Lymphovascular invasion as a criterion for adjuvant chemotherapy for FIGO stage I-IIa clear cell carcinoma, mucinous, low grade serous and low grade endometrioid ovarian cancer.

BACKGROUND: The aim of this study was to evaluate the impact of lymphovascular space invasion (LVSI) on overall survival (OS) and recurrence-free survival (RFS) in patients managed for stage I-IIa clear cell carcinoma, mucinous, low-grade serous and low-grade endometrioid ovarian cancer MATERIAL AND METHODS: Retrospective multicentre study of the research group FRANCOGYN between January 2001 and December 2018. All patients managed for stage I-IIa clear cell carcinoma, mucinous /low grade serous and endometrioid ovarian cancer and for whom the presence of histological slides for the review of LVSI was available, were included. Patient's characteristics with LVSI (LVSI group) were compared to those without LVSI (No LVSI group). A cox analysis for OS and RFS analysis were performed in all population. RESULTS: Over the study period, 133 patients were included in the thirteen institutions. Among them, 12 patients had LVSI (9%). LVSI was an independent predictive factor for poorer Overall and recurrence free survivals. LVSI affected OS (p < 0.001) and RFS (p = 0.0007), CONCLUSION: The presence of LVSI in stage I-IIa clear cell carcinoma, mucinous /low grade serous and endometrioid ovarian cancer has an impact on OS and RFS and should put them at high risk and consider the option of adjuvant chemotherapy.

The prognostic roles of the prognostic nutritional index in patients with intraductal papillary mucinous neoplasm.

The preoperative accurate diagnosis is difficult in the patients with intraductal papillary mucinous neoplasm (IPMN). The aim of the present study was to elucidate the roles of systemic inflammation responses and nutritional status indexes in IPMN. High-grade dysplasia was classified as a malignant neoplasm in the study. We retrospectively reviewed 155 patients who underwent pancreatectomy. The correlation between the clinical factors and several indexes of a systemic inflammation response and nutritional status was analyzed. Among the biomarkers, prognostic nutritional index (PNI) value of malignant IPMN patients was significantly lower than that of benign IPMN patients (P = 0.023), whereas PNI was not significant predictor for malignant IPMN. The multivariate analysis showed that a PNI < 43.5 (odds ratio [OR] 16.1, 95% CI 1.88-138.5, P = 0.011) and a carbohydrate antigen (CA) 19-9 level > 22.5 U/mL (OR 6.64, 95% CI 1.73-25.6, P = 0.006) were significant independent predictors of the presence of lymph node metastasis (LNM). Our scoring system developed based on these two factors. Patients with a score of 0 had no LNM and zero disease-related death. The present study suggested the roles of PNI on the IPMN patients who undergo curative pancreatectomy.

Mucinous adenocarcinoma of renal pelvis in a young male: a diagnostic challenge.

Primary mucinous adenocarcinoma of the renal pelvis is an extremely rare tumor with only a handful of cases reported to date. Clinical and radiological features are not specific, and hence, histopathological examination holds the key for definitive diagnosis. This tumor has mainly been described in the elderly population, with less than five cases reported in individuals aged <35 years. Here, we report a case of primary mucinous adenocarcinoma of the renal pelvis in a young male. A 31-year-old male presented with a history of right-sided flank pain for the past year. On examination, he had right-sided costovertebral tenderness. Computed tomography (CT) scan revealed the presence of a hyperdense mass lesion in the right renal pelvis with severe hydronephrosis and cortical thinning. Because of the non-functioning status, right nephrectomy was performed. To our surprise, histopathology showed the presence of mucinous adenocarcinoma of the renal pelvis with carcinoma in situ of the ureter. This case describes a rare presentation of primary mucinous adenocarcinoma of the renal pelvis, and highlights the importance of histopathological examination in reaching the correct diagnosis.

Spread through air spaces (STAS) in invasive mucinous adenocarcinoma of the lung: Incidence, prognostic impact, and prediction based on clinicoradiologic factors.

BACKGROUND: Spread through air spaces (STAS) has recently been demonstrated to exhibit a negative impact on lung adenocarcinoma prognosis. However, most of these studies investigated STAS in nonmucinous adenocarcinoma. Here, we investigated the incidence of STAS in invasive mucinous adenocarcinoma (IMA) of the lung and evaluated whether tumor STAS was a risk factor of disease recurrence in IMA. We also examined clinicoradiologic factors in patients with IMA harboring STAS. METHODS: We reviewed pathologic specimens and imaging characteristics of primary tumors from 132 consecutive patients who underwent surgical resection for IMA to evaluate STAS. Patients with and without STAS were compared with respect to clinical characteristics as well as computed tomography (CT) imaging using logistic regression. The relationships between all variables including STAS and survival were analyzed. RESULTS: Among a total of 132 patients, full pathologic specimens were available for 119 patients, and STAS was observed in 86 (72.3%). IMA patients with STAS were significantly associated with older age, presence of lobulated and spiculated margins on CT scan (P = 0.009, P = 0.006, and P = 0.027). In multivariate analysis for overall survival (OS), STAS was a borderline independent poor prognostic predictor (P = 0.028). Older age, history of smoking, higher T stage, presence of lymph node metastasis, and consolidative morphologic type remained independent predictors for OS. CONCLUSIONS: STAS was associated with reduced OS and was a borderline independent poor prognostic factor in IMA. IMA with STAS was associated with older age and presence of lobulated and spiculated margins on CT scan. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Compared with other subtypes, IMA shows a higher incidence of STAS, which is an independent poor prognostic predictor even in IMA. Lobulated and spiculated margins on CT are associated with STAS. WHAT THIS STUDY ADDS: Considering that STAS can carry the potential for aerogenous metastasis, predicting STAS using preoperative surrogate CT imaging is desirable to avoid limited resection.

Validation of the clinical utility of 4 guidelines in the initial triage of mucinous cystic lesions of the pancreas based on cross-sectional imaging: Experience with 188 surgically-treated patients.

INTRODUCTION: Over the years, several guidelines have been introduced to guide management of mucinous pancreatic cystic neoplasms (mPCN). In this study, we aimed to evaluate and compare the clinically utility of the Sendai-06, Fukuoka-12, Fukuoka-17 and European-18 guidelines in predicting malignancy of mPCN. METHODS: One hundred and eighty-eight patients with mucinous cystic neoplasms (MCN) or intraductal papillary mucinous neoplasm (IPMN) who underwent surgery were retrospectively reviewed and classified under the 4 guidelines. Malignancy was defined as high grade dysplasia and invasive carcinoma. RESULTS: Raised CA19-9>37U/ml, enhancing mural nodule≥5 mm and main pancreatic duct≥10 mm were significantly associated with malignancy on multivariate analysis. Increasing number of high risk features, absolute indications (European-18), worrisome risk or relative indications (European-18) were significantly associated with an increased likelihood of malignancy. The positive predictive values (PPV) of high risk features for Sendai-06, Fukuoka-12, Fukuoka-17 and absolute indications (European-18) for malignancy were 53%, 76%, 78% and 78% respectively. The negative predictive values (NPV) of the Sendai-06, Fukuoka-12 and Fukuoka-17 were 100%, while that of the European-18 was 92%. Risk of malignancy for patients with ≥4 worrisome features (Fukuoka-17) and ≥3 relative indications (European-18) was 66.7% and 75.0% respectively. CONCLUSIONS: All 4 guidelines studied were useful in the initial triage of mPCN for the risk stratification of malignancy. The Fukuoka-17 had the highest PPV and NPV.

Fistula Formation Secondary to Mucinous Appendiceal Adenocarcinoma May Be Related to a Favorable Prognosis: A Case Report and Literature Review.

A 90-year-old man was referred to our hospital because of a positive fecal occult blood test. Colonoscopy revealed a lesion with multiple nodules covered with abundant mucus at the hepatic flexure. Computed tomography showed a dilated appendix attached distally to the hepatic flexure. Right hemicolectomy was performed, and the pathological examination revealed a mucinous appendiceal adenocarcinoma infiltrating the hepatic flexure without pseudomyxoma peritonei. The patient is doing well without recurrence 12 months postoperatively. Extraperitoneal drainage of the malignant ascites caused by the fistula may allow for an early diagnosis, while also making it possible to successfully resect the lesion, thus resulting in a favorable outcome.

Resection of benign side-branch intraductal papillary mucinous neoplasm of the pancreas-is long term follow-up indicated?: A case report and review of the literature.

RATIONALE: Intraductal papillary mucinous neoplasms of the pancreas (IPMNs) are benign cystic tumors with a relevant risk of malignant transformation over time. Currently, follow-up after surgical resection of benign IPMNs remains controversial. PATIENT CONCERNS: This is a case report of a 68-year-old male who underwent pancreatic head resection for a multicystic side-branch IPMN with low-grade epithelial dysplasia in March 2009 at the Katharinenhospital Stuttgart, Germany. DIAGNOSES: During postoperative follow-up, a new solid, slightly hypodense lesion in the tail of the pancreas measuring 2.4 cm in diameter was diagnosed in July 2016. Preoperative staging revealed no signs of distant metastasis. INTERVENTION: Subsequently, the patient underwent pancreatic tail resection including splenectomy. Histology revealed IPMN-associated adenocarcinoma of the pancreas pT3, pN1 (2/24), M0, R0. OUTCOMES: Patients with IPMN bare a relatively high overall risk of developing pancreatic cancer. The 5-year incidence has been described to be as high as 6.9%. The current Consensus-Guidelines therefore recommend a structural life-time follow-up. In contrast, in 2015 the American Gastroenterological Association (AGA) explicitly states that follow-up is not recommended for resected benign IPMN. Currently, a general and international consensus is lacking. LESSONS: The presented case demonstrates that even more than 5 years following resection of benign IPMN, pancreatic cancer can occur in a separate location of the pancreatic gland. We believe that IPMNs can be considered as indicator lesions for pancreatic cancer. Patients with resected side-branch IPMN should therefore undergo long term follow-up.

Clinical and Prognostic Significance of Pathological and Inflammatory Markers in Mucinous Rectal Cancer Patients Receiving Neoadjuvant Chemoradiotherapy and Curative Surgery.

BACKGROUND The aim of this study was to investigate the clinical and prognostic significance of pathological and inflammatory marker in mucinous rectal cancer patients receiving neoadjuvant chemoradiotherapy and curative surgery. MATERIAL AND METHODS We retrospectively evaluated the patient records of mucinous rectal cancer patients receiving neoadjuvant chemoradiotherapy and curative surgery at Liaoning Cancer Hospital and Institute from January 2006 to December 2013. The relationship between overall survival (OS) and clinicopathologic variables, pretreatment neutrophil-to-lymphocyte ratio (NLR), pretreatment platelet-to-lymphocyte ratio (PLR), pretreatment lymphocyte-to-monocyte ratio (LMR), and other biomarkers were analyzed by using Kaplan-Meier analysis and log-rank testing. Subsequently a Cox proportional hazard model was used to calculate hazard ratios for the risk of death. RESULTS A total of 100 mucinous rectal cancer patients were included for analysis during the study period. The median age at presentation was 60.5 years (range, 26-81 years). The median overall survival (OS) for the whole group was 94 months. On univariate analysis, time interval from CCRT to operation (HR 0.37, p=0.03), lymphovascular invasion (HR 3.23, p=0.009), pretreatment NLR (HR 3.87, p=0.012), and LMR (HR 0.31, p=0.002) were significant prognostic factors for OS. In a multivariate analysis, pretreatment LMR was found to be an independent prognostic factor for overall survival (HR, 0.43; 95%CI, 0.18 to 1.00, p=0.045). CONCLUSIONS Pretreatment lymphocyte-to-monocyte ratio is a useful prognostic marker of OS in patients with mucinous rectal carcinoma treated with neoadjuvant chemoradiotherapy and curative surgery.

Overinterpretation is common in pathological diagnosis of appendix cancer during patient referral for oncologic care.

CONTEXT: Low-grade appendiceal mucinous neoplasm (LAMN) and appendiceal adenocarcinoma are known to cause the majority of pseudomyxoma peritonei (PMP, i.e. mucinous ascites); however, recognition and proper classification of these neoplasms can be difficult despite established diagnostic criteria. OBJECTIVE: To determine the pathological diagnostic concordance for appendix neoplasia and related lesions during patient referral to an academic medical center specialized in treating patients with PMP. DESIGN: The anatomic pathology laboratory information system was searched to identify cases over a two-year period containing appendix specimens with mucinous neoplasia evaluated by an outside pathology group and by in-house slide review at a single large academic medical center during patient referral. RESULTS: 161 cases containing appendix specimens were identified over this period. Forty-six of 161 cases (28.6%) contained appendiceal primary neoplasia or lesions. Of these, the originating pathologist diagnosed 23 cases (50%) as adenocarcinoma and 23 cases (50%) as LAMN; however, the reference pathologist diagnosed 29 cases (63.0%) as LAMN, 13 cases (28.3%) as adenocarcinoma, and 4 cases (8.7%) as ruptured simple mucocele. Importantly, for cases in which the originating pathologist rendered a diagnosis of adenocarcinoma, the reference pathologist rendered a diagnosis of adenocarcinoma (56.5%, 13 of 23), LAMN (39.1%, 9 of 23), or simple mucocele (4.3%, 1 of 23). The overall diagnostic concordance rate for these major classifications was 71.7% (33 of 46) with an unweighted observed kappa value of 0.48 (95% CI, 0.27-0.69), consistent with moderate interobserver agreement. All of the observed discordance (28.3%) for major classifications could be attributed to over-interpretation. In addition, the majority of LAMN cases (65.5%) had potential diagnostic deficiencies including over-interpretation as adenocarcinoma and lacking or discordant risk stratification (i.e. documentation of extra-appendiceal neoplastic epithelium). CONCLUSIONS: Appendiceal mucinous lesions remain a difficult area for appropriate pathological classification with substantial discordance due to over-interpretation in this study. The findings highlight the critical need for recognition and application of diagnostic criteria regarding these tumors. Recently published consensus guidelines and a checklist provided herein may help facilitate improvement of diagnostic concordance and thereby reduce over-interpretation and potential overtreatment. Further studies are needed to determine the extent of this phenomenon and its potential clinical impact.

Expression of unusual immunohistochemical markers in mucinous breast carcinoma.

BACKGROUND: Mucinous breast carcinoma is characterized by the production of variable amounts of mucin. Some studies have addressed immunohistochemical characterization of mucinous breast carcinoma using a limited set of antibodies. However, the purpose of the present study was to investigate a larger panel of markers not widely used in daily practice and to determine their pathological implications. METHODS: Forty patients diagnosed with mucinous breast carcinoma were enrolled. An immunohistochemical study was performed on whole sections of paraffin embedded tissue, using antibodies for the following markers: estrogen receptor alpha and beta, progesterone receptor, androgen receptor, HER2, EGFR, Ki-67, E-cadherin, ß-catenin, p53, chromogranin, synaptophysin, GCDFP15, mammaglobin, and CDX2. RESULTS: The pure mucinous type was more prevalent in older patients and more frequently expressed GCDFP15. Capella type B presented more frequently with a high Ki-67 index and neuroendocrine differentiation. Although there was a lower frequency of vascular invasion and lymph node metastases in the pure type, the difference was not statistically significant. No case expressed CDX2 (a marker for gastrointestinal tumors), while 85% of the cases expressed at least one of the two typical breast markers (GCDFP15 and mammaglobin), suggesting that these markers may be reliably used for differential diagnosis. Expression of estrogen receptor beta was related to the presence of mucin cell producing lymph node metastasis, with potential prognostic and predictive value. CONCLUSION: our findings support the immunohistochemical homogeneity of mucinous breast carcinomas because only minor differences were found when subgrouping them into Capella types A and B or into types pure and mixed.

Epithelial to mesenchymal transition might be induced via CD44 isoform switching in colorectal cancer.

BACKGROUND: Isoform switching of CD44 is associated with epithelial to mesenchymal transition (EMT) in several cancers; however, the clinical implications of this remain unclear for colorectal cancer (CRC). METHODS: We measured expression levels of E-cadherin, vimentin, CD44 standard (CD44s) and CD44 variant 9 (CD44v9) transcripts in 14 CRC cell lines and 150 CRC patients. We determined EMT and CD44 status by calculating vimentin/E-cadherin and CD44s/CD44v9 expression ratios, respectively. Associations between EMT status and CD44 isoform switching, and between clinicopathological factors and prognosis were analyzed. RESULTS: CD44s was highly expressed in mesenchymal-type cell lines, while CD44v9 was highly expressed in epithelial-type cell lines. CD44 knockdown resulted in decreased levels of vimentin expression, and significantly reduced proliferation, migration and invasion of cells. In CRC patients, the mesenchymal group and the high CD44 status group exhibited significantly poorer survival than that for the epithelial group (5-year survival; 62.1% vs. 85.5%, P = 0.0085) and the low CD44 status group (5-year survival; 66.1% vs. 85.0%, P = 0.0251). On multivariate analysis, CD44 status was an independent prognostic factor. CONCLUSIONS: The status of EMT and CD44 is a critical prognostic factor, with CD44 isoform switching a possible trigger for EMT in CRC.

Mucinous breast carcinoma with a lobular neoplasia component: a subset with aberrant expression of cell adhesion and polarity molecules and lack of neuroendocrine differentiation.

We investigated whether some mucinous carcinomas (MUCs) are associated with lobular neoplasia (LN) components, and if so, whether this subset has any distinct biological properties. MUC specimens from 41 patients were stratified into pure and mixed types. The LN components adjacent to MUC lesions were examined histopathologically. We also tested immunohistochemically for E-cadherin, ß-catenin, and the neuroendocrine markers chromogranin A and synaptophysin; and compared results between MUCs with and without LN. Of 41 patients with MUC, LN was detected in 12 patients (29%); LN alone was the noninvasive component in 8 patients (20%). Decreased E-cadherin and ß-catenin expression in the MUC component was detected in 2 (17%) and 7 (58%) cases, respectively, of MUC with LN, compared with 0% (P = 0.080) and 21% (P = 0.018) in MUCs without LN. Neuroendocrine factors were frequently detected in MUCs with LN (42%) and without LN (52%), but tended to be less frequent in MUCs with only LN components (25%) than in other MUCs (55%; P = 0.133). MUCs associated with LN components appear to be a biologically characteristic subset that frequently shows decreased cell-cell adhesion, cell polarity molecules and lack of neuroendocrine differentiation.

Signet ring cell adenocarcinoma of the lung with an EML4-ALK fusion gene mimicking mucinous (colloid) adenocarcinoma: a case report.

We herein report a case of signet ring cell adenocarcinoma of the lung with an EML4-ALK fusion gene mimicking mucinous (colloid) adenocarcinoma. A 79-year-old female presented with a pulmonary tumor located in the right lower lobe measuring 21 mm in size. A right lower lobectomy was performed. The postoperative pathological examination revealed signet ring cell carcinoma with abundant mucin pools, and a multiplex RT-PCR analysis revealed the variant 2 inversion of the EML4-ALK gene.

Genomic profiling of papillary renal cell tumours identifies small regions of DNA alterations: a possible role of HNF1B in tumour development.

AIMS: Papillary renal cell tumours (RCT) are characterized by specific trisomies. The aim of this study was to identify small regions of duplication marking putative tumour genes. METHODS AND RESULTS: Full-tiling path bacterial artificial chromosome (BAC) array hybridization of 20 papillary RCTs confirmed the duplication of chromosomes 7 and 17 and also displayed smaller regions of gains/amplifications of 1.3-13.1 Mb in size. Detailed analysis showed a microamplification of BAC clones containing the MET at the 7q31.2 and also amplification of a DNA segment harbouring the transcription factor hepatocyte nuclear factor 1 beta (HNF1B) at chromosome 17q12. Nuclear expression of HNF1B protein was detected in 38 of 67 papillary RCTs, in five of five mucinous tubular and spindle cell carcinomas (MTSCC) and five of five metanephric adenomas by immunohistochemistry. Moreover, nine nephrogenic rests containing tubular differentiated structures and all 14 and five precursor lesions associated with papillary RCTs and MTSCCs, respectively, showed strong nuclear positivity when compared to the expression level in proximal tubules of the corresponding normal kidney. CONCLUSIONS: Our findings indicate a role of HNF1B in association with the high frequency of chromosome 17q duplication in the development of papillary RCTs and MTSCCs as well as in their precursor lesions.

The prognostic value of p73 overexpression in colorectal carcinoma: a clinicopathologic, immunohistochemical, and statistical study of 204 patients.

INTRODUCTION: The protein p73 is the first identified homolog of the tumor suppressor gene p53, but its function in tumor development has not been established. Indeed, the results regarding the p73 implication in colorectal cancers is still controversial. AIM: We investigated whether the p73 is implicated in colorectal cancer, whether the p73 expression is related to prognosis and whether the p73 expression is correlated with p21-ras or p53. MATERIALS AND METHODS: We performed a comparative immunohistochemical analysis of p73, p53, and p21ras proteins in primary colorectal tumor with matched normal mucosa and metastasis from 204 patients with colorectal cancer. We correlated these expressions with clinicopathologic variables and we compared the different profiles between nonmucinous carcinoma and mucinous carcinoma. RESULTS: In this study, we did not find any correlation between p73 expression, sex, age, site, differentiation and stage. Overexpression of p73 was significantly correlated with infiltrating growth pattern (P<0.0001) and nonmucinous carcinoma (P<0.0001). Furthermore, frequency and intensity of p73 expression were marquedly increased from normal mucosa (26%), to primary tumors (75%) and to metastasis (97%). Furthermore, expression of p73 was also correlated with shorter survival period. The prognostic significance of p73 expression remained, even after adjustment for the clinical and pathologic variables. The p73 expression was positively correlated only with p21ras expression (P<0.0001). CONCLUSIONS: All these findings prove that p73 expression should be considered as a valuable poor prognostic marker. Our data also suggest that TP73 gene may play a role in colorectal carcinoma development.

Non-mucinous and mucinous subtypes of adenocarcinoma with bronchioloalveolar carcinoma features differ by biomarker expression and in the response to gefitinib.

There is no optimal established therapy for treating advanced or recurrent adenocarcinoma with bronchioloalveolar carcinoma features (ADC-BAC), and it remains unclear whether chemotherapy achieves therapeutic results comparable to those seen in the more common non-small lung carcinoma subtypes. In order to improve the decisions made during the treatment of advanced ADC-BAC, we attempted to better characterize the mucinous and non-mucinous ADC-BAC subtypes. Fifty pathological samples were obtained from 62 patients included in a multicenter prospective phase II trial (IFCT0401) conducted to evaluate gefitinib as a first-line therapy for non-resectable ADC-BAC. These samples were centrally reviewed and re-classified as non-mucinous (n=25) or mucinous (n=25) subtypes. We demonstrated that demographic data, clinical characteristics and stage at presentation (extrathoracic versus lung metastasis, as well as TNM staging) did not distinguish between the two subtypes. In contrast, three biological markers (PAS staining, TTF-1 expression and EGFR genomic gain combined with mutation analysis) enabled us to independently segregate all but 2 of the 50 patients into the mucinous and non-mucinous ADC-BAC subtypes. Finally, only mucinous tumors appeared to be resistant to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Additional prospective studies are required to better approach therapeutic strategy in mucinous tumors, which are a distinct entity from non-mucinous tumors.

The reduction in pigment epithelium-derived factor is a sign of malignancy in ovarian cancer expressing low-level of vascular endothelial growth factor.

BACKGROUND: Angiogenesis is a critical factor in the progression of solid tumors and metastasis. The aim of this study was to characterise the roles of angiogenic and anti-angiogenic factors on ovarian cancer. METHODS: The expression levels of vascular endothelial growth factor (VEGF, angiogenic factor) and pigment epithelial growth factor (PEDF, anti-angiogenic factor) were measured by real-time polymerase chain reaction and Western blotting in ovarian tumors. Microvessel density (MVD) was evaluated by the total microvessel length in high-power field of tumor tissue preparations. RESULTS: MVD correlated with tumor malignancy. The tissues with the highest expression levels of VEGF (VEGF-H) were malignant tumors. The VEGF expression levels in some malignant tumors (VEGF-L) were as low as that in benign tumors. Therefore, the expression of PEDF was examined. The PEDF expression levels in VEGF-L malignant tumors were significantly lower than those in benign tumors. On the other hand, the PEDF expression levels in VEGF-H malignant tumor tissues were not significantly different from those in benign tumors. CONCLUSION: The reduction in PEDF expression levels may be, in part, responsible for tumor malignancy in VEGF-L ovarian tumors. Furthermore, PEDF may be a useful marker of malignancy in VEGF-L ovarian tumors.