Vestibular schwannoma: care for soft tissues and subperineural dissection: how I do it.

BACKGROUND: Recognition of the right surgical cleavage plane of a vestibular schwannoma is mandatory to preserve the facial nerve function. METHOD: We describe here our surgical technique that is focused on soft tissues preservation and on subperineural dissection, avoiding direct exposure of the acoustico-facial complex in order to preserve facial nerve function. CONCLUSION: Soft tissue dissection helps in reducing patient's postoperative discomfort. Meticulously keeping a subperineural plan of dissection enables to preserve facial nerve function while offering satisfying resection rates.

Can Extraprostatic Extension Be Predicted by Tumor-Capsule Contact Length in Prostate Cancer? Relationship With International Society of Urological Pathology Grade Groups.

OBJECTIVE. The objective of our study was to evaluate the relationship between the tumor-capsule contact length, defined as tumor contact length (TCL), and extraprostatic extension (EPE) using the MRI-based TCL measurements and the real TCL measurements from pathology and to determine whether the International Society of Urological Pathology (ISUP) grade group of the tumors influenced this relationship. MATERIALS AND METHODS. In this retrospective study, we reviewed prostate multiparametric MRI (mpMRI) studies performed between 2012 and 2018 of 1576 patients and found that 134 patients also underwent radical prostatectomy (RP) after mpMRI. Finally, 86 patients with index lesions in contact with the prostate capsule in RP specimens were enrolled in the study. ROC analysis was used to evaluate the cutoff values of TCLs measured at pathology and TCLs measured on MRI in terms of EPE according to ISUP grade groups. RESULTS. There was no statistically significant cutoff value for pathology-based TCL measurements in individual ISUP grade groups and subgroups. Although not statistically significant, pathology-based TCL cutoff values decreased (from 21.0 to 11.0 mm) as ISUP grade group increased in terms of EPE positivity. When the relationship between MRI-based TCL measurements and EPE was considered, statistically significant cutoff values (range, 14.5-16.6 mm) could be determined in many groups and subgroups with low ISUP grades (sensitivity, 66.7-100%; specificity, 52.8-93.0%; p = 0.006-0.042). However, no statistically significant cutoff value was found for high ISUP grades. CONCLUSION. ISUP grade groups may have an effect on the TCL-EPE relationship. When the MRI-based TCL and EPE relationship is evaluated independent of ISUP grade group, a cutoff value around 15-16 mm may be usable to predict EPE.

3D MR Elastography of Hepatocellular Carcinomas as a Potential Biomarker for Predicting Tumor Recurrence.

BACKGROUND: Preoperative prediction of tumor recurrence is important in the management of patients with hepatocellular carcinoma (HCC). PURPOSE: To investigate whether tumor stiffness derived by magnetic resonance elastography (MRE) could predict early recurrence of HCC after hepatic resection. STUDY TYPE: Retrospective. POPULATION: In all, 99 patients with pathologically confirmed HCCs after surgical resection. FIELD STRENGTH/SEQUENCE: 3.0T; preoperative MRE with 60-Hz mechanical vibrations using an active acoustic driver. ASSESSMENT: Regions of interest (ROIs) were manually drawn in the tumors to measure mean tumor stiffness. Surgical specimens were reviewed for histological grade, capsule, vascular invasion, and surgical margins. The early recurrence of HCC was defined as that occurring within 2 years after resection. STATISTICAL TESTS: Cox proportional hazard models were used to evaluate risk factors associated with the time to early recurrence. RESULTS: HCCs with recurrence had higher tumor stiffness, higher rate of advanced T stage, vascular invasion, lower rate of capsule formation, larger tumor size, higher aspartate aminotransferase (AST), and hepatitis B virus (HBV)-DNA level and aspartate aminotransferase / alanine aminotransferase ratio (P = 0.031, 0.007, 0.01, <0.001, 0.015, 0.034, 0.01, and 0.014, respectively) than HCCs without recurrence. Vascular invasion (hazard ratio [HR] = 2.922; 95% confidence interval [CI]: [1.079, 7.914], P = 0.035) and mean tumor stiffness (HR = 1.163; 95% CI: [1.055, 1.282], P = 0.002) were risk factors associated with early recurrence. Each 1-kPa increase in tumor stiffness was associated with a 16.3% increase in the risk for tumor recurrence. DATA CONCLUSION: The mean stiffness of HCCs may be a useful, noninvasive, quantitative biomarker for the prediction of early HCC recurrence after hepatic resection. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019;49:719-730.

A prospective study evaluating indirect MRI-signs for the prediction of extraprostatic disease in patients with prostate cancer: tumor volume, tumor contact length and tumor apparent diffusion coefficient.

OBJECTIVE: The aim of this study was to evaluate three indirect MRI signs for predicting extraprostatic disease in patients referred to radical prostatectomy: index tumor volume (MTV), apparent diffusion coefficient (ADC) and tumor contact length (TCL). MATERIALS AND METHODS: This prospective study included 183 patients with biopsy proven prostate cancer. In all patients the MTV (ml), ADC (× 10-5 mm2/s) and TCL (mm) of the index tumor were registered at the preoperative MRI. Whole-mounted microscopical examination classified each patient as having either localized- or extraprostatic disease. The Youden index was used to identify the optimal cut-off values for predicting extraprostatic disease. Univariate regression analyses were conducted to estimate the odds ratio (OR) with 95% confidence intervals (CI). Results were stratified upon zonal location of the index tumor. RESULTS: Extraprostatic disease was identified in 103 (56%) patients. The risk of extraprostatic disease was nine times higher in peripheral zone tumors with ADC ≤ 89 (OR 9.1, 95% CI 4.2-19.6), five times higher in MTV ≥ 0.9 ml (OR 5.5, 95% CI 2.6-11.4) and five times higher in case of TCL ≥ 14 mm (OR 4.9, 95% CI 2.3-10.2). None of the indirect MRI signs could predict extraprostatic disease for transition zone tumors. CONCLUSION: The MTV, ADC and TCL are all significant predictors of extraprostatic disease for peripheral zone tumors, while none of the indirect signs were useful for transition zone tumors.

Prediction of microvascular invasion of hepatocellular carcinoma: preoperative CT and histopathologic correlation.

OBJECTIVE: The objective of our study was to prospectively investigate whether nonsmooth margins detected on multiphasic CT images correlate with the presence and location of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: A total of 102 patients with preoperative CT findings of solitary HCC were prospectively enrolled. Tumor size, tumor capsule, tumor margins, and peritumoral enhancement on preoperative CT images were assessed. Histopathologic results including the following were also recorded: tumor differentiation; liver fibrosis score; presence or absence of MVI; and, if present, the location of MVI. Correlation between tumor margin on preoperative CT images and histopathologic location of MVI was determined. RESULTS: Pathologic examination revealed MVI in 60 of the 102 HCC specimens. Although the results of the univariate analysis showed that tumor size, higher Edmondson-Steiner grade, and nonsmooth tumor margins were associated with MVI, multivariate analysis revealed that only nonsmooth margins correlated with the presence of MVI in HCC (p < 0.001). Of the 60 HCC specimens with histopathologic evidence of MVI, 40 exhibited focal nonsmooth margins. In addition, the locations of the nonsmooth margins and MVI were similar in 36 of the 40 specimens. CONCLUSION: Nonsmooth tumor margins correlated with the histopathologic presence and location of MVI. Therefore, nonsmooth margins detected on multiphasic CT may be predictive of MVI in HCC.

Prognostic Value of Combined Neutrophil-to-Lymphocyte Ratio and Imaging Tumor Capsule in Solitary Hepatocellular Carcinoma Patients after Narrow-Margin Hepatectomy.

BACKGROUND: The study aimed to investigate the clinical value and prognostic patterns of the neutrophil-to-lymphocyte ratio (NLR) and imaging tumor capsule (ITC) in solitary hepatocellular carcinoma (HCC) patients undergoing narrow-margin hepatectomy. METHODS: Data for solitary HCC patients treated with narrow-margin surgery were extracted from Shanghai General Hospital. Clinical features of recurrence-free survival (RFS), overall survival (OS), and early recurrence were investigated by Cox/logistic regression. The significant variables were subsequently incorporated into the nomogram pattern. Survival analysis stratified by NLR and ITC was also performed. RESULTS: The study included a cohort of 222 patients, with median RFS and OS of 24.083 and 32.283 months, respectively. Both an NLR ≥ 2.80 and incomplete ITC had a significant impact on prognosis. NLR and ITC independently affected RFS and OS, whereas alpha-fetoprotein (AFP) and ITC were identified as independent factors for early relapse. The RFS and OS nomogram, generated based on the Cox model, demonstrated good performance in validation. The combination of NLR and ITC showed greater predictive accuracy for 5-year RFS and OS. Subgroups with an NLR ≥ 2.80 and incomplete ITC had the worst prognosis. CONCLUSIONS: Both NLR and ITC significantly affected RFS, OS, and early recurrence among solitary HCC patients who underwent narrow-margin hepatectomy. The combination of NLR and ITC has the potential to guide rational clinical treatment and determine the prognosis.

Tumor-infiltrating immune cells: triggers for tumor capsule disruption and tumor progression?

BACKGROUND: Our previous studies of human breast and prostate cancer have shown that aberrant immune cell infiltration is associated with focal tumor capsule disruption and tumor cell budding that facilitate invasion and metastasis. Our current study attempted to determine whether aberrant immune cell infiltration would have similar impact on colorectal cancer (CRC). MATERIALS AND METHODS: Tissue sections from 100 patients with primary CRC were assessed for the frequencies of focal basement membrane (BM) disruption, muscularis mucosa (MM) fragmentation, and tumor cell dissemination in epithelial structures adjacent and distal to infiltrating lymphoid aggregates using a panel of biomarkers and quantitative digital imaging. RESULTS: Our study revealed: (1) epithelial structures adjacent to lymphoid follicles or aggregates had a significantly higher (p<0.001) frequency of focally disrupted BM, dissociated epithelial cells in the stroma, disseminated epithelial cells within lymphatic ducts or blood vessels, and fragmented MM than their distal counterparts, (2) a majority of dissociated epithelial cells within the stroma or vascular structures were immediately subjacent to or physically associated with infiltrating immune cells, (3) the junctions of pre-invasive and invasive lesions were almost exclusively located at sites adjacent to lymphoid follicles or aggregates, (4) infiltrating immune cells were preferentially associated with epithelial capsules that show distinct degenerative alterations, and (5) infiltrating immune cells appeared to facilitate tumor stem cell proliferation, budding, and dissemination. CONCLUSIONS: Aberrant immune cell infiltration may have the same destructive impact on the capsule of all epithelium-derived tumors. This, in turn, may selectively favor the proliferation of tumor stem or progenitor cells overlying these focal disruptions. These proliferating epithelial tumor cells subsequently disseminate from the focal disruption leading to tumor invasion and metastasis.

Hepatocellular Carcinoma in Non-Fibrotic Liver: A Narrative Review.

Hepatocellular carcinoma (HCC) in a non-fibrotic liver (F0) is considered to be rare, and there is a marked paucity of studies in the literature on this HCC type. A review of the literature shows some important clinical and tumor characteristics: (a) it occurs mainly in young female and elder male patients; (b) clinically, under normal hepatic function, alpha-fetoprotein level is often normal, and there are no risk factors; (c) associated with metabolic disease; (d) macroscopically, single large lesions are noted; and (e) microscopically, the lesions are well-differentiated and encapsulated. Radiological imaging results are straightforward, showing arterial hyperenhancement and later wash-out. The combined use of B-mode and contrast-enhanced (CE) ultrasound (US) is the most reliable and cost-effective diagnostic method. Few peri-and post-operative complications are noted and 5-year survival is not inferior to patients with HCC on fibrosis liver despite the lesion's large size. Most clinicians believe that HCC is unlikely to occur if patients have no symptoms and normal hepatic function. Although detailed clinical data are very limited, we expect that this review will help to improve the clinical management of HCC in non-fibrotic livers.

The most likely but largely ignored triggering factor for breast (or all) cancer invasion.

Breast cancer development and progression are believed to be a sequential process, from normal to hyperplastic, to in situ, and to invasive and metastatic stages. Given that over 90% of cancer deaths are caused by invasive and metastatic lesions, countless factors and multiple theories have been proposed as the triggering factor for the cascade of actions of cancer invasion. However, those factors and theories are largely based on the studies of cell lines or animal models. In addition, corresponding interventions based on these factors and theories have failed to reduce the incidence rate of invasive and metastatic lesions, suggesting that previous efforts may have failed to arm at the right target. Considering these facts and observations, we are proposing "A focal aberrant degeneration in the myoepithelial cell layer (MECL) as the most likely triggering factor for breast cancer invasion". Our hypothesis is based on our recent studies of breast and multiple other cancers. Our commentary provides the rationale, morphologic, immunohistochemical, and molecular data to support our hypotheses. As all epithelium-derived cancers share a very similar architecture, our hypothesis is likely to be applicable to invasion of all cancer types. We believe that human tissue-derived data may provide a more realistic roadmap to guide the clinic practice.

Does the presence of capsule influence prognosis in poorly differentiated thyroid carcinoma?

We collected all cases of poorly differentiated thyroid carcinoma at our institution diagnosed between 2007 and 2022 to investigate the role of tumor capsule in these neoplasms along with other histologic factors that may lead to adverse patient outcomes. After the exclusion of those meeting criteria for differentiated high-grade thyroid carcinoma or anaplastic carcinoma, we were left with 65 cases with a poorly differentiated component. Four of those cases (6.2%) were entirely encapsulated with no invasion of the tumor capsule. Unencapsulated tumors showed significantly greater rates of extrathyroidal extension (75.0% versus 41.5%) and death from disease (45.5% versus 12.5%) than encapsulated tumors, regardless of capsular invasion, with no differences in sex, tumor size, angioinvasion, local recurrence, or metastasis. Compared with encapsulated tumors with invasion, encapsulated tumors without capsular invasion showed a strong male predominance (100% versus 38.8%). No encapsulated tumors without capsular invasion demonstrated local recurrence, metastasis, or death from disease. No differences in the percentage of poorly differentiated components were noted among the 3 groups, although there was a trend for encapsulated tumors to have a higher percentage of poorly differentiated components than unencapsulated tumors. We conclude that invasive tumors lacking a capsule demonstrate greater rates of disease-related death despite showing similar adverse histologic features to invasive encapsulated tumors. Moreover, we confirm that encapsulated tumors without capsular invasion have excellent long-term outcomes in terms of recurrences, metastases, and survival.

The most effective but largely ignored target for prostate cancer early detection and intervention.

Over the past two decades, the global efforts for the early detection and intervention of prostate cancer seem to have made significant progresses in the basic researches, but the clinic outcomes have been disappointing: (1) prostate cancer is still the most common non-cutaneous cancer in Europe in men, (2) the age-standardized prostate cancer rate has increased in nearly all Asian and African countries, (3) the proportion of advanced cancers at the diagnosis has increased to 8.2% from 3.9% in the USA, (4) the worldwide use of PSA testing and digital rectal examination have failed to reduce the prostate cancer mortality, and (5) there is still no effective preventive method to significantly reduce the development, invasion, and metastasis of prostate cancer… Together, these facts strongly suggest that the global efforts during the past appear to be not in a correlated target with markedly inconsistent basic research and clinic outcomes. The most likely cause for the inconsistence appears due to the fact that basic scientific studies are traditionally conducted on the cell lines and animal models, where it is impossible to completely reflect or replicate the in vivo status. Thus, we would like to propose the human prostate basal cell layer (PBCL) as "the most effective target for the early detection and intervention of prostate cancer". Our proposal is based on the morphologic, immunohistochemical and molecular evidence from our recent studies of normal and cancerous human prostate tissues with detailed clinic follow-up data. We believe that the human tissue-derived basic research data may provide a more realistic roadmap to guide the clinic practice and to avoid the potential misleading from in vitro and animal studies.

Whole Tumor Capsule Is Prognostic of Very Good Outcome in the Classical Variant of Papillary Thyroid Cancer.

CONTEXT: Tumor capsule integrity is becoming a relevant issue to predict the biological behavior of human tumors, including thyroid cancer. OBJECTIVE: This work aims to verify whether a whole tumor capsule in the classical variant of papillary thyroid carcinoma (CVPTC) could have as a predictive role of a good outcome as for follicular variant (FVPTC). METHODS: FVPTC (n = 600) and CVPTC (n = 554) cases were analyzed. We distinguished between encapsulated-FVPTC (E-FVPTC) and encapsulated-CVPTC (E-CVPTC) and, thereafter, invasive (Ei-FVPTC and Ei-CVPTC) and noninvasive (En-FVPTC and En-CVPTC) tumors, according to the invasion or integrity of the tumor capsule, respectively. Cases without a tumor capsule were indicated as invasive-FVPTC (I-FVPTC) and invasive-CVPTC (I-CVPTC). The subgroup of each variant was evaluated for BRAF mutations. RESULTS: E-FVPTC was more frequent than E-CVPTC (P < .001). No differences were found between En-FVPTC and En-CVPTC or between Ei-FVPTC and Ei-CVPTC. After 18 years of follow-up, a greater number of not-cured cases were observed in Ei-CVPTC with respect to Ei-FVPTC, but not in En-CVPTC to En-FVPTC. Multivariate clustering analysis showed that En-FVPTC, En-CVPTC, and Ei-FVPTC have similar features but different from I-FVPTC and I-CVPTC and, to a lesser extent, from Ei-CVPTC. A total of 177 of 614 (28.8%) cases were BRAFV600E mutated, and 10 of 614 (1.6%) carried BRAF-rare alterations. A significantly higher rate of En-CVPTC (22/49, 44.9%) than En-FVPTC (15/195, 7.7%) (P < .0001) were BRAFV600E mutated. CONCLUSION: En-CVPTC is less prevalent than En-FVPTC. However, it has good clinical/ pathological behavior comparable to En-FVPTC. This finding confirms the good prognostic role of a whole tumor capsule in CVPTC as well. New nomenclature for En-CVPTC, similar to that introduced for En-FVPTC (ie, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NIFTP) could be envisaged.

Extraprostatic extension in prostate cancer: primer for radiologists.

The presence of extraprostatic extension (EPE) on multiparametric MRI (mpMRI) is an important factor in determining the management of prostate cancer. EPE is an established risk factor for biochemical recurrence of prostate cancer after radical prostatectomy (RP) and patients with EPE may be considered for wider resection margins, non-nerve-sparing surgery, adjuvant radiation therapy (RT), or androgen deprivation therapy (ADT). Several statistical nomograms and scoring systems have been developed to predict pathological stage at time of RP but with varying accuracies. Using the current PI-RADS v2 mpMRI staging guidelines results in high specificity but lacks in sensitivity. These findings reveal the need for more standardization and further refinement of existing MRI protocols and prostate cancer prediction tools. Current studies have looked into indirect additional imaging criteria such as index tumor volume, length of capsular contact, and apparent diffusion coefficient. Measuring for these features can improve the robustness of mpMRI in staging prostate cancer, as they have been shown to be independent predictors of EPE. MRI/ultrasound fusion-guided targeted biopsy can detect EPE not found on standard biopsy. Collectively, these measurements and imaging techniques can augment the detection of EPE and subsequent risk stratification.

Outcome of classical (CVPTC) and follicular (FVPTC) variants of papillary thyroid cancer: 15 years of follow-up.

PURPOSE: To compare the epidemiological, clinical, and pathological features of follicular (FVPTC) and classical (CVPTC) variants of papillary thyroid cancer and to correlate their outcomes according to different features. METHODS: Retrospective analysis of FVPTC and CVPTC patients selected at the moment of surgical treatment from 1999 to 2004, with a median follow-up of 15 years. RESULTS: Several significant differences were found between FVPTC and CVPTC such as the mean age at diagnosis, the presence of tumor capsule, the presence of thyroid capsule invasion, the presence of perithyroid soft tissue invasion, the lymph node metastases, the multifocality and bilaterality. At the end of follow-up only 9% (77/879) patients were not cured. However, a statistically significant lower percentage of persistent disease was found in the FVPTC than in the CVPTC group (3% vs. 14.5%, respectively, p < 0.0001). In multivariate analysis, the absence of the tumor capsule (OR = 6.75) or its invasion (OR = 7.89), the tumor size ≥4 cm (OR = 4.29), the variant CVPTC (OR = 3.35), and the presence of lymph node metastases (OR = 3.16) were all independent risk factors for the persistence of the disease. CONCLUSIONS: Despite an overall excellent prognosis of both variants, a higher percentage of CVPTC than FVPTC patients had a persistent disease. The absence of tumor capsule or its invasion, the tumor size ≥4 cm and the presence of lymph node metastases are other prognostic factors for the persistence of the disease. In contrast, the presence of an intact tumor capsule is the only good prognostic factor for their outcome.

Thick tumor capsule is a valuable risk factor for distant metastasis in follicular thyroid carcinoma.

OBJECTIVE: While the biological behavior of follicular thyroid carcinoma (FTC) has been studied in great detail using clinical experience, few studies have investigated pre- or intraoperative factors related to the risk of distant metastasis (DM) among patients with FTC. The aim of this study was to analyze the characteristics of FTC with DM. METHODS: This study retrospectively investigated 102 patients with FTC who underwent surgery between 1988 and 2013. We compared clinicopathological characteristics between FTC with and without DM. RESULTS: Univariate analysis revealed nodal metastasis (p=0.045), serum thyroglobulin (Tg) at initial operation (≥1000ng/ml; p<0.0001), widely invasive appearance according to macroscopic findings (p<0.0001), thick tumor capsule (≥1mm; p<0.0001), vascular invasion (p=0.0003), extrathyroidal invasion (p=0.047), and venous tumor embolism (p=0.045) as significant risk factors for DM. Multivariate analysis conducted using pre- and intraoperative factors identified thick tumor capsule (≥1mm), serum Tg at initial operation (≥1000ng/ml), and macroscopically widely invasive appearance as risk factors independently associated with development of DM. CONCLUSION: Patients with these risk factors should undergo total thyroidectomy and radioactive iodine ablation.

Validated preoperative computed tomography risk estimation for postoperative hepatocellular carcinoma recurrence.

AIM: To develop and validate a risk estimation of tumor recurrence following curative resection of operable hepatocellular carcinoma (HCC). METHODS: Data for 128 patients with operable HCC (according to Barcelona Clinic Liver Cancer imaging criteria) who underwent preoperative computed tomography (CT) evaluation at our hospital from May 1, 2013 through May 30, 2014 were included in this study. Follow-up data were obtained from hospital medical records. Follow-up data through May 30, 2016 were used to retrospectively analyze preoperative multiphasic CT findings, surgical histopathology results, and serum α-fetoprotein and thymidine kinase-1 levels. The χ2 test, independent t-test, and Mann-Whitney U test were used to analyze data. A P-value of < 0.05 was considered statistically significant. RESULTS: During the follow-up period, 38 of 128 patients (29.7%) had a postoperative HCC recurrence. Microvascular invasion (MVI) was associated with HCC recurrence (χ2 = 13.253, P < 0.001). Despite postoperative antiviral therapy and chemotherapy, 22 of 44 patients with MVI experienced recurrence after surgical resection. The presence of MVI was 57.9% sensitive, 75.6% specific and 70.3% accurate in predicting postoperative recurrence. Of 84 tumors without MVI, univariate analysis confirmed that tumor margins, tumor margin grade, and tumor capsule detection on multiphasic CT were associated with HCC recurrence (P < 0.05). Univariate analyses showed no difference between groups with respect to hepatic capsular invasion, Ki-67 proliferation marker value, Edmondson-Steiner grade, largest tumor diameter, necrosis, arterial phase enhanced ratio, portovenous phase enhanced ratio, peritumoral enhancement, or serum α-fetoprotein level. CONCLUSION: Non-smooth tumor margins, incomplete tumor capsules and missing tumor capsules correlated with postoperative HCC recurrence. HCC recurrence following curative resection may be predicted using CT.

Ruptured clear cell carcinoma of the ovary presenting as acute abdomen.

BACKGROUND: Ovarian cancer remains one of the leading causes of cancer-related deaths among women. Clear cell ovarian carcinoma is a rare histologic subtype accounting for 5-10% of all epithelial ovarian cancers and is often associated with endometriosis. Patients generally present with vague abdominal and pelvic complaints. However, patients can present in the acute setting with pleural effusions, ascites, bowel obstructions, and deep vein thrombosis. CASE: A 54 year old woman presenting with an acute abdomen secondary to rupture of ovarian clear cell carcinoma. CONCLUSION: Ovarian clear cell carcinoma should remain in the differential diagnosis in a patient presenting with an acute abdomen and imaging suspicious for a gynecologic malignancy originating from the ovary.

Cell budding from normal appearing epithelia: a predictor of colorectal cancer metastasis?

BACKGROUND: Colorectal carcinogenesis is believed to be a multi-stage process that originates with a localized adenoma, which linearly progresses to an intra-mucosal carcinoma, to an invasive lesion, and finally to metastatic cancer. This progression model is supported by tissue culture and animal model studies, but it is difficult to reconcile with several well-established observations, principally among these are that up to 25% of early stage (Stage I/II), node-negative colorectal cancer (CRC) develop distant metastasis, and that circulating CRC cells are undetectable in peripheral blood samples of up to 50% of patients with confirmed metastasis, but more than 30% of patients with no detectable metastasis exhibit such cells. The mechanism responsible for this diverse behavior is unknown, and there are no effective means to identify patients with pending, or who are at high risk for, developing metastatic CRC. NOVEL FINDINGS: Our previous studies of human breast and prostate cancer have shown that cancer invasion arises from the convergence of a tissue injury, the innate immune response to that injury, and the presence of tumor stem cells within tumor capsules at the site of the injury. Focal degeneration of a capsule due to age or disease attracts lymphocyte infiltration that degrades the degenerating capsules resulting in the formation of a focal disruption in the capsule, which selectively favors proliferating or "budding" of the underlying tumor stem cells. Our recent studies suggest that lymphocyte infiltration also triggers metastasis by disrupting the intercellular junctions and surface adhesion molecules within the proliferating cell buds causing their dissociation. Then, lymphocytes and tumor cells are conjoined through membrane fusion to form tumor-lymphocyte chimeras (TLCs) that allows the tumor stem cell to avail itself of the lymphocyte's natural ability to migrate and breach cell barriers in order to intravasate and to travel to distant organs. Our most recent studies of human CRC have detected nearly identical focal capsule disruptions, lymphocyte infiltration, budding cells, and the formation of TLCs. Our studies have further shown that age- and type-matched node-positive and -negative CRC have a significantly different morphological and immunohistochemical profile and that the majority of lymphatic ducts with disseminated cells are located within the mucosa adjacent to morphologically normal appearing epithelial structures that express a stem cell-related marker. NEW HYPOTHESIS: Based on these findings and the growth patterns of budding cells revealed by double immunohistochemistry, we further hypothesize that metastatic spread is an early event of carcinogenesis and that budding cells overlying focal capsule disruptions represent invasion- and metastasis-initiating cells that follow one of four pathways to progress: (1) to undergo extensive in situ proliferation leading to the formation of tumor nests that subsequently invade the submucosa, (2) to migrate with associated lymphocytes functioning as "seeds" to grow in new sites, (3) to migrate and intravasate into pre-existing vascular structures by forming TLCs, or (4) to intravasate into vascular structures that are generated by the budding cells themselves. We also propose that only node-positive cases harbor stem cells with the potential for multi-lineage differentiation and unique surface markers that permit intravasation.

Malignant transformation and stromal invasion from normal or hyperplastic tissues: true or false?

Carcinogenesis is believed to be a multi-step process, progressing sequentially from normal to hyperplastic, to in situ, and to invasive stages. A number of studies, however, have detected malignancy-associated alterations in normal or hyperplastic tissues. As the molecular profile and clinical features of these tissues have not been defined, the authors invited several well-recognized pathologist, oncologists, biologist, surgeons, and molecular biologist to offer their opinion on: (1) whether these tissues belong to a previously unrevealed malignant entity or focal alterations with no significant consequence? (2) whether these alterations are linked to early onset of cancer or cancer of unknown primary site, and (3) how to further define these lesions?