BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: An aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features

Reetesh K. Pai, Priya Jayachandran, Albert C. Koong, Daniel T. Chang, Shirley Kwok, Lisa Ma, Daniel A. Arber, Raymond Balise, Raymond R. Tubbs, Bonnie Shadrach, Rish K. Pai

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

The association of BRAF V600E mutation and the presence of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) often confound analysis of BRAF mutation status and survival in colorectal carcinoma. We evaluated a consecutive series of proximal colonic adenocarcinomas for mismatch repair protein abnormalities/MSI, BRAF V600E mutation, and KRAS mutations in an attempt to determine the prognostic significance of these abnormalities and to correlate histopathologic features with molecular alterations. Of the 259 proximal colon adenocarcinomas analyzed for mismatch repair protein abnormalities and/or MSI, 181 proximal colonic adenocarcinomas demonstrated proficient DNA mismatch repair using either MSI PCR (n=78), mismatch repair protein immunohistochemistry (n=91), or both MSI PCR and mismatch repair immunohistochemistry (n=12); these were tested for the BRAF V600E mutation and KRAS mutations. Compared with BRAF wild-type adenocarcinomas, BRAF-mutated adenocarcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (16/20, 80% vs. 75/161, 47%; P=0.008), mean number of lymph node metastases (4.5 vs. 2.2; P=0.01), perineural invasion (8/20, 40% vs. 13/161, 8%; P=0.0004), and high tumor budding (16/20, 80% vs. 83/161, 52%; P=0.02). BRAF-mutated adenocarcinomas frequently contained areas with mucinous histology (P=0.0002) and signet ring histology (P=0.03), compared with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Clinical follow-up data were available for 173 proximal colonic adenocarcinomas with proficient DNA mismatch repair. Patients with BRAF-mutated adenocarcinomas had a median survival of 12.3 months with a 1-year probability of survival of 54% and a 1-year disease-free survival of 56%. Patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas had significantly improved overall survival (unadjusted log-rank P=0.03 and unadjusted log-rank P=0.0002, respectively) and disease-free survival (unadjusted log-rank P=0.02 and unadjusted log-rank P=0.02, respectively) compared with patients with BRAF-mutated adenocarcinomas. When adjusting for tumor stage, survival analysis demonstrated that patients with BRAF-mutated adenocarcinoma had a significantly poor overall survival and disease-free survival (hazard ratios 6.63, 95% CI, 2.60-16.94; and 6.08, 95% CI, 2.11-17.56, respectively) compared with patients with KRAS/BRAF wild-type adenocarcinomas. No significant difference in overall or disease-free survival was identified between patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Our results demonstrate that BRAF-mutated proximal colon adenocarcinomas with proficient DNA mismatch repair have a dismal prognosis with an aggressive clinical course and often display mucinous differentiation, focal signet ring histology, and other adverse histologic features such as lymphatic and perineural invasion and high tumor budding.

Original languageEnglish (US)
Pages (from-to)744-752
Number of pages9
JournalAmerican Journal of Surgical Pathology
Volume36
Issue number5
DOIs
StatePublished - May 2012
Externally publishedYes

Fingerprint

Microsatellite Repeats
Colon
Adenocarcinoma
DNA Mismatch Repair
Microsatellite Instability
Mutation
Disease-Free Survival
Survival
Histology
Immunohistochemistry
Neoplasms
Polymerase Chain Reaction
CpG Islands
Proteins
Survival Analysis
Colorectal Neoplasms
Lymph Nodes

Keywords

  • adenocarcinoma
  • BRAF
  • colon
  • KRAS
  • mismatch repair
  • MSI
  • proximal

ASJC Scopus subject areas

  • Anatomy
  • Pathology and Forensic Medicine
  • Surgery

Cite this

BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon : An aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. / Pai, Reetesh K.; Jayachandran, Priya; Koong, Albert C.; Chang, Daniel T.; Kwok, Shirley; Ma, Lisa; Arber, Daniel A.; Balise, Raymond; Tubbs, Raymond R.; Shadrach, Bonnie; Pai, Rish K.

In: American Journal of Surgical Pathology, Vol. 36, No. 5, 05.2012, p. 744-752.

Research output: Contribution to journalArticle

Pai, Reetesh K. ; Jayachandran, Priya ; Koong, Albert C. ; Chang, Daniel T. ; Kwok, Shirley ; Ma, Lisa ; Arber, Daniel A. ; Balise, Raymond ; Tubbs, Raymond R. ; Shadrach, Bonnie ; Pai, Rish K. / BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon : An aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features. In: American Journal of Surgical Pathology. 2012 ; Vol. 36, No. 5. pp. 744-752.
@article{b698d85b2def4dd480e17c46d6dc229f,
title = "BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon: An aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features",
abstract = "The association of BRAF V600E mutation and the presence of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) often confound analysis of BRAF mutation status and survival in colorectal carcinoma. We evaluated a consecutive series of proximal colonic adenocarcinomas for mismatch repair protein abnormalities/MSI, BRAF V600E mutation, and KRAS mutations in an attempt to determine the prognostic significance of these abnormalities and to correlate histopathologic features with molecular alterations. Of the 259 proximal colon adenocarcinomas analyzed for mismatch repair protein abnormalities and/or MSI, 181 proximal colonic adenocarcinomas demonstrated proficient DNA mismatch repair using either MSI PCR (n=78), mismatch repair protein immunohistochemistry (n=91), or both MSI PCR and mismatch repair immunohistochemistry (n=12); these were tested for the BRAF V600E mutation and KRAS mutations. Compared with BRAF wild-type adenocarcinomas, BRAF-mutated adenocarcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (16/20, 80{\%} vs. 75/161, 47{\%}; P=0.008), mean number of lymph node metastases (4.5 vs. 2.2; P=0.01), perineural invasion (8/20, 40{\%} vs. 13/161, 8{\%}; P=0.0004), and high tumor budding (16/20, 80{\%} vs. 83/161, 52{\%}; P=0.02). BRAF-mutated adenocarcinomas frequently contained areas with mucinous histology (P=0.0002) and signet ring histology (P=0.03), compared with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Clinical follow-up data were available for 173 proximal colonic adenocarcinomas with proficient DNA mismatch repair. Patients with BRAF-mutated adenocarcinomas had a median survival of 12.3 months with a 1-year probability of survival of 54{\%} and a 1-year disease-free survival of 56{\%}. Patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas had significantly improved overall survival (unadjusted log-rank P=0.03 and unadjusted log-rank P=0.0002, respectively) and disease-free survival (unadjusted log-rank P=0.02 and unadjusted log-rank P=0.02, respectively) compared with patients with BRAF-mutated adenocarcinomas. When adjusting for tumor stage, survival analysis demonstrated that patients with BRAF-mutated adenocarcinoma had a significantly poor overall survival and disease-free survival (hazard ratios 6.63, 95{\%} CI, 2.60-16.94; and 6.08, 95{\%} CI, 2.11-17.56, respectively) compared with patients with KRAS/BRAF wild-type adenocarcinomas. No significant difference in overall or disease-free survival was identified between patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Our results demonstrate that BRAF-mutated proximal colon adenocarcinomas with proficient DNA mismatch repair have a dismal prognosis with an aggressive clinical course and often display mucinous differentiation, focal signet ring histology, and other adverse histologic features such as lymphatic and perineural invasion and high tumor budding.",
keywords = "adenocarcinoma, BRAF, colon, KRAS, mismatch repair, MSI, proximal",
author = "Pai, {Reetesh K.} and Priya Jayachandran and Koong, {Albert C.} and Chang, {Daniel T.} and Shirley Kwok and Lisa Ma and Arber, {Daniel A.} and Raymond Balise and Tubbs, {Raymond R.} and Bonnie Shadrach and Pai, {Rish K.}",
year = "2012",
month = "5",
doi = "10.1097/PAS.0b013e31824430d7",
language = "English (US)",
volume = "36",
pages = "744--752",
journal = "American Journal of Surgical Pathology",
issn = "0147-5185",
publisher = "Lippincott Williams and Wilkins",
number = "5",

}

TY - JOUR

T1 - BRAF-mutated, microsatellite-stable adenocarcinoma of the proximal colon

T2 - An aggressive adenocarcinoma with poor survival, mucinous differentiation, and adverse morphologic features

AU - Pai, Reetesh K.

AU - Jayachandran, Priya

AU - Koong, Albert C.

AU - Chang, Daniel T.

AU - Kwok, Shirley

AU - Ma, Lisa

AU - Arber, Daniel A.

AU - Balise, Raymond

AU - Tubbs, Raymond R.

AU - Shadrach, Bonnie

AU - Pai, Rish K.

PY - 2012/5

Y1 - 2012/5

N2 - The association of BRAF V600E mutation and the presence of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) often confound analysis of BRAF mutation status and survival in colorectal carcinoma. We evaluated a consecutive series of proximal colonic adenocarcinomas for mismatch repair protein abnormalities/MSI, BRAF V600E mutation, and KRAS mutations in an attempt to determine the prognostic significance of these abnormalities and to correlate histopathologic features with molecular alterations. Of the 259 proximal colon adenocarcinomas analyzed for mismatch repair protein abnormalities and/or MSI, 181 proximal colonic adenocarcinomas demonstrated proficient DNA mismatch repair using either MSI PCR (n=78), mismatch repair protein immunohistochemistry (n=91), or both MSI PCR and mismatch repair immunohistochemistry (n=12); these were tested for the BRAF V600E mutation and KRAS mutations. Compared with BRAF wild-type adenocarcinomas, BRAF-mutated adenocarcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (16/20, 80% vs. 75/161, 47%; P=0.008), mean number of lymph node metastases (4.5 vs. 2.2; P=0.01), perineural invasion (8/20, 40% vs. 13/161, 8%; P=0.0004), and high tumor budding (16/20, 80% vs. 83/161, 52%; P=0.02). BRAF-mutated adenocarcinomas frequently contained areas with mucinous histology (P=0.0002) and signet ring histology (P=0.03), compared with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Clinical follow-up data were available for 173 proximal colonic adenocarcinomas with proficient DNA mismatch repair. Patients with BRAF-mutated adenocarcinomas had a median survival of 12.3 months with a 1-year probability of survival of 54% and a 1-year disease-free survival of 56%. Patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas had significantly improved overall survival (unadjusted log-rank P=0.03 and unadjusted log-rank P=0.0002, respectively) and disease-free survival (unadjusted log-rank P=0.02 and unadjusted log-rank P=0.02, respectively) compared with patients with BRAF-mutated adenocarcinomas. When adjusting for tumor stage, survival analysis demonstrated that patients with BRAF-mutated adenocarcinoma had a significantly poor overall survival and disease-free survival (hazard ratios 6.63, 95% CI, 2.60-16.94; and 6.08, 95% CI, 2.11-17.56, respectively) compared with patients with KRAS/BRAF wild-type adenocarcinomas. No significant difference in overall or disease-free survival was identified between patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Our results demonstrate that BRAF-mutated proximal colon adenocarcinomas with proficient DNA mismatch repair have a dismal prognosis with an aggressive clinical course and often display mucinous differentiation, focal signet ring histology, and other adverse histologic features such as lymphatic and perineural invasion and high tumor budding.

AB - The association of BRAF V600E mutation and the presence of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) often confound analysis of BRAF mutation status and survival in colorectal carcinoma. We evaluated a consecutive series of proximal colonic adenocarcinomas for mismatch repair protein abnormalities/MSI, BRAF V600E mutation, and KRAS mutations in an attempt to determine the prognostic significance of these abnormalities and to correlate histopathologic features with molecular alterations. Of the 259 proximal colon adenocarcinomas analyzed for mismatch repair protein abnormalities and/or MSI, 181 proximal colonic adenocarcinomas demonstrated proficient DNA mismatch repair using either MSI PCR (n=78), mismatch repair protein immunohistochemistry (n=91), or both MSI PCR and mismatch repair immunohistochemistry (n=12); these were tested for the BRAF V600E mutation and KRAS mutations. Compared with BRAF wild-type adenocarcinomas, BRAF-mutated adenocarcinomas more frequently demonstrated adverse histologic features such as lymphatic invasion (16/20, 80% vs. 75/161, 47%; P=0.008), mean number of lymph node metastases (4.5 vs. 2.2; P=0.01), perineural invasion (8/20, 40% vs. 13/161, 8%; P=0.0004), and high tumor budding (16/20, 80% vs. 83/161, 52%; P=0.02). BRAF-mutated adenocarcinomas frequently contained areas with mucinous histology (P=0.0002) and signet ring histology (P=0.03), compared with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Clinical follow-up data were available for 173 proximal colonic adenocarcinomas with proficient DNA mismatch repair. Patients with BRAF-mutated adenocarcinomas had a median survival of 12.3 months with a 1-year probability of survival of 54% and a 1-year disease-free survival of 56%. Patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas had significantly improved overall survival (unadjusted log-rank P=0.03 and unadjusted log-rank P=0.0002, respectively) and disease-free survival (unadjusted log-rank P=0.02 and unadjusted log-rank P=0.02, respectively) compared with patients with BRAF-mutated adenocarcinomas. When adjusting for tumor stage, survival analysis demonstrated that patients with BRAF-mutated adenocarcinoma had a significantly poor overall survival and disease-free survival (hazard ratios 6.63, 95% CI, 2.60-16.94; and 6.08, 95% CI, 2.11-17.56, respectively) compared with patients with KRAS/BRAF wild-type adenocarcinomas. No significant difference in overall or disease-free survival was identified between patients with KRAS-mutated and KRAS/BRAF wild-type adenocarcinomas. Our results demonstrate that BRAF-mutated proximal colon adenocarcinomas with proficient DNA mismatch repair have a dismal prognosis with an aggressive clinical course and often display mucinous differentiation, focal signet ring histology, and other adverse histologic features such as lymphatic and perineural invasion and high tumor budding.

KW - adenocarcinoma

KW - BRAF

KW - colon

KW - KRAS

KW - mismatch repair

KW - MSI

KW - proximal

UR - http://www.scopus.com/inward/record.url?scp=84859885193&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84859885193&partnerID=8YFLogxK

U2 - 10.1097/PAS.0b013e31824430d7

DO - 10.1097/PAS.0b013e31824430d7

M3 - Article

C2 - 22314188

AN - SCOPUS:84859885193

VL - 36

SP - 744

EP - 752

JO - American Journal of Surgical Pathology

JF - American Journal of Surgical Pathology

SN - 0147-5185

IS - 5

ER -