1981;209:121-4.  Back to cited text no. 11
    
12.
Howlett SA, Caranasos GJ. Metastatic renal cell carcinoma producing arteriovenous shunt. Arch Int Med 1970;125:493-5.  Back to cited text no. 12
    
13.
Blay JY, Rossi JF, Wijdenes J, Menetrier-Caux C, Schemann S, Négrier S, et al. Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal-cell carcinoma. Int J Cancer 1997;72:424-30.  Back to cited text no. 13
    
14.
Peeters D, Clercx C, Thiry A, Hamaide A, Snaps F, Henroteaux M, et al. Resolution of paraneoplastic leukocytosis and hypertrophic osteopathy after resection of a renal transitional cell carcinoma producing granulocyte-macrophage colony-stimulating factor in a young Bull Terrier. J Vet Int Med 2001;15:407-11.  Back to cited text no. 14
    
15.
Petterino C, Luzio E, Baracchini L, Ferrari A, Ratto A. Paraneoplastic leukocytosis in a dog with a renal carcinoma. Vet Clin Pathol 2011;40:89-94.  Back to cited text no. 15
    
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Aghaji AE, Odoemene CA. Renal cell carcinoma in Enugu, Nigeria. West Afr J Med 2000;19:254-8.  Back to cited text no. 16
    
17.
Tijani K, Anunobi C, Ezenwa E, Lawal A, Habeebu M, Jeje E, et al. Adult renal cell carcinoma in Lagos: Experience and challenges at the Lagos university teaching hospital. Afr J Urol 2012;18:20-3.  Back to cited text no. 17
    
18.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893-917.  Back to cited text no. 18
    
19.
Fall B, Diao B, Sow Y, Sarr A, Thiam A, Fall PA, et al. [Adult renal cancer in Senegal: Current epidemiological, clinical features, profile's evolution over the two past decades]. Prog Urol 2011;21:521-6.  Back to cited text no. 19
    
20.
Tanaka Y, Sasaki M, Kaneuchi M, Fujimoto S, Dahiya R. Estrogen receptor alpha polymorphisms and renal cell carcinoma—A possible risk. Mol Cell Endocrinol 2003;202:109-16.  Back to cited text no. 20
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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