Patients with low nicotinamide N-methyltransferase expression benefit significantly from bevacizumab treatment in ovarian cancer.

BACKGROUND: The role of nicotinamide N-methyltransferase (NNMT) in ovarian cancer is still elusive. Our aim is to explore the expression of NNMT in ovarian cancer and to assess its association with patient prognosis and treatment response. METHODS: We first analyzed the differential expression of NNMT among fallopian tube epithelium, primary ovarian cancers, metastatic ovarian cancers, and recurrent ovarian cancers using Gene Expression Ominus (GEO) database (GSE10971, GSE30587, GSE44104 and TCGA datasets). Then, we assessed the association of NNMT expression with clinical and molecular parameters using CSIOVDB database and GSE28739 dataset. Next, we evaluate the association of NNMT expression with the prognosis of ovarian cancer patients in both GSE9891 dataset and TCGA dataset. Finally, GSE140082 dataset was used to explore the association of NNMT expression with bevacizumab response. RESULTS: NNMT expression was significantly elevated in lymphovascular space invasion (LVSI)-positive ovarian cancers compared with that in LVSI-negative ovarian cancers (TCGA dataset, P < 0.05), Moreover, increased expression of NNMT was associated with increased tumor stage, grade, and mesenchymal molecular subtype (CSIOVDB database). Survival analysis indicated that increased expression of NNMT was associated with a reduced OS in both GSE9891 dataset (HR: 2.28, 95%CI: 1.51-3.43, Log-rank P < 0.001) and TCGA dataset (HR: 1.55, 95%CI: 1.02-2.36, Log-rank P = 0.039). Multivariate analysis further confirmed the negative impact of NNMT expression on OS in ovarian cancer patients in those two datasets. Furthermore, the NNMT-related nomogram showed that NNMT shared a larger contribution to OS, compared with debulking status. More interestingly, bevacizumab conferred significant improvements in OS for patients with low NNMT expression (HR: 0.56, 95%CI: 0.31-0.99, Log-rank P = 0.049). In contrast, patients with high NNMT expression didn't benefit from bevacizumab treatment significantly (HR: 0.85, 95%CI: 0.48-1.49, Log-rank P = 0.561). NNMT expression was positively correlated with the expression of genes, LDHA and PGAM1, involved in Warburg effect. CONCLUSIONS: In conclusion, NNMT expression is associated with the aggressive behavior of ovarian cancer, correlates with a poor prognosis, and is predictive of sensitivity to bevacizumab treatment.

Ovarian Mixed Epithelial Carcinoma With Extensive Bilateral Fallopian Tubes Metastases by the Low-grade Serous Carcinoma Component Mimicking Serous Tubal Intraepithelial Carcinoma: Case Presentation and Literature Review.

Seromucinous carcinoma of the ovary was a newly defined category in the revised 2014 World Health Organization Classification of Tumors of Female Reproductive Organs. It was defined as a carcinoma composed of predominantly of serous and endocervical-type mucinous epithelium. Foci containing clear cells, and areas of endometrioid and squamous differentiation are not uncommon. It is a rare entity with morphologic and immunophenotypic features overlapping other types of ovarian carcinoma. There are different opinions as to whether it is a distinct entity or a histologic variant of well-established entities. Subsequent, to the writing of this manuscript the WHO 2020 reclassified this tumor as a type of endometrioid carcinoma. Here we present a case of seromucinous carcinoma of bilateral ovaries that had variable differentiation and morphology at different sites. Tumor in the fallopian tubes, ovarian surfaces, omentum, and peritoneal surfaces displayed predominant features of low-grade serous carcinoma, while the tumor in the ovaries had predominant mucinous carcinoma morphology with a confluent/expansile growth pattern. The mucosal involvement of the fallopian tubes morphologically mimicked serous tubal intraepithelial carcinoma.

Transtubal Spread of a Superficially Invasive Cervical Adenocarcinoma to the Ovaries After 11 Years.

We report a 55-yr-old woman who presented with bilateral ovarian masses, 11 yr after hysterectomy for superficially invasive stage IA1 cervical adenocarcinoma of usual (human papillomavirus-associated) type. The bilateral ovarian tumors were composed of glands lined by malignant mucinous epithelium and these tumors were metastases from her previous cervical adenocarcinoma, based on morphology, immunophenotype, and positive in situ hybridization for human papillomavirus. In addition, there was extensive involvement of the mucosa of the left fallopian tube by malignant mucinous epithelium. The patient is alive and well 2 yr after the ovarian recurrence. The phenomenon of minimally invasive cervical adenocarcinoma metastasizing to the ovary has been described previously; the extrauterine disease is typically limited to the ovaries and associated with a relatively favorable prognosis. The presence of fallopian tube involvement by cervical adenocarcinoma has rarely been reported, and suggests transtubal spread of tumor. Unique to this case is the >11 yr interval between diagnosis of the cervical and ovarian disease, with previously described cases showing up to a 7 yr latency period. This case demonstrates that spread of cervical adenocarcinoma to the ovaries, via the fallopian tube lumen, can occur after a very long latent period and this possibility must be considered when examining adnexal mass(es) in women who have previously had a hysterectomy for cervical adenocarcinoma.

Malignant Female Adnexal Tumor of Probable Wolffian Origin: Case Report and Literature Review.

Although most female adnexal tumors of probable Wolffian origin have a benign biologic behavior, occasional cases have exhibited malignant potential. We encountered a 50-yr-old woman with an uncommon female adnexal tumors of probable Wolffian origin, which involved bilateral ovaries, invaded the ipsilateral fallopian tube, and extended to the uterine serosa. The initial histopathologic presentation caused significant confusion in pathologic diagnosis. Multiple differential diagnoses including ovarian endometrioid carcinoma, Sertoli cell tumor, and metastasis from nongynecologic organs were considered. After careful examination of the histologic findings and a thorough investigation with multiple immunohistochemical stains, the diagnosis was ultimately established. A literature review on female adnexal tumors of probable Wolffian origin including a malignant form is presented.

Microscopic Omental Metastasis in Clinical Stage I Endometrial Cancer: A Meta-analysis.

BACKGROUND: A patient with early-stage endometrial cancer may possibly have microscopic metastasis in the omentum, which is associated with a poor prognosis. The purpose of this study was to identify risk factors for microscopic omental metastasis in patients with clinical stage I endometrial cancer to establish the indications for selective omentectomy. METHODS: We searched the PubMed, EMBASE, and Cochrane Library databases for published studies from inception to August 2014, using terms such as 'endometrial cancer' or 'uterine cancer' for disease, 'omentectomy' or 'omental biopsy' for intervention, and 'metastasis' for outcome. Two reviewers independently identified the studies that matched the selection criteria. We calculated the pooled risk ratios (RRs) with 95 % confidence intervals (CI) of each surgicopathologic finding for microscopic omental metastases in clinical stage I endometrial cancer. We also calculated the prevalence of microscopic omental metastases. RESULTS: Among 1163 patients from ten studies, 22 cases (1.9 %) of microscopic omental metastases were found, which accounted for 26.5 % of all omental metastases. Positive lymph nodes (RR 8.71, 95 % CI 1.38-54.95), adnexal metastases (RR 16.76, 95 % CI 2.60-107.97), and appendiceal implants (RR 161.67, 95 % CI 5.16-5061.03) were highly associated with microscopic omental metastases. CONCLUSIONS: Microscopic omental metastases were not negligible in patients with clinical stage I endometrial cancer. Those with a risk factor of microscopic omental metastases were recommended for selective omentectomy.

Secondary Involvement of the Adnexa and Uterine Corpus by Carcinomas of the Uterine Cervix: A Detailed Morphologic Description.

Cervical carcinoma infrequently involves the uterine corpus or adnexa. Metastatic adenocarcinoma (AC) to the ovaries can be difficult to distinguish from primary ovarian tumors, and metastatic squamous cell carcinoma (SCC) to these sites has not been well described. Our aim was to provide a detailed description of the morphologic patterns of adnexal and corpus involvement by cervical carcinoma. Cases were identified over a 15-yr period and the following features were recorded: visible lesion, depth of invasion, lymphovascular invasion, and patterns of spread. Only usual human papillomavirus-associated tumors were included. Twenty cases with available slides were identified (2 in situ and 8 invasive SCC; 10 AC); 17 had visible lesions, usually with deep cervical and lymphovascular invasion. Sixteen involved the corpus (1 in situ, 7 SCC, 8 AC), all colonizing endometrium and 10 invading myometrium. SCC involved the ovary and fallopian tube in 4 and 6 cases, respectively, whereas AC involved the ovary in 4 (2 unilateral, 2 bilateral) and the tube in 8 cases. SCC in the ovary usually showed parenchymal invasion, and parenchymal and mucosal involvement in the tube. AC in the ovary ranged from small nodules to confluent expansile growth, whereas in the tube it often showed mucosal colonization mimicking a primary tubal process. Adnexal metastasis of cervical carcinoma is rare and usually coexists with endometrial and myometrial extension from the cervix. Both squamous and ACs can colonize tubal and endometrial mucosa; AC in particular can mimic primaries at those sites. Bilaterality is not a common feature of metastatic endocervical AC.

FIGO 2013 staging system for ovarian cancer: what is new in comparison to the 1988 staging system?

PURPOSE OF REVIEW: Recent progress in the understanding of the molecular events in ovarian cancer has prompted the need for a revised International Federation of Gynecology and Obstetrics (FIGO) staging system that may provide more accurate prognostic information and more specific guidance on personalized management of ovarian cancer than the older staging system that was last revised in 1988. In particular, it is now realized that cancer of ovary, fallopian tube, and peritoneum share similar molecular characteristics and should be considered collectively. With that, a new FIGO staging guideline for cancer of the ovary, fallopian tube, and peritoneum was approved by the FIGO executive board in October 2012 and published in the International Journal of Gynecology Obstetrics [2014; 124:1-5]. Several revisions have been made to the older staging system that needs to be elucidated so that accurate and appropriate patient care may be practiced. RECENT FINDINGS: The standardization of the staging system allows for a smoother transition of patient care between institutions and overall better communication and continuity of management. SUMMARY: Our article briefly reviews and discusses the differences between the new and the old staging system of 1988.

Fallopian tube metastases of non-gynaecological origin: a series of 20 cases emphasizing patterns of involvement including intra-epithelial spread.

AIMS: To determine the frequency and distribution of Fallopian tube involvement in patients with ovarian metastases of non-gynaecological origin. METHODS AND RESULTS: All Fallopian tube tissue was processed for histological examination in a consecutive series of 31 patients with ovarian metastases of non-gynaecological origin. The most common primary sites were appendix (n = 10) colon (n = 7), stomach (n = 6) and breast (n = 4). Twenty cases (65%) showed at least one type of tubal spread. Mural involvement was most common (14 cases) but serosal, intra-vascular, intra-epithelial and intra-lumenal spread were also identified in 12, 9, 8 and 11 cases respectively. Intra-epithelial involvement was restricted to the fimbrial epithelium and mimicked tubal carcinoma in situ (CIS) architecturally. Pagetoid invasion was noted in two of the cases. CONCLUSIONS: The Fallopian tubes are commonly involved in patients who have neoplasms metastatic to the ovaries. Metastases may show a CIS-like pattern of intra-epithelial spread and therefore small serous CIS-type lesions may not represent proof of tubal tumour origin in patients who have high-stage pelvic serous carcinomas. The frequency of intra-lumenal tumour cells supports transtubal spread as a likely mechanism for mucosal involvement by metastatic tumours involving the lower genital tract.

Is comprehensive surgical staging needed for thorough evaluation of early-stage ovarian carcinoma?

OBJECTIVE: Patients with ovarian cancer may have occult metastasis at the time of surgery. Our purpose was to determine the prevalence and sites of occult metastasis in epithelial ovarian cancer grossly confined to the ovary and examine the significance of routine omentectomy and peritoneal biopsies as part of a comprehensive staging procedure. STUDY DESIGN: Data were retrospectively abstracted from patients presenting to University of Texas Southwestern Medical Center Hospitals from 1993 through 2009 with ovarian cancer without gross spread beyond the ovary who underwent comprehensive surgical staging. RESULTS: A total of 86 patients with ovarian cancer grossly confined to the ovary who underwent complete surgical staging were identified. Of patients, 29% were upstaged following comprehensive surgical staging; 6% had metastatic disease in uterus and/or fallopian tubes, 6% in lymph nodes, and 17% in peritoneal, omental, or adhesion biopsies. CONCLUSION: Patients with epithelial ovarian cancer should continue to undergo comprehensive surgical staging, since it identifies occult metastasis in a significant number of patients.

Treatment of fallopian tube metastasis in cervical cancer after laparoscopic ovarian transposition.

A 40-year-old woman, gravida 2, para 2, with squamous cell carcinoma of the cervix, stage IIB, underwent ovarian transposition. Bilateral salpingectomy was performed as part of the operative technique. Histopathologic analysis revealed mucosal spread of the tumor to one of the fallopian tubes. The patient underwent radiation of the ovaries in their new location in addition to standard chemoradiotherapy to the pelvis. There has been no evidence of disease for more than 5 years. Inasmuch as performance of bilateral salpingectomy in ovarian transposition is not standard practice, the finding of fallopian tube metastasis presented a dilemma to the clinician. It remains to be proved whether the finding of metastasis to the fallopian tubes can be evidence for ovarian metastasis in grossly normal-appearing ovaries to validate this practice. Literature review demonstrates that fallopian tube metastasis is usually associated with endometrial involvement.

Metastatic gastric adenocarcinoma primarily presenting in the fallopian tube.

We report a 48-year-old woman presenting with gastric adenocarcinoma metastatic only to the left fallopian tube. In addition to invasive, poorly differentiated adenocarcinoma, there were areas simulating intraepithelial carcinoma, suggesting a primary fallopian tube lesion. The differential diagnosis included a metastatic process, based on unusual morphologic patterns with occasional signet-ring cells, single-cell linear pattern of infiltration, and abundant lymphvascular space invasion. Metastasis from an upper gastrointestinal primary was confirmed by immunostains (cytokeratin 7, CDX-2, and p53 positive in the tumor cells and cytokeratin 20, WT-1, estrogen, and progesterone receptors negative). Imaging studies and a posterior biopsy demonstrated primary gastric adenocarcinoma with similar histology and immunoprofile. We report an unusual case of primary gastric adenocarcinoma presenting only in the fallopian tube and discuss its mimics and differential diagnosis.

Incidence of lymph node and adnexal metastasis in endometrial stromal sarcoma.

OBJECTIVE: To determine the incidence of adnexal and lymph node (LN) metastasis in newly diagnosed endometrial stromal sarcoma (ESS). METHODS: We identified all cases with a diagnosis of ESS evaluated at our institution from January 1, 1980 to October 31, 2009. All uterine pathology was reviewed at our center. High-grade or undifferentiated tumors and ESS arising in extrauterine sites were excluded. Pertinent clinical data were abstracted from electronic medical records. Appropriate statistical tests were performed using SPSS16.0. RESULTS: We identified 94 cases of ESS. LN metastasis was identified in 7 (19%) of 36 patients who underwent LN evaluation. Six of the 7 cases with LN metastasis had lymphovascular invasion (LVI). LVI status was not reported in the other case. Five of the 7 patients with LN metastasis had grossly positive LNs with or without other gross extrauterine disease. Of 20 patients with disease grossly limited to the uterus and grossly normal LNs, 2 (10%) had LN metastasis. Both of these cases had LVI and extensive myoinvasion. Eighty-seven cases (93%) underwent salpingo-oophorectomy. Adnexal metastasis was identified in 11 (13%) of 87 cases, all manifested by gross adnexal tumor and occurring in patients with other gross pelvic extrauterine disease. CONCLUSION: The incidence of LN metastasis in ESS is commonly associated with gross extrauterine disease, extensive myoinvasion, and LVI. Since myoinvasion and LVI status often are not assessable at the time of hysterectomy, LN dissection remains a reasonable option at primary surgery. The rate of adnexal metastasis appears to be negligible in the absence of gross adnexal and extrauterine tumor.

Mucinous metaplasia of the fallopian tube: a diagnostic pitfall mimicking metastasis.

Interpretation of the mucinous change in the fallopian tubes has been difficult because several reports consider this mucinous change as a metastasis from a mucinous tumor. To clarify this issue, we decided to retrospectively review salpingectomies from 3 institutions looking for mucinous change in the fallopian tubes and documented the clinical history of these patients. Twenty-three cases of fallopian tubes with mucinous changes were found, including 11 patients without evidence of malignancy, 4 patients with mucinous ovarian tumors, 5 patients with nonmucinous gynecologic tumors, 2 patients with mucinous appendiceal neoplasm, and 1 patient with colon carcinoma. As mucinous changes are seen in several patients who do not have a malignant tumor, we believe that these changes represent a metaplastic process. The mucinous changes are frequently seen with chronic inflammation and/or other metaplastic changes and without cytologic evidence of malignancy.

Bilateral ovarian squamous cell carcinoma with an antecedent dermoid cyst in the left ovary.

Ovarian squamous cell carcinoma is a rare malignancy and its occurrence is commonly attributed to malignant transformation of a pre-existing mature cystic teratoma. The de novo occurrence of primary squamous cell carcinoma is extremely rare. Malignant transformation in a mature cystic teratoma is almost always unilateral; however, there have been isolated reports of an uncomplicated mature cystic teratoma in the contralateral ovary. We report here a case of a 40-year-old woman presenting with squamous cell carcinoma of both ovaries with antecedent dermoid cyst in the left ovary, along with involvement of the fallopian tubes, cervix and omentum.

Unusual form of superficial spreading squamous cell carcinoma of cervix involving the endometrium, bilateral tubes and ovaries: a case report with literature review.

OBJECTIVE: Although the majority of metastatic ovarian tumors arise within the female genital tract, squamous cell carcinoma of the cervix is a rare form of metastases to the bilateral ovaries by endometrial and transtubal spreading. CASE: A 53-year-old woman was referred to the oncology clinic with postmenopausal bleeding. On vaginal examination, a 3 cm tumor arising from the cervix was inspected. Multiple cervical biopsies and endocervical curettage revealed large cell, non-keratinized squamous cell cervix carcinoma. Radical hysterectomy and bilateral salpingo-oophorectomy were performed. Bilateral pelvic and para-aortic lymph nodes were also removed. The final pathology report revealed endometrial, focal myometrial, bilateral tubal mucosal, fimbrial and bilateral ovarian squamous cell carcinoma involvement. Pelvic and para-aortic nodes were free from metastases. CONCLUSION: Although the incidence of ovarian metastases of adenocarcinoma of the cervix is significantly higher, squamous cell carcinoma may also metastasize to the ovaries by endometrial and transtubal spreading in the absence of lymph node involvement. Especially in young patients for whom preservation of the ovaries is supposed, gross intraoperative inspection of the radical hysterectomy specimen and endometrium should be done and ovaries should be evaluated carefully.

Second Primary Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancers after Breast Cancer Diagnosis: Korea Central Cancer Registry.

PURPOSE: A prior history of breast cancer is a risk factor for the subsequent development of primary peritoneal, epithelial ovarian, and fallopian tubal (POFT) cancers. This study aimed to estimate the incidence of secondary POFT malignancy in breast cancer patients and the clinical outcomes of primary and secondary POFT cancer. MATERIALS AND METHODS: We searched the Korea Central Cancer Registry to find patients with primary and secondary POFT cancer who had breast cancer in 1999-2017. The incidence rate and standardized incidence ratio were calculated. Additionally, we compared the overall survival of patients with primary and secondary POFT cancer. RESULTS: Based on the age-standardized rate, the incidence of second primary POFT cancer after breast cancer was 0.0763 per 100,000 women, which increased in Korea between 1999 and 2017. Among the 30,366 POFT cancer patients, 25,721 were primary POFT cancer only, and 493 had secondary POFT cancer after a breast cancer diagnosis. Second primary POFT cancer patients were older at the time of diagnosis (55 vs. 53, p < 0.001) and had a larger proportion of serous histology (68.4% vs. 51.2%, p < 0.001) than patients with primary POFT. There were no differences between the two groups in tumor stage at diagnosis. The 5-year overall survival rates were 60.2% and 56.3% for primary and secondary POFT cancer, respectively (p=0.216). CONCLUSION: The incidence of second primary POFT cancer after breast cancer increased in Korea between 1999 and 2017. Besides, second primary POFT cancer patients were diagnosed at older ages and had more serous histology.

Serous Tubal Intraepithelial Carcinoma-Like and Pagetoid Tubal Metastasis of an Ovarian Large Cell Neuroendocrine Carcinoma: Peculiar Metastatic Growth Patterns of a Rare Tumor.

A large cell neuroendocrine carcinoma of the ovary is presented because of tubal metastases with peculiar growth patterns: pagetoid and serous tubal intraepithelial carcinoma-like. The possibility that a tubal intraepithelial carcinoma could represent a metastasis should be considered by pathologists.

[Secondary malignant tumors of the female genital tract]. / Sekundární malignity zenského genitálu.

OBJECTIVE: Information sheet about metastatic tumors of the female genital tract. DESIGN: Literature review with case reports. SETTING: Department of Gynaecology and Obstetrics, Faculty of Medicine, Masaryk's University and Fakulty Hospital, Brno. METHODS: Literature review about metastatic tumors of the female genital tract with illustrative case reports. CONCLUSIONS: Secondary gynecological malignant tumors are much less common than primary tumors of the female genital tract with the exception cancer of the fallopian tube and the vagina. Primary malignant tumors of the fallopian tube and the vagina are rare, the primary location of the tumor usually is in other areas of the female genital tract and the tumor grows directly into the above-mentioned organs secondarily. There is talking about metastatic malignant tumors of the female genital tract in the strict sense in the case of extragenital primary origin the cancer. Metastases can be caused by direct penetration of the tumor from anatomically adjacent organs, particularly from the bladder and the rectum, or are going through the lymph or the blood vessels. The most common primary location of the tumor are the breast, the stomach and the bowel in this case. Secondary laesions of the female genital tract can be sometimes the first clinical manifestation of the primary extragenital malignant tumor, simultaneously represent clearly negative prognostic factor for the disease. Differential diagnostic algorithm for solving the secondary laesions of the female genital tract requires a multidisciplinary approach and cooperation with the pathologist and the clinical oncologist. Surgical treatment, the indication and extent based on adequately performed staging, is essential for the diagnosis of the primary tumor and is necessary as the palliative treatment for the elimination event, clinical symptoms and for the improving quality of the life.

Fallopian Tube Neoplasia and Mimics.

This review discusses select fallopian tube entities and their associated mimics. It first focuses on adenomatoid tumors, the most common benign tumor of the fallopian tube. High-grade serous carcinoma and its precursor, serous tubal intraepithelial carcinoma, are then addressed. Finally, attention is turned to endometrioid proliferations of the fallopian tube. A diagnostic approach is provided for these lesions, with an emphasis on differential diagnoses and situations in which a benign lesion may appear malignant, and vice-versa.

[Malignant epithelial ovarian cancer: Role of intra peritoneal chemotherapy and hyperthermic intra peritoneal chemotherapy (HIPEC): Article drafted from the French Guidelines in oncology entitled "Initial management of patients with epithelial ovarian cancer" developed by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY under the aegis of CNGOF and endorsed by INCa]. / Tumeurs épithéliales malignes de l'ovaire : place de la chimiothérapie intrapéritonéale et de la chimiothérapie hyperthermique intrapéritonéale (CHIP). Article rédigé sur la base de la recommandation nationale de bonnes pratiques cliniques en cancérologie intitulée « Conduites à tenir initiales devant des patientes atteintes d'un cancer épithélial de l'ovaire ¼ élaborée par FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY sous l'égide du CNGOF et labellisée par l'INCa.

Intraperitoneal drug delivery in first-line treatment of advanced ovarian cancer have been widely studied. After a complete primary surgery or with residual disease<1cm, intraperitoneal chemotherapy significantly improves disease-free and overall survival (NP1), but with more local and systemic toxicities. Whenever this therapeutic option is under consideration, the ratio efficacy/toxicity must be carefully discussed. Intraperitoneal chemotherapy has to be considered after complete or optimal primary surgery in ovarian, tubal or primitive peritoneal carcinomatosis FIGO IIIC. This treatment must be performed by trained teams and after an assessment of the ratio efficacy/toxicity. In one randomized study, hyperthermic intraperitoneal chemotherapy (HIPEC) using cisplatinum at interval surgery demonstrated an improvement in recurrence free and overall survival compared to surgery alone, in patients initially not resectable and with residual tumor less than 1cm (complete or optimal surgery) (NP1). HIPEC has to be considered after a complete or optimal interval surgery (residu<10mm) in patients with ovarian, tubal or primitive carcinomatosis FIGO IIIC, initially not resectable (Grade B).