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Expression of mismatch repair proteins in urothelial carcinoma of the urinary bladder
Rasheeda Mohamedali1, Amit K Adhya1, Swarnendu Mandal2, Suvradeep Mitra1
1 Department of Pathology and Lab Medicine, AIIMS, Bhubaneswar, Odisha, India
2 Department of Urology, AIIMS, Bhubaneswar, Odisha, India
|Date of Submission||24-Feb-2021|
|Date of Decision||30-Jun-2021|
|Date of Acceptance||11-Jul-2021|
|Date of Web Publication||29-Jun-2022|
Department of Pathology and Lab Medicine, AIIMS, Bhubaneswar, Odisha
Source of Support: None, Conflict of Interest: None
Background: Urothelial carcinoma of the urinary bladder (UCUB) is a frequently diagnosed malignancy. Mismatch repair (MMR), a proofreading machinery of the DNA, prevents tumorigenesis. The role of MMR deficiency in UCUB in eastern Indian population is not known.
Methods: Immunohistochemistry panel for MLH1, PMS2, MSH2, and MSH6 (MMR proteins) was performed on the biopsy specimens of UCUB (N=100).
Results: MMR deficiency by immunohistochemistry was demonstrated in two cases (2%). One case showed deficiency of MSH2 and MSH6 and the other case showed the deficiency of all four mismatch proteins. Both cases showed high-grade invasive urothelial carcinoma by histomorphology.
Conclusion: The prevalence of MMR deficiency by immunohistochemistry is 2% in eastern Indian population.
Keywords: Urothelial carcinoma; Urinary bladder; Mismatch repair; Immunohistochemistry
The carcinoma of the urinary bladder is the 10th most frequently diagnosed malignancy worldwide and accounts for approximately 7% of cancer in men and 3% in women. Mismatch repair (MMR) proteins aid in the proofreading of the newly replicated DNA. MMR deficiency predisposes and promotes errors in the DNA (deoxyribonucleic acid) strands denoted by microsatellite instability (MSI). The role of MMR deficiency in the tumorigenesis of lower urinary tract malignancies is only recently highlighted with a relatively high (0%–43%) prevalence in a few Western studies, although the Indian data are scarce.,, We aimed at detecting the prevalence of MMR deficiency in urothelial carcinoma of the urinary bladder (UCUB) in our population by immunohistochemical analysis along with elucidation of their clinico-histomorphological features.
We employed an immunohistochemistry panel of four MMR proteins (MLH1, PMS2, MSH2, and MSH6) on 100 consecutive cases of UCUB (62% high grade; 38% low grade; pTa 43%; pT1 38%; pT2 16%; pT3 1%; pT4 2%) diagnosed in our institute (obtained by transurethral resection of bladder tumor [TURBT] 87% or cystectomy 13%). Complete absence of the nuclear expression of any MMR proteins (repeated twice) with positive internal controls (lymphocytes, endothelial cells, and stromal cells) was considered negative (absence of MMR proteins; MMR deficiency).
The mean age of the patients with urothelial carcinoma was 59.8 years (range: 20–90 years, standard deviation: 13.3). Only 17% of the subjects (n=17) were young adults (age <50 years). There was a preponderance of men (men:women = 5.7:1) (85 men and 15 women). The majority of the men were farmers (52.1%)(n=44), and the women were homemakers (20%)(n=3). More than half of the patients (52%)(n=52) were either addicted to cigarette smoking (26%)(n=26), pan chewing (22%)(n=22), or bidi smoking (14%)(n=14).
Hematuria (87%)(n=87), dysuria (20%)(n=20), abdominal pain (6%)(n=6), and palpable mass (4%)(n=4) were the common presentations. Besides, four cases (4%) were detected incidentally. About 3% of the cases (n=3) had a prior history of other malignancies, two with ureteric carcinoma, and one with renal cell carcinoma. On radiography, the most common location of these tumors was right and left lateral walls (73%)(n=73), followed by posterior walls (36%)(n=36).
MMR deficiency by immunohistochemistry was demonstrated in two cases (2%). Both these cases showed high-grade invasive urothelial carcinoma (pT1) in TURBT specimens with the limitation of detrusor muscle sampling. Both the biopsies showed the presence of necrosis (25% and 5%) and tumor-infiltrating lymphocytes (Case 1 > Case 2), respectively. The first case (a 60-year-old lady) presented with two episodes of hematuria in a month and showed a deficiency of MSH2 and MSH6 [Figure 1]. The lady remained asymptomatic after 6 months of follow-up. The second case (a 66-year-old gentleman) showed a deficiency of all four MMR proteins [Figure 2]. He presented with intermittent hematuria for the past 6 years, increased frequency and urgency for 1 year, and dysuria with suprapubic pain for the past 1 month. The patient was a chronic tobacco chewer for the previous 30 years. He had an endoluminal mass measuring 8 cm that extended till the lateral pelvic wall. He was put on neoadjuvant chemotherapy (gemcitabine). On a follow-up period of 12 months, the patient was found to be symptomatic on and off. None of these cases showed the occurrence of any synchronous or metachronous malignancy. No special or variant histological pattern was noted in either of these cases.
|Figure 1: Immunohistochemistry panel of Case 1 showing deficiency of MSH2 and MSH6 proteins while MLH1 and PMS2 expressions were retained. (Note the lymphocytes, stromal, and endothelial cells as positive internal controls especially in the MMR-deficient immunostains)|
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|Figure 2: Immunohistochemistry panel of Case 2 showing deficiency of all four mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6)|
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The index study showed a 2% frequency of MMR deficiency in the UCUB by immunohistochemistry. This result is in concordance with a few other previous studies., The variability in the results between the various studies could be attributed primarily to the difference in the selection criteria, sample size, sampling bias, and ethnicity. The application of different diagnostic modalities (immunohistochemistry or polymerase chain reaction [PCR]-based techniques) is another reason for the variability of the frequency with the PCR-based techniques estimating a higher frequency as high as 72%., We have not employed a parallel PCR-based technique to highlight and characterize the mutants/methylation status of the MLH1 and MSH2 genes due to the limitation of resources. This is the major limitation of the index study.
The index study estimated the prevalence of MMR deficiency in our population (2%) highlighting the role of MMR deficiency in the pathogenesis of a small subset of UCUB. Hematuria, high-grade invasive morphology, presence of necrosis, and presence of tumor-infiltrating lymphocytes are the common accompanying features.
This study has been approved by the Institutional Ethics Committee (IEC/PG Thesis/AIIMS BBSR/2018-19/11).
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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