Constitutional Mismatch Repair Gene Defect Syndrome Presenting With Adenomatous Polyposis and Cafe au Lait Spots: A Case Report

Abstract Adrenocortical carcinoma (ACC) is a rare cancer with a very poor prognosis with median survival of around 17 months. We present a patient with metastatic ACC in whom the response to PD1 inhibitor pembrolizumab has been promising. Case report: A Caucasian female patient presented at the age of 19 y with weight gain, hypertension, moon facies, supraclavicular fullness and increased hair growth on her upper back. Serum potassium concentration was 2.6 mmol/l, cortisol was 46 mcg/dL (nl = 3-12mcg/dL), and plasma ACTH concentration was < 5 pg/ml (nl = 6-58pg/ml). CT abdomen revealed a 5.4 cm right adrenal mass. For ACTH-independent Cushing’s Syndrome, she underwent right adrenalectomy within 1 week of presentation. Pathology revealed a 6.5 cm ACC with negative margins, with sinusoidal invasion, but no vascular or capsular invasion. Mitosis rate was 15-20/HPF with atypical mitotic figures. Immunohistochemistry showed no loss of expression of mismatch repair gene products associated with microsatellite instability. She was unable to tolerate mitotane. Genetic analysis was negative for TP53 mutation, and she underwent radiation to the adrenal bed within 6 months following adrenalectomy. She remained without biochemical or structural evidence of disease recurrence until 2.5 years following adrenalectomy, when AM cortisol was 6 mcg/dL (nl < 1.8) after 1 mg and after 2 mg of dexamethasone the previous evening. CT scan of the pelvis, abdomen, and chest revealed 5 solid masses scattered within the lungs. The largest of these being 2.3 cm and 2 cm, and the other 3 being approximately 1 cm. Fine needle aspiration biopsy of the lung lesion revealed ACC metastases. Immunotherapy with pembrolizumab 200 mg every 3 weeks was initiated and continued for 2 years, with a side effect being grade 1 diarrhea. At 1 year after initiating pembrolizumab, she developed primary adrenal insufficiency that is being treated with 0.1 mg/d of fludrocortisone and low dose glucocorticoid replacement (hydrocortisone: 10mg in the morning and 5 mg in the evening), to avoid immune suppression. Pulmonary nodules decreased in size to 6 mm over the 2 years of pembrolizumab therapy and remained stable in size 1 year following completion of pembrolizumab therapy at which time the early morning serum cortisol concentration remained undetectable with a plasma ACTH concentration of 1177 pg/ml (nl = 6-50 pg/ml). In summary, this patient with ACC with normal mismatch repair gene expression demonstrated both structural and biochemical responses to 2 years of pembrolizumab therapy. The major side effect has been primary adrenal insufficiency. The biochemical and structural responses have been durable for 1 year after completion of pembrolizumab therapy. Conclusion: This patient with microsatellite stable ACC has had a 36-month response to pembrolizumab.

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Effect of nifedipine in metastatic colon cancer with DNA mismatch repair gene defect

The Lancet ◽

10.1016/s0140-6736(00)04892-3 ◽

2001 ◽

Vol 357 (9270) ◽

pp. 1767-1768 ◽

Cited By ~ 14

Author(s):

Jia-Lin Yang ◽

Michael L Friedlander

Keyword(s):

Colon Cancer ◽

Mismatch Repair ◽

Dna Mismatch Repair ◽

Mismatch Repair Gene ◽

Metastatic Colon Cancer ◽

Gene Defect ◽

Repair Gene ◽

Dna Mismatch ◽

Dna Mismatch Repair Gene

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Prevalence and prognostic role of mismatch repair gene defect in endometrial cancer patients

Tumor Biology ◽

10.1177/1010428317725834 ◽

2017 ◽

Vol 39 (9) ◽

pp. 101042831772583 ◽

Cited By ~ 6

Author(s):

Siriwan Tangjitgamol ◽

Thannaporn Kittisiam ◽

Sujitra Tanvanich

Keyword(s):

Endometrial Cancer ◽

Confidence Interval ◽

Mismatch Repair ◽

Early Stage ◽

Progression Free Survival ◽

Mismatch Repair Gene ◽

Gene Defect ◽

Cancer Specific Survival ◽

Repair Gene ◽

Free Survival

The study was to evaluate the prevalence of mismatch repair gene defect among Thai patients with endometrial cancer and its association with clinico-pathological features and survivals. The formalin fixed paraffin-embedded blocks of EMC tissue from hysterectomy specimens of patients having surgery in our institution between 1 Jan 1995 and 31 December 2016 were assessed for the immunohistochemical expression of 4 mismatch repair proteins (MLH1, PMS, MSH2, MSH 6). Mismatch repair gene defect was determined by a negative expression of at least 1 protein. Among 385 EMC patients included in the study, mean age was 57.3 ± 10.8 years with 62.3% aged ⩽ 60 years. The most frequent mismatch repair gene defect was MSH6 (38.7%), followed by PMS2 (34.3%), MLH1 (33.2%), and MSH2 (16.4%). Overall, 55.1% showed negative expression of at least one protein. We found significantly higher mismatch repair gene defect in patients aged ⩽ 60 years, with early stage disease, and negative lymph node status than the other comparative groups: 59.2% vs 48.3% for age (p = 0.037), 58.2% vs 45.2% (p = 0.027) for stage, and 58.1% vs 44.6% (p = 0.048) for nodal status. The 5-year progression-free survival, overall survival, and endometrial cancer-specific survival of patients with mismatch repair gene defect was higher than those without gene defect. The differences were statistically significant for only progression-free survival and endometrial cancer-specific survival: 87.7% (95% confidence interval = 83.0%–92.4%) vs 81.5% (95% confidence interval = 75.4%–87.6%) (p = 0.049) for progression-free survival and 91.0% (95% confidence interval = 86.9%–95.1%) vs 85.5% (95% confidence interval = 80.0%–91.0%) (p = 0.044) for endometrial cancer-specific survival, respectively. In conclusion, more than half of Thai endometrial cancer patients had mismatch repair gene defect. The patients with mismatch repair gene defect had significantly younger age (⩽ 60 years) and better prognosis in terms of early stage, negative nodal status, and longer survivals.

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