Ryan M. Kahn

Clinicopathologic Features, Molecular Landscape, and Prognostic Implications of Ovarian Low-grade Serous Tumors with Histologic Transformation

Abstract Purpose: The purpose of this study was to characterize the clinicopathologic features, molecular genetic landscape, and clinical behavior of ovarian low-grade serous tumors with histologic transformation (LGS-HT) to indeterminate/high-grade carcinoma. Experimental Design: LGS-HT were retrospectively identified from an institutional cohort of patients with ovarian cancer and underwent central pathology re-review. Data on clinicopathologic characteristics, including age, stage, surgical outcomes, systemic treatments, and overall survival (OS), were collected. IHC profiling and next-generation sequencing were performed. OS comparisons were performed with our institutional cohorts of ovarian low-grade serous carcinoma (n = 109) and high-grade serous carcinoma (n = 1,672). Results: From 4,371 ovarian serous cancers, 40 (0.9%) LGS-HT were identified: 30 with synchronous low-grade and higher-grade tumor components at initial diagnosis and 10 with an ovarian low-grade serous neoplasm that recurred as a higher-grade carcinoma. The most common somatic driver mutations included TP53 (38.5%), KRAS (21.8%), NF1 (15.6%), BRAF (15.6%), and NRAS (12.5%), with coexisting TP53 and RAS/RAF mutations in 18.8% of cases. Alterations in DNA damage response genes (BRCA2, PALB2, CHEK2, ATM, NBN, and RECQL4) were identified in LGS-HT lacking TP53 genetic alterations. Synchronous low-grade and higher-grade tumor components at initial diagnosis were associated with poorer OS (median, 59.7 months) compared with low-grade serous carcinoma (median, 105.4 months; P = 0.026) and were similar to high-grade serous carcinoma (median, 48.8 months; P = 0.61). Severe nuclear atypia and the absence of RAS/RAF-driver mutations were significant adverse prognostic factors. Conclusions: LGS-HT exhibit both low-grade and high-grade morphologic and molecular features, representing an exception to the dualistic classification of ovarian serous neoplasms. The presence of a definitive high-grade carcinoma component in a low-grade serous tumor portends aggressive clinical behavior.

A pre-operative scoring model to estimate the risk of blood transfusion over an ovarian cancer debulking surgery (BLOODS score): a Memorial Sloan Kettering Cancer Center Team Ovary study

To develop a pre-operative tool to estimate the risk of peri-operative packed red blood cell transfusion in primary debulking surgery. We retrospectively reviewed an institutional database to identify patients who underwent primary debulking surgery for ovarian cancer at a single center between January 1, 2001 and May 31, 2019. Receiver operating characteristic curve and area under the receiver operating characteristic curve (AUC) were calculated. Five-fold cross-validation was applied to the multivariate model. Significant variables were assigned a 'BLOODS' (BLood transfusion Over an Ovarian cancer Debulking Surgery) score of +1 if present. A total BLOODS score was calculated for each patient, and the odds of receiving a transfusion was determined for each score. Overall, 1566 patients met eligibility criteria; 800 (51%) underwent a peri-operative blood transfusion. Odds ratios (OR) were statistically significant for American Society of Anesthesiologists scores of 3 and 4 (OR 1.34, 95% confidence interval (95% CI) 1.09 to 1.63), pre-operative levels of cancer antigen 125 (CA125) (OR 2.43, 95% CI 1.98 to 2.99), platelets (OR 1.59, 95% CI 1.45 to 1.74), obesity (OR 0.76, 95% CI 0.60 to 0.96), presence of carcinomatosis (OR 2.45, 95% CI 1.93 to 3.11), bulky upper abdominal disease (OR 2.86, 95% CI 2.32 to 3.54), pre-operative serum albumin level (OR 0.31, 95% CI 0.24 to 0.40), and pre-operative hemoglobin level (OR 0.56, 95% CI 0.51 to 0.61). The corrected AUC was 0.748 (95% CI 0.693 to 0.804). BLOODS scores of 0 and 5 corresponded to 11% and 73% odds, respectively, of receiving a peri-operative blood transfusion. We developed a universal pre-operative scoring system, the BLOODS score, to help identify patients with ovarian cancer who would benefit from surgical planning and blood-saving techniques. The BLOODS score was directly proportional to the American Society of Anesthesiologists score, presence of upper abdominal disease, carcinomatosis, CA125 level, and platelets level. We believe this model can help physicians with surgical planning and can benefit patient outcomes.

Extra-abdominal cytoreductive techniques in ovarian cancer: how far can (should) we go?

Complex surgery is an essential component in the management of advanced ovarian cancer. Furthermore, achieving complete gross resection in cytoreductive surgery appears to be associated with significant survival benefits in patients with advanced ovarian cancer. The goal of this review is to demonstrate the advancement of surgical techniques in gynecologic oncology surgery, including resection of disease within the intrathoracic and inguinal regions. This progress has expanded the option of surgery to more patients, especially those who would have previously been deemed inoperable. In this review we describe the most notable studies and reports of surgical resection of ovarian cancer involving cardiophrenic/supradiaphragmatic lymph nodes, mediastinum, lung pleura or parenchyma, and the inguinal region. We also describe the growing role that video-assisted thoracic surgery has played in advanced ovarian cancer diagnosis and management. The studies, series, and reports described demonstrate that comprehensive surgical procedures outside of the abdomen or pelvis can be both safe and feasible in properly selected patients. They also suggest that resection of disease outside of the abdomen or pelvis may benefit appropriately selected patients. Future studies are necessary to identify which patients may benefit most from upfront surgery versus neoadjuvant chemotherapy when ovarian cancer metastasis is present in the thoracic or inguinal regions.

Cardiophrenic lymph nodes in advanced ovarian cancer

Epithelial ovarian cancer most commonly presents at advanced stages, and prognosis is influenced by residual disease following cytoreduction. The significance of cardiophrenic lymph node resection at the time of cytoreductive surgery in advanced ovarian cancer remains a topic of debate. Enlarged cardiophrenic lymph nodes are detected through high-resolution imaging; however, the optimal imaging technique in determining feasibility of node resection remains uncertain. Similarly, the impact of excision of cardiophrenic lymph nodes on progression-free and overall survival remains elusive. The indications for resection of cardiophrenic lymph nodes are not addressed in standard ovarian cancer guidelines. Patients with cardiophrenic lymph nodes exceeding 1 cm in size may be considered for resection if complete intra-abdominal cytoreduction is feasible to no gross residual. The surgical approach might be either by open access or by video-assisted thoracoscopic surgery (minimally invasive approach), and major complications following cardiophrenic lymph nodes resection are low. Pathological cardiophrenic lymph nodes are associated with a poorer overall prognosis and can serve as a prognostic parameter; however, the therapeutic benefit of cardiophrenic lymph nodes resection remains inconclusive.

Mapping the landscape of sentinel lymph nodes in endometrial cancer: let us continue in the right direction

Barriers to completion of cascade genetic testing: how can we improve the uptake of testing for hereditary breast and ovarian cancer syndrome?

Cascade testing for familial cancer syndromes has historically been difficult to execute. As part of a facilitated cascade testing pathway, we evaluated barriers to completion of cascade testing. Our previously published study evaluated a facilitated cascade testing pathway whereby a genetics team facilitated at-risk relative (ARR) cascade testing through telephone genetic counseling and mailed saliva kit testing. This follow-up study evaluated barriers to completion of cascade genetic testing through six-month follow-up telephone interviews. Probands identified 114 ARRs, of whom 97 were successfully contacted by telephone. Among those contacted, 83 (86%) reported interest in genetic testing and 14 (14%) declined. Among those reporting interest in testing, 71% (69/83) completed testing. Follow-up telephone interviews revealed that 14 ARRs did not complete testing despite reporting interest for the following reasons: concern about genetic discrimination, fear of a positive result and belief that the pathogenic variant was not relevant to his/her health. Five ARRs reported that they remained interested in testing and the telephone call prompted completion of testing. Even when facilitated by a medical team with prioritization of relative convenience, significant barriers to cascade testing ARRs for hereditary breast and ovarian cancer syndrome persist due to concern about genetic discrimination, cost, and fear of positive test results.

Is hysterectomy necessary for the treatment of preinvasive stratified mucin producing intraepithelial lesions of the cervix?

Stratified mucin producing intraepithelial lesion (SMILE) is an uncommon premalignant cervical intraepithelial lesion, characterized by histopathologic features resembling those observed in high grade squamous intraepithelial lesions and adenocarcinoma in situ of the cervix. Its hybrid morphology poses a pathologic challenge with no specific management guidelines. The goal of this study was to review the natural history of SMILE and treatment based outcomes. A retrospective pathology review of all cases of cervical intraepithelial lesions, with confirmation of all SMILE lesions, at one institution between 2007 and 2019, was performed. Clinical and pathologic characteristics, management options, and patient outcomes were reviewed and analyzed. Inclusion criteria included all patients diagnosed initially with SMILE on biopsy, excisional procedure, or simple hysterectomy. Patients diagnosed with SMILE had to fulfill the following pathologic features: stratified columnar epithelium with nuclear atypia and mucin production throughout the epithelial thickness with increased mitotic activity, and/or apoptotic bodies. Pathologic slides were re-evaluated by a pathologist to confirm the diagnosis and review margin status. 24 patients with SMILE were identified. Mean age at diagnosis was 36.2 years (range 25-53) with 67% (16/24) diagnosed before the age of 40. The majority (54%, 13/24) were nulliparous and 63% (15/24) had a past history of abnormal Pap smears. 92% (22/24) of patients were positive for high risk human papillomavirus, with 13% (n=3) presenting with a normal Pap smear. Diagnosis was made primarily on colposcopy (n=16), cold knife cone/loop electrosurgical excision procedure (n=7), or hysterectomy (n=1). Most patients (71%, 17/24) had a co-existing precancerous lesion at the time of diagnosis and the most common was high grade squamous intraepithelial lesion (53%). Five invasive lesions were also identified at the time of diagnosis of SMILE (2 adenocarcinoma, 3 adenosquamous), 1 of which underwent chemoradiation. Among all patients, 25% (6/24) underwent hysterectomy (4 simple, 2 radical), while 63% (17/24) of patients underwent a fertility sparing excisional procedure; 4% (1/24) were incidentally diagnosed on hysterectomy. 18 patients had negative margins and 2 patients had positive margins. Over a median follow-up of 29 months (range 3-105), all of the fertility sparing patients with negative margins had no recurrence. Among the two patients with positive margins, one had no recurrence on repeat excision and the other underwent repeat excision with persistent SMILE identified, subsequent negative margin, and no recurrence since. Our data showed that most patients with SMILE were young, positive for high risk human papillomavirus, nulliparous, and presented with coexisting lesions. Excisional procedures with negative margins may be sufficient fertility sparing treatment in patients with preinvasive SMILE with a low risk of recurrence. There should be consideration of hysterectomy at the completion of childbearing.