Interdisciplinary Spanish consensus on a watch-and-wait approach for rectal cancer.

Watch-and-wait has emerged as a new strategy for the management of rectal cancer when a complete clinical response is achieved after neoadjuvant therapy. In an attempt to standardize this new clinical approach, initiated by the Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD), and with the participation of the Spanish Association of Coloproctology (AECP), the Spanish Society of Pathology (SEAP), the Spanish Society of Gastrointestinal Endoscopy (SEED), the Spanish Society of Radiation Oncology (SEOR), and the Spanish Society of Medical Radiology (SERAM), we present herein a consensus on a watch-and-wait approach for the management of rectal cancer. We have focused on patient selection, the treatment schemes evaluated, the optimal timing for evaluating the clinical complete response, the oncologic outcomes after the implementation of this strategy, and a protocol for surveillance of these patients.

Towards standardization of lymph-node ratio classifications: Validation and comparison of different lymph node ratio classifications for predicting prognosis of patients with resected gastric cancer.

INTRODUCTION: The TNM staging system is the main prognostic tool for GC, but the number of metastatic lymph nodes (LN) can be affected by surgical, pathological, tumor or host factors. Several authors have shown that lymph node ratio (LNR) may be superior to TNM staging in GC. However, cut-off values vary between studies and LNR assessment is not standardized. MATERIAL AND METHODS: Retrospective study of all GC resected in a western tertiary center (N = 377). Clinical features were collected and pathological features were assessed by two independent pathologists. Eight LNR classifications were selected and applied to our patients. Statistical analyses were performed. RESULTS: 315 patients were included. Most tumors were T3 (49.2%) N+ (59.3%). During follow-up, 36.7% of patients progressed and 27.4% died due to tumor. All LNR classifications were significantly associated with clinicopathological features such as Laurén subtype, lymphovascular invasion, perineural infiltration, T stage, tumor progression or death. All LNR classifications were independent prognostic factors for OS and DFS, and ROC analyses calculated similar AUC values for all staging systems. Kaplan-Meier curves showed that Pedrazzani, Wang, Liu and Huang classifications stratified patients better into three (Pedrazzani) or four categories. These classifications tended to downstage TNM N2 and N3 tumors. In cases with less than 16 LNs resected, Pedrazzani and Wang classifications showed the best prognostic performance. CONCLUSIONS: Pedrazzani, Wang, Liu and Huang classifications showed good prognostic performance in western GC patients. Larger studies in other cohorts are needed to identify the most consistent LNR classification for GC.

Ber-EP4 staining in effusion cytology: A potential source of false positives.

The distinction between reactive mesothelium and carcinoma in serous effusions can be very difficult. Immunocytochemistry (ICC) is the most widely used tool to improve the diagnostic accuracy of body fluid cytology, with several ICC markers being proposed. Ber-EP4 antibody has shown high sensitivity and specificity rates for diagnosing metastatic carcinoma. In our department, we have detected Ber-EP4 positivity in mesothelium in some cytological specimens. We reviewed all articles on Ber-EP4 staining in effusion cytology, summarized current findings and analyzed the staining pattern of all cases expressing Ber-EP4. Some cases showing Ber-EP4 positivity in mesothelium have been reported, most of which showed only weak Ber-EP4 staining or staining of less than 50% of mesothelial cells. However, some cases may show strong positivity both in cytological and histological specimens. Clinicians and pathologists should be aware of this source of misdiagnosis, and ICC results in mesothelium should be always interpreted cautiously and correlated with clinical tests, other ICC markers and patient's previous history.

Is there still a place for conventional histopathology in the age of molecular medicine? Laurén classification, inflammatory infiltration and other current topics in gastric cancer diagnosis and prognosis.

Gastric cancer (GC) is the fifth most common cancer and the third cause of cancer-related deaths worldwide. In western countries, more than half of GC patients are diagnosed at advanced stages and 5-year survival rates range between 20-30%. The only curative treatment is surgery, and despite recent advances in oncological therapies, GC prognosis is still poor. The main prognostic tool for patient categorization and treatment selection is the TNM classification, but its limitations are being increasingly recognized. Early recurrences may occur in early-stage disease, and patients at the same stage show heterogeneous outcomes. Thus, there is a need to improve GC stratification and to identify new prognostic factors, which may allow us to select drug-susceptible populations, refine patient grouping for clinical trials and discover new therapeutic targets. Molecular classifications have been developed, but they have not been translated to the clinical practice. On the other hand, histological assessment is cheap and widely available, and it is still a mainstay in the era of molecular medicine. Furthermore, histological features are acquiring new roles as reflectors of the genotype-phenotype correlation, and their potential impact on patient management is currently being analyzed. The aim of this literature review is to provide a modern overview of the histological assessment of GC. In this study, we discuss recent topics on the histological diagnosis of GC, focusing on the current role of Laurén classification and the potential value of new histological features in GC, such as inflammatory infiltration and tumor budding.

Development of a simplified tumor-lymph node ratio classification system for patients with resected gastric cancer: A western study.

INTRODUCTION: Gastric cancer (GC) shows high recurrence and mortality rates. The AJCC TNM staging system is the best prognostic predictor, but lymph node assessment is a major source of controversy. Recent studies have found that lymph node ratio (LNR) may overcome TNM limitations. Our aim is to develop a simplified tumor-LNR (T-LNR) classification for predicting prognosis of resected GC. METHODS: Retrospective study of all GC resected in a tertiary center in Spain (N = 377). Clinicopathological features were assessed, LNR was classified into N0:0%, N1:1-25%, N2:>25%, and a T-LNR classification was developed. Statistical analyses were performed. RESULTS: 317 patients were finally included. Most patients were male (54.6%) and mean age was 72 years. Tumors were intestinal (61%), diffuse (30.8%) or mixed (8.1%). During follow-up, 36.7% and 27.4% of patients progressed and died, respectively. T-LNR classification divided patients into five prognostic categories (S1-S5). Most cases were S1-S4 (26.2%, 19.9%, 22.6% and 23.6%, respectively). 7.6% of tumors were S5. T-LNR classification was significantly associated with tumor size, depth, macroscopical type, Laurén subtype, signet ring cells, histologic grade, lymphovascular invasion, perineural infiltration, infiltrative growth, patient progression and death. Kaplan-Meier curves for OS showed an excellent patient stratification with evenly spaced curves. As for DFS, T-LNR classification also showed good discriminatory ability with non-overlapping curves. T-LNR classification was independently related to both OS and DFS. CONCLUSIONS: T-LNR classifications can successfully predict prognosis of GC patients. Larger studies in other geographic regions should be performed to refine this classification and to validate its prognostic relevance.

Prognostic Role of Aryl Hydrocarbon Receptor Interacting Protein (AIP) Immunohistochemical Expression in Patients with Resected Gastric Carcinomas.

Aryl hydrocarbon receptor (AHR) interacting protein (AIP) is a chaperone which binds to inactive AHR in the cell cytoplasm. AHR is best known for mediating the toxicity of halogenated aromatics, but it has also been linked to carcinogenesis and tumor progression in several tumor types. Our aims are to assess the features of AIP immunohistochemical (IHC) staining and to evaluate its possible role as a prognostic marker in gastric cancer (GC). Retrospective study of 147 cases of resected GC. Clinicopathological features were collected, tissue microarrays were constructed for AIP IHC and statistical analysis were performed. AIP staining was observed in 50.3% of tumors. All AIP-positive cases exhibited cytoplasmic or membranous staining, variably associated with nuclear co-staining. 93.2% of AIP-positive tumors showed AIP immunoreactivity in 100% of cells. Staining intensity was mild, moderate and intense in 33.8%, 13.5% and 52.7% of cases. Tumors were stratified according to AIP staining intensity into low expression (no or mild AIP immunoreactivity) and high expression (moderate or intense AIP immunoreactivity). 36.6% of our cases showed high AIP expression. High AIP expression was significantly and independently correlated to tumor progression and cancer death. Tumors with high AIP expression showed lower survival and higher progression rates. AIP expression might be useful for determining GC prognosis. More studies are needed to clarify the role of AHR pathway in GC, AIP expression and its potential use as a surrogate marker for selecting patients for AHR modulation therapy.

Identification and Validation of Stage-Associated Serum Biomarkers in Colorectal Cancer Using MS-Based Procedures.

PURPOSE: Successful prevention of colorectal cancer (CRC) would benefit from a rapid serum screening for early detection. Here, a novel strategy for CRC biomarker discovery and validation exclusively based on MS procedures is reported. EXPERIMENTAL DESIGN: Identification of CRC serum biomarkers is initially made using label-free quantification on pooled serum samples from different CRC stages followed by two consecutive steps of targeted parallel reaction monitoring assays in different serum cohorts. Relevance of different protein depletion and peptide fractionation extent is investigated. Absolute quantification of a selected peptide is performed as a proof-of-concept. RESULTS: A total of 945 proteins showed differential abundance in the discovery phase. Based on their statistical significance and relative expression in disease stages, 123 potential biomarkers are selected for a training step. In the final validation step, five peptides belonging to four proteins are consistently quantified in individual CRC serum samples and controls. Different statistical analyses indicate that peptides GWVTDGFSSLK (APOC3) and LCNNPTPQFGGK (THBS1) are candidate biomarkers. Absolute quantification of LCNNPTPQFGGK shows statistical significance for the diagnosis of early respect to late CRC stages. CONCLUSIONS AND CLINICAL RELEVANCE: Two peptides from APOC3 and THBS1 are validated by PRM as potential biomarkers for non-invasive diagnosis of colorectal cancer.

Distribution of cervical lesions in young and older women.

INTRODUCTION: Age range for cervical screening varies widely between countries. In addition, sexual behavior has changed, life expectancy is increasing, and new insights have been gained into the pathogenesis of HPV infection. Our aim is to evaluate the distribution of cervical lesions in young and older patients. METHODS: Review of all cervical smears diagnosed in a public institution (2010-2017) and a private institution (2016-2017) in Madrid, Spain. We have included all women aged younger than 30 and older than 65 years with atypical smears (n = 1573). RESULTS: Women younger than 30 years were diagnosed with ASCUS, ASC-H, LSIL, and HSIL in 47%, 5.3%, 45.17%, and 2.6% of atypical cases, respectively. Women older than 65 years were diagnosed with ASCUS, ASC-H, LSIL, HSIL, and SCC in 38%, 12.39%, 16.8%, 13.27%, and 19.5% of atypical cases, respectively. Medical records of patients from the public institution were reviewed. Of note, 76.3% of young women showed negative smears at follow-up and 14.1% showed high-grade dysplasia (HGD). Mean ages for low-grade and HGD were 24.7 and 25.7 years, respectively. HGD was found in 37.9% of women with histological examination (33.5%). As for older patients, 25% of them had no Pap smears performed before age 65, and in 60% of the previously screened women, the screening program had not been used adequately. Mean age of first smear was 69.5 years. Carcinoma was subsequently detected in 20.7% of patients. CONCLUSIONS: Current guidelines seem to be adequately preventing carcinoma in young women. However, screening adherence should be encouraged to detect important lesions in both age groups, especially among older women.

Role of fine needle aspiration cytology in the management of supraclavicular lymph node metastasis: Review of our experience.

INTRODUCTION: In the 19th century Virchow described that metastasis to left supraclavicular lymph nodes (SLN) could originate in neoplasms located under the diaphragm. In the same way, right SLN metastasis are usually thought to arise from thoracic neoplasms. Our aims are to review our experience with metastatic SLN diagnosed by fine-needle aspiration cytology (FNAC) and to discuss the location of the primary in these cases. METHODS: We have reviewed all lymph node FNACs diagnosed in a single tertiary hospital between 2010 and 2017 and we have included all cases of metastatic SLN. RESULTS: We have found 57 cases of SLN FNAC with a diagnosis of malignancy, 39 of which had no previous diagnosis (17 left, 20 right and 2 bilateral SLN). The most frequent diagnosis were adenocarcinoma, squamous cell carcinoma and small cell carcinoma. Right and bilateral SLN showed mainly lung metastasis. Left lesions were more widely distributed, with 11 originating in the lung, followed by the breast, gastroesophageal junction and prostate gland. In two cases, the primary origin was not identified. In SLN with metastasis of a known origin, the main source of the tumor was again the lung and only one case originated in the stomach (left SLN metastasis). CONCLUSIONS: The origin of SLN metastasis seems to be dependent on both the frequency of tumor types in each geographic area and tumor location. Left SLN are more frequently involved by infradiaphragmatic primary tumors, while right SLN are exclusively involved by supradiaphragmatic neoplasms.

Immunohistochemical classification of gastric cancer based on new molecular biomarkers: a potential predictor of survival.

Several classification systems have been described for stratifying patients with gastric carcinoma (GC). However, their prognostic value is low, and there is an urgent need for identification of molecular markers and development of new classifications. Retrospective study of 206 cases of GC diagnosed and surgically resected in our hospital between 2000 and 2017. Clinicopathological features of all cases were assessed and tissue microarrays were constructed for immunohistochemical (IHC) study. Patients were stratified based on IHC results. Mean patient age was 71 years and most patients were male (54.6%). Most tumors were located in the gastric antrum and body, and they were mostly fungoid or ulcerative lesions. GC were mainly intestinal-type tumors and 60.3% were diagnosed at pT3. 56.2% of patients showed recurrences and 29.4% died due to GC. According to our IHC classification, 23.5% of tumors showed microsatellite instability, 6% were E-cadherin negative, 53.5% were stable-p53 not overexpressed, and 17% were stable with p53 overexpression. IHC classification was significantly correlated with patient gender, gross morphology, Laurén classification, tumor necrosis, perineural infiltration, type of leading edge, and patient outcome. Multivariate analysis showed that IHC subtype was significantly and independently associated with overall survival, together with clinical symptoms, signet cell phenotype, tumor grade and vessel invasion. The application of IHC classifications based on molecular biomarkers in clinical practice can aid in the stratification of GC patients. More studies are needed to evaluate the reproducibility and clinical significance of these classifications.

Neuroendocrine Neoplasms in Rare Locations: Clinicopathological Features and Review of the Literature.

INTRODUCTION: Neuroendocrine tumors (NETs) occur more often in lungs, gastrointestinal tract, or pancreas. Data about terminology and grading of NETs in rare locations are scarce and variable, and they have been reported mainly as case reports. MATERIALS AND METHODS: We here describe our experience with NETs in unusual locations. We have reviewed all NETs diagnosed in our institution and summarized their clinicopathological features. We have also reviewed the literature and discussed the main characteristics of NETs in each site. RESULTS: Two hundred and forty-three primary NETs were diagnosed. About 55.2% of patients were men and the mean age was 62 years. About 90.7% of NETs were located in lungs, gastrointestinal tract, or pancreas, and 50.8% of them were low-grade tumors. We identified 13 NETs in rare locations: breast, ovary, endometrium, vulva, uterine cervix, extrahepatic biliary tract, kidney, sinonasal tract, and thymus. Three additional tumors were diagnosed by the senior author in other institution. Patients were asymptomatic or presented with nonspecific symptoms. All NETs were treated with surgery and 31% of patients received adjuvant therapy. There were 10 Grade 3 (62.5%), 2 Grade 2 (12.5%), and 4 Grade 1 (25%) tumors. Mean follow-up was 72 months. About 60% of G3 tumors recurred or progressed. G2 tumors were located in breast, and both patients are stable. About 50% of G1 tumors recurred or progressed (both renal NETs). CONCLUSIONS: NETs in rare locations are heterogeneous, and their behavior does not seem to correlate absolutely with tumor grade. More studies are needed to clarify the role of proliferation rate in these tumors.

Molecular diagnostic techniques in cytopathology: From the bench to the patient's bedside.

Molecular techniques are increasingly used in everyday practice for patient diagnosis and also to guide therapy. Their application in cytological specimens can allow a more cost-effective management with fewer risks. However, standardized protocols are needed to guarantee accurate and reproducible results. We herein report five practical examples of the application of ancillary techniques in cytopathology and review the literature on the issue, highlighting the practical aspects of sample management.

Lymphoepithelioma-like carcinoma of the large intestine: A case report and literature review.

Lymphoepithelioma like carcinoma (LELC) is a well-known neoplastic lesion that mainly involves the stomach and which has been linked to Epstein Barr virus infection. There are exceptional cases of intestinal involvement by LELC, with 7 reported cases to date. We report a new case of LELC affecting the right colon and review the literature on this rare disorder, with special emphasis on pathogenesis, molecular features and differential diagnosis.

Histiocytic sarcoma with bladder involvement: Case report and literature review.

We report an unusual case of histiocytic sarcoma with bladder involvement. An 80 year-old man with a previous history of diffuse large B-cell malignant lymphoma presented with hematuria and back pain. Serial urine cytologies revealed no urothelial malignant cells, but cystoscopy showed a large intravesical mass. The patient underwent transurethral resection (TUR) of the tumor. The bladder TUR specimen showed a widely infiltrating epithelioid neoplasm, with intense immunohistochemical positivity for CD45 and histiocytic markers (CD68, lysozime and fascin). Histopathological diagnosis was histiocytic sarcoma. As the patient's condition was progressively deteriorating, only palliative care was indicated and he died one month after TUR. Although histiocytic sarcoma can often be widespread at the time of diagnosis, to our knowledge, this is the first report of a case presenting with urinary symptoms. Histiocytic sarcoma can mimic many other malignant lesions, and only immunohistochemistry can define the tumor cells, allowing correct therapy. We discuss the differential diagnosis and possible associations.

Eosinophilic colitis: Case series and literature review.

INTRODUCTION: Primary eosinophilic colitis (EC) in adults is a rare and poorly studied disease, with 3 case series, 2 database-based studies and 52 case reports published to date. METHODS: Retrospective study of all adult EC cases diagnosed in a large tertiary hospital (Hospital Clínico San Carlos, Madrid) between 2006 and 2016. We included all cases with a histopathological diagnosis of EC and we selected only those cases that were clinically recognized primary EC. We report their clinical, endoscopic and histopathological features and review the literature on this topic. RESULTS: We identified 22 primary EC cases. Patients were mostly women (77%) with a mean age of 41 years. 4 patients (18%) had coexistent allergic diseases. Most patients consulted with diarrhea (86%) and 3 patients also suffered from rectal bleeding. Blood tests showed peripheral eosinophilia in 4 cases (18%). 19 patients had no endoscopic lesions, 2 had features of unspecific colitis and one showed features suggestive of IBD. Mean and maximum number of eosinophils per high power field ranged from 16 to 199 and 20 to 253 (mean: 48 and 70). They were mainly located in the lamina propria and most cases were associated with signs of eosinophil activation. Most patients were treated by corticosteroids, diet or budesonide and the result of treatment was generally good. No complications or recurrences were reported. CONCLUSIONS: EC etiology and pathogenesis is unknown. Its clinical, endoscopical and imaging features are not specific, and clear histopathological criteria are lacking. Identification of signs of eosinophilic activation could be helpful.

Biphasic axillary synovial sarcoma diagnosed by preoperative fine-needle aspiration cytology.

Synovial sarcoma (SS) is a soft-tissue sarcoma which usually occurs in lower extremities. Less than 20 cases of SS located in shoulder or axillary region have been reported, and these studies describe histopathological features. We report a case of axillary SS diagnosed by fine-needle aspiration cytology, immunocytochemistry, and molecular techniques performed on cytology smears. A 48-year-old woman presented with a palpable and well-defined axillary mass which measured 4 cm. On-site smears showed high cellularity with spindle cells, and a mesenchymal tumor was suspected. Definitive cytological analysis showed cells with ovoid- or comma-shaped nuclei arranged in loose sheets and fascicles, associated with naked nuclei and isolated cells. Mitotic count was 2 mitoses/HPF. Immunocytochemical studies showed vimentin and focal CK AE1-AE3 positivity. A PCR was performed and the specific translocation t(X;18) was detected. The lesion was excised and the diagnosis of biphasic SS was confirmed. The identification of SS on cytology specimens is difficult and differential diagnosis is broad. Complementary studies are necessary and they can be performed on FNA smears or cell blocks.