Reporting Subclonal Immunohistochemical Staining of Mismatch Repair Proteins in Endometrial Carcinoma in the Times of Ever-Changing Guidelines

Context.— The current College of American Pathologists reporting guideline for mismatch repair protein (MMRP) immunohistochemistry for Lynch syndrome (LS) screening considers the presence of any positive nuclear staining as intact MMRP expression. This would include tumors with combined areas of subclonal retention and loss of MMRP staining. Objective.— To evaluate the clinical significance of reporting subclonal staining patterns of MMRP immunohistochemistry in endometrial carcinoma. Design.— We retrospectively reviewed 455 consecutive MMRP immunohistochemistry results of endometrial carcinoma in hysterectomy specimens from 2012 through 2017 and identified cases with subclonal MMRP staining. These results were correlated with the patient's personal and family history of LS-associated carcinoma, MLH1 promoter methylation status, and LS genetic testing. Results.— Subclonal staining of MMRP was seen in 48 of 455 cases (10.5%) on review. Thirty cases demonstrated isolated subclonal staining and were reported by pathologists as follows: subclonal (n = 5), complete MMRP loss (n = 4), and intact MMRP (n = 21). Eighteen cases had subclonal staining in combination with complete loss of other MMRP. Cases reported as subclonal or complete MMRP loss had appropriate clinical follow-up. Two of 2 cases with isolated subclonal MSH6 loss tested positive for LS. One of 3 cases with isolated subclonal MLH1/PMS2 loss was negative for MLH1 promoter methylation; LS genetic testing was not performed because of cost. Conclusions.— Our study reveals that LS germline mutation can be detected in endometrial carcinoma patients whose tumors display sole subclonal MMRP staining. Our results stress the importance of reporting subclonal staining patterns to ensure appropriate clinical follow-up.

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Clinicopathological significance of deficient DNA mismatch repair and MLH1 promoter methylation in endometrioid endometrial carcinoma

Modern Pathology ◽

10.1038/s41379-020-0501-8 ◽

2020 ◽

Vol 33 (7) ◽

pp. 1443-1452 ◽

Cited By ~ 4

Author(s):

Annukka Pasanen ◽

Mikko Loukovaara ◽

Ralf Bützow

Keyword(s):

Endometrial Carcinoma ◽

Mismatch Repair ◽

Promoter Methylation ◽

Dna Mismatch Repair ◽

Dna Mismatch ◽

Mlh1 Promoter ◽

Clinicopathological Significance ◽

Endometrioid Endometrial Carcinoma

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Natural history of mucinous ovarian cancer in Ireland.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e17056 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e17056-e17056

Author(s):

Darren Cowzer ◽

Emily O'Donovan ◽

Therese Brown ◽

Noreen Gleeson ◽

David James Gallagher

Keyword(s):

Ovarian Cancer ◽

Mismatch Repair ◽

Treatment Protocols ◽

Gastrointestinal Malignancy ◽

Patient Demographics ◽

History Of ◽

Mismatch Repair Proteins ◽

Cancer Treatment Protocols ◽

Carcinoma Of The Ovary

e17056 Background: Mucinous ovarian neoplasmscan arise as benign, borderline or malignant disease. Primary mucinous epithelial ovarian carcinoma (mEOC) represents 3% of invasive EOC. Differentiating primary from metastatic mucinous ovarian cancer is challenging. Systemic management of mucinous ovarian cancer increasingly follow GI cancer treatment protocols. We examined retrospective data at our institution to investigate incidence, management and site of origin of mEOC. Methods: 1,333 ovarian malignancies either diagnosed at or referred to St James Hospital, Dublin (from 2000 – 2016) were evaluated. The diagnosis was based on reported pathology. Patient demographics and investigations were retrospectively analyzed. Tumours were graded according to FIGO criteria. Results: Between 1/1/2000 and 9/12/2016 1,333 primary ovarian malignancies were diagnosed at our institution. 48 (3.6%) of these were mucinous adenocarcinoma and a further 5 (0.38%) were endometriod carcinoma of the ovary with mucinous differentiation. The average age at diagnosis was 48 (range 19-77 years). The majority of cases (87.5%) were stage I (IA 23, IB 2, IC 17, II 0, IIIA 1, IIIB 1, IIIC 3, IV 1) Staging CT thorax, abdomen and pelvis was completed in 44/48 cases and 24/48 (50%) patients underwent endoscopic evaluation of the uper or lower GI tract: 11 (22.9%) patients had both upper and lower GI endoscopy, 8 (16.7%) underwent OGD only and 5 (10.4%) had colonoscopy only. Gastrointestinal malignancy was not diagnosed in any of the patients. A total of 3 patients had immunohistochemistry for mismatch repair proteins performed, all of which demonstrated normal staining. All patients underwent surgical resection, 14 (29.2%) received adjuvant chemotherapy. 12 (25%) patients have died with a median OS of 11.5 months (range 7-108 months). Median follow up is 20.5 months (range 1-85 months) Conclusions: The incidence of mEOC in our population is 3.6%. The majority of patients diagnosed with mEOC over a 16 year period are still alive without evidence of disease, suggesting the diagnosis were ovarian in origin rather than metastatic. Immunohistochemistry for mismatch repair proteins is ongoing and will be presented at the meeting.

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Endometrial tumour BRAF mutations and MLH1 promoter methylation as predictors of germline mismatch repair gene mutation status: a literature review

Familial Cancer ◽

10.1007/s10689-013-9671-6 ◽

2013 ◽

Vol 13 (1) ◽

pp. 1-12 ◽

Cited By ~ 25

Author(s):

Alexander M. Metcalf ◽

Amanda B. Spurdle

Keyword(s):

Literature Review ◽

Mismatch Repair ◽

Gene Mutation ◽

Promoter Methylation ◽

Mismatch Repair Gene ◽

Braf Mutations ◽

Repair Gene ◽

Mutation Status ◽

Mlh1 Promoter

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MLH1 Promoter Methylation, Diet, and Lifestyle Factors in Mismatch Repair Deficient Colorectal Cancer Patients From EPIC-Norfolk

Nutrition and Cancer ◽

10.1080/01635581.2011.596987 ◽

2011 ◽

Vol 63 (7) ◽

pp. 1000-1010 ◽

Cited By ~ 22

Author(s):

Laura J. Gay ◽

Mark J. Arends ◽

Panagiota N. Mitrou ◽

Richard Bowman ◽

Ashraf E. Ibrahim ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Mismatch Repair ◽

Promoter Methylation ◽

Lifestyle Factors ◽

Mlh1 Promoter ◽

Colorectal Cancer Patients ◽

Diet And Lifestyle

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MSI in endometrial carcinoma: Absence of MLH1 promoter methylation is associated with increased familial risk for cancers

International Journal of Cancer ◽

10.1002/ijc.10429 ◽

2002 ◽

Vol 99 (5) ◽

pp. 697-704 ◽

Cited By ~ 28

Author(s):

Alison J. Whelan ◽

Sheri Babb ◽

David G. Mutch ◽

Janet Rader ◽

Thomas J. Herzog ◽

...

Keyword(s):

Endometrial Carcinoma ◽

Promoter Methylation ◽

Familial Risk ◽

Mlh1 Promoter

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Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications

Blood ◽

10.1182/blood.v95.6.1942 ◽

2000 ◽

Vol 95 (6) ◽

pp. 1942-1949 ◽

Cited By ~ 137

Author(s):

Ivy H. N. Wong ◽

Margaret H. L. Ng ◽

Dolly P. Huang ◽

Joseph C. K. Lee

Keyword(s):

Promoter Methylation ◽

Chromosomal Abnormalities ◽

Lymphoblastic Leukemia ◽

Methylation Status ◽

Disease Stage ◽

Acute Leukemias ◽

Prognostic Implications ◽

Methylation Patterns ◽

First Time

Abstract We prospectively analyzed p15 and p16 promoter methylation patterns using methylation-specific polymerase chain reaction (PCR) in patients with adult and childhood acute leukemias and studied the association of methylation patterns with chromosomal abnormalities and prognostic variables. In nearly all French-American-British leukemia subtypes, we found p15methylation in bone marrow or peripheral blood cells from 58% (46/79) of patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or acute biphenotypic leukemia (ABL). An identical alteration was detected in blood plasma from 11 of 12 of these patients (92%). We also demonstrated for the first time concomitant p16and p15 methylation in 22% (8/37) of adults with AML or ALL, exclusively in those with M2, M4, or L2 subtypes. According to cytogenetic data from 35 patients with ALL, AML, or ABL, 82% (14/17) of those with unmethylated p15 alleles had normal karyotypes or hyperdiploidies associated with a favorable prognosis. Conversely, 44% (8/18) of patients with p15 methylation had chromosomal translocations, inversions, or deletions, suggesting an interplay of these abnormalities with p15 methylation. As a prognostic marker for disease monitoring, p15 methylation appears to be more widely applicable than BCR-ABL, AF4-MLL, andAML1-ETO transcripts, which were detectable in only 8% (4/48) of patients by reverse transcriptase-PCR. Thirty-nine of 43 blood samples (91%) sequentially collected from 12 patients with AML, ALL, or ABL showed p15 methylation status in excellent concordance with morphologic disease stage. Early detection of p15methylation at apparent remission or its acquisition during follow-up may prove valuable for predicting relapse. Overall survival of patients with p15 methylation was notably shortened among 38 adults with AML and 12 adults with ALL. Aberrant p15 methylation may have important prognostic implications for clinical monitoring and risk assessment.

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Expression and promoter methylation status of mismatch repair gene hMLH1 and hMSH2 in epithelial ovarian cancer

Australian and New Zealand Journal of Obstetrics and Gynaecology ◽

10.1111/j.1479-828x.2008.00892.x ◽

2008 ◽

Vol 48 (5) ◽

pp. 505-509 ◽

Cited By ~ 20

Author(s):

Hui ZHANG ◽

Shiqian ZHANG ◽

Jing CUI ◽

Aifeng ZHANG ◽

Liang SHEN ◽

...

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Mismatch Repair ◽

Promoter Methylation ◽

Methylation Status ◽

Mismatch Repair Gene ◽

Repair Gene ◽

Promoter Methylation Status

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Colorectal tumour BRAF V600E and MLH1 promoter methylation status in the assessment of mismatch repair gene sequence variants of unknown clinical significance

Hereditary Cancer in Clinical Practice ◽

10.1186/1897-4287-10-s2-a75 ◽

2012 ◽

Vol 10 (S2) ◽

Author(s):

M Parsons ◽

◽

B Thompson ◽

D Goldgar ◽

J Hopper ◽

...

Keyword(s):

Mismatch Repair ◽

Clinical Significance ◽

Promoter Methylation ◽

Gene Sequence ◽

Methylation Status ◽

Braf V600e ◽

Mismatch Repair Gene ◽

Sequence Variants ◽

Repair Gene ◽

Colorectal Tumour

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Rare intraparenchymal choroid plexus carcinoma resembling atypical teratoid/rhabdoid tumor diagnosed by immunostaining for INI1 protein

Journal of Neurosurgery Pediatrics ◽

10.3171/2009.5.peds0955 ◽

2009 ◽

Vol 4 (4) ◽

pp. 368-371 ◽

Cited By ~ 6

Author(s):

E. Andrew Stevens ◽

Constance A. Stanton ◽

Kyle Nichols ◽

Thomas L. Ellis

Keyword(s):

Choroid Plexus ◽

Rhabdoid Tumor ◽

Choroid Plexus Carcinoma ◽

Nuclear Staining ◽

Atypical Teratoid Rhabdoid Tumor ◽

Imaging Studies ◽

Atypical Teratoid ◽

History Of ◽

The Right

The authors present the case of a rare extraventricular, intraparenchymal choroid plexus carcinoma (CPC). This 6-year-old girl presented to the emergency department with a 1-week history of headaches, nausea, and vomiting. Imaging studies revealed an intraaxial cystic and solid mass located in the right frontal lobe with central nodular enhancement and minimally enhancing cyst walls. Gross-total resection was accomplished via craniotomy without complications. The initial pathological diagnosis was atypical teratoid/rhabdoid tumor (AT/RT); however, immunostaining for INI1 protein (using the BAF47/SNF5 antibody) showed retention of nuclear staining in the tumor cells, resulting in a change in the diagnosis to CPC. There was no evidence of recurrence at the last follow-up 2.5 years after treatment, which supports the diagnosis of CPC over AT/RT. This case emphasizes the importance of immunostaining for INI1 protein for distinguishing CPC from AT/RT in cases with atypical or indeterminate features.

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