Hepatitis B vs. hepatitis C infection on viral hepatitis-associated hepatocellular carcinoma.

BACKGROUND: To determine clinical-pathologic variables in patients with a new diagnosis of hepatocellular carcinoma (HCC) and underlying hepatitis B vs. C infection. METHODS: Patients presenting to a single urban hospital with a new diagnosis of HCC were entered into a clinical database. Variables including number and size of tumors, presence of metastases, serum alpha-Fetoprotein, hepatitis serologies, severity of hepatic dysfunction, and presence of cirrhosis were evaluated in 127 patients. RESULTS: Patients with hepatitis B (HBV) were more likely to develop HCC at a younger age than patients with hepatitis C (HCV) (HBV-26% under age 40, HCV-0% under age 40; p < 0.001), with greater serum alpha-Fetoprotein production (median level: HBV-1000 ng/ml vs. HCV-37 ng/ml; p = 0.002), with larger tumors (HBV-78% >5 cm, HCV-28% >5 cm; p < 0.001), in the absence of cirrhosis (HBV-40%, HCV-0%; p < 0.001), and a decreased eligibility for curative treatment (HBV-14%, HCV-34%; p < 0.05). Conversely, patients with HCV were more likely to develop HCC in association with multiple co-morbidities, cirrhosis, and older age. CONCLUSIONS: Significant clinical-pathologic differences exist among HCC patients with underlying HBV vs. HCV. These differences impact eligibility for potentially-curative therapy and prognosis.

Clinical prognostic variables in young patients (under 40 years) with hepatitis B virus-associated hepatocellular carcinoma.

OBJECTIVE: The aim of this study was to determine the impact of hepatocelluar carcinoma (HCC) screening in chronic hepatitis B patients who did not meet the current screening recommendations. METHODS: Patients who were admitted to Bellevue Hospital Center with HCC were assessed for risk factors, cirrhosis and tumor-specific factors. Eligibility for liver transplantation or resection with favorable outcome was determined by applying Milan criteria. RESULTS: In all 93 patients were diagnosed with hepatitis B virus (HBV)-associated HCC, 18 of whom were under 40 years. Cirrhosis was infrequently associated with HCC in this group, with most cancers occurring in non-cirrhotic patients (12/18, 66.7%). No patient developed HCC outside the American Association for the Study of Liver Diseases (AASLD) cancer screening recommendations (young age, non-cirrhotic) were eligible for liver transplantation or resection with favorable outcomes (within Milan criteria). However, HCC patients who were diagnosed within AASLD screening recommendations did meet Milan criteria in 17.3% (14/81) patients. CONCLUSIONS: Current guidelines for HCC screening in patients with HBV may lead to a delay in diagnosis in non-cirrhotic patients under 40 years. Consideration should be given to modifying current recommendations to advocate entering HBV patients into a cancer-screening program at young age.

Wnt pathway in pulmonary fibrosis in the bleomycin mouse model.

BACKGROUND: The Wnt/beta-catenin signaling pathway plays an important role in regulating cellular differentiation, proliferation, and polarity. METHODS: We used bleomycin to induce lung fibrosis in a transgenic Wnt reporter mouse to characterize the expression pattern of cyclin D1, MMP-7, and TGF-beta in conjunction with the Wnt/beta-catenin signaling pathway. LacZ expression reveals the Wnt/beta-catenin signaling pathway through the activated (nuclear) beta-catenin and coactivation of LEF/TCF transcription factors. X-gal staining and immunohistochemical staining of beta-catenin, cyclin D1, MMP-7, and TGF-beta were assessed after bleomycin administration. RESULTS: We observed LacZ expression in bronchiolar proliferative lesions and the epithelium in remodeled cystic and fibrotic areas at both 1 and 3 weeks. Nuclear beta-catenin staining was prominent in epithelial cells of remodeled and fibrotic areas at 3 weeks. MMP-7 was faint in basement membranes of airways and matrix zones in fibrotic areas at 3 weeks. Cyclin D1 was observed in alveolar macrophages (AM), alveolar epithelium, and fibrotic areas consistent with rapid cell turnover in these areas at both 1 and 3 weeks. TGF-beta was faintly staining in alveolar macrophages and epithelial cells at 3 weeks. CONCLUSION: The Wnt/beta-catenin pathway is activated in bleomycin-induced lung fibrosis, and downstream genes were localized in AM, alveolar epithelium, and interstitium.

Intrahepatic levels of CXCR3-associated chemokines correlate with liver inflammation and fibrosis in chronic hepatitis C.

UNLABELLED: Chemokines, chemotactic cytokines, may promote hepatic inflammation in chronic hepatitis C virus (HCV) infection through the recruitment of lymphocytes to the liver parenchyma. We evaluated the association between inflammation and fibrosis and CXCR3-associated chemokines, interferon-gamma (IFN-gamma)-inducible protein 10 (IP-10/CXCL10), monokine induced by IFN-gamma (Mig/CXCL9), and interferon-inducible T cell alpha chemoattractant (I-TAC/CXCL11), in HCV infection. Intrahepatic mRNA expression of these chemokines was analyzed in 106 chronic HCV-infected patients by real-time PCR. The intrahepatic localization of chemokine producer cells and CXCR3(+) lymphocytes was determined in selected patients by immunohistochemistry. We found elevated intrahepatic mRNA expression of all three chemokines, most markedly CXCL10, in chronic HCV-infected patients with higher necroinflammation and fibrosis. By multivariable multivariate analysis, intrahepatic CXCL10 mRNA expression levels were significantly associated with lobular necroinflammatory grade and HCV genotype 1. In the lobular region, CXCL10-expressing and CXCL9-expressing hepatocytes predominated in areas with necroinflammation. Strong CXCL11 expression was observed in almost all portal tracts, whereas CXCL9 expression varied considerably among portal tracts in the same individual. Most intrahepatic lymphocytes express the CXCR3 receptor, and the number of CXCR3(+) lymphocytes was increased in patients with advanced necroinflammation. CONCLUSION: These findings suggest that the CXCR3-associated chemokines, particularly CXCL10, may play an important role in the development of necroinflammation and fibrosis in the liver parenchyma in chronic HCV infection.

Interwoven dendritic processes of follicular dendritic cell sarcoma demonstrated on ultrafast papanicolaou-stained smears: a case report.

BACKGROUND: Follicular dendritic cell (FDC) tumor is a rare tumor derived from accessory cells in the lymphoid follicles. FDC tumors are typically diagnosed on histology based on immunoreactivity to at least 1 of the FDC markers (CD21, CD23 or CD35) or based on the characteristic ultrastructural feature of long, interwoven, cytoplasmic, dendritic processes connected by desmosomes. CASE: We observed novel cytologic features of FDC sarcoma in a liver fine needle aspirate of a 46-year-old man status post surgery and chemotherapy for FDC sarcoma, originating in the gastrointestinal tract with metastases to the liver, pancreas and spleen. In the Diff-Quik- and Papanicolaou-stained smears, the tumor cells presented in syncytial fragments as well as single cells, as previously reported in the cytologic literature. However, the single cells were interconnected to neighboring single cells via long, thin, threadlike cytoplasmic processes in ultrafast Papanicolaou (UFP)-stained smears. The tumor cells possessed multipolar cytoplasmic processes rather than unipolar ones, as previously reported. CONCLUSION: The ultrastructural features of a web of interwoven, dendritic, cytoplasmic processes of FDC tumor was demonstrated for the first time on cytology. Observation of this feature may allow the diagnosis to be made on cytology prior to histology, immunohistochemistry or electron microscopy.

Primary squamous cell carcinoma of the colon associated with hypercalcemia and hyperleukocytosis. Report of a case.

BACKGROUND/AIMS: Squamous cell carcinoma of the colon is a rare entity. We report a case of a patient who presented with a perforated squamous cell carcinoma of the sigmoid colon. RESULTS: A 45-year-old female presented with a 2-month history of worsening abdominal pain, bloody diarrhea, and vomiting. She underwent an exploratory laparotomy and was found to have keratinizing squamous cell carcinoma of the sigmoid colon that had perforated forming multiple abscess cavities. The postoperative course was complicated by hypercalcemia and persistent hyperleukocytosis, ultimately resulting in the patient's death. CONCLUSIONS: We present the second reported case of squamous cell carcinoma of the colon associated with hypercalcemia and the first reported case of associated hyperleukocytosis.

Subdiaphragmatic bronchogenic cysts: a comprehensive review of the literature.

Bronchogenic cysts are foregut-derived developmental anomalies most commonly encountered in the mediastinum and rarely in the abdomen or retroperitoneally. A comprehensive review of the English-language literature of subdiaphragmatic bronchogenic cysts (sBCs) revealed only 48 reported cases of sBC. Although most cases are incidentally discovered, preoperative differential diagnosis often includes tumors with malignant potential and necessitates surgical resection to obtain a definitive diagnosis. Herein, we describe a case of a 46-year-old female presenting with intermittent left flank pain, upon which computed tomography demonstrated a retroperitoneal mass. Upon resection, histopathology revealed the mass to be a thin-walled cystic mass lined by ciliated columnar cells and cartilage, consistent with a subdiaphragmatic bronchogenic cyst. A comprehensive literature review of sBC was also performed.

Human T-lymphotropic virus type-1 related adult T-cell leukemia/lymphoma presenting as a parotid mass diagnosed by fine-needle aspiration biopsy.

A 48-yr-old black woman with a history of blood transfusions for menorrhagia secondary to uterine fibroids but no known Caribbean association presented with a 6-wk history of a rapidly enlarging right parotid mass. At the time of presentation, she could not close her right eye. An aspiration biopsy showed small, medium, and large lymphoma cells with angulated nuclei, red macronucleoli, and basophilic cytoplasm with fine vacuoles. Flow cytometry indicated a (CD25(+)/CD7(-)) T-cell lineage, suggesting an human T-lymphotropic virus (HTLV) 1-related T-cell leukemia/lymphoma, which was confirmed by polymerase chain reaction (PCR)-based amplification on DNA extracted from fresh tissue with specific oligonucleotide primers for HTLV-1 DNA sequence. Histology showed interstitial infiltration and destruction of the parotid parenchyma by lymphoma cells without involvement of adjacent lymph nodes. Total body CT scan and magnetic resonance imaging (MRI) studies were negative for lymphadenopathy but showed liver metastasis. To our knowledge, this is the first reported case of HTLV-1-related primary parotid lymphoma as the initial presentation of adult T-cell leukemia/lymphoma.

Intrahepatic CD4+ cell depletion in hepatitis C virus/HIV-coinfected patients.

Coinfection with HIV and hepatitis C virus (HCV)-specific immune responses, increases hepatic inflammation, accelerates hepatic fibrosis, and is associated with deceased treatment responses. We quantified intrahepatic lymphocyte and hepatocyte phenotypes in HCV-infected patients with (n = 38) and without (n = 41) HIV infection. A single pathologist counted positive cells in 5 portal and 5 lobular areas. Coinfected patients had 6.81 +/- 1.9 fewer CD4 cells per portal field (10.58 +/- 1.12 vs. 4.97 +/- 1.09 cells/high-power field [HPF]; P < 0.001) and 0.48 +/- 0.15 more apoptotic lymphocytes per lobular field (0.16 +/- 0.06 vs. 0.64 +/- 0.15 cell/HPF; P = 0.002) than monoinfected patients. The number of portal CD4 cells was not associated with the peripheral CD4 cell number. Portal and lobular CD8 cells did not differ between the 2 groups. Portal proliferative hepatocytes were increased in coinfected patients with HIV RNA levels of >400 copies/mL (1.13 +/- 0.32 cells/HPF; P = 0.01) compared with those with undetectable HIV RNA (0.46 +/- 0.09 cell/HPF) and monoinfected patients (0.45 +/- 0.08 cell/HPF). In conclusion, HIV coinfection is associated with fewer portal CD4 cells and increased lobular lymphocyte apoptosis that may impact on the natural history of HCV infection.

AA-type amyloidosis associated with non-Hodgkin's lymphoma: a case report.

Amyloid-associated protein (AA)-type systemic amyloidosis has been referred to as secondary amyloidosis because it is secondary to an associated inflammatory condition. It is extremely rare in patients with non-Hodgkin's lymphoma (NHL). Here we report an autopsy case of follicular small cleaved cell lymphoma with focal large B-cell lymphoma transformation in association with systemic AA-type amyloidosis. Formalin-fixed, paraffin-embedded tissues from autopsy and the patient's previous surgical specimen were studied by Congo red stain; electron microscopy; and immunostaining with antibodies against AA protein, P component, and kappa and lambda light chains. There was a marked AA amyloid deposition in the glomeruli of both kidneys, the retroperitoneal lymphoma mass, the blood vessels, the adrenal glands, and the adipose tissues. The patient's previous surgical specimens were negative for amyloid. We propose that this patient's systemic AA-type amyloidosis developed along the course of his NHL.

Role of fine-needle aspiration cytology in breast lymphoma.

Lymphomas of the breast are rare and may mimic carcinoma clinically. We investigated the ability of fine-needle aspiration (FNA) biopsy combined with adjunctive flow cytometry (FC), immunofluorescence microscopy (IFM), and immunocytochemistry (ICH) to diagnose and eventually subclassify lymphomas of the breast according to the Revised European American Lymphoma/World Health Organization classification. We retrieved 21 breast aspirates from 19 patients with a cytologic diagnosis of lymphoma or plasmacytoma over a 10-year period (1992-2002), excluding 98 benign intramammary lymph nodes and 1 atypical lymphohistiocytic proliferation (Rosai Dorfman disease). FC was performed in 15/21 aspirates, IFM in 1/21, ICH in 3/21. Histologic follow-up (HF) was obtained for 10 patients, most of them with primary lymphoma. For the remaining nine patients without HF, flow cytometric analysis, comparative morphology, or remission after chemotherapy regimens supported the cytologic diagnosis. Of 19 patients, 11 patients had a secondary lymphoma (SL) and 8 patients had a primary lymphoma (PL). FNA and FC/IFM/ICH classified 7/8 PLs as B-cell lymphomas and 1/8 PLs as plasmacytoma. However, FNA could only subclassify 3 of 8 PLs. FNA and/or FC subclassified accurately 10/11 SLs. All cases were accurately immunophenotyped as B-, T-cell non-Hodgkin's lymphomas or plasmacytoma. World Health Organization classification was achieved in 3/8 PLs (42%) and 10/11 SLs (91%; P = 0.04). Subclassification (which has an impact on long-term management and prognosis) was significantly better in SL, when a previous histologic diagnosis had already been made, when compared to PL, of which 5/8 cases (62.5%) could not be accurately classified.

Metaplastic carcinoma of the breast with rhabdomyosarcomatous element: aspiration cytology with histological, immunohistochemical, and ultrastructural correlations.

We studied a metaplastic breast carcinoma with a rhabdomyosarcomatous element from a 62-yr-old woman. In the fine-needle aspirates processed by Ultrafast Papanicolaou stain, there were small undifferentiated cells with scanty cytoplasm and differentiated cells with red macronucleoli and abundant cytoplasm. Some differentiated cells contained a brown inclusion with a blue rim. Ultrastructurally, the brown inclusion correlated to a central aggregate of sarcomeres and the blue rim correlated to actin filaments surrounding the sarcomeres. The differentiated cells without cytoplasmic inclusions expressed cytokeratin and contained tonofilaments. A transitional cell type containing both sacromeres and tonofilaments was absent. Immunohistochemically, the small undifferentiated cells expressed vimentin diffusely and showed >90% MIB-1 proliferating index, whereas the differentiated cells expressed cytokeratin, actin, or myoglobin and had virtually absent MIB-1 nuclear labeling. Histologically, the small cells were more concentrated along the capsule and the large cells were more concentrated in the center of the tumor. These findings suggest the bidirectional differentiation of the small undifferentiated cells into carcinoma cells and rhabdomyosarcoma cells in this tumor.

Vascularized acellular dermal matrix island flaps for the repair of abdominal muscle defects.

The potential widespread use of tissue-engineered matrices in soft-tissue reconstruction has been limited by the difficulty in fabricating and confirming a functional microcirculation. Acellular dermal matrix placed in a soft-tissue pocket acts as a scaffold to be incorporated by the host's fibrovascular tissue. A new method for noninvasive real-time observation of functional microvascular networks using orthogonal polarization spectral (OPS) imaging has recently been reported. Arterioles, venules, and capillaries can be directly visualized, and the movement of individual blood cells through them can be observed. The present study was performed to investigate the use of prefabricated acellular dermal matrix with an arteriovenous unit for the repair of abdominal muscle defects. OPS imaging was used to determine the presence of a functional microcirculation in the neovascularized matrix. In Sprague-Dawley rats, vascularized matrix was prefabricated by placing the superficial epigastric artery and vein on a 2-cm x 2-cm implant-type acellular dermal matrix in the thigh. Three weeks after implantation, the matrix-arteriovenous unit was elevated as an axial-type flap and a 2-cm x 2-cm full-thickness block of abdominal muscle immediately superior to the inguinal ligament was resected. Additional procedures were performed according to group: no repair (group 1, n = 20); repair with nonvascularized acellular dermal matrix (group 2, n = 20); repair with devascularized acellular dermal matrix (group 3, = 20); and repair with vascularized acellular dermal matrix (group 4, n = 20). OPS imaging (field of view, 1 mm in diameter; scan depth range, 0.2 mm) was performed on both sides of each flap on a total of 10 random distal regions before and after pedicle transection in group 3 and with the pedicle preserved in group 4. Hernia rate and duration of survival were compared for 21 days. OPS imaging showed directional blood cell movement through the capillary network in all areas scanned in group 4. No microvascular perfusion was observed after pedicle transection in group 3. Hernia rates of 100, 80, 90, and 0 percent were seen in groups 1, 2, 3, and 4, respectively. Median survival times of 9, 11.5, 9, and 21 postoperative days were noted in groups 1, 2, 3, and 4, respectively. Histopathologic analysis with factor VIII revealed full-thickness infiltration of the matrix by endothelial cells, signifying newly formed blood vessels. Repair of abdominal muscle defects using vascularized acellular dermal matrix resulted in no hernia and survival of all animals for the duration of study. However, repairs using avascular or devascularized matrix resulted in significant rates of hernia and decreased survival. Acellular dermal matrix can be prefabricated into vascularized tissue using an arteriovenous unit and used successfully to repair abdominal muscle defects. OPS imaging allowed for high-contrast direct visualization of microcirculation in previously acellular tissue following prefabrication with an arteriovenous unit.

Fine-needle aspiration cytology of unusual germ cell tumors of the mediastinum: atypical seminoma and parietal yolk sac tumor.

A 30-yr-old man presented with a mediastinal germ cell tumor that combined the histologic pattern of seminoma with the immunohistochemical profile of embryonal carcinoma (beta-HCG+/PLAP-). In FNA smears, this atypical seminoma presented as fragile large cells with scanty cytoplasm, vesicular nuclei, irregular and indistinct nucleoli, scattered singly and in loosely cohesive fragments without the characteristic lymphocytic or tigroid background. The cytologic features were more suggestive of a poorly differentiated carcinoma than seminoma, potentially leading to misdiagnosis and mismanagement. The second case was a 51-yr-old female smoker who presented with mediastinal parietal yolk sac tumor with extension to the lung, a rare occurrence, and contrary to the clinical impression of lung cancer with hilar lymph node metastasis. This case illustrates the value of using the unique cytologic features of parietal yolk sac tumor, i.e., the abundant, viscous, stringy metachromatic extracellular hyaline material associated with the tumor cells in reaching the accurate diagnosis.

TIA-1+ cytotoxic large T-cell lymphoma of the mediastinum: case report.

A 52-year-old previously healthy Caucasian woman presented with superior vena cava syndrome, secondary to compression of a bulky anterior mediastinal mass involving the right lung. Fine-needle aspiration biopsy of the mediastinum yielded large epithelioid cells intermingled with small mature lymphocytes. The epithelioid cells are LCA positive, expressing cytoplasmic CD3 diffusely and TIA-1 focally, but negative for EMA, CD4, CD8, CD15, CD20, CD30, and CD56. The TIA-1+ cytoplasmic granules correlated to the azurophilic granules in Diff-Quik-stained cells, pink granules in Ultrafast Papanicolaou-stained cells, and dense core granules in electron microscopy. In situ hybridization for Epstein-Barr viral RNA was negative. The background small lymphocytes were composed of a majority of CD4+ T-lymphocytes and minority of CD8+ T-lymphocytes. The patient responded well to six cycles of CHOP chemotherapy, followed by radiation with a total dose of 4140 cGy delivered to the mediastinum in 23 fractions. On the chest X-ray taken 6 mo later, there was minimal apical fibrosis with no evidence of an acute intrathoracic pathology. To the best of our knowledge, this case may be the first report of cytotoxic large T-cell lymphoma of the mediastinum.