Christopher A. Sattler

Association of HER2/ErbB2 Expression and Gene Amplification with Pathologic Features and Prognosis in Esophageal Adenocarcinomas

Purpose: We examined the frequency, tumor characteristics, and prognostic impact of HER2 protein expression and gene amplification in patients with curatively resected esophageal adenocarcinoma (EAC). Experimental Design: HER2 expression was analyzed by immunohistochemistry (IHC) in surgical EAC specimens (n = 713). Gene amplification was examined by FISH in a large subset (n = 344). Most tumors were T3–4 (66%) or node positive (72%); 95% were located in the esophagus or gastroesophageal junction. No patient received neoadjuvant therapy. Cox models were used. Results: Overall, 17% of EACs were HER2 positive (i.e., IHC3+ or IHC2+ with amplification), with strong agreement between HER2 amplification (HER2/CEP17 ratio ≥2) and expression (κ = 0.83). HER2 positivity was significantly associated with lower tumor grade, less invasiveness, fewer malignant nodes, and the presence of adjacent Barretts esophagus (BE). EACs with BE had higher odds of HER2 positivity than EACs without BE, independent of pathologic features [OR = 1.8 (95% CI: 1.1–2.8), P = 0.014]. Among all cases, HER2 positivity was significantly associated with disease-specific survival (DSS) in a manner that differed by the presence or absence of BE (Pinteraction = 0.0047). In EACs with BE, HER2 positivity was significantly associated with improved DSS [HR = 0.54 (95% CI: 0.35–0.84), P = 0.0065] and overall survival (P = 0.0022) independent of pathologic features, but was not prognostic among EACs without BE. Conclusions: HER2 positivity was shown in 17% of resected EACs and associated with reduced tumor aggressiveness. EACs with BE had nearly twice the odds of being HER2 positive and, within this subgroup, HER2 positivity was independently associated with improved survival. Clin Cancer Res; 18(2); 546–54. ©2012 AACR.

Adverse Prognostic Impact of Intratumor Heterogeneous HER2 Gene Amplification in Patients With Esophageal Adenocarcinoma

PURPOSE There is increasing recognition of the existence of intratumoral heterogeneity of the human epidermal growth factor receptor (HER2), which affects interpretation of HER2 positivity in clinical practice and may have implications for patient prognosis and treatment. We determined the frequency and prognostic impact of heterogeneous HER2 gene amplification and polysomy 17 in patients with esophageal adenocarcinoma (EAC). PATIENTS AND METHODS HER2 amplification (by fluorescence in situ hybridization) was examined in surgical EAC specimens (n = 675). HER2 heterogeneity was defined according to consensus guidelines as gene amplification (HER2/CEP17 ratio ≥ 2.0) in more than 5% but less than 50% of cancer cells. No patient received neoadjuvant or HER2-targeted therapy. Cox models were used to assess disease-specific survival (DSS) and overall survival (OS). RESULTS Overall, 117 EACs (17%) demonstrated HER2 amplification, of which 20 (17%) showed HER2 heterogeneity. All HER2-heterogeneous tumors were amplified. Among HER2-amplified tumors, heterogeneous tumors had significantly higher frequency of poor histologic grade and polysomy 17. In multivariable models that included number of metastatic lymph nodes, grade, tumor stage, and polysomy 17, only HER2 heterogeneity and node number were prognostic among HER2-amplified tumors, with heterogeneity showing worse DSS (hazard ratio, 2.04; 95% CI, 1.09 to 3.79; P = .025) and OS (P = .026). Among HER2-nonamplified EACs, polysomy 17 was independently associated with worse DSS (P = .012) and OS (P = .023). CONCLUSION Among HER2-amplified EACs, 17% show HER2 heterogeneity, which independently predicts for worse cancer-specific death. Among HER2-nonamplified EACs, polysomy 17 is independently associated with worse survival. These novel findings demonstrate aggressive subgroups in HER2-amplified and -nonamplified EACs that have important implications for HER2 analysis and determination of benefit from HER2-targeted therapy.

Morphologic Features of ALK-negative Anaplastic Large Cell Lymphomas With DUSP22 Rearrangements

Systemic anaplastic large cell lymphomas (ALCLs) are classified into ALK-positive and ALK-negative types. We recently reported that ALK-negative ALCLs are genetically heterogenous. The largest subset, representing 30% of cases, had rearrangements of the DUSP22 locus. These cases had favorable outcomes similar to ALK-positive ALCL, and superior to other ALK-negative ALCLs. Here, we examined the morphologic features of these cases in more detail. First, we conducted blinded review of hematoxylin and eosin slides of 108 ALCLs from our previous study, scoring cases for the presence of 3 histologic patterns and 5 cell types. Cases then were unblinded and re-reviewed to understand these features further. DUSP22-rearranged ALCLs were more likely than other ALK-negative ALCLs to have so-called doughnut cells (23% vs. 5%; P=0.039), less likely to have pleomorphic cells (23% vs. 49%; P=0.042), and nearly always (95%) had areas with sheet-like growth (common pattern). To examine the reproducibility of these findings, we conducted blinded review of hematoxylin and eosin slides of 46 additional ALK-negative ALCLs using a 0 to 3 scoring system to predict likelihood of DUSP22 rearrangement, the results of which correlated strongly with subsequent findings by fluorescence in situ hybridization (P<0.0001). Although all ALCLs share certain morphologic features, ALCLs with DUSP22 rearrangements show significant differences from other ALK-negative ALCLs, typically showing sheets of hallmark cells with doughnut cells and few large pleomorphic cells. These morphologic findings and our previous outcome data suggest that ALK-positive ALCLs and DUSP22-rearranged ALCLs represent prototypical ALCLs, whereas ALCLs lacking rearrangements of both DUSP22 and ALK require further study.

DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort study

To the editor: Peripheral T-cell lymphomas (PTCLs) represent a group of rare hematological cancers of mature T-cell or natural killer cell origin accounting for 10% to 15% of all lymphomas.[1][1] Although many patients have poor outcomes, some achieve long-term survival.[2][2],[3][3] Thus,

Selection of Embryos for Day-3 Transfer at the Pronuclear-Stage and Pronuclear-Stage Cryopreservation Results in High Delivery Rates in Fresh and Frozen Cycles

AbstractPurpose: Evaluate IVF-ET outcome data for a unique culture and cryopreservation strategy. Methods: Retrospective study of 92 patients. Embryos for day-3 transfer were selected at pronuclear-stage; all extra zygotes were cryopreserved at pronuclear-stage. Results: Delivery rates for Anonymous Oocyte Donation (Group I), patients <35 years (Group II), and 35–38 years (Group III) were 52.9%, 61.5%, and 51.7% for fresh and 38.5%, 33.3%, and 40.0% for frozen transfer. Deliveries per retrieval were 82.3%, 71.8%, and 58.6%. Only 0.88, 0.80, and 0.61 more zygotes were cultured than what were used for fresh transfer. Singleton, twin, and triplet rates were 64.6%, 31.2%, and 4.2% for fresh and 69.2%, 30.8%, and 0% for frozen. Conclusions: Selection of day-3 transfer embryos at the pronuclear-stage and cryopreservation of extra zygotes results in high delivery rates in fresh and frozen cycles. This approach optimizes deliveries per retrieval and provides many patients with more than one pregnancy per retrieval.

Central nervous system relapse in patients with untreated HER2-positive esophageal or gastroesophageal junction adenocarcinoma

Although HER2‐positive breast cancers demonstrate a propensity for central nervous system (CNS) metastasis, it is unknown whether other HER2‐positive tumors, including adenocarcinomas of the esophagus/gastroesophageal junction (EAC), share this characteristic. Insight into this association may inform the development of HER2‐targeted therapies that penetrate the blood‐brain barrier. We examined HER2 overexpression and gene amplification in 708 patients with EAC who underwent curative‐intent surgery during a time period (1980–1997) when no patient received HER2‐targeted therapy. We identified patients whose site of first cancer recurrence was CNS and those who had a CNS relapse at any time. After a median follow‐up of 61.2 months, 3.4% (24/708) of patients developed CNS relapse (all involved the brain). Patients with HER2‐positive (vs ‐negative) primary tumors showed a higher 5‐year cumulative incidence of CNS relapse as first recurrence (5.8% vs. 1.2%; p = 0.0058) and at any time (8.3% vs. 2.4%; p = 0.0062). In a multivariable model that included covariates previously associated with HER2 or with CNS relapse in breast cancer, HER2 positivity was the only variable that was statistically significantly associated with shorter time to CNS relapse as first recurrence (p = 0.0026) or at any time (hazard ratio 4.3 [95% confidence interval 1.8 to 10.3]; p = 0.001). These are the first data in a non‐breast cancer to demonstrate an association between HER2 positivity and higher CNS relapse risk after surgery, and suggest that HER2‐positive EACs have a predilection for CNS metastases.

Spindle Cell Lipomas Arising at Atypical Locations

OBJECTIVES Spindle cell lipomas (SCLs) are benign lipomatous neoplasms that classically arise in the posterior neck, upper back, and shoulders of older male patients. We sought to characterize the occurrence of this entity at nonclassic sites. METHODS All cases of SCL arising at atypical sites were retrieved from our archives. RESULTS Of 439 total cases of SCL, 57 arose at atypical locations in 32 men and 25 women (age range, 27-79 years). The tumor sites included leg (n = 23), buttock/perineum/inguinal (n = 10), forearm (n = 9), finger (n = 9), foot (n = 2), toe (n = 2), hand (n = 1), and flank (n = 1). CD34 was positive staining in all cases tested (52/52), while desmin was negative in most tumors (48/50). Thirty-eight of 38 cases tested exhibited loss of Rb expression. No cases showed CPM/MDM2 amplification (0/48). No local recurrences have been reported (n = 39). CONCLUSIONS SCLs may arise in the trunk, lower extremities, and distal upper extremities. While most SCLs arising in classic sites occur in male patients, there is a relatively equal sex distribution in tumors at atypical sites. Pathologists should be aware that SCLs arise at atypical locations to avoid misclassification as other lipomatous neoplasms, including atypical lipomatous tumor.

Genetic subtyping of breast implant–associated anaplastic large cell lymphoma

TO THE EDITOR: Anaplastic large cell lymphomas (ALCLs) represent a group of CD30-positive T-cell non-Hodgkin lymphomas with unifying morphological characteristics but variable clinical and genetic features. ALCLs are classified by their clinical presentation and the presence or absence of

DUSP22 AND TP63 REARRANGEMENTS PREDICT OUTCOME OF ALK-NEGATIVE ANAPLASTIC LARGE CELL LYMPHOMA: A DANISH COHORT STUDY

useful information for assessing prognosis. Meanwhile, data of the role of specific circulating lymphocyte subsets as host immune factor in the progression of ENKTL is limited. This study aims to investigate the clinical correlation and distribution of circulating absolute CD4 T cell counts (ACD4C) in ENKTL. Methods: We retrospectively searched the medical records of 88 patients with untreated ENKTL diagnosed at the Department of Hematology at the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital) from August 1, 2009 to May 31, 2016. The distribution and prognostic value of ACD4C at diagnosis was analyzed. Results: The result showed that low ACD4C at diagnosis was significantly associated with stage III/IV (P = 0.001), B symptoms (P = 0.020), elevated serum lactate dehydrogenase (LDH) (P < 0.001), regional lymphadenopathy (P = 0.015), high‐intermediate and high‐risk International Prognosis Index (IPI) (P < 0.001) and Korean Prognostic Index (KPI) (P < 0.001). As well, we also found that low ACD4C have significant link to decreasing monocytes (P = 0.001), anemia (P = 0.049) and thrombocytopenia (P = 0.014). There were significant differences in both overall survival (OS) (P < 0.001) and progression‐ free survival (PFS) (P < 0.001) between ACD4C < 0.3 × 10/L cohort and ACD4C ≥ 0.3 × 10/L cohort (Fig. A and B). With the median follow‐up time of 33 months, patients who had ACD4C < 0.30 × 10/L had worse survival with the 3‐year OS of 36.9% versus 81.2% in patients with high ACD4C, and the 3‐year PFS of 32.1% versus 67.0%. The 5‐year OS and PFS were 36.9% vs. 62.8% and 24.1% vs. 67.0% between ACD4C < 0.3 × 10/L cohort and ACD4C0.3 × 10/L cohort, respectively. The median OS time was 14 months, and the median PFS was 5.5 months in low ACD4C cohort, while the median OS and PFS were not reached in ACD4C ≥ 0.3 × 109/L cohort. In univariate analysis, the results also demonstrated that B symptoms, poor PS, stage III/IV, primary extranasal presentation, regional lymphadenopathy, anemia, high and intermediate‐high risk IPI and KPI were related with worse OS and PFS. Moreover, the multivariate Cox analysis identified the ACD4C as an independent predictor for OS (P = 0.029; relative risk, 2.632; 95% CI 1.104–6.276) and PFS (P = 0.010; relative risk, 2.719; 95% CI 1.264–5.849). Conclusions: This retrospective study demonstrated that low ACD4C as important immune factor was associated with poorer survival and could act as a negative predictor for patients with ENKTL. It was supposed that ACD4C play an important role in the pathogenesis and progression of ENKTL.