Keywords
Clear cell - hematuria - renal cell cancer
Introduction
Renal cell cancer (RCC) is an uncommon malignancy. It constitutes <3% of all cancers.[1] Nonetheless, incidence is currently increasing at a rate of 2% per year in many
developed countries.[2],[3] Its frequency is also expected to rise in India due to increasing life expectancy,
rising awareness, better diagnostic facilities, and growing prevalence of risk factors
such as obesity.[4] However, there is a paucity of data for RCC from the Indian subcontinent.[5],[6] Hence, to generate more information on Indian cohort of RCC, we retrospectively
analyzed data of 423 consecutive patients treated over 10 years.
Materials and Methods
We collected data of patients registered with histopathological diagnosis of RCC from
January 2004 to December 2013 from hospital case records. Clinical and laboratory
parameters were entered in the predesigned pro forma. Clinical parameters assessed
included age, sex, place of residence, family history, occupation, history of smoking,
comorbidities, presenting complaints and duration of illness, stage at the time of
diagnosis, duration of follow-up, and time of death. Histopathological parameters
included subtypes of RCC, Fuhrman grading, and tumor and lymph nodal staging. Follow-up
details were gathered from the date of last outpatient visit, telephonic inquiry,
or with the help of a reply postcard. The primary end point was overall survival (OS),
calculated from the time of diagnosis to death due to any cause.
Statistical analysis
Descriptive statistics were used to describe demographic and clinical characteristics.
Kaplan–Meier method was used to estimate OS. All analyses were performed using SPSS
version 20 statistical software (SPSS Inc., Chicago, Illinois, USA). Data were censored
on December 31, 2014, or on the date of last follow-up.
Results
Overall, 477 patients were registered with the diagnosis of RCC at our center between
January 2004 and December 2013. Fifty-four individuals were excluded due to lack of
sufficient information regarding baseline parameters. Out of the 423 patients included
in the analysis, data regarding OS were available for 331 (78.3%) patients. [Table 1] lists various baseline characteristics and associated comorbidities. Maximum patients
belonged to the age group of 51–60 years [Figure 1]. Twenty-four (4.7%) and 85 (20.1%) patients were <30 and 40 years of age, respectively.
Figure 1: Age distribution of patients
Table 1
Baseline characteristics and symptomatology of the patients
|
Parameter
|
n (%)
|
|
BPH – Benign prostatic hyperplasia; COPD – Chronic obstructive pulmonary disease
|
|
Age (years), median (range)
|
52 (18-87)
|
|
Sex
|
|
Male
|
330(78)
|
|
Female
|
93 (22)
|
|
History of smoking
|
181 (42.8)
|
|
Comorbidities
|
|
Hypertension
|
115 (27.2)
|
|
Diabetes mellitus
|
62 (14.9)
|
|
Coronary artery disease
|
23 (5.5)
|
|
BPH
|
28 (8.4)
|
|
Hypothyroidism
|
14 (3.4)
|
|
Bronchial asthma/COPD
|
11 (2.7)
|
|
Cerebrovascular disease
|
8(1.9)
|
|
Others
|
16 (3.8)
|
|
Clinical features
|
|
Hematuria
|
225 (53.2)
|
|
Flank pain
|
196 (46.3)
|
|
Weight loss
|
139 (32.9)
|
|
Lump abdomen
|
114 (22.5)
|
|
Fever
|
81 (19.5)
|
|
Loss of appetite
|
41 (9.9)
|
|
Bone pains
|
33 (8.0)
|
|
Cough
|
31 (7.7)
|
|
Shortness of breath
|
28 (7.9)
|
|
Varicocele
|
10 (2.4)
|
|
Triad of hematuria, lump, and flank pain
|
84 (20.2)
|
There were no patients with hereditary syndromes implicated in RCC. Most common comorbidities
detected were hypertension and type 2 diabetes mellitus [Table 1]. Three patients had chronic kidney disease and two patients each had hepatitis B
infection, hepatitis C infection, or renal transplantation.
Clinical presentation
Thirty-five (8.3%) patients had incidental detection of RCC, where abdominal imaging
for some other indication led to detection of tumors. The median duration of symptoms
was 3 months (range: 0–24 months). Three hundred and eleven (74.1%) patients had symptom
duration <6 months and 108 (25.9%) patients had> 6 months' duration. The classical
triad of hematuria, lump in abdomen, and flank pain was present in 84 (20.2%) patients
[Table 1].
Histopathology
The most common histology was clear cell subtype (71.4%) followed by papillary Type
I (9.9%) [Table 2]. Nine patients had pure sarcomatoid histology and one patient had rhabdoid subtype.
There were two cases of mucinous spindle cell tumors, one each of tubulocystic and
Xp11.2 translocation RCC. Fuhrman grading was available in 90.8% of patients with
clear cell or papillary cell histology. Grade 1, Grade 2, Grade 3, and Grade 4 were
identified in 30 (9%), 140 (41.8%), 110 (32.8%), and 55 (16.4%) patients, respectively.
Table 2
Histopathology, pathological tumor stage, and metastatic sites of involvement
|
n (%)
|
|
Histopathology
|
|
Clear cell
|
302 (71.4)
|
|
Papillary type 1
|
42 (9.9)
|
|
Papillary type 2
|
25 (5.9)
|
|
Chromophobe
|
4 (3.5)
|
|
Oncocytoma
|
6 (1.4)
|
|
Collecting duct
|
6 (1.4)
|
|
Sarcomatoid/rhabdoid
|
10 (2.4)
|
|
Unclassified
|
14 (3.3)
|
|
Others
|
4 (1)
|
|
Tumor stage
|
|
T1a
|
36 (12.5)
|
|
T1b
|
52 (18)
|
|
T2a
|
49 (17)
|
|
T2b
|
37 (12.8)
|
|
T3a
|
70 (24.2)
|
|
T3b
|
28 (9.7)
|
|
T3c
|
6 (2.1)
|
|
T4
|
12 (4.2)
|
|
Site of metastases
|
|
Lungs
|
77 (59.2)
|
|
Bones
|
68 (51.9)
|
|
Distant lymph nodes
|
41 (31.5)
|
|
Liver
|
33 (25.4)
|
|
Soft tissue
|
21 (16.2)
|
|
Adrenals
|
18 (13.9)
|
|
Brain
|
13(10)
|
|
Skin
|
7 (5.4)
|
|
Other sites
|
21 (16.2)
|
Stage at presentation
The number of patients in Stages 1, 2, 3, and 4 was 86 (20.3%), 84 (19.9%), 110 (26.7%),
and 142 (33%), respectively. Overall, 293 (69.3%) individuals presented with nonmetastatic
disease. [Table 2] shows tumor stage of patients undergoing curative nephrectomy (289). The most common
tumor stage was T3a followed by T1b and T2a. Stage 4 comprised patients with either
metastatic (130) or T4 disease (12).
Metastatic sites
Lungs followed by bones were the most common site of distant metastases [Table 2]. Nearly 48% of patients had distant metastases to two or more organ sites whereas
51.5% of patients had single organ site of involvement.
Survival analysis
The median duration of follow-up was 68.7 months (range: 0.5–279 months). Median OS
was 79.1 months (range: 0.5–279 months). One-year and 2-year OS were 77.8% and 68.5%,
respectively, whereas 5-year OS was 55.1%. [Figure 2] shows 5-year survival according to stage at the time of diagnosis.
Figure 2: Five-year overall survival according to various stages
Discussion
In this analysis, we evaluated the various clinical and histopathological parameters
and survival outcomes from a tertiary care center. Median age in our study was 52
years. This is almost a decade lower compared to the median age of 62–64 years reported
in studies from Europe and North America.[2] Other Indian studies have also shown similar age pattern.[7] Precise mechanisms for this age difference are unclear. The population pyramid in
India constitutes of higher proportion of younger population as compared to the West,
and this might be one of the reasons for younger age at presentation. Importantly,
24 patients (4.7%) were <30 years of age in our study. There was no feature to suggest
a hereditary causation in any of these patients. RCC in the young should be extensively
investigated for genetic causes.
Male-to-female ratio was 3.5:1. Many reports have revealed higher male representation
for RCC.[8] The strongest risk factor for RCC is smoking. In many countries, smoking is more
common in males than females and this might account for higher proportion of men for
RCC.[9] In India also, the frequency of smoking in men is much higher than that of women.[10] Besides, some studies have hypothesized hormonal influences including protective
effect of oral contraceptive pills for the lower incidence of RCC in women.[11],[12]
The most common comorbidities detected were hypertension and type 2 diabetes mellitus.
Hypertension is one of the established risk factors as well as a paraneoplastic manifestation
of RCC.[13],[14] In addition, it has a bearing on the treatment. Anti-angiogenesis therapy, currently
the standard of care in metastatic RCC, leads to worsening of hypertension in many
patients. This converts into more outpatient visits, higher pill burden by addition
of multiple antihypertensive drugs, and increased rate of treatment discontinuation.
Patients of diabetes and/or hypertension have propensity to develop chronic kidney
disease with radical nephrectomy and hence should undergo functional scans prior to
nephrectomy. Partial nephrectomy should be encouraged in such patients.
Two patients had RCC developing in native kidney after renal transplantation. Both
these patients were on strong immunosuppressive drugs. RCC of native end-stage kidneys
is found in about 4% of patients. End-stage renal disease as well as immunosuppression
are risk factors for RCC.[15],[16],[17] The lifetime risk of developing RCC in this group is at least 10 times larger than
in the general population.[16] In addition, these patients have aggressive disease and dismal outcomes.[17]
Approximately 8.3% of patients were detected in asymptomatic condition. This figure
is markedly lower than reports from North America and Europe.[2],[18] In India, thresholds to use abdominal imaging for any indication are higher due
to lack of affordability and limited availability. Hence, India is still to see the
stage migration of RCC, being seen in the West.[19] The most common manifestation was hematuria followed by flank pain and weight loss.
Interestingly, 20% of patients presented with the conventional triad of hematuria,
flank pain, and palpable lump in abdomen. Occurrence of this triad depicts advanced
disease. Previous descriptions report its frequency in not> 10% of patients.[20] It reflects greater percentage of patients presenting with advanced disease in our
study.
Clear cell carcinoma was the most common histological subtype followed by papillary
type I. These findings are similar to that described in literature.[21] Fuhrman Grade 2 tumors were most common followed by Grade 3. Importantly, there
were 16% of patients with Grade 4 tumors which is higher than reported in other retrospective
studies.[22] Pure sarcomatoid subtype was detected in nine patients. It denotes aggressive disease
and is associated with poor survival outcomes.[23] Two patients had mucinous, tubular, and spindle cell tumor. It is a recently described
entity, seen more commonly in females and considered to be a low-grade renal malignancy.[24] In our study, both patients with this subtype were females with early-stage tumor.
Stage 4 and 3 diseases were more common than Stage 1 and 2 diseases at the time of
diagnosis. Majority of studies are currently reporting Stage 1 disease in> 50% of
patients due to a greater number of asymptomatic detection.[19] This finding has implications on deciding the line of management and survival outcomes
as stage is the most important independent prognostic factor. Furthermore, in our
study, higher number of patients presented with thrombus formation. Other than determining
stage and prognosis, thrombus removal demands greater surgical expertise and more
invasive surgery.
Five-year survival in the study for Stage 1 was equivalent to those reported elsewhere,
however 5-year OS for Stages 2, 3, and 4 was lower.[2],[25],[26] Five-year OS was 55.1%. This figure is again low compared to many other analyses
that have revealed 5-year OS> 60%.[26],[27] Few causes can be deciphered for this. First, higher percentage of our patients
had Fuhrman Grade 3 and 4 diseases (49.2%) which is an established maker of aggressive
disease. Second, in Stage 3, higher number of patients had 3b and 3c Stage due to
inferior vena cava (IVC) involvement.[28] Any kind of IVC involvement adversely affects prognosis.[29] Third, in the metastatic setting, many patients were not able to afford targeted
therapies, lowering survival in Stage 4 disease.
Important limitations in the present study are: first, we did not have follow-up details
regarding OS in approximately 22% of patients. Often patients change their contact
numbers that do not get updated in the record system and hence could not be traced
after stopping outpatient visits. Second, there was missing data regarding body mass
index, therefore we could not document the prevalence of obesity in our patients which
is a proven risk factor for RCC. Similarly, occupation history was also missing from
many case records and consequently no consistent occupational exposure could be found.
Last but not the least, this analysis included patients from a single tertiary center,
causing potential biases in patient population.
Conclusion
Younger patient population, higher male: female ratio, fewer asymptomatic detection,
and higher stage at the time of diagnosis were characteristic features of RCC in this
study. Stage-wise survival was inferior in our patients. Though some causes can be
deciphered for low survival, we need to have prospective studies to characterize disease
biology and validate risk factors.
