Paraganglioma in pregnancy, a mimic of preeclampsia: a case report.

BACKGROUND: The new presentation of pheochromocytoma or paraganglioma in pregnancy is very rare and can be life-threatening for mother and child. CASE PRESENTATION: We present the case of a 26-year-old gravida 3 para 2 otherwise healthy Caucasian woman at 34 weeks gestation who presented with new onset hypertension associated with headaches, dry heaves, diaphoresis, and palpitations. She was initially diagnosed with preeclampsia and treated with labetalol and an urgent cesarean section, delivering a healthy baby girl. The diagnosis of preeclampsia came into question when, 6 weeks postpartum, she continued to have hypertension with atypical features. Testing revealed metastatic paraganglioma associated with a succinate dehydrogenase B gene mutation. The patient was then started on alpha-adrenergic blockade and has had close blood pressure monitoring while discussion of advances therapies is ongoing. CONCLUSION: This case demonstrates how paraganglioma/pheochromocytoma can be misdiagnosed as preeclampsia due to the overlapping features of new-onset hypertension late in pregnancy accompanied by headache and proteinuria. It is impractical to routinely screen for paraganglioma/pheochromocytoma in all pregnant patients diagnosed with preeclampsia due to the rarity of these tumors and the harm from high false-positive rates. Therefore, it is incumbent on the provider to have a high degree of suspicion for paraganglioma/pheochromocytoma when clinical features are unusual for preeclampsia, such as intermittent palpitations, diaphoresis, orthostatic hypotension, or hyperglycemia. Early detection of paraganglioma/pheochromocytoma with interventions to mitigate the risk of hypertensive crisis greatly reduce maternal and fetal mortality. Fortunately, our patient delivered a healthy baby and did not have any additional pregnancy complications despite the delay in her diagnosis.

Comprehensive Care of Women With Genetic Predisposition to Breast and Ovarian Cancer.

Women at risk for hereditary breast and ovarian cancer syndromes are frequently seen in primary care and gynecology clinics. They present with a distinctive set of clinical and emotional needs that revolve around complex risk management discussions and decision making. The care of these women calls for the creation of individualized care plans that facilitate adjustment to the mental and physical changes associated with their choices. This article provides an update on comprehensive evidence-driven care of women with hereditary breast and ovarian cancer. The aim of this review is to aid clinicians in identifying those at risk for hereditary cancer syndromes and provide practical advice on patient-centered medical and surgical risk management. Topics of discussion include enhanced surveillance, preventive medications, risk-reducing mastectomy and reconstruction, risk-reducing bilateral salpingo-oophorectomy, fertility, sexuality, and menopausal management, with attention to the importance of psychological support. High-risk patients may benefit from a multidisciplinary team that provides realistic expectations with consistent messaging. The primary care provider must be aware of the special needs of these patients and the consequences of their risk management interventions.

Reduced Risk of Corporal Tumors in Patients With Head and Neck Paragangliomas With p.Pro81Leu Mutations.

OBJECTIVE: Patients with head and neck paragangliomas who are positive for the SDHD p.Pro81Leu (P81L) mutation are thought to have a distinct phenotype from other SDHx mutations, but few studies have focused on this mutation. The objective of this study was to determine the hazard of developing a second primary, metastatic, or recurrent paraganglioma in SDHx patients with or without P81L. STUDY DESIGN: Retrospective chart review of 60 patients with head and neck paragangliomas and genetic testing, followed for a median of 9 years. SETTING: Single academic medical center. METHODS: Univariable Cox proportional hazards regression evaluated second primary and recurrent paragangliomas in patients with SDHD P81L, SDHx non-P81L, and nonhereditary paraganglioma. RESULTS: This series comprised 31 patients without SDHx, 14 with SDHD P81L, and 15 with other SDHx mutations. At a median 9 years of follow-up, corporal (not head and neck) second primary paragangliomas occurred in 31% of patients with SDHx non-P81L mutations, compared with 0% and 4% of patients with SDHD P81L and without SDHx mutations, respectively. Second corporal paragangliomas were more likely in patients with SDHx non-P81L mutations than in those without a mutation (hazard ratio = 5.461, 95% confidence interval: 0.596-50.030, p = .13). CONCLUSION: This is the first study to report a lower likelihood of corporal tumors for patients with head and neck paragangliomas with SDH mutations positive for P81L. Larger studies are needed to determine if head and neck paraganglioma patients with P81L qualify for less intensive imaging surveillance to screen for second primary paragangliomas outside the head and neck.

Using chatbots to screen for heritable cancer syndromes in patients undergoing routine colonoscopy.

BACKGROUND: Hereditary colorectal cancer (HCRC) syndromes account for 10% of colorectal cancers but remain underdiagnosed. This feasibility project tested the utility of an artificial intelligence-based chatbot deployed to patients scheduled for colonoscopy to identify HCRC risk factors, educate participants about HCRC and obtain consent to genetic testing as an extension of genetic counselling of appropriate subjects. Genetic counsellor (GC) and genetic counselling assistant (GCA) time spent per subject was also measured. METHODS: Patients scheduled for colonoscopy at Cleveland Clinic were invited via electronic medical record patient portal or letter prior to colonoscopy with a link to a chatbot administering the Colon Cancer Risk Assessment Tool (CCRAT) to screen for HCRC syndromes. Those with ≥1 positive response to a CCRAT question received chatbot-deployed genetic education and the option to receive genetic testing. An order for a 55-gene pan-cancer panel was placed for those consenting, and the subject had blood drawn on the day of colonoscopy. Results were disclosed by a GC or GCA by telephone. Subject demographics, progression through the chat, responses to CCRAT, personal and family history, genetic test results and communication with the subject were recorded. Descriptive statistics and two-tailed unpaired t-test and Fisher's exact test were used. RESULTS: 506/4254 (11.9%) initiated and 487 (96.2%) completed the chat with the chatbot. 215 (44.1%) answered 'yes' to ≥1 CCRAT question and all completed pretest education. 129/181 (71.3%) subjects who consented completed testing, and 12 (9.3%) were found to have a germline pathogenic variant. Per subject, the GC spent a mean of 14.3 (SD 7.3) and the GCA a mean of 19.2 (SD 9.8) minutes. CONCLUSION: The use of a chatbot in this setting was a novel and feasible method, with the potential of increasing genetic screening and testing in individuals at risk of HCRC syndromes.

Clinicopathologic characteristics and outcomes of endometrial Cancer patients with mismatch repair deficiency in the era of universal Lynch syndrome screening.

OBJECTIVE: To evaluate clinicopathologic characteristics and survival impact associated with mismatch repair (MMR) deficient subgroups of endometrial cancer (EC) in patients undergoing universal screening for Lynch Syndrome. METHODS: A retrospective cohort study using a prospectively maintained gynecologic oncology registry of patients who underwent surgery for EC was conducted. All pathology specimens underwent tumor testing using immunohistochemistry for MMR deficiency with reflex MLH1 promotor methylation testing. Tumors were classified as MMR-I (intact MMR expression), MMR-DM (MMR deficient due to MLH1 methylation), and MMR-DU (MMR deficient without MLH1 methylation). Univariate and multivariate analysis performed to determine factors associated with MMR-DM. Progression-free survival (PFS) and overall survival (OS) analyzed by stage and endometrioid subgroup. RESULTS: From 2012 to 2016, 1018 EC patients were identified and screened. Overall, 71.6% were classified as MMR-I, 23.8% MMR-DM, and 4.6% MMR-DU. In comparison to MMR-DU, MMR-DM tumors were associated with older age, postmenopausal status, lymphovascular space invasion, and pure endometrioid histology. Compared to MMR-I, MMR-DM tumors were associated with older age, endometrioid histology, lymphovascular space invasion, and higher grade on multivariable analysis. There was no difference in PFS and OS between the three groups overall. In patients with endometrioid EC, MMR-DM tumors were associated with lower PFS vs. MMR-I (HR:2.51, CI:1.54, 4.10, P < 0.001). This effect persisted for stage I/II endometrioid EC (HR 2.66, CI:1.34, 5.26 p = 0.005). No difference in PFS or OS was noted among stage III/IV endometrioid tumors. CONCLUSION: MMR deficiency is associated with adverse prognostic factors and worse PFS among endometrioid tumors, particularly in early stage EC. MMR testing outside of LS screening has prognostic value, warranting consideration for inclusion as a biomarker in prospective clinical trials.

Endometrial cancer in young women: prognostic factors and treatment outcomes in women aged ≤40 years.

OBJECTIVE: Endometrial cancer in pre-menopausal patients aged ≤40 years is rare and poses both diagnostic and management challenges. The goal of this study was to investigate the clinical and pathologic factors associated with endometrial cancer in this group and their impact on survival. METHODS: Patients with endometrial cancer treated between January 2004 and August 2016 were retrospectively reviewed. Patients who underwent either primary surgical treatment or fertility-sparing therapy were included. Exclusion criteria were age >60 years and patients who received neoadjuvant chemotherapy or primary radiation. Age at diagnosis was used to classify patients into two groups: ≤40 and 41-60 years. Clinical and pathologic variables were compared between the groups. Progression-free survival and overall survival were estimated using Cox proportional hazards. RESULTS: A total of 551 patients were evaluated, of which 103 (18.7%) patients were ≤40 years and 448 (81.3%) were 41-60 years. Age ≤40 years was associated with higher body mass index (38.8 vs 35.8 kg/m2, p=0.008), non-invasive cancers (54.2% vs 32.6%, p<0.001), lower uterine segment involvement (27.2% vs 22.5%, p<0.001), and less lymphovascular space invasion (16.8% vs 29.1%, p=0.015). The rate of synchronous ovarian cancer was 9.2% vs 0.7% in age 41-60 years (p<0.001), and 19% of women with endometrial cancer aged ≤40 years underwent fertility-sparing therapy. Grade, stage, myometrial invasion, lymphovascular space invasion, and lymph node status were associated with survival, and fertility-sparing therapy adversely affected the recurrence rate of the age ≤40 years cohort. Among all patients aged ≤60 years, mismatch repair deficiency due to MLH1 methylation was associated with worse progression-free survival, 48.6% vs 83.3% (HR 1.98, 95% CI 1.06 to 3.17, p=0.032), and overall survival, 56.5% vs 90.0% (HR 2.58, 95% CI 1.13 to 5.90, p=0.025). CONCLUSIONS: Patients aged ≤40 years with endometrial cancer have more favorable prognostic factors and higher rates of synchronous tumors. Fertility-sparing therapy was associated with higher recurrence rates. The prognostic value of MLH1 methylation in this population warrants further investigation.

Primer on Hereditary Cancer Predisposition Genes Included Within Somatic Next-Generation Sequencing Panels.

PURPOSE: It has been estimated that 5% to 10% of cancers are due to hereditary causes. Recent data sets indicate that the incidence of hereditary cancer may be as high as 17.5% in patients with cancer, and a notable subset is missed if screening is solely by family history and current syndrome-based testing guidelines. Identification of germline variants has implications for both patients and their families. There is currently no comprehensive overview of cancer susceptibility genes or inclusion of these genes in commercially available somatic testing. We aimed to summarize genes linked to hereditary cancer and the somatic and germline panels that include such genes. METHODS: Germline predisposition genes were chosen if commercially available for testing. Penetrance was defined as low, moderate, or high according to whether the gene conferred a 0% to 20%, 20% to 50%, or 50% to 100% lifetime risk of developing the cancer or, when percentages were not available, was estimated on the basis of existing literature descriptions. RESULTS: We identified a total of 89 genes linked to hereditary cancer predisposition, and we summarized these genes alphabetically and by organ system. We considered four germline and six somatic commercially available panel tests and quantified the coverage of germline genes across them. Comparison between the number of genes that had germline importance and the number of genes included in somatic testing showed that many but not all germline genes are tested by frequently used somatic panels. CONCLUSION: The inclusion of cancer-predisposing genes in somatic variant testing panels makes incidental germline findings likely. Although somatic testing can be used to screen for germline variants, this strategy is inadequate for comprehensive screening. Access to genetic counseling is essential for interpretation of germline implications of somatic testing and implementation of appropriate screening and follow-up.

Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention.

IMPORTANCE: Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE: To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS: This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES: Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS: Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P < .001). CONCLUSIONS AND RELEVANCE: The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

Strategies for clinical implementation of screening for hereditary cancer syndromes.

Hereditary cancer syndromes generally account for 5%-10% of malignancies. While these syndromes are rare, affected patients carry significantly elevated risks of developing cancer, as do their at-risk relatives. Identification of these patients is critical to ensure timely and appropriate genetic testing relevant to cancer patients and their relatives. Several guidelines and tools are available to assist clinicians. Patients suspected to have hereditary cancer syndromes should be offered genetic testing in the setting of genetic counseling by a qualified genetics professional. Germline testing ranges from testing for a known specific familial mutation to testing of a broad differential diagnosis using a pan-cancer multi-gene panel. Taking a family history, referring specific types of tumors with higher likelihood of heredity, implementing universal screening protocols such as microsatellite instability/immunohistochemistry (MSI/IHC) for specific tumors, and referring patients with somatic tumor testing that have potentially germline consequences are all important components to the identification of hereditary cancer syndromes in the oncology clinic.

Assessment of clinical workload for general and specialty genetic counsellors at an academic medical center: a tool for evaluating genetic counselling practices.

With genomics influencing clinical decisions, genetics professionals are exponentially called upon as part of multidisciplinary care. Increasing demand for genetic counselling, a limited workforce, necessitates practices improve efficiency. We hypothesised that distinct differences in clinical workload exist between various disciplines of genetic counselling, complicating practice standardisation and patient volume expectations. We thus sought to objectively define and assess workload among various specialties of genetic counselling. Twelve genetic counsellors (GCs), representing 9.3 clinical FTE, in general or specialty (cancer, cardiovascular or prenatal) services at an academic health system developed a data collection tool for assessing time and complexity. Over a 6-week period, the data were recorded for 583 patient visits (136 general and 447 specialty) and analysed comparing general versus specialty GCs. Variables were compared with hierarchical linear models for ordinal or continuous data and hierarchical logistic models for binary data. General GCs completed more pre- and post-visit activities (P=0.011) and spent more time (P=0.009) per case. General GCs reported greater case discussion with other providers (P<0.001), literature review (P=0.026), exploring testing options (P=0.041), electronic medical record review (P=0.040), insurance preauthorization (P=0.05) and fielding patient inquiries (P=0.003). Lesser redundancy in referral indication was observed by general GCs. GCs in general practice carry a higher pre- and post-visit workload compared with GCs in specialty practices. General GCs may require lower patient volumes than specialty GCs to allow time for additional pre- and post-visit activities. Non-clinical activities should be transferred to support staff.

Paraganglioma Presenting as Postpartum Fever of Unknown Origin.

A young healthy postpartum mother presented with intermittent high fevers and tachycardia. Appropriate testing was done to rule out infectious causes including pan cultures but no identifiable infectious source was found. A CT of the abdomen showed a retroperitoneal mass with two small pulmonary nodules and a bony metastatic lesion. She was found to have stage 4 extra-adrenal paraganglioma with metastases to the lungs and spine. She underwent resection of the mass and is currently undergoing palliative radiation to the spine for pain control. Subsequent genetic testing identified a likely pathogenic variant in SDHB, confirming a diagnosis of Hereditary Paraganglioma-Pheochromocytoma syndrome.

Outcome of neoadjuvant chemotherapy in BRCA1/2 mutation positive women with advanced-stage Müllerian cancer.

OBJECTIVES: To investigate whether patients with germline BRCA1/2 mutations who received neoadjuvant chemotherapy (NAC) for advanced-stage Müllerian cancer (MC) have an improved outcome compared to patients who did not undergo genetic testing. METHODS: Three hundred and two patients who received NAC for stage III-IV MC were identified from a multi-institutional study involving Cleveland Clinic and Brigham and Women's Hospital for 2000-2014 and 2010-2014 respectively. Patients were divided into 3 cohorts: patients with germline BRCA1/2 mutations (BRCA_mut+; N=30), patients with no genetic testing (BRCA_mut_unk; N=166) and patients with negative genetic testing (BRCA_mut-, N=106). RESULTS: There were no differences in the clinical characteristics and rates of complete cytoreduction and bowel resection between the three groups. BRCA_mut+ had longer PFS compared to BRCA_mut_unk and BRCA_mut- (19.1 vs. 15.1 vs. 15.7months respectively. However, this difference was not statistically significant (p=0.48). Patients with BRCA2 mutation had non-significant trend toward longer PFS compared to patients with unknown BRCA or BRCA1 mutation (20.2 vs. 15.1 vs. 14.8months respectively, p=0.58). BRCA_mut+ and BRCA_mut- had longer overall survivals (OS) compared to BRCA_mut_unk patients (50.5 vs. 54.1 vs. 36.5months respectively, p=0.009). In multivariable analyses, controlling for age, stage and complete cytoreduction, BRCA_mut_unk was associated with worse PFS (HR 1.44, 95% CI 1.01-2.05, p=0.045) and OS (HR 2.67, 95% CI 1.33-5.36, p=0.006). CONCLUSIONS: Patients with germline BRCA mutations had improved outcomes with NAC compared to patients with unknown BRCA status. These outcomes were more favorable compared to the outcome of NAC in prior studies.

Abrupt loss of MLH1 and PMS2 expression in endometrial carcinoma: molecular and morphologic analysis of 6 cases.

Given that endometrial cancer (EC) is often the sentinel cancer for female Lynch syndrome patients, we have successfully implemented universal screening of ECs and have previously shown that this is the preferred method to identify these patients. However, during the course of universal screening of EC, we encountered 6 cases with an unusual pattern of mismatch-repair protein immunohistochemistry that has not been previously described in this setting. In these 6 cases, there was an abrupt loss of MLH1 and PMS2 expression in a portion of the tumor. In 3 cases, marked histologic differences were identified between the areas of the tumor with retained expression and areas with loss of expression. In 2 cases, the areas with loss of expression were of higher grade (1 demonstrated solid growth and the other demonstrated increased nuclear atypia with diffuse p53 expression). In 4 tumors, histologic features associated with microsatellite instability (MSI) were present, including increased intraepithelial lymphocytes. The areas with loss of and retained MLH1/PMS2 expression were separately microdissected and assessed for MSI and MLH1 promoter methylation. The areas with loss of MLH1 and PMS2 more commonly demonstrated MSI compared with the areas with intact expression (83% vs. 33%). MLH1 promoter methylation analysis demonstrated heterogenous hypermethylation, as all areas with loss of MLH1/PMS2 expression had more extensive methylation of MLH1 compared with those areas with retained expression. In summary, we describe the histologic and molecular features of 6 cases of EC with abrupt loss of MLH1 and PMS2 expression and demonstrate that heterogenous methylation of the MLH1 promoter results in this distinct and unusual pattern of immunohistochemical expression.