Impact of pelvic radiation therapy in patients with early neuroendocrine cervical carcinoma and no residual disease in the radical hysterectomy specimen: a NeCTuR study.

OBJECTIVE: The impact of adjuvant pelvic radiation therapy on the rate and location of recurrences was evaluated in patients with early-stage (IA1-IB2) neuroendocrine cervical carcinoma who underwent prior conization or polypectomy with no residual disease and negative nodes in the subsequent upfront radical hysterectomy specimen. As a secondary objective, disease-free and overall survival were analyzed. METHODS: We searched the Neuroendocrine Cervical Tumor Registry (NeCTuR) to identify patients with clinical early-stage neuroendocrine cervical carcinoma with no residual disease in the specimen from upfront radical surgery and negative nodes. Patients who received pelvic radiation therapy were compared with those who did not, regardless of whether they received adjuvant chemotherapy. RESULTS: Twenty-seven patients met the inclusion criteria, representing 17% of all patients with clinical early-stage disease who underwent upfront radical hysterectomy included in the NeCTuR registry. The median age was 36.0 years (range 26.0-51.0). Six (22%) patients had stage IA, 20 (74%) had stage IB1, and one (4%) had stage IB2 disease. Seven (26%) patients received adjuvant radiation therapy and 20 (74%) did not. All seven patients in the radiation group and 14 (70%) in the no-radiation group received adjuvant chemotherapy (p=0.16). Fifteen percent (4/27) of patients had a recurrence, 14% (1/7) in the radiation group and 15% (3/20) in the no-radiation group (p=0.99). In the radiation group the recurrence was outside the pelvis, and in the no-radiation group, 67% (2/3) recurred outside the pelvis and 33% (1/3) recurred both inside and outside the pelvis (p=0.99). In the radiation group the 5-year disease-free and overall survival rates were 100% while, in the no-radiation group, the 5-year disease-free and overall survival rates were 81% (95% CI 61% to 100%) (p=0.99) and 80% (95% CI 58% to 100%) (p=0.95), respectively. CONCLUSIONS: For patients with no residual disease and negative nodes in the upfront radical hysterectomy specimen, our study did not find that pelvic radiation therapy improves survival.

PET/CT scan improves detection of metastatic disease compared with CT scan alone in women with high-grade neuroendocrine cervical cancer: a NeCTuR study.

OBJECTIVE: To determine the optimal imaging modality for women with high-grade neuroendocrine carcinoma of the cervix. METHODS: Women with high-grade neuroendocrine carcinoma of the cervix who had undergone a computed tomography (CT) scan and combined positron emission tomography with computed tomography (PET/CT) scan within 4 weeks of each other were identified from the NeCTuR Cervical Tumor Registry. One radiologist reviewed all CT scans, and another radiologist reviewed all PET/CT scans. The radiologists denoted the presence or absence of disease at multiple sites. Each radiologist was blinded to prior reports, patient outcomes, and the readings of the other radiologist. With findings on PET/CT used as the gold standard, sensitivity, specificity, and accuracy were calculated for CT scans. RESULTS: Fifty matched CT and PET/CT scans were performed in 41 patients. For detecting primary disease in the cervix, CT scan had a sensitivity of 85%, a specificity of 46%, and an accuracy of 74%. For detecting disease spread to the liver, CT scan had a sensitivity of 80%, a specificity of 89%, and an accuracy of 86%. For detecting disease spread to the lung, CT had a sensitivity of 89%, a specificity of 68%, and an accuracy of 77%. Of the 14 patients who had scans for primary disease work-up, 4 (29%) had a change in their treatment plan due to the PET/CT scan. Had treatment been prescribed on the basis of the CT scan alone, 2 patients would have been undertreated, and 2 would have been overtreated. CONCLUSION: A CT scan is inferior to a PET/CT scan in assessment of metastatic disease in women with high-grade neuroendocrine carcinoma of the cervix. Almost one-third of patients with newly diagnosed high-grade neuroendocrine cervical cancer would have received incorrect therapy had treatment planning been based solely on a CT scan. We recommend a PET/CT scan for both initial work-up and surveillance in women with high-grade neuroendocrine carcinoma of the cervix.

Social media use is associated with higher levels of anxiety and depression in patients with neuroendocrine carcinoma of the cervix: A NeCTuR study.

OBJECTIVE: Neuroendocrine cervical carcinoma (NECC) is rare. Educational resources are limited for NECC patients, leading many to seek information online through patient-led social networks. We sought to characterize the relationships between anxiety and depression levels and social media use among NECC patients. METHODS: Seven surveys assessing social media use, anxiety, and depression were distributed to living NECC patients enrolled in our NECC registry. The primary outcomes were associations between Social Network Time Use Scale (SONTUS) global score and Generalized Anxiety Disorder (GAD-7) and Center for Epidemiologic Studies Depression Scale (CESD) total scores. RESULTS: Eighty-eight patients enrolled; 81 who completed at least 1 survey were included. Ninety-seven percent (70/72) of patients completing SONTUS were low-to-average social media users. Seventy-four percent (53/72) of patients visited a patient-led NECC support-group page on Facebook within the past 4 weeks, and of those, 79% (42/53) reported receiving useful information. Among the patients who did not visit the page, 47% (9/19) reported that the page elicited anxiety and/or sadness. The mean GAD-7 and CES-D scores for the entire cohort were 7.3 and 18.1, respectively. The Spearman correlations between social media use and these scores were significant (GAD-7: 0.23 [p = 0.05]; CESD: 0.25 [p = 0.04]). The estimated odds ratios for moderate/severe anxiety and depression as a function of SONTUS global score were 1.26 (95% CI 1.03-1.55; p = 0.03) and 1.23 (95% CI 1.01-1.49; p = 0.04), respectively. CONCLUSIONS: NECC patients demonstrated low-to-average social media use and relatively high anxiety and depression. Increased social media use was associated with elevated anxiety and depression.

Clinicopathologic characteristics, oncologic outcomes, and prognostic factors in neuroendocrine cervical carcinoma: a Neuroendocrine Cervical Tumor Registry study.

OBJECTIVE: To evaluate clinicopathologic features and oncologic outcomes of patients with neuroendocrine cervical carcinoma in an institutional neuroendocrine cervical tumor registry. METHODS: Retrospective study including patients with neuroendocrine cervical carcinomas diagnosed between 1986 and 2022. Patients were categorized into International Federation of Gynecology and Obstetrics 2018 stage groups: early-stage (IA1-IB2, IIA1); locally advanced (IB3, IIA2-IVA); and advanced (IVB). Clinicopathologic characteristics and oncologic outcomes were evaluated by stage. Survival was compared between patients diagnosed in 1986-2003 and those diagnosed in 2004-2016. Progression-free and overall survival were estimated using the Kaplan-Meier product-limit estimator. RESULTS: A total of 453 patients was included, 133 (29%) with early-stage, 226 (50%) with locally advanced, and 94 (21%) with advanced disease. Median age was 38 years (range 21-93). Sixty-nine percent (306/453) had pure and 32% (146/453) had mixed histology. The node positivity rate (surgical or radiological detection) was 19% (21/108) for tumors ≤2 cm, 37% (39/105) for tumors >2 to ≤4 cm, and 61% (138/226) for tumors >4 cm (p<0.0001). After primary treatment, rates of complete response were 86% (115/133) for early-stage, 65% (147/226) for locally advanced, and 19% (18/94) for advanced disease (p<0.0001). The recurrence/progression rate was 43% for early-stage, 69% for locally advanced, and 80% for advanced disease (p<0.0001). Five-year progression-free and overall survival rates were 59% (95% CI 50% to 68%) and 71% (95% CI 62% to 80%), respectively, for early-stage, 28% (95% CI 22% to 35%) and 36% (95% CI 29% to 43%), respectively, for locally advanced, and 6% (95% CI 0% to 11%) and 12% (95% CI 5% to 19%), respectively, for advanced disease. For early-stage disease, the 5-year progression-free survival rate was 68% for tumors ≤2 cm and 43% for tumors >2 to ≤4 cm (p=0.0013). Receiving cisplatin/carboplatin plus etoposide (HR=0.33, 95% CI 0.17 to 0.63, p=0.0008) and receiving curative radiotherapy (HR=0.32, 95% CI 0.17 to 0.6, p=0.0004) were positive predictors of survival for patients with advanced disease. CONCLUSION: Among patients with neuroendocrine cervical carcinomas, overall survival is favorable for patients with early-stage disease. However, most patients present with locally advanced disease, and overall survival remains poor in this subgroup. For patients with advanced disease, receiving cisplatin/carboplatin plus etoposide and curative radiation therapy is associated with improved overall survival.

The role of postoperative radiation after radical hysterectomy for women with early-stage neuroendocrine carcinoma of the cervix: A meta-analysis.

INTRODUCTION: Neuroendocrine carcinoma of the cervix (NECC) is an aggressive disease with high rates of nodal disease spread even in seemingly cervix-confined disease. Many providers routinely prescribe postoperative radiation therapy in an effort to reduce recurrences despite a lack of supporting studies. The objective of this study was to determine recurrence and mortality in patients with early-stage NECC who had pelvic radiation after radical hysterectomy compared to those who did not receive radiation. METHODS: We performed a meta-analysis of 13 unique studies that reported recurrence and/or mortality for patients with early-stage NECC who underwent radical hysterectomy with or without adjuvant radiation therapy. RESULTS: In 5 studies that reported overall recurrence rates, 63 (52.5%) of 120 patients who received postoperative radiation recurred compared to 70 (37.8%) of 185 patients who did not (RR 1.21, 95% CI: 0.85-1.70, p = 0.29). In 5 studies that reported pelvic recurrence rates, there were 15 pelvic recurrences (12.5%) in the 120 patients who received postoperative radiation compared to 45 pelvic recurrences (24.3%) in the 185 patients who did not (RR 0.60, 95% CI: 0.34-1.08, p = 0.09). In 13 studies that reported mortality rate, there were 138 deaths (34.8%) in 396 patients who received postoperative radiation therapy compared to 223 (35.2%) in 632 patients who did not (RR 1.08, 95% CI: 0.75-1.56, p = 0.66). CONCLUSIONS: The addition of routine postoperative radiation therapy in all patients with early-stage NECC after radical hysterectomy may reduce pelvic recurrences but does not appear to decrease overall recurrence or death. However, there may still be a role for postoperative radiation therapy in patients with additional high-risk pathologic factors.

RB1 alteration and poor prognosis in women with high-grade neuroendocrine carcinoma of the uterine cervix: a NeCTuR study.

OBJECTIVE: To describe the gene alteration status in high-grade neuroendocrine cervical carcinoma (NECC) specimens and to explore the potential association of unique gene alterations with survival. METHODS: Results from tumor-based molecular testing on specimens from women with high-grade NECC in the Neuroendocrine Cervical Tumor Registry were reviewed and analyzed. Tumor specimens could be from primary or metastatic sites and obtained at initial diagnosis, during treatment, or at recurrence. RESULTS: Molecular testing results were available for 109 women with high-grade NECC. The genes most frequently mutated were PIK3CA (mutated in 18.5% of patients), TP53 (17.4%), and MYC (14.5%). Other targetable alterations identified were alterations in KIT (7.3%), KRAS (7.3%), and PTEN (7.3%). Women with tumors having an RB1 alteration (6.4%) had a median overall survival (OS) of 13 months, compared to 26 months for women with tumors that did not have an RB1 alteration (p=0.003). None of the other genes evaluated were shown to be associated with OS. CONCLUSION: Although no individual alteration was found in a majority of tumor specimens from patients with high-grade NECC, a large proportion of women with this disease will have at least one targetable alteration. Treatments based on these gene alterations may offer additional targeted therapies for women with recurrent disease, who currently have very limited therapeutic options. Patients with tumors that harbor RB1 alterations have decreased OS.

Combination therapy with topotecan, paclitaxel, and bevacizumab improves progression-free survival in patients with recurrent high-grade neuroendocrine cervical cancer: a Neuroendocrine Cervical Tumor Registry (NeCTuR) study.

BACKGROUND: Recurrent high-grade neuroendocrine cervical cancer has a very poor prognosis and limited active treatment options. OBJECTIVE: This study aimed to evaluate the efficacy of the 3-drug regimen of topotecan, paclitaxel, and bevacizumab in women with recurrent high-grade neuroendocrine cervical cancer. STUDY DESIGN: This retrospective cohort study used data from the Neuroendocrine Cervical Tumor Registry (NeCTuR), which include data abstracted directly from medical records of women diagnosed with high-grade neuroendocrine carcinoma of the cervix from English- and Spanish-speaking countries. The study compared women with recurrent high-grade neuroendocrine cervical cancer who received the topotecan, paclitaxel, and bevacizumab regimen as first- or second-line therapy for recurrence and women with recurrent high-grade neuroendocrine cervical cancer who received chemotherapy but not the topotecan, paclitaxel, and bevacizumab regimen. Patients continued chemotherapy until disease progression or the development of unacceptable toxic effects. Progression-free survival from the start of therapy for recurrence to the next recurrence or death, overall survival from the first recurrence, and response rates were evaluated. RESULTS: The study included 62 patients who received the topotecan, paclitaxel, and bevacizumab regimen as first- or second-line therapy for recurrence and 56 patients who received chemotherapy but not the topotecan, paclitaxel, and bevacizumab regimen for recurrence. The median progression-free survival rates were 8.7 months in the topotecan, paclitaxel, and bevacizumab regimen group and 3.7 months in the non-topotecan, paclitaxel, and bevacizumab regimen group, with a hazard ratio for disease progression of 0.27 (95% confidence interval, 0.17-0.48; P<.0001). In the topotecan, paclitaxel, and bevacizumab regimen group, 15% of patients had stable disease, 39% of patients had a partial response, and 18% of patients had a complete response. Compared with patients in the non-topotecan, paclitaxel, and bevacizumab regimen group, significantly more patients in the topotecan, paclitaxel, and bevacizumab regimen group remained on treatment at 6 months (31% vs 67%, respectively; P=.0004) and 1 year (9% vs 24%, respectively; P=.02). The median overall survival rates were 16.8 months in the topotecan, paclitaxel, and bevacizumab regimen group and 14.0 months in the non-topotecan, paclitaxel, and bevacizumab regimen group, with a hazard ratio for death of 0.87 (95% confidence interval, 0.55-1.37). CONCLUSION: Combination therapy with topotecan, paclitaxel, and bevacizumab was an active regimen in women with recurrent high-grade neuroendocrine cervical cancer and improved progression-free survival while decreasing the hazard ratio for disease progression.

Definitive pelvic radiation therapy improves survival in stage IVB neuroendocrine cervical carcinoma: A NeCTuR study.

OBJECTIVE: To evaluate the survival impact of adding definitive pelvic radiation therapy (RT) to chemotherapy among patients with stage IVB neuroendocrine cervical carcinoma (NECC). METHODS: We retrospectively studied patients with FIGO 2018 stage IVB NECC diagnosed during 1998-2020 who received chemotherapy with or without definitive whole pelvic RT (concurrent or sequential). Demographic, oncologic, and treatment characteristics were summarized. Progression-free (PFS) and overall survival (OS) were plotted using the Kaplan-Meier method, and hazard ratios (HRs) were calculated using Cox regression. RESULTS: The study included 71 patients. Median age was 43 years (range, 24-75). Fifty-nine patients (83%) had pure neuroendocrine histology, and 57 (80%) had pretreatment tumor size >4 cm. Fifty-six patients (79%) received chemotherapy alone with (n = 15) or without (n = 41) palliative pelvic RT, and 15 (21%) received chemotherapy and definitive pelvic RT (chemo+RT). Median follow-up time was 20.1 months (range, 11.3-170.3) for the chemo+RT group and 13.5 months (range, 0.9-73.6) for the chemotherapy-alone group. Median PFS was 10.3 months (95% CI, 7.5-∞) for the chemo+RT group vs 6.6 months (95% CI, 6.1-8.7) for the chemotherapy-alone group (p = 0.0097). At 24 months, the PFS rate was 24% for chemo+RT vs 7.8% for chemotherapy alone. Median OS was 20.3 months (95% CI, 18.5-∞) for the chemo+RT group vs 13.6 months (95% CI, 11.3-19.2) for the chemotherapy-alone group (p = 0.0013). At 24 months, the OS rate was 49.2% for chemo+RT vs 21.5% for chemotherapy alone. In a Cox regression model, definitive RT was associated with improved PFS (HR, 0.44; 95% CI, 0.23-0.83; p = 0.0119) and OS (HR, 0.31; 95% CI, 0.14-0.65; p = 0.0022). CONCLUSIONS: Addition of definitive pelvic RT to chemotherapy may improve survival in patients with stage IVB NECC.

Open vs minimally invasive radical trachelectomy in early-stage cervical cancer: International Radical Trachelectomy Assessment Study.

BACKGROUND: Minimally invasive radical trachelectomy has emerged as an alternative to open radical hysterectomy for patients with early-stage cervical cancer desiring future fertility. Recent data suggest worse oncologic outcomes after minimally invasive radical hysterectomy than after open radical hysterectomy in stage I cervical cancer. OBJECTIVE: We aimed to compare 4.5-year disease-free survival after open vs minimally invasive radical trachelectomy. STUDY DESIGN: This was a collaborative, international retrospective study (International Radical Trachelectomy Assessment Study) of patients treated during 2005-2017 at 18 centers in 12 countries. Eligible patients had squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma; had a preoperative tumor size of ≤2 cm; and underwent open or minimally invasive (robotic or laparoscopic) radical trachelectomy with nodal assessment (pelvic lymphadenectomy and/or sentinel lymph node biopsy). The exclusion criteria included neoadjuvant chemotherapy or preoperative pelvic radiotherapy, previous lymphadenectomy or pelvic retroperitoneal surgery, pregnancy, stage IA1 disease with lymphovascular space invasion, aborted trachelectomy (conversion to radical hysterectomy), or vaginal approach. Surgical approach, indication, and adjuvant therapy regimen were at the discretion of the treating institution. A total of 715 patients were entered into the study database. However, 69 patients were excluded, leaving 646 in the analysis. Endpoints were the 4.5-year disease-free survival rate (primary), 4.5-year overall survival rate (secondary), and recurrence rate (secondary). Kaplan-Meier methods were used to estimate disease-free survival and overall survival. A post hoc weighted analysis was performed, comparing the recurrence rates between surgical approaches, with open surgery being considered as standard and minimally invasive surgery as experimental. RESULTS: Of 646 patients, 358 underwent open surgery, and 288 underwent minimally invasive surgery. The median (range) patient age was 32 (20-42) years for open surgery vs 31 (18-45) years for minimally invasive surgery (P=.11). Median (range) pathologic tumor size was 15 (0-31) mm for open surgery and 12 (0.8-40) mm for minimally invasive surgery (P=.33). The rates of pelvic nodal involvement were 5.3% (19 of 358 patients) for open surgery and 4.9% (14 of 288 patients) for minimally invasive surgery (P=.81). Median (range) follow-up time was 5.5 (0.20-16.70) years for open surgery and 3.1 years (0.02-11.10) years for minimally invasive surgery (P<.001). At 4.5 years, 17 of 358 patients (4.7%) with open surgery and 18 of 288 patients (6.2%) with minimally invasive surgery had recurrence (P=.40). The 4.5-year disease-free survival rates were 94.3% (95% confidence interval, 91.6-97.0) for open surgery and 91.5% (95% confidence interval, 87.6-95.6) for minimally invasive surgery (log-rank P=.37). Post hoc propensity score analysis of recurrence risk showed no difference between surgical approaches (P=.42). At 4.5 years, there were 6 disease-related deaths (open surgery, 3; minimally invasive surgery, 3) (log-rank P=.49). The 4.5-year overall survival rates were 99.2% (95% confidence interval, 97.6-99.7) for open surgery and 99.0% (95% confidence interval, 79.0-99.8) for minimally invasive surgery. CONCLUSION: The 4.5-year disease-free survival rates did not differ between open radical trachelectomy and minimally invasive radical trachelectomy. However, recurrence rates in each group were low. Ongoing prospective studies of conservative management of early-stage cervical cancer may help guide future management.

Minimally invasive radical trachelectomy: Considerations on surgical approach.

Current evidence supports that radical trachelectomy is a safe and feasible alternative to patients with early-stage cervical cancer who wish to preserve fertility. In addition, published retrospective literature supports that oncologic outcomes are equivalent to those of radical hysterectomy. First published as a vaginal approach, a number of other approaches have been reported including laparotomic, laparoscopic, and robotic. In 2018, the first ever prospective randomized trial (LACC) comparing open vs. minimally invasive radical hysterectomy showed worse disease-free and overall survival for the minimally invasive (both laparoscopic and robotic) approach than the open approach. This landmark publication raised concerns regarding the oncologic safety of minimally invasive radical trachelectomy. In the United States, minimally invasive became the dominant approach by 2011 for radical trachelectomy. Given that radical trachelectomy is an infrequent performed procedure, only small retrospective studies, systematic reviews, and large database studies have been published. These studies are limited by their retrospective nature, small sample size, patient selection bias, unbalanced groups, and sequential surgical approach comparisons. However, the available evidence thus far shows that oncologic outcomes for both open and minimally invasive radical trachelectomy are equivalent. Given the rarity of the procedure and the low recurrence and death rates of patients with early-stage cervical cancer undergoing radical trachelectomy, a prospective randomized trial seems unlikely. A multi-institutional international registry study (International Radical Trachelectomy Assessment - IRTA - study) has been recently completed evaluating open vs. minimally invasive radical trachelectomy. There are three ongoing prospective studies evaluating the possibility of less radical surgery in a low-risk early-stage cervical cancer population, ConCerv, SHAPE, and GOG 278. We look forward to the final results of these studies that will hopefully shed light on the optimal treatment option for patients with early-stage cervical cancer wishing to preserve fertility. This article will review the most impacting publications comparing open vs. minimally invasive radical trachelectomy and analyze the limitations of the current available literature.

Role of radical hysterectomy in patients with early-stage high-grade neuroendocrine cervical carcinoma: a NeCTuR study.

OBJECTIVE: Patients with early-stage, high-grade neuroendocrine cervical carcinoma typically undergo radical hysterectomy with pelvic lymphadenectomy followed by adjuvant radiotherapy and/or chemotherapy. To explore the role of radical surgery in patients with this disease, who have a high likelihood of undergoing postoperative adjuvant therapy, we aimed to determine the rate of parametrial involvement and the rate of parametrial involvement without other indications for adjuvant treatment in these patients. METHODS: We retrospectively studied patients in the Neuroendocrine Cervical Tumor Registry (NeCTuR) at our institution to identify those with International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IA1-IB2, high-grade neuroendocrine cervical carcinoma who underwent up-front radical surgery with or without adjuvant therapy. RESULTS: One hundred patients met the inclusion criteria. The median age was 35 years (range 22-65), and 51% (51/100) had pure high-grade neuroendocrine carcinoma. No patient had a tumor >4 cm or suspected parametrial or nodal disease before surgery. Ten patients (10%) had microscopic parametrial compromise in the final surgical specimens. Ninety-four (94%) patients underwent nodal assessment, and 19 (19%) had positive nodes. Ten patients underwent both sentinel lymph node biopsy and pelvic lymphadenectomy, and none had false-negative findings. Patients with parametrial compromise were more likely to have positive pelvic nodes (80% vs 12%, p<0.0001), and a positive vaginal margin (20% vs 1%, p=0.03). All patients with parametrial compromise had lymphovascular space invasion (100% vs 73%, p=0.10). Of the 100 patients, 95 (95%) were recommended adjuvant therapy and 89 (89%) were known to have received it. Adjuvant pelvic radiotherapy reduced the likelihood of local recurrence by 62%. CONCLUSIONS: In carefully selected patients with high-grade neuroendocrine cervical carcinoma, the rate of microscopic parametrial involvement is 10%. As most patients receive adjuvant treatment, we hypothesize that simple hysterectomy may be adequate when followed by adjuvant radiotherapy with concurrent cisplatin and etoposide followed by additional chemotherapy.

mTOR Pathway Activation Assessed by Immunohistochemistry in Cervical Biopsies of HPV-associated Endocervical Adenocarcinomas (HPVA): Correlation With Silva Invasion Patterns.

The Silva pattern of invasion, recently introduced to stratify patients at risk for lymph node metastases in human papillomavirus-associated endocervical adenocarcinomas (HPVAs), can only be assessed in cone and loop electrosurgical excision procedure excisions with negative margins or in a hysterectomy specimen. Previous studies found associations between destructive stromal invasion patterns (Silva patterns B and C) and mutations in genes involved in the MEK/PI3K pathways that activate the mammalian target of rapamycin (mTOR) pathway. The primary aim of this study was to use cervical biopsies to determine whether markers of mTOR pathway activation associate with aggressive invasion patterns in matched excision specimens. The status of the markers in small biopsy specimens should allow us to predict the final and biologically relevant pattern of invasion in a resection specimen. Being able to predict the final pattern of invasion is important, since prediction as Silva A, for example, might encourage conservative clinical management. If the pattern in the resection specimen is B with lymphovascular invasion or C, further surgery can be performed 34 HPVA biopsies were evaluated for expression of pS6, pERK, and HIF1α. Immunohistochemical stains were scored semiquantitatively, ranging from 0 to 4+ with scores 2 to 4+ considered positive, and Silva pattern was determined in follow-up excisional specimens. Silva patterns recognized in excisional specimens were distributed as follows: pattern A (n=8), pattern B (n=4), and pattern C (n=22). Statistically significant associations were found comparing pS6 and pERK immunohistochemistry with Silva pattern (P=0.034 and 0.05, respectively). Of the 3 markers tested, pERK was the most powerful for distinguishing between pattern A and patterns B and C (P=0.026; odds ratio: 6.75, 95% confidence interval: 1.111-41.001). Although the negative predictive values were disappointing, the positive predictive values were encouraging: 90% for pERK, 88% for pS6 and 100% for HIF1α. mTOR pathway activation assessed by immunohistochemistry in cervical biopsies of HPVA correlate with Silva invasion patterns.

Measurement of tumor size in early cervical cancer: an ever-evolving paradigm.

The major tenets in accurately assessing tumor size in patients with early stage cervical cancer currently include physical examination, imaging studies, and pathologic evaluation. It is estimated that when comparing clinical stage based on physical examination and final pathology, the concordance diminishes as stage increases: 85.4%, 77.4%, 35.3%, and 20.5% for stage IB1, IB2, IIA, and IIB, respectively. Vaginal involvement and larger tumor diameter are considered the main causes of stage inaccuracy. When considering imaging studies, magnetic resonance imaging (MRI) provides the highest level of accuracy in the assessment of cervical tumor size. Its accuracy in determining tumor location within the cervix is approximately 91% and in predicting tumor size 93%. MRI imaging is also significantly more accurate in measuring tumor size, delineating cervical tumor boundaries, and local tumor extension when compared with computed tomography (CT) scan. When comparing with pelvic ultrasound, the accuracy of both imaging techniques (MRI and pelvic ultrasound) in the assessment of tumor size in small versus large tumors is comparable. Pertaining to pathology, the depth of invasion should be measured by convention from the nearest surface epithelium, which equates to tumor thickness. In the setting where tumor is found both in the conization and hysterectomy specimen, the horizontal extent should be measured by summing the maximum horizontal measurement in the different specimens and the depth of invasion measured as the maximum depth in either specimen. A new pattern-based classification for endocervical adenocarcinomas recommends the description of patterns of invasion for human papillomavirus (HPV)-related adenocarcinomas as this is associated with differing risks of lymph node involvement.

Evaluation of PARP and PDL-1 as potential therapeutic targets for women with high-grade neuroendocrine carcinomas of the cervix.

OBJECTIVES: Women with recurrent high-grade neuroendocrine cervical cancer have few effective treatment options. The aim of this study was to identify potential therapeutic targets for women with this disease. METHODS: Specimens from patients with high-grade neuroendocrine carcinomas of the cervix were identified from pathology files at MD Anderson Cancer Center. Immunohistochemical stains for PD-L1 (DAKO, clone 22-C3), mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), somatostatin, and Poly (ADP-ribose) polymerase (PARP) were performed on sections from formalin-fixed paraffin-embedded tissue blocks. Nuclear PARP-1 staining was quantified using the H-score with a score of <40 considered low, 40-100 moderate, and ≥100 high. RESULTS: Forty pathologic specimens from patients with high-grade neuroendocrine carcinomas of the cervix were examined (23 small cell, 5 large cell, 3 high-grade neuroendocrine, not otherwise specified, and 9 mixed). The mean age of the cohort was 43 years and the majority of patients (70%) were identified as white non-Hispanic. All 28 (100%) samples tested stained for mismatch repair proteins demonstrated intact expression, suggesting they were microsatellite stable tumors. Of the 31 samples tested for PD-L1 expression, only two (8%) of the 25 pure high-grade neuroendocrine carcinomas were positive whereas three (50%) of the six mixed carcinoma tumors tested positive. Of the 11 small cell specimens tested for PARP-1, 10 (91%) showed PARP expression with six (55%) demonstrating high expression and four (36%) showing moderate expression. Somatostatin staining was negative in 18 of 19 small cell cases (95%). CONCLUSIONS: Pure high-grade neuroendocrine cervical carcinomas were microsatellite stable and overwhelmingly negative for PD-L1 expression. As the majority of tumors tested expressed PARP-1, inclusion of PARP inhibitors in future clinical trials may be considered.

Phase II study of pembrolizumab efficacy and safety in women with recurrent small cell neuroendocrine carcinoma of the lower genital tract.

OBJECTIVE: To investigate the efficacy and safety of pembrolizumab in women with recurrent small cell neuroendocrine tumors of the lower genital tract. METHODS: We conducted an open-label, investigator-initiated phase II basket trial of pembrolizumab 200 mg intravenously every 3 weeks in patients with rare tumors (ClinicalTrials.gov: NCT02721732). The trial had prespecified cohorts, including small cell malignancies of extrapulmonary origin. Eligibility criteria included disease progression during standard treatment in the 6 months before study enrollment. Patients were enrolled from February 2017 to February 2019. The primary endpoint was the proportion of patients alive without progression at 27 weeks. Response to pembrolizumab was evaluated every 9 weeks (3 cycles) with radiographic imaging. RESULTS: Seven women with gynecologic extrapulmonary small cell carcinoma were enrolled, 6 with cervical and 1 with vulvar carcinoma. No patient was progression free at 27 weeks. At first radiologic assessment, 1 patient had stable disease, while 6 had progression. The single patient with stable disease at 6 weeks had disease progression at 14 weeks. The median progression-free interval was 2.1 months (range 0.8-3.3 months). Severe treatment-related adverse events (≥grade 3) were seen in 2 of 7 patients (29%); 1 patient had grade 3 asymptomatic elevation of serum alkaline phosphatase, and 1 had grade 3 asymptomatic elevation of serum alanine aminotransferase. CONCLUSIONS: Pembrolizumab alone showed minimal activity in women with recurrent small cell neuroendocrine tumors of the lower genital tract. Treatment was well tolerated in the majority of study participants, and the rate of severe adverse events was low.