High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.

BACKGROUND: Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University. METHODS: The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m2 carboplatin and 750 mg/m2 etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities. RESULTS: The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths. CONCLUSIONS: Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.

Esophageal Cancer: Associations With (pN+) Lymph Node Metastases.

OBJECTIVES: To identify the associations of lymph node metastases (pN+), number of positive nodes, and pN subclassification with cancer, treatment, patient, geographic, and institutional variables, and to recommend extent of lymphadenectomy needed to accurately detect pN+ for esophageal cancer. SUMMARY BACKGROUND DATA: Limited data and traditional analytic techniques have precluded identifying intricate associations of pN+ with other cancer, treatment, and patient characteristics. METHODS: Data on 5806 esophagectomy patients from the Worldwide Esophageal Cancer Collaboration were analyzed by Random Forest machine learning techniques. RESULTS: pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected. Lymphadenectomy necessary to accurately detect pN+ is 60 for shorter, well-differentiated cancers (<2.5 cm) and 20 for longer, poorly differentiated ones. CONCLUSIONS: In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers. Consequently, if the goal of lymphadenectomy is to accurately define pN+ status of such cancers, few nodes need to be removed. Conversely, superficial, shorter, and well-differentiated cancers require a more extensive lymphadenectomy to accurately define pN+ status.

A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas.

BACKGROUND: Thymomas are one of the most rarely diagnosed malignancies. To better understand its biology and to identify therapeutic targets, we performed next-generation RNA sequencing. METHODS: The RNA was sequenced from 13 thymic malignancies and 3 normal thymus glands. Validation of microRNA expression was performed on a separate set of 35 thymic malignancies. For cell-based studies, a thymoma cell line was used. RESULTS: Hierarchical clustering revealed 100% concordance between gene expression clusters and WHO subtype. A substantial differentiator was a large microRNA cluster on chr19q13.42 that was significantly overexpressed in all A and AB tumours and whose expression was virtually absent in the other thymomas and normal tissues. Overexpression of this microRNA cluster activates the PI3K/AKT/mTOR pathway. Treatment of a thymoma AB cell line with a panel of PI3K/AKT/mTOR inhibitors resulted in marked reduction of cell viability. CONCLUSIONS: A large microRNA cluster on chr19q13.42 is a transcriptional hallmark of type A and AB thymomas. Furthermore, this cluster activates the PI3K pathway, suggesting the possible exploration of PI3K inhibitors in patients with these subtypes of tumour. This work has led to the initiation of a phase II clinical trial of PI3K inhibition in relapsed or refractory thymomas (http://clinicaltrials.gov/ct2/show/NCT02220855).

Micronodular thymic neoplasms: case series and literature review with emphasis on the spectrum of differentiation.

We report nine cases of micronodular thymoma with lymphoid B-cell hyperplasia and one case of micronodular thymic carcinoma with lymphoid hyperplasia from our institution. For a better understanding of these rare tumors, clinical records, and histological features of these cases were reviewed, with detailed review of additional 64 literature cases of micronodular thymic neoplasms. The joint analysis identified 64 cases of micronodular thymoma with lymphoid B-cell hyperplasia and 9 cases of micronodular thymic carcinoma with lymphoid hyperplasia. Both groups revealed slight male predilection, with male:female ratio of 1.3:1 and 5:4, and occurred at >40 years of age, with a mean of 64 (41-83) and 62 (42-78) years, respectively. Myasthenia gravis was noted in 3/64 (5%) and 1/9 (11%) patients, respectively. Other systemic, disimmune, or hematologic disorders were noted in 6/64 (9%) and 1/9 (11%) patients, respectively. Components of conventional thymoma were reported in 11/64 (17%) micronodular thymomas with lymphoid B-cell hyperplasia, with transitional morphology between the two components in most of them. Cellular morphology was predominantly spindle in micronodular thymoma with lymphoid B-cell hyperplasia when specified (30/43), and epithelioid in micronodular thymic carcinoma with lymphoid hyperplasia (6/9), and cytological atypia was more encountered in the latter. Dedifferentiation/transformation from micronodular thymoma with lymphoid B-cell hyperplasia to micronodular thymic carcinoma with lymphoid hyperplasia seems to occur in a small subset of cases. Three cases of micronodular thymomas with lymphoid B-cell hyperplasia were described with co-existent low-grade B-cell lymphomas. Follow-up data were available for 30 micronodular thymomas with lymphoid B-cell hyperplasia and 6 micronodular thymic carcinomas with lymphoid hyperplasia, with a mean of 47 (0.2-180) months and 23 (3-39) months, respectively. Patients were alive without disease, except for five micronodular thymoma with lymphoid B-cell hyperplasia patients (dead from unrelated causes), and one micronodular thymic carcinoma with lymphoid hyperplasia patient (dead of disease).

The prognostic value of architectural patterns in a study of 37 type AB thymomas.

Spindle cell thymomas with prominent amount of lymphocytes are classified as WHO type AB tumors. However, there are architectural pattern differences in these tumors. We investigated the importance of architectural pattern in type AB thymomas in relation to prognostic value. Archival hematoxylin-eosin stained slides of 37 AB type thymomas were reviewed for the presence (type 1) or absence (type 2) of reticular growth pattern. Reticular growth pattern is defined as the presence of a network of elongated bland spindle cells separating nests of tumor cells admixed with lymphoid cells. The architectural patterns were correlated with tumor stage at diagnosis and presence or absence of recurrent disease. The analysis identified 18 cases of type 1 AB thymoma and 19 cases of type 2. Type 2 cases also had greater cytologic atypia within the spindle cells. Patients with type 1 tumors were more likely to have early stage disease. In contrast, type 2 pattern was associated with higher stage at diagnosis (P<0.001) and greater likelihood for recurrence (P<0.05) and metastases. Architectural features are prognostically relevant in classification of WHO AB type thymomas and may constitute a form of personalized medicine. Independent confirmation of the findings is necessary to confirm the association of architectural pattern with outcomes.

NUT midline carcinomas in the thymic region.

NUT midline carcinomas (NMCs) are rare tumors described predominantly in the pediatric age group. We recently reported two cases of these tumors occurring in the thymic region. In order to establish the true incidence of these tumors, we examined a large series of thymic carcinomas for morphological features of NUT tumor and further assessed the expression of NUTM1 (also known as NUT) protein by immunohistochemistry. The histological review of slides from 110 cases of thymic carcinoma was undertaken to identify carcinomas with mixed undifferentiated and squamous features that are typically associated with NUT carcinomas. The presenting symptoms, morphological spectrum of tumors and outcome data of patients with these histologies are presented. Immunohistochemistry for NUTM1 was performed on 35 cases of thymic carcinoma with available blocks (3 with these histological features and 32 without these features) to exclude the possibility of midline carcinoma. Tumors from 10 patients had features of mixed small cell undifferentiated squamous cell carcinoma (M:F, 1.5:1; age range, 22-79). These patients predominantly presented with advanced disease and had respiratory-related symptoms or chest pain; four had paraneoplastic syndromes. The squamous component in all cases was well differentiated with little or no atypia. The undifferentiated component varied in cell size and lacked characteristic features of small cell carcinoma. All but one patients developed metastases or died within 3 years of diagnosis. NUTM1 expression was seen in two of three tumors with these histological features and in none of the 32 cases without. Mixed small cell undifferentiated carcinomas share histological and immunohistochemical similarity with NMCs and have aggressive clinical course. These tumors are not uncommon and should be considered in the differential diagnosis of carcinomas in the thymic region as novel therapies might be available.

Treatment of clinical T2N0M0 esophageal cancer.

BACKGROUND: Management of clinical T2N0M0 (cT2N0M0) esophageal cancer remains controversial. We reviewed our institutional experience over 21 years (1990-2011) to determine clinical staging accuracy, optimal treatment approaches, and factors predictive of survival in this patient population. METHODS: Patients with cT2N0M0 esophageal cancer determined by endoscopic ultrasound (EUS) were identified through a prospectively collected database. Demographics, perioperative data, and outcomes were examined. Cox regression model and Kaplan-Meier plots were used for statistical survival analysis. RESULTS: A total of 731 patients underwent esophagectomy, of whom 68 cT2N0M0 patients (9 %) were identified. Fifty-seven patients (84 %) had adenocarcinoma. Thirty-three patients (48.5 %) were treated with neoadjuvant chemoradiation followed by surgery, and 35 underwent surgical resection alone. All resections except one included a transthoracic approach with two-field lymph node dissection. Thirty-day operative mortality was 2.9 %. Only 3 patients (8.5 %) who underwent surgery alone had T2N0M0 disease identified by pathology: the disease of 15 (42.8 %) was found to be overstaged and 17 (48.5 %) understaged after surgery. Understaging was more common in poorly differentiated tumors (p = 0.03). Nine patients (27.2 %) had complete pathologic response after chemoradiotherapy. Absence of lymph node metastases (pN0) was significantly more frequent in the neoadjuvant group (29 of 33 vs. 21 of 35, p = 0.01). Median follow-up was 44.2 months. Overall 5-year survival was 50.8 %. On multivariate analysis, adenocarcinoma (p = 0.001) and pN0 after resection (p = 0.01) were significant predictors of survival. CONCLUSIONS: EUS was inaccurate in staging cT2N0M0 esophageal cancer in this study. Poorly differentiated tumors were more frequently understaged. Adenocarcinoma and absence of lymph node metastases (pN0) were independently predictive of long-term survival. pN0 status was significantly more common in patients undergoing neoadjuvant therapy, but long-term survival was not affected by neoadjuvant therapy. A strategy of neoadjuvant therapy followed by resection may be optimal in this group, especially in patients with disease likely to be understaged.

Treatment of esophageal leaks, fistulae, and perforations with temporary stents: evaluation of efficacy, adverse events, and factors associated with successful outcomes.

BACKGROUND: Factors associated with successful endoscopic therapy with temporary stents for esophageal leaks, fistulae, and perforations (L/F/P) are not well known. OBJECTIVES: To evaluate the safety, efficacy, and outcomes of esophageal stenting in these patients and identify factors associated with successful closure. DESIGN: Retrospective. SETTING: Academic tertiary referral center. PATIENTS: All patients with attempted stent placement for esophageal L/F/P between January 2003 and May 2012. INTERVENTION: Esophageal stent placement and removal. MAIN OUTCOME MEASUREMENTS: Factors predictive of therapeutic success defined as complete closure after index stent removal (primary closure) or after further endoscopic stenting (secondary closure). RESULTS: Sixty-seven patients with 132 attempted stents for esophageal L/F/P were considered; 13 patients were excluded. Among the remaining 54 patients, 117 stents were placed for leaks (29 patients; 64 stents), fistulae (15 patients; 36 stents), and perforations (10 patients; 17 stents). Procedural technical success was achieved in all patients (100%). Primary closure was successful in 40 patients (74%) and secondary closure in an additional 5 (83% overall). On short-term (<3 months) follow-up, 27 patients (50%) were asymptomatic, whereas 22 (41%) had technical adverse events, including stent migration in 15 patients (28%). Factors associated with successful primary closure include a shorter time between diagnosis of esophageal L/F/P and initial stent insertion (9.03 vs 22.54 days; P = .003), and a smaller luminal opening size (P = .002). LIMITATIONS: Retrospective, single-center study. CONCLUSIONS: Temporary stents are safe and effective in treating esophageal L/F/P. Defect opening size and time from diagnosis to stent placement appear to be candidate predictors for successful closure.

Barriers to mental health service use and preferences for addressing emotional concerns among lung cancer patients.

OBJECTIVE: This study examined barriers to mental health service use and preferences for addressing emotional concerns among lung cancer patients (N=165) at two medical centers in the Midwestern United States. METHODS: Lung cancer patients completed an assessment of anxiety and depressive symptoms, mental health service use, barriers to using these services, and preferences for addressing emotional concerns. RESULTS: Only 45% of distressed patients received mental health care since their lung cancer diagnosis. The most prevalent patient-reported barriers to mental health service use among non-users of these services (n=110) included the desire to independently manage emotional concerns (58%) and inadequate knowledge of services (19%). In addition, 57% of distressed patients who did not access mental health services did not perceive the need for help. Seventy-five percent of respondents (123/164) preferred to talk to a primary care physician if they were to have an emotional concern. Preferences for counseling, psychiatric medication, peer support, spiritual care, or independently managing emotional concerns also were endorsed by many patients (range=40-50%). Older age was associated with a lower likelihood of preferring to see a counselor. CONCLUSIONS: Findings suggest that many distressed lung cancer patients underuse mental health services and do not perceive the need for such services. Efforts to increase appropriate use of services should address patients' desire for autonomy and lack of awareness of services.

The role of histology in predicting recurrence of type A thymomas: a clinicopathologic correlation of 23 cases.

Spindle cell thymomas (type A), as per the WHO definition, are benign tumors with an excellent prognosis. However, recent studies document aggressive behavior with local recurrences as well as extrathoracic metastases. More recently, Nonaka and Rosai have raised the question as to whether atypical features like cellular atypia, mitotic activity, necrosis, and vascular permeation could predict the adverse outcomes of these tumors. In an effort to address the 'atypia and outcome' issue of spindle cell thymomas, we analyzed our database of over 600 cases of thymic tumors to identify type A thymomas. The presence of histomorphological features like tumor size, nuclear shape and variability, mitotic rate, and presence/absence of necrosis were correlated with Masaoka stage, relapse/recurrence, and extrathoracic metastases. The study identified 23 patients of pure spindle cell thymomas (WHO type A) ranging in age from 40 to 88 years (median age, 54 years) and with male-to-female ratio of 1:0.9. Approximately 43% of the cases had recurrence or metastases during the followup period (average, 49 months). The presence of necrosis correlates with both relapse and extrathoracic metastases but not with the stage of diagnosis. However, none of the other clinical or histological features, including size, predominant nuclear shape, nuclear variability, and mitotic activity, were correlated with the outcome parameters, such as stage at diagnosis, presence or absence of relapse, and extrathoracic metastases. Histological atypia is fairly common in WHO type A thymomas. The presence of necrosis was associated with both locoregional and systemic disease. However, none of the other clinical or histological features correlated with aggressive behavior.

Support service use and interest in support services among distressed family caregivers of lung cancer patients.

OBJECTIVE: This study examined support service use and interest in support services among distressed family caregivers of patients recently entering comprehensive cancer care facilities. METHODS: Primary family caregivers of lung cancer patients (N=83) were recruited from three medical centers within 12 weeks of the patient's new visit to the oncology clinic. All family caregivers were screened for psychological distress, and those reporting significant anxiety or depressive symptoms were eligible for this study. Caregivers completed a baseline assessment of support service use (i.e., use of mental health services and complementary and alternative medicine [CAM]) and interest in support services. Support service use was also assessed 3 months later. RESULTS: Although all caregivers reported clinically meaningful distress, only 26% used mental health and 39% used CAM services during the 3-month study period. Patients' receipt of chemotherapy was positively associated with caregivers' mental health service use, whereas greater education and receiving assistance with caregiving tasks were associated with CAM use. Forty percent of caregivers who did not use CAM at baseline were interested in CAM. In addition, 29% of caregivers who did not receive mental health services at baseline were interested in professional psychosocial support, and 29% of caregivers who did not receive staff assistance with practical needs at baseline were interested in this service. CONCLUSIONS: Findings suggest that distressed family caregivers of lung cancer patients underuse mental health services and that a sizable minority are interested in professional help with psychosocial and practical needs.

Economic and social changes among distressed family caregivers of lung cancer patients.

PURPOSE: Although costs of lung cancer care have been documented, economic and social changes among lung cancer patients' family caregivers have yet to be fully examined. In addition, research has not focused on caregivers with greater need for support services. This study examined various economic and social changes among distressed family caregivers of lung cancer patients during the initial months of cancer care in the USA. METHODS: Lung cancer patients' primary family caregivers with significant anxiety or depressive symptoms were recruited from three medical centers within 12 weeks of the patient's new oncology visit. Caregivers (N = 83) reported demographic and medical information and caregiving burden at baseline. Seventy-four caregivers reported anxiety and depressive symptoms and economic and social changes 3 months later. RESULTS: Seventy-four percent of distressed caregivers experienced one or more adverse economic or social changes since the patient's illness. Common changes included caregivers' disengagement from most social and leisure activities (56%) and, among employed caregivers (n = 49), reduced hours of work (45%). In 18% of cases, a family member quit work or made another major lifestyle change due to caregiving. Additionally, 28% of caregivers reported losing the main source of family income, and 18% reported losing most or all of the family savings. Loss of the main source of family income and disengagement from most social and leisure activities predicted greater caregiver distress. CONCLUSIONS: Findings suggest that distressed caregivers of lung cancer patients experience high rates of adverse economic and social changes that warrant clinical and research attention.

Safety and usability of an endo staple line reinforcement device for pulmonary resections.

Background: Pulmonary resection can present technical challenges for surgeons due to the dissection and closure of tissues, which vary in thickness and elastic properties, occasionally leading to prolonged air leaks. Staple line reinforcements (SLRs) are widely utilized tools for fortifying the stability and integrity of closures in thoracic surgery, however, materials available and ease of use for both surgeon and scrub nurse have been suboptimal. A novel "click-and-go" device pre-loaded with bioabsorbable buttress material was recently developed, the Echelon Endopath SLR (ESLR, Ethicon, Inc., Cincinnati, OH, USA). This prospective study examines the safety and efficacy of this novel device in lung resections. Methods: Adult surgical candidates undergoing primary pulmonary resection (both open and thoracoscopic) where the ESLR would be used were enrolled. Exclusion included reoperation/revision in same anatomical location, hypersensitivity to polyglactin or related products, and body mass index (BMI) ≥46.0 kg/m2. The primary endpoint assessed the incidence of specific device-related adverse events (AEs): prolonged air leak and empyema. Additional endpoints included number of devices replaced during surgery due to slippage or bunching, and surgeon-reported usability responses. Data was summarized for AEs deemed device-related and usability questionnaire responses. Results: A total of 131 subjects were included in the primary endpoint analysis data set with 120 subjects completing the study (91.6%). The mean age at consent was 62.8±12.0 years and 55.7% were female. The most common primary indication for the procedure was malignancy 61.1%, and primary non-malignant lung disease (non-chronic obstructive pulmonary disease) 12.2%. Common procedures performed were wedge resection (58.0%) and lobectomy (34.4%). There were zero reported device-specific/-related AEs which counted toward the primary endpoint. Responses from a usability questionnaire found all surgeons (100.0%) reported the ease of setup was superior to previous devices utilized. Surgeons expressed greater confidence in the buttress material of the ESLR than that of previous SLR devices (strongly agree 88.9%; slightly agree 11.1%). Most also felt that there was less wastage with the click-and-go ESLR (strongly agree 77.8%, slightly agree 11.1%, neutral 11.1%). Conclusions: The ESLR device demonstrates safe and effective performance in this post-market study of specific thoracic procedures. Furthermore, surgeons found this was easier to use.

Establishment and characterization of a novel cell line derived from human thymoma AB tumor.

Thymomas are low-grade epithelial tumors of the anterior mediastinum. The complexity of the disease and the lack of in vitro and in vivo models hamper the development of better therapeutics. In this study, we report a novel cell line, designated as IU-TAB-1, which was established from a patient with stage II thymoma (World Health Organization-type AB). The IU-TAB-1 cell line was established in vitro and characterized using histological and immunohistochemical staining, fluorescence-activated cell sorting, cytogenetic analyses and functional assays including in vitro and a NOD/SCID xenograft model. A whole-genome gene expression analysis (Illumina) was performed on the IU-TAB-1 cell line and 34 thymomas to determine the clinical relevance of the cell line. The IU-TAB-1 cell line was positive for epithelial markers (pan-cytokeratin and EpCAM/CD326) including thymic epithelial (TE) surface markers (such as CD29, CD9, CD54/ICAM-1, CD58 and CD24) and p63, and negative for B- and T-cell lineage markers. Gene expression profiling demonstrated overlapping and distinct genes between IU-TAB-1 and primary thymomas including the primary tumor (from which the cell line was derived). IU-TAB-1 cells are tumorigenic when implanted in immunodeficient mice with tumors reaching a volume of 1000 mm³ at around 130 days. The established cell line represents a biologically relevant new tool to investigate the molecular pathology of thymic malignancies and to evaluate the efficacy of novel therapeutics both in vitro and in vivo.

Extrathoracic metastases of thymic origin: a review of 35 cases.

Thymic tumors are categorized as types A, AB, B1, B2, B3, and thymic carcinoma under the World Health Organization (WHO) classification. Thymomas are typically slow growing tumors that predominantly involve the surrounding structures through direct invasion, while thymic carcinomas tend to be more aggressive. A significant number of patients are asymptomatic and can present with metastases as the first presentation. The exact incidence of extrathoracic metastases from thymoma is not known. This study describes a series of 35 cases of histologically documented metastatic thymomas and thymic carcinomas at extrathoracic sites. These cases were classified according to the current World Health Organization (WHO) classification criteria, and we present their clinical data as well as discuss the differential diagnoses of these lesions. Our study shows that all types of thymic tumors, regardless of histologic type, can be associated with invasion and metastases to thoracic and extrathoracic sites.

Risk factors for bronchopleural fistula after right pneumonectomy: does eliminating the stump diverticulum provide protection?

PURPOSE: Bronchopleural fistula (BPF) remains an important source of morbidity and mortality after right pneumonectomy. We reviewed our 18-year institutional experience with right pneumonectomy to identify risks factors for BPF. METHODS: From 1992 to 2010, a total of 145 patients who underwent right pneumonectomy were identified from an institutional database. Median age was 56 years. Most patients (66.2%) underwent surgery for non-small cell lung cancer. Sixty-seven patients (46.2%) received either chemotherapy or radiotherapy before surgery. Medical records were reviewed for 14 variables potentially predictive for BPF, including two airway closure techniques (standard bronchial closure and carinal closure). Variables predictive of BPF by univariate analysis were entered into a logistic regression model. RESULTS: The overall mortality rate was 13.1% (n=19), with 15.9 and 10.5% mortality in the bronchial closure and carinal closure groups, respectively (P=0.33). The overall BPF rate was 7.6% (n=11), with a 3.9% (3 of 76) rate in the carinal closure group compared to 11.6% (8 of 69) in the bronchial closure group (P=0.08). Seven of eight bronchial closure patients who developed BPF required operative repair. Only one of three patients who developed BPF after carinal closure did not spontaneously heal after open drainage. Multivariate analysis identified preoperative radiation dose (P=0.042) and bronchial closure (P=0.041) as independent risk factors for BPF, while the length of postoperative ventilation before development of BPF approached significance (P=0.057). CONCLUSIONS: In our experience, higher preoperative radiation doses are a risk factor for BPF after right pneumonectomy, while carinal closure exerts a protective effect.

Thymic Carcinomas and Second Malignancies: A Single-Center Review.

Thymic carcinomas account for less than 0.01% of new cancer diagnoses annually and are more aggressive than thymomas. Autoimmune disorders have been associated with thymomas and only recently with thymic carcinomas. Second malignancies are well described after thymomas. The aim of this study was to analyze the incidence of second malignancies in patients with thymic carcinomas. All cases of thymic carcinomas were identified from the pathology archives of Indiana University. Histological materials were reviewed and further correlated with clinical data to identify incidence of second cancers in patients with thymic carcinomas. Histological material was available for review in 92 cases of thymic carcinoma. Clinical data were available for 85 patients. Fourteen of these (16.5%) patients had a second malignancy; these included small cell lung carcinoma, "testicular cancer", embryonal carcinoma, seminoma, breast carcinoma (two cases), prostatic adenocarcinoma, Hodgkin's lymphoma, thyroid carcinoma, bladder carcinoma (two cases), renal cell carcinoma, and melanoma. The latter could precede, be concurrent with, or follow the diagnosis thymic carcinoma. The incidence of second cancers in patients with thymic carcinomas is similar to that reported for thymomas. Abnormalities in immunological surveillance may be responsible for this high incidence of second malignancies in thymic tumors.

Outcomes following surgery for primary mediastinal nonseminomatous germ cell tumors in the cisplatin era.

OBJECTIVE: Treatment of primary mediastinal nonseminomatous germ cell tumors involves cisplatin-based chemotherapy followed by surgery to remove residual disease. We undertook a study to determine short and long-term outcomes. METHODS: A retrospective analysis of patients with primary mediastinal nonseminomatous germ cell tumors who underwent surgery at our institution from 1982 to 2017 was performed. RESULTS: A total of 255 patients (mean age, 29.2 years) were identified. Acute respiratory distress syndrome occurred postoperatively in 27 patients (10.9%), which was responsible for all 11 (4.3%) postoperative deaths. Of patients who developed acute respiratory distress syndrome, more patients received bleomycin-containing chemotherapy (25 out of 169; 14.8%) than non-bleomycin regimens (2 out of 77; 2.6%) (P = .004). With respect to variables independently predictive of long-term survival, evidence of choriocarcinoma before chemotherapy (n = 12) was determined to be an adverse factor (P = .006). In contrast, biopsy-proven elements of seminoma (n = 34) were predictive of improved survival (P = .04). The worst pathology identified in the residual mediastinal mass after chemotherapy was necrosis in 61 patients (25.0%), teratoma in 84 patients (34.4%), and malignant (persistent germ cell or non-germ cell cancer) in 97 patients (39.8%), which influenced overall survival (P < .001). Additionally, teratoma with stromal atypia (n = 18) demonstrated decreased survival compared with teratoma without atypia (n = 66; P = .031). Patients with malignancy involving >50% of the residual mass (n = 47) had a 2.3-fold increased risk of death compared with ≤50% malignancy (n = 45; P = .008). Finally, elevated postoperative serum tumor markers (n = 40) was significantly predictive of adverse survival (P < .001). CONCLUSIONS: In the treatment of primary mediastinal nonseminomatous germ cell tumors, avoiding bleomycin-containing chemotherapy is important. Pre- and postchemotherapy pathology and postoperative serum tumor markers are independent predictors of long-term survival.

Vasculogenic Mesenchymal Tumor: A Clinicopathologic and Molecular Study of 55 Cases of a Distinctive Neoplasm Originating From Mediastinal Yolk Sac Tumor and an Occasional Precursor to Angiosarcoma.

We report 55 postchemotherapy resections of primary nonseminomatous mediastinal germ cell tumors with prominent vasculogenic features showing the formation of rudimentary to well-developed neoplastic vessels within primitive mesenchyme. These cases represented 25% of a cohort of 221 such specimens. The patients were 19 to 49 years old (mean, 28 y) and 98% had serological evidence of yolk sac tumor. The vasculogenic lesions, felt to represent a neoplastic reiteration of embryonic vasculogenesis in the splanchnic mesoderm of the yolk sac, were further subdivided into teratoma with vasculogenic stroma (n=9), vasculogenic mesenchymal tumor (VMT) (n=42, further classified into low grade [n=24] and high grade [n=18]), and angiosarcoma (n=4). The distinction of teratoma with vasculogenic stroma from VMT was based solely on the greater extent of VMT (exceeding 1 low power [×4 objective] microscopic field), with both categories showing a spectrum of vessels lined by atypical endothelium in a nonendothelial neoplastic stroma that often also generated vascular walls comprised of atypical smooth muscle. The angiosarcomas showed stratification of highly atypical endothelial cells or anastomosing vessels lined by nonstratified but cytologically similar endothelium. Immunohistochemical studies supported the generation of neoplastic vessels from the tumor stroma, most commonly by the development of stromal clefts showing reactivity for podoplanin, CD34, and occasionally ERG, followed by the gradual development from the clefts of thin-walled vessels that later became encircled by stromal cells showing smooth muscle differentiation by immunohistochemistry. Occasionally, round collections of stromal erythrocytes became surrounded by stromal cells to generate blood vessels. Fluorescence in situ hybridization showed chromosome 12p copy number increase in both the endothelial component and stromal component in 8/9 VMT cases and in 1/1 angiosarcoma. On follow-up, no patient with teratoma with vasculogenic stroma had evidence of a subsequent vascular tumor or sarcoma, whereas 8 of the 35 (23%) patients with VMTs (2 low grade and 6 high grade) and meaningful follow-up developed sarcoma (1 angiosarcoma, 2 rhabdomyosarcomas, and 5 not further characterized). The difference between low-grade and high-grade tumors was of borderline significance (P=0.058). Two of the 4 patients with angiosarcoma died of metastatic angiosarcoma, with the other 2 disease-free at 6.8 and 7 years. Compared with the 165 patients with follow-up and no vasculogenic lesions, there was a highly significant (P=4.3×10-5) association of any vasculogenic lesion with sarcomatoid tumors during the clinical course of VMT patients. In addition, 5/46 patients with follow-up and vasculogenic lesions (11%) died of either leukemia or myelodysplastic syndrome compared with 2 of 166 (1%) lacking them (P=0.0012). Three of the 5 patients had identifiable immature hematopoietic cells within their vasculogenic lesions, but 4 other VMT patients with these did not develop leukemia or myelodysplasia. We conclude: (1) vasculogenic lesions are frequent in postchemotherapy resections of primary mediastinal germ cell tumors with yolk sac tumor components; (2) they mostly consist of neoplastic vessels in a stroma that also generates neoplastic vascular walls of smooth muscle; (3) VMTs are associated with an increased incidence of sarcomas, even though most vasculogenic lesions in this context do not meet criteria for angiosarcoma; (4) the presence of vasculogenic lesions in postchemotherapy resections of primary mediastinal germ cell tumors place patients at increased risk for leukemia or myelodysplasia.

Optimum lymphadenectomy for esophageal cancer.

OBJECTIVE: Using Worldwide Esophageal Cancer Collaboration data, we sought to (1) characterize the relationship between survival and extent of lymphadenectomy, and (2) from this, define optimum lymphadenectomy. SUMMARY BACKGROUND DATA: What constitutes optimum lymphadenectomy to maximize survival is controversial because of variable goals, analytic methodology, and generalizability of the underpinning data. METHODS: A total of 4627 patients who had esophagectomy alone for esophageal cancer were identified from the Worldwide Esophageal Cancer Collaboration database. Patient-specific risk-adjusted survival was estimated using random survival forests. Risk-adjusted 5-year survival was averaged for each number of lymph nodes resected and its relation to cancer characteristics explored. Optimum number of nodes that should be resected to maximize 5-year survival was determined by random forest multivariable regression. RESULTS: For pN0M0 moderately and poorly differentiated cancers, and all node-positive (pN+) cancers, 5-year survival improved with increasing extent of lymphadenectomy. In pN0M0 cancers, no optimum lymphadenectomy was defined for pTis; optimum lymphadenectomy was 10 to 12 nodes for pT1, 15 to 22 for pT2, and 31 to 42 for pT3/T4, depending on histopathologic cell type. In pN+M0 cancers and 1 to 6 nodes positive, optimum lymphadenectomy was 10 for pT1, 15 for pT2, and 29 to 50 for pT3/T4. CONCLUSIONS: Greater extent of lymphadenectomy was associated with increased survival for all patients with esophageal cancer except at the extremes (TisN0M0 and >or=7 regional lymph nodes positive for cancer) and well-differentiated pN0M0 cancer. Maximum 5-year survival is modulated by T classification: resecting 10 nodes for pT1, 20 for pT2, and >or=30 for pT3/T4 is recommended.