Early esophageal neuroendocrine tumor.

Esophageal neuroendocrine tumors are rare and often found incidentally on endoscopy. We present a unique case of an esophageal neuroendocrine tumor found in the setting of dysplasia associated with Barrett's esophagus. The tumor was removed endoscopically. This case highlights the incidence, prognosis, and management of esophageal neuroendocrine tumors.

Clinicopathological Analysis of Uterine Allografts Including Proposed Scoring of Ischemia Reperfusion Injury and T-cell-mediated Rejection-Dallas UtErus Transplant Study: A Pilot Study.

BACKGROUND: Uterus transplantation (UTx) enables pregnancy in infertile women. This study describes the histopathological changes of ischemia reperfusion injury and mostly acute T-cell-mediated rejection (TCMR) in UTx and proposes modification toward a working formulation grading system with associated treatments. METHODS: Protocol and indication biopsies from 11 living and 2 deceased donor UTx recipients were analyzed. Serving as a control were 49 age-matched nontransplanted uteri. All posttransplant histopathological specimens were evaluated in a blinded fashion by 3 pathologists. Response to treatment was assessed by follow-up biopsies. Serial serum donor-specific antibody (DSA) responses were also recorded. RESULTS: Changes attributed to ischemia reperfusion resolved within 2 wk of UTx in most of the patients. For TCMR grading, perivascular inflammation, focal capillary disruption, and interstitial hemorrhage were added to interface inflammation, intercellular edema, stromal inflammation, and epithelial apoptotic bodies. Of the 173 protocol biopsies, 98 were classified as negative for TCMR; 34 as indeterminate-borderline; 35 as mild; 3 as moderate; and 3 as severe, 1 of which occurred in a DSA-positive recipient and also showed microvascular injury. Corticosteroids successfully treated all moderate-to-severe TCMR episodes. Mild TCMR was treated by increasing existing baseline immunosuppression. Indeterminate-borderline episodes were not treated. Neither ischemia-reperfusion injury nor TCMR with DSA adversely affected embryo transfer. CONCLUSIONS: Relying on a modified histopathological grading system, we developed a treatment strategy resulting in resolution of TCMR and successful pregnancies.

Primary rectal monophasic synovial sarcoma.

Synovial sarcoma is a rare malignant mesenchymal neoplasm that often occurs in the extremities. Less than 70 cases of primary synovial sarcoma occurring in the digestive system have been reported. We present a case of a 48-year-old woman with a spindle cell tumor in the rectum that stained positive for AE1/3 (focal), vimentin, CD99, BCL2, EMA (focal), and MiB-1 (15%). Ultimately, the lesion was diagnosed as a primary rectal monophasic synovial sarcoma and confirmed by molecular testing for SYT/SSX1 gene fusion. Analysis of previous publications indicated that patients of advanced age or a large tumor size (≥5 cm) have a higher risk of progressing rapidly to death after diagnosis of synovial sarcoma in the digestive system.

Primary pulmonary Ewing sarcoma/peripheral primitive neuroectodermal tumor.

Ewing sarcoma/peripheral primitive neuroectodermal tumor (ES/pPNET) is a malignant small round cell sarcoma commonly occurring among children, adolescents, and adults. We report a rare case of ES/pPNET arising from the lung in a 49-year-old woman. She was found to have a mass in the right lung on a screening imaging study for her BRCA2 mutation. A lobectomy was performed and the mass had histological, immunohistochemical, and molecular features of ES/pPNET. Few cases of primary pulmonary Ewing sarcoma have been reported.

Cutaneous signet-ring cell squamous cell carcinoma.

Cutaneous signet-ring cell squamous cell carcinoma (SRCSCC) is a rare variant, most commonly occurring in the head and neck. We report a case of a 66-year-old transgender woman with an ulcerated growing facial mass measuring 5.6 × 4.0 × 2.0 cm. Histological analysis showed features consistent with SRCSCC. Immunohistochemical analysis showed positive staining for high-molecular-weight cytokeratin, estrogen receptor (1-2+ in 10%), E-cadherin (mostly positive with partial loss), and p40 and negative staining for Ber EP-4, cytokeratin 7, low-molecular-weight cytokeratin, mucicarmine, Alcian blue PAS, HER2, and MUC4. The tumor had invaded the perineurium, lymphovascular spaces, and subcutaneum. Additionally, microsatellite instability testing was negative. This case adds to the limited knowledge of this poorly characterized entity.

Cribriform-morular variant of papillary thyroid carcinoma and its association with familial adenomatous polyposis.

The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is an uncommon variant of papillary thyroid carcinoma. CMV-PTC can be associated with familial adenomatous polyposis (FAP), an autosomal-dominant polyposis syndrome caused by a mutation in the APC gene that leads to a disruption of the Wnt/beta-catenin pathway. Understanding the relation between CMV-PTC and FAP is a diagnostic tool for both pathologists and clinicians, because FAP has several implications for patients and their families.

Myxoma versus myxoid liposarcoma involving the kidneys.

Myxoid lesions of the kidney are rare. We present a case of a 74-year-old man who presented with an 8.5 × 8.0 × 6.0 cm left kidney mass that was grossly confined to the kidney and had a gelatinous cut surface. Histology of the tumor showed bland spindle cells in a myxoid stroma with interspersed thin-walled vessels. The tumor was negative for smooth muscle actin, desmin, CD34 (highlighted vessels), S100, and HMB-45 by immunohistochemistry. There was focal, nonspecific staining of MDM2 and CDK4. The lesion appeared more vascular than would be expected for a classic myxoma and, therefore, fluorescence in situ hybridization was performed for the 12q13 (DDIT3 or CHOP) rearrangement to rule out myxoid liposarcoma and the result was negative for a rearrangement. This case highlights the difficulty of delineating a primary myxoma of the kidney from a well-differentiated myxoid liposarcoma.

Intraductal papillary neoplasm of the bile duct.

Intraductal papillary neoplasm of the bile duct is characterized by intraductal papillary growth with fibrovascular cores that can grow anywhere along the biliary tree. Most cases have high-grade intraepithelial neoplasia or an associated invasive carcinoma. These tumors can spread superficially along the biliary tree and be multifocal, and preoperative biopsy cannot always reflect the maximum degree of atypia. Frozen section to assess the distal common bile duct margin is crucial to avoid the risk of recurrence. Theoretically, resection of the entire biliary tree by liver transplantation and pancreaticoduodenectomy is regarded as the only curative treatment.

Phosphohistone-H3 and Ki67: Useful Markers in Differentiating Dermatofibroma From Dermatofibrosarcoma Protuberans and Atypical Fibrohistiocytic Lesions.

Dermatofibromas (DF) are common, benign, skin tumors, usually easily differentiated from dermatofibrosarcoma protuberans (DFSP) by the presence of a relative low cellularity, lesser degree of infiltration of subcutaneous tissue, and immunohistochemical pattern (eg, FXIIIa in DF and CD34 in DFSP). Atypical fibrohistiocytic lesions (AFL) have features intermediate to DF and DFSP (trunk location, storiform pattern, infiltration of the subcutaneous tissue, and focal expression of both CD34 and Factor XIIIa). It is unclear if mitotic counts/degree of proliferation is helpful to distinguish DF from DFSP. To study the mitotic rate and proliferation index in DF, AFL/DFSP, anti-ki67, and anti-PHH3 were performed on 10 cases of DF (including 4 cellular DF), 10 standard DFSP, and 2 AFL. The proliferation index and mitotic figures were counted per square millimeter in a "hotspot" (in a fashion similar to mitotic counts in melanoma). All cases of DF showed much higher Ki67 proliferation index (P = 0.0001) along with increased mitotic figures both on H&E and with anti-PHH3 (P = 0.0001) when compared to AFL/DFSP. Our data indicate that DF has a higher proliferation index and mitotic counts when compared to superficial/peripheral portion of AFL and DFSP. This finding may be helpful in the differential diagnosis among these fibrohistiocytic lesions.

Signet ring cells in esophageal adenocarcinoma predict poor response to preoperative chemoradiation.

BACKGROUND: The purpose of this study was to examine the significance of signet ring cell histology to predict response to preoperative chemoradiotherapy in patients with esophageal adenocarcinoma. METHODS: Two groups of patients with locoregional esophageal adenocarcinoma treated with neoadjuvant chemoradiation and surgery were studied: those with signet ring cell adenocarcinoma (n = 85) and a reference group (n = 638) with usual and other types of adenocarcinoma. Surgical specimens were reviewed for degree of pathologic response and pathologic stage. Cox regression models were used to assess the effects of clinicopathologic variables on survival. RESULTS: Tumors from patients in the signet ring cell group had a lower rate of complete pathologic response (9% versus 26%, p < 0.001) and more frequent positive margins (24% versus 10%, p < 0.001) compared with tumors from the reference group. Median overall survival (22 versus 48 months, p = 0.003) and disease-free survival (16 versus 35 months, p = 0.007) were shorter in the signet ring cell group than in the reference group. Signet ring cell histology and high pathologic stage were significant predictors of decreased overall survival and disease-free survival. Survival durations for patients whose resected specimens showed downstaging after neoadjuvant chemoradiation did not significantly differ from survival durations of patients whose specimens did not show downstaging in the signet ring cell group, unlike the reference group. CONCLUSIONS: Signet ring cell histology on pretreatment biopsy predicts a decreased likelihood of complete pathologic response and survival for patients with esophageal adenocarcinoma treated with preoperative chemoradiation and surgery.

Quantified pathologic response assessed as residual tumor burden is a predictor of recurrence-free survival in patients with rectal cancer who undergo resection after neoadjuvant chemoradiotherapy.

BACKGROUND: The current study was conducted to determine whether quantified pathologic response assessed as a percentage of residual tumor cells is predictive of recurrence-free survival (RFS) in patients with rectal cancer. METHODS: The authors studied 251 patients with rectal adenocarcinoma who were treated with neoadjuvant chemoradiation and radical resection. Quantified pathologic response was defined as an estimated percentage of residual cancer cells in relation to the tumor bed: complete, no residual cancer cells; near-complete, ≤ 5% residual cancer cells; major, > 5%, and < 50% residual cancer cells; and minor, ≥ 50% residual cancer cells. The reproducibility of quantified pathologic response between 2 pathologists was assessed using tumors from 55 randomly selected patients who did not demonstrate a complete response. RESULTS: Pathologic response was complete in 21% of patients, near-complete in 20% of patients, major in 37% of patients, and minor in 22% of patients. Nineteen percent of patients had ypT0N0 disease, 27% had ypT1-2N0 disease, 21% had ypT3-4N0 disease, and 33% had N+ disease. The 5-year RFS rates by category of quantified pathologic response were as follows: complete, 95%; near-complete, 88%; major, 69%; and minor, 61% (P < .001). Major and minor response, high histologic grade, and perineural invasion were found to be significant predictors of decreased RFS on multivariate analysis. The 5-year RFS rates for patients with ypT3-4 or N+ disease were better for those with a near-complete response (94%) compared with those with a major (64%) or minor (61%) response (P < .02). Moderate to substantial agreement was observed between the 2 pathologists (κ = 0.72). CONCLUSIONS: Quantified pathologic response is a predictor of RFS in patients with rectal adenocarcinoma and stratifies patients with high pathologic stage disease.

Multicenter validation study of pathologic response and tumor thickness at the tumor-normal liver interface as independent predictors of disease-free survival after preoperative chemotherapy and surgery for colorectal liver metastases.

BACKGROUND: To validate pathologic markers of response to preoperative chemotherapy as predictors of disease-free survival (DFS) after resection of colorectal liver metastases (CLM). METHODS: One hundred seventy-one patients who underwent resection of CLM after preoperative chemotherapy at 4 centers were studied. Pathologic response-defined as the proportion of tumor cells remaining (complete, 0%; major, <50%; minor, ≥50%) and tumor thickness at the tumor-normal liver interface (TNI) (<0.5 mm, 0.5 to <5 mm, ≥5 mm)-was assessed by a central pathology reviewer and local pathologists. RESULTS: Pathologic response was complete in 8% of patients, major in 49% of patients, and minor in 43% of patients. Tumor thickness at the TNI was <0.5 mm in 21% of patients, 0.5 to <5 mm in 56% of patients, and ≥5 mm in 23% of patients. On multivariate analyses, using either pathologic response or tumor thickness at TNI, pathologic response (P = .002, .009), tumor thickness at TNI (P = 0.015, <.001), duration of preoperative chemotherapy (P = .028, .043), number of CLM (P = .038, . 037), and margin (P = .011, .016) were associated with DFS. In a multivariate analysis using both parameters, tumor thickness at TNI (P = .004, .015), duration of preoperative chemotherapy (P = .025), number of nodules (P = .027), and margin (P = .014) were associated with DFS. Tumor size by pathology examination was the predictor of pathologic response. Predictors of tumor thickness at the TNI were tumor size and chemotherapy regimen. There was near perfect agreement for pathologic response (κ = .82) and substantial agreement (κ = .76) for tumor thickness between the central reviewer and local pathologists. CONCLUSIONS: Pathologic response and tumor thickness at the TNI are valid predictors of DFS after preoperative chemotherapy and surgery for CLM.

Neoadjuvant treatment response as an early response indicator for patients with rectal cancer.

PURPOSE: Neoadjuvant chemoradiotherapy for rectal cancer is associated with improved local control and may result in complete tumor response. Associations between tumor response and disease control following radical resection should be established before tumor response is used to evaluate treatment strategies. The purpose of this study was to assess and compare oncologic outcomes associated with the degree of pathologic response after chemoradiotherapy. PATIENTS AND METHODS: All patients with locally advanced (cT3-4 or cN+ by endorectal ultrasonography, computed tomography, or magnetic resonance imaging) rectal carcinoma diagnosed from 1993 to 2008 at our institution and treated with preoperative chemoradiotherapy and radical resection were identified, and their records were retrospectively reviewed. The median radiation dose was 50.4 Gy with concurrent chemotherapy. Recurrence-free survival (RFS), distant metastasis (DM), and local recurrence (LR) rates were compared among patients with complete (ypT0N0), intermediate (ypT1-2N0), or poor (ypT3-4 or N+) response by using Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression. RESULTS: In all, 725 patients were classified by tumor response: complete (131; 18.1%), intermediate (210; 29.0%), and poor (384; 53.0%). Age, sex, cN stage, and tumor location were not related to tumor response. Tumor response (complete v intermediate v poor) was associated with 5-year RFS (90.5% v 78.7% v 58.5%; P < .001), 5-year DM rates (7.0% v 10.1% v 26.5%; P < .001), and 5-year LR only rates (0% v 1.4% v 4.4%; P = .002). CONCLUSION: Treatment response to neoadjuvant chemoradiotherapy among patients with locally advanced rectal cancer undergoing radical resection is an early surrogate marker and correlate to oncologic outcomes. These data provide guidance with response-stratified oncologic benchmarks for comparisons of novel treatment strategies.

Durable complete responses in metastatic colorectal cancer treated with chemotherapy alone.

BACKGROUND/PURPOSE: The median survival for patients with metastatic colorectal cancer (mCRC) has progressively increased over the past decades. Since the introduction of 5-fluorouracil (5-FU)-based chemotherapy, followed by hepatic resection of metastases, and more recently the adoption of newer chemotherapeutic regimens associated with targeted therapy, the gains are getting more substantial. Despite the recognition of the potential for long-term survival after surgical resection of metastatic disease, long-term survival data to determine the potential curative role of chemotherapy alone is lacking. METHODS: We performed a retrospective review of 2751 patients who presented with mCRC at The MD Anderson Cancer Center from 1990 through 2003. Patients alive at 5 years who achieved complete response with chemotherapy and were not submitted to any surgical or interventional procedures directed to the metastatic sites were included in the analysis. RESULTS: The 5-year overall survival rate for all patients with mCRC during this period was 10.8%. Among these long-term survivors, 2.2% achieved a sustained complete response after chemotherapy (all 6 with fluoropyrimidines and 2 with irinotecan) as the only treatment modality and were without evidence of disease until the last follow-up visit (median of 10.3 years). This number corresponds to 0.24% (6 of 2541) of all patients with mCRC included in this review. CONCLUSION: Cure with chemotherapy alone is possible for a very small number of patients with metastatic colorectal cancer. Improved therapies are increasing complete response rates, but the impact of modern chemotherapy on durable complete responses will require additional follow up.

Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer.

BACKGROUND: It is hypothesized that BRAF mutant cancers represent a discrete subset of metastatic colorectal cancer (CRC) defined by poorer survival. This study investigates whether BRAF mutant CRC is further defined by a distinct pattern of metastatic spread and explores the impact of BRAF mutation and microsatellite instability (MSI) on prognosis in metastatic CRC. METHODS: By using prospective clinical data and molecular analyses from 2 major centers (Royal Melbourne Hospital and The University of Texas MD Anderson Cancer Center), patients with known BRAF mutation status were analyzed for clinical characteristics, survival, and metastatic sites. RESULTS: The authors identified 524 metastatic CRC patients where BRAF mutation status was known; 57 (11%) were BRAF mutant tumors. BRAF mutant tumors were significantly associated with right-sided primary tumor, MSI, and poorer survival (median, 10.4 months vs 34.7 months, P < .001). A distinct pattern of metastatic spread was observed in BRAF mutant tumors, namely higher rates of peritoneal metastases (46% vs 24%, P = .001), distant lymph node metastases (53% vs 38%, P = .008), and lower rates of lung metastases (35% vs 49%, P = .049). In additional survival analyses, MSI tumors had significantly poorer survival compared with microsatellite stable tumors (22.1 months vs 11.1 months, P = .017), but this difference was not evident in the BRAF mutant population. CONCLUSIONS: The pattern of metastatic spread observed in this study further defines BRAF mutant CRC as a discrete disease subset. The authors demonstrated that, unlikely early stage disease, MSI is associated with poorer survival in metastatic CRC, although this is driven by its association with BRAF mutation.

Tumor thickness at the tumor-normal interface: a novel pathologic indicator of chemotherapy response in hepatic colorectal metastases.

BACKGROUND: Progress in the treatment of hepatic colorectal metastases (HCRM) demands pathologic indicators of therapy response. We observed that a majority of residual tumor cells are seen at the tumor-normal interface (TNI) in resected HCRM specimens and hypothesized that tumor thickness at the TNI correlates with radiologic and pathologic response and recurrence-free survival (RFS). DESIGN: This study included 103 patients with HCRM resected after preoperative chemotherapy with or without bevacizumab. Imaging response was assessed by response evaluation criteria in solid tumors (RECIST) and recently described CT morphology criteria by Chun et al. The pathologic response was categorized as complete (no tumor cells), major (<50% residual tumor cells), or minor (> or =50% residual tumor cells). The maximum thickness of uninterrupted layers of tumor cells was measured perpendicular to the TNI by 2 pathologists independently, followed by consensus review for discrepant cases. For specimens containing >1 tumor, the average tumor thickness at the TNI was used. RESULTS: Sixty-five patients received oxaliplatin-based chemotherapy, 38 received irinotecan-based chemotherapy, and 75 received concurrent bevacizumab. A complete pathologic response was seen in 9 patients, a major response in 44, and a minor response in 50. Median tumor thickness at the TNI was 2.8 mm (interquartile range, 0.5 to 6 mm). Tumor thickness correlated better with radiologic response as determined by Chun et al (P<0.0001) than by RECIST criteria (Spearman r=0.35, P<0.001). Tumor thickness correlated with pathologic response (Spearman r=0.80, P<0.0001). Greater thickness predicted shorter recurrence-free survival, and this correlation remained in multivariate analysis (P=0.015). Tumor thickness was smaller in patients treated with bevacizumab than in patients not given bevacizumab (P=0.03). CONCLUSIONS: Tumor thickness measured at the TNI is potentially a new prognostic factor for therapy response and survival outcome in patients with resected HCRM.

Monophasic synovial sarcoma of tongue.

Synovial sarcoma is a well defined morphologic entity extensively researched in literature. Synovial sarcoma displays a wide spectrum of clinical presentations and histologic appearances that may give rise to diagnostic dilemmas. One such unusual site in the head and neck area is the tongue. We report a case of monophasic synovial sarcoma of the tongue in a 22-year-old male. Microscopically, this tumor mimicked a poorly differentiated carcinoma which is more common at this site though the patient was young for this type of tumor. On immunohistochemistry, neoplastic cells were positive for cytokeratin, vimentin, calponin, CD99 and bcl2. Molecular studies--viz. reverse transcriptase polymerase chain reaction revealed a SYT-SSX translocation clinching the diagnosis. This paper highlights the immunohistochemistry profile and SYT-SSX translocation which helped arrive at an accurate diagnosis only because the index of suspicion for a monophasic synovial sarcoma is high.

Portal hypertension associated with oxaliplatin administration: clinical manifestations of hepatic sinusoidal injury.

Oxaliplatin-based chemotherapy regimens are currently a standard of care for the treatment of colorectal cancer (CRC) in both the adjuvant treatment and metastatic disease settings. Significant improvements in outcomes have been achieved with oxaliplatin-based combinations in these settings when compared with administration of 5-fluorouracil alone. Pathologic evaluation of normal liver from patients undergoing neoadjuvant oxaliplatin treatment has identified histologic evidence of sinusoidal injury, although the effect of this finding on patient outcomes after hepatic resection appears to be minimal. This article describes the use of oxaliplatin-based chemotherapy in 6 patients with stage III or IV CRC who developed evidence of noncirrhotic portal hypertension. These patients developed complications of portal hypertension including esophageal or hemorrhoidal varices with bleeding, splenomegaly with associated thrombocytopenia, and ascites. In each case, oxaliplatin-induced hepatic sinusoidal injury was identified as the most likely factor contributing to the development of noncirrhotic portal hypertension. The literature on hepatic sinusoidal injury after oxaliplatin is reviewed and the proposed pathophysiology is discussed.