Grace E Kim

University of California, San Francisco, San Francisco, California, United States

Are you Grace E Kim?

Claim your profile

Publications (24)145.11 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND The natural history of pancreatic neuroendocrine tumors (panNETs) is extremely variable. One of the most controversial problems in diagnosis is the accurate prediction of the clinical behavior of these tumors. PanNETs that behave aggressively with a malignant course may have bland cytologic features, while some tumors with previously described “malignant” features may behave in a benign or indolent fashion. Various classification schemes have been proposed for grading panNETs. The European Neuroendocrine Tumor Society (ENETS) and 2010 World Health Organization (WHO) classification schemes include counting the mitotic index and/or the Ki-67 proliferation index for grading. The current study was undertaken to determine whether tumors sampled by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) can be accurately graded based on the Ki-67 index when compared to surgical samples.METHODS Corresponding EUS-FNA cytology and surgical tissue specimens were obtained for 22 tumors and stained for hematoxylin and eosin (H&E) and the Ki-67 proliferation marker (MIB-1 antibody). Samples were graded by scoring Ki-67 staining indices in accordance with the 2010 ENETS/WHO criteria. The grading scores assigned to the EUS-FNA cytology samples were compared with the scores assigned to the corresponding histological samples.RESULTSThe majority (86%) of EUS-FNA cytology samples and corresponding surgical tissue specimens demonstrated concordant grading based on Ki-67 indices.CONCLUSIONS These results indicate that EUS-FNA cytology samples can be accurately graded based on the WHO Ki-67 labeling scheme. Thus, Ki-67 scoring in EUS-FNA cytology samples is an alternative approach for establishing the grade of panNETs. Accurate grading of panNETs is critical for predicting tumor biology, patient prognosis, and making informed decisions regarding patient management and treatment. Cancer (Cancer Cytopathol) 2014. © 2014 American Cancer Society.
    Cancer Cytopathology 07/2014; · 4.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) develops through distinct precursor lesions, including pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). However, genetic features resulting in IPMN-associated PDA (IPMN-PDA) versus PanIN-associated PDA (PanIN-PDA) are largely unknown. Here we find that loss of Brg1, a core subunit of SWI/SNF chromatin remodelling complexes, cooperates with oncogenic Kras to form cystic neoplastic lesions that resemble human IPMN and progress to PDA. Although Brg1-null IPMN-PDA develops rapidly, it possesses a distinct transcriptional profile compared with PanIN-PDA driven by mutant Kras and hemizygous p53 deletion. IPMN-PDA also is less lethal, mirroring prognostic trends in PDA patients. In addition, Brg1 deletion inhibits Kras-dependent PanIN development from adult acinar cells, but promotes Kras-driven preneoplastic transformation in adult duct cells. Therefore, this study implicates Brg1 as a determinant of context-dependent Kras-driven pancreatic tumorigenesis and suggests that chromatin remodelling may underlie the development of distinct PDA subsets.
    Nature Cell Biology 02/2014; · 20.76 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: miRNA levels are altered in pancreatic ductal adenocarcinoma (PDA), the most common and lethal pancreatic malignancy, and intact miRNA processing is essential for lineage specification during pancreatic development. However, the role of miRNA processing in PDA has not been explored. Here we study the role of miRNA biogenesis in PDA development by deleting the miRNA processing enzyme Dicer in a PDA mouse model driven by oncogenic Kras. We find that loss of Dicer accelerates Kras driven acinar dedifferentiation and acinar to ductal metaplasia (ADM), a process that has been shown to precede and promote the specification of PDA precursors. However, unconstrained ADM also displays high levels of apoptosis. Dicer loss does not accelerate development of Kras driven PDA precursors or PDA, but surprisingly, we observe that mouse PDA can develop without Dicer, although at the expense of proliferative capacity. Our data suggest that intact miRNA processing is involved in both constraining pro-tumorigenic changes in pancreatic differentiation as well as maintaining viability during PDA initiation.
    PLoS ONE 01/2014; 9(5):e95486. · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Loss-of-function of alpha thalassemia/mental retardation syndrome X-linked (ATRX) protein leads to a phenotype called alternative lengthening of telomeres (ALT) in some tumors. High-grade astrocytomas comprise a heterogeneous group of central nervous system tumors. We examined a large cohort of adult (91) and pediatric (n=88) high-grade astrocytomas as well as lower grade forms (n=35) for immunohistochemical loss of ATRX protein expression and the presence of ALT using telomere-specific fluorescence in situ hybridization, with further correlation to other known genetic alterations. We found that in pediatric high-grade astrocytomas, 29.6% of tumors were positive for ALT and 24.5% were immunonegative for the ATRX protein, these two alterations being highly associated with one another (P<0.0001). In adult high-grade astrocytomas, 26.4% of tumors were similarly positive for ALT, including 80% of ATRX protein immunonegative cases (P<0.0001). Similar frequencies were found in 11 adult low-grade astrocytomas, whereas all 24 pilocytic astrocytomas were negative for ALT. We did not find any significant correlations between isocitrate dehydrogenase status and either ALT positivity or ATRX protein expression in our adult high-grade astrocytomas. In both cohorts, however, the ALT positive high-grade astrocytomas showed more frequent amplification of the platelet-derived growth factor receptor alpha gene (PDGFRA; 45% and 50%, respectively) than the ALT negative counterparts (18% and 26%; P=0.03 for each). In summary, our data show that the ALT and ATRX protein alterations are common in both pediatric and adult high-grade astrocytomas, often with associated PDGFRA gene amplification.Modern Pathology advance online publication, 14 June 2013; doi:10.1038/modpathol.2013.90.
    Modern Pathology 06/2013; · 5.25 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The decision to perform pancreas-preserving procedures or standard resections for pancreatic neuroendocrine tumors (PNETs) is often based on the perceived risk of malignancy, including potential nodal involvement. We sought to identify clinicopathological factors that predict nodal disease. This is a retrospective review of pathology database for PNET resections from January 1, 1988, to March 15, 2010. Univariate analysis and multivariate logistic regression were used to identify predictors of nodal metastasis. A total of 149 patients were identified. Enucleations had lower lymph node sampling rates compared to major resections. Excluding enucleations, 23% of patients had no lymph nodes sampled. For patients who did have lymph nodes evaluated, a median of 5 lymph nodes were examined. On multivariate analysis, only distant disease predicted nodal metastasis (odds ratio = 3.80, P = 0.02); tumor size did not (P = 0.48). One third of patients with lymph node metastasis had tumors less than 3 cm. Lymph nodes are not evaluated in many major pancreatic resections for PNET, and preoperative prediction of nodal metastasis is difficult, even when tumor size is considered. Consequently, many patients may be understaged and undergo potentially inadequate resection. Inconsistent lymph node sampling may explain conflicting conclusions in the literature regarding the prognostic value of lymph node involvement in PNET patients.
    Pancreas 08/2012; 41(6):840-4. · 2.95 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An essential regulator of gene transcription, nuclear receptor liver receptor homologue 1 (LRH-1) controls cell differentiation in the developing pancreas and maintains cholesterol homeostasis in adults. Recent genome-wide association studies linked mutations in the LRH-1 gene and its up-stream regulatory regions to development of pancreatic cancer. In this work, we show that LRH-1 transcription is activated up to 30-fold in human pancreatic cancer cells compared to normal pancreatic ductal epithelium. This activation correlates with markedly increased LRH-1 protein expression in human pancreatic ductal adenocarcinomas in vivo. Selective blocking of LRH-1 by receptor specific siRNA significantly inhibits pancreatic cancer cell proliferation in vitro. The inhibition is tracked in part to the attenuation of the receptor's transcriptional targets controlling cell growth, proliferation, and differentiation. Previously, LRH-1 was shown to contribute to formation of intestinal tumors. This study demonstrates the critical involvement of LRH-1 in development and progression of pancreatic cancer, suggesting the LRH-1 receptor as a plausible therapeutic target for treatment of pancreatic ductal adenocarcinomas.
    Proceedings of the National Academy of Sciences 09/2011; 108(41):16927-31. · 9.81 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glypican-3 (GPC3) is an oncofetal protein that has been demonstrated to be a useful diagnostic immunomarker for hepatocellular carcinoma and hepatoblastoma. Its expression in mesenchymal tumors of the liver, particularly undifferentiated embryonal sarcoma (UES) and mesenchymal hamartoma (MH), has not been investigated. In this study, a total of 24 UESs and 18 MHs were immunohistochemically stained for GPC3 expression. The results showed cytoplasmic staining for GPC3 in 14 (58%) UESs, of which 6 exhibited diffuse immunoreactivity and the remaining 8 showed focal positivity. The patients with GPC3-positive UES tended to be younger (mean 18 years; median 11 years) than those with GPC3-negative tumors (mean 39.4 years; median 27 years), although the difference did not reach statistical significance (P = .06). Eight MHs also exhibited GPC3 immunoreactivity (44%; 4 diffuse and 4 focal). Positive staining in all 8 cases was primarily seen in entrapped nonlesional hepatocytes with a canalicular and cytoplasmic staining pattern. In only 4 cases (22%) was GPC3 immunoreactivity also observed in the mesenchymal component. The patients with positive staining also tended to be younger (mean 2.6 years; median 1.1 years) compared with those with negative staining (mean 16.3 years; median 4.5 years), but the difference was not statistically significant (P = .15). Our data demonstrate that GPC3 is expressed in a subset of UES and MH of the liver. Caution should thus be exercised when evaluating a GPC3-expressing hepatic neoplasm, particularly on a needle biopsy when the differential diagnosis includes poorly differentiated hepatocellular carcinoma or hepatoblastoma.
    Human pathology 09/2011; 43(5):695-701. · 3.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Progressive familial intrahepatic cholestasis, type 2 (PFIC2), characterized by cholestasis in infancy that may progress to cirrhosis, is caused by mutation in ABCB11, which encodes bile salt export pump (BSEP). We correlated histopathologic, immunohistochemical, and ultrastructural features in PFIC2 with specific mutations and clinical course. Twelve patients with clinical PFIC2 and ABCB11 mutations were identified, and 22 liver biopsy and explant specimens were assessed. All had hepatocellular cholestasis; most had canalicular bile plugs. At least 1 specimen from every patient had centrizonal/sinusoidal fibrosis, often with periportal fibrosis. Neonatal hepatitis-like features (inflammation, giant cells, necrosis) varied. In 2 of the 5 patients with paired specimens obtained >6 months apart, lobular and portal fibrosis worsened. Transmission electron microscopy (EM) in all 9 patients studied showed canalicular dilatation, microvilli loss, abnormal mitochondrial internal structure, and varying intracanalicular accumulation of finely granular bile. Canalicular staining for BSEP was absent in 10 patients and present in 2 patients, 1 of whom had intermittent symptoms. ABCB11 sequencing of all patients identified 6 novel and 10 previously described mutations, with nonsense, missense, and/or noncoding mutations in the 10 patients without immunohistochemically demonstrable BSEP. Missense and/or noncoding mutations were identified in the 2 patients with demonstrable BSEP, whose clinical course was more indolent. Mutations ending ABCB11 transcription appear linked, through hepatocellular necrosis and fibrosis, to worse outcome. In conclusion, light microscopy and electron microscopy findings in clinical PFIC2 can support diagnosis, but are variable and nonspecific. Therefore, no correlation between specific mutations and histopathology is yet possible.
    The American journal of surgical pathology 05/2011; 35(5):687-96. · 4.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic pancreatitis is a well-known risk factor for pancreatic ductal adenocarcinoma (PDA) development in humans, and inflammation promotes PDA initiation and progression in mouse models of the disease. However, the mechanistic link between inflammatory damage and PDA initiation is unclear. Using a Kras-driven mouse model of PDA, we establish that the inflammatory mediator Stat3 is a critical component of spontaneous and pancreatitis-accelerated PDA precursor formation and supports cell proliferation, metaplasia-associated inflammation, and MMP7 expression during neoplastic development. Furthermore, we show that Stat3 signaling enforces MMP7 expression in PDA cells and that MMP7 deletion limits tumor size and metastasis in mice. Finally, we demonstrate that serum MMP7 level in human patients with PDA correlated with metastatic disease and survival.
    Cancer cell 04/2011; 19(4):441-55. · 25.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pathologists participating in the National Institutes of Health-sponsored Biliary Atresia Research Consortium (BARC) developed and then evaluated a standardized system for histologic reporting of liver biopsies from infants with cholestasis. A set of 97 anonymous liver biopsy samples was sent to 10 pathologists at BARC centers. A semiquantitative scoring system that had 16 histologic features was developed and then used by the pathologists, who had no knowledge of clinical history, imaging results, or laboratory data. Interobserver agreement was evaluated statistically. Agreement on scoring of each feature and on the pathologists' diagnosis, compared with the final clinical diagnosis, was evaluated by using weighted kappa statistics. There was moderate to substantial interobserver agreement in identification of bile plugs in ducts, giant-cell transformation, extramedullary hematopoiesis, and bile duct proliferation. The pathologists' diagnosis of obstruction in clinically proven cases of biliary atresia (BA) ranged from 79%-98%, with a positive predictive value of 90.7%. Histologic features that best predicted BA, on the basis of logistic regression, included bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis (each P<.0001). The BARC histologic assessment system identified features of liver biopsies from cholestatic infants, with good interobserver agreement, that might be used in diagnosis and determination of prognosis. The system diagnosed BA with a high level of sensitivity and identified infants with biliary obstruction with reasonable interobserver agreement. However, distinguishing between BA and disorders such as total parenteral nutrition-associated liver disease and alpha(1)-antitrypsin deficiency is not possible without adequate clinical information.
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2011; 9(4):357-362.e2. · 5.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Liposarcoma is a soft-tissue sarcoma typically seen in adults. It is extremely rare in children. It most often occurs in the extremities or in the retroperitoneum. We present a very rare case of an anterior mediastinal liposarcoma of the pleomorphic subtype in a 17-year-old girl, along with radiological and pathological correlation. The location, patient age and histological subtype are exceedingly uncommon for this tumor.
    Pediatric Radiology 12/2010; 40 Suppl 1:S68-70. · 1.57 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We determined the relationship between clinical variables and testicular histopathological changes associated with decreased fertility potential in children with cryptorchidism. Testis biopsies of 274 children who underwent orchiopexy and concurrent testicular biopsy between 1991 and 2001 were analyzed for germ and Leydig cell loss, and testicular fibrosis. Multivariable logistic regression was used to determine if age at orchiopexy (analyzed as continuous and ordinal variables), preoperative testis palpability, unilateral vs bilateral disease and/or side of undescended testis was predictive of these pathological outcomes. Age at orchiopexy was associated with germ and Leydig cell depletion. Each month of testis undescent was associated with development of moderate/severe germ cell depletion (OR 1.02 for each month of age, p <0.005) and Leydig cell loss (OR 1.01 for each month of age, p <0.02). Nonpalpable testes were associated with severe germ cell depletion. Children with palpable testes had lower odds of germ cell depletion than those with nonpalpable testes (OR 0.46, p <0.005). This finding corresponds to a significant 2% risk per month of severe germ cell loss and 1% risk per month of Leydig cell depletion for each month a testis remains undescended, and a 50% greater risk of germ cell depletion in nonpalpable relative to palpable cryptorchid testes. Testes that remain undescended are associated with progressive loss of germ and Leydig cells, and nonpalpable testes predict severe germ cell loss.
    The Journal of urology 06/2009; 182(2):704-9. · 4.02 Impact Factor
  • Journal of Urology - J UROL. 01/2009; 181(4):119-119.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Chemoresistance in neuroblastoma is a significant issue complicating treatment of this common pediatric solid tumor. MYCN-amplified neuroblastomas are infrequently mutated at p53 and are chemosensitive at diagnosis but acquire p53 mutations and chemoresistance with relapse. Paradoxically, Myc-driven transformation is thought to require apoptotic blockade. We used the TH-MYCN transgenic murine model to examine the role of p53-driven apoptosis on neuroblastoma tumorigenesis and the response to chemotherapy. Tumors formed with high penetrance and low latency in p53-haploinsufficient TH-MYCN mice. Cyclophosphamide (CPM) induced a complete remission in p53 wild type TH-MYCN tumors, mirroring the sensitivity of childhood neuroblastoma to this agent. Treated tumors showed a prominent proliferation block, induction of p53 protein, and massive apoptosis proceeding through induction of the Bcl-2 homology domain-3-only proteins PUMA and Bim, leading to the activation of Bax and cleavage of caspase-3 and -9. Apoptosis induced by CPM was reduced in p53-haploinsufficient tumors. Treatment of MYCN-expressing human neuroblastoma cell lines with CPM induced apoptosis that was suppressible by siRNA to p53. Taken together, the results indicate that the p53 pathway plays a significant role in opposing MYCN-driven oncogenesis in a mouse model of neuroblastoma and that basal inactivation of the pathway is achieved in progressing tumors. This, in part, explains the striking sensitivity of such tumors to chemotoxic agents that induce p53-dependent apoptosis and is consistent with clinical observations that therapy-associated mutations in p53 are a likely contributor to the biology of tumors at relapse and secondarily mediate resistance to therapy.
    Neoplasia (New York, N.Y.) 12/2008; 10(11):1268-74. · 5.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: beta-Catenin signaling within the canonical Wnt pathway is essential for pancreas development. However, the pathway is normally down-regulated in the adult organ. Increased cytoplasmic and nuclear localization of beta-catenin can be detected in nearly all human solid pseudopapillary neoplasms (SPN), a rare tumor with low malignant potential. Conversely, pancreatic ductal adenocarcinoma (PDA) accounts for the majority of pancreatic tumors and is among the leading causes of cancer death. Whereas activating mutations within beta-catenin and other members of the canonical Wnt pathway are rare, recent reports have implicated Wnt signaling in the development and progression of human PDA. Here, we sought to address the role of beta-catenin signaling in pancreas tumorigenesis. Using Cre/lox technology, we conditionally activated beta-catenin in a subset of murine pancreatic cells in vivo. Activation of beta-catenin results in the formation of large pancreatic tumors at a high frequency in adult mice. These tumors resemble human SPN based on morphologic and immunohistochemical comparisons. Interestingly, stabilization of beta-catenin blocks the formation of pancreatic intraepithelial neoplasia (PanIN) in the presence of an activating mutation in Kras that is known to predispose individuals to PDA. Instead, mice in which beta-catenin and Kras are concurrently activated develop distinct ductal neoplasms that do not resemble PanIN lesions. These results demonstrate that activation of beta-catenin is sufficient to induce pancreas tumorigenesis. Moreover, they indicate that the sequence in which oncogenic mutations are acquired has profound consequences on the phenotype of the resulting tumor.
    Gastroenterology 08/2008; 135(4):1288-300. · 12.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inflammatory myofibroblastic tumor (IMT) is a distinctive spindle cell lesion and occurs primarily in soft tissue. Recent evidence suggests a neoplastic nature, although historically, both neoplastic and nonneoplastic processes were combined in this category. Originally described as a nonneoplastic process, the term inflammatory pseudotumor (IP) has been used synonymously with IMT. IMTs have been linked to ALK gene (2p23) rearrangements, and some have suggested an association with the human herpesvirus 8 (HHV-8). IMT in the central nervous system (CNS) is rare, its characteristics are poorly defined, and its relation to similar tumors at other sites is unclear. To better characterize IMT within the CNS, we studied clinicopathologic features of 6 IMTs and compared them with 18 nonneoplastic lesions originally classified as IP. The IMT group consisted of 2 male and 4 female patients with a median age of 29 years. Of the six IMTs, 5 occurred within the cerebral hemispheres, and one was in the posterior fossa. All tumors were composed of neoplastic spindle cells and a variable amount of inflammatory infiltrate. Eighteen IPs included in this study consisted of predominantly inflammatory masses occasionally seen in the setting of systemic diseases. Only 1 IMT and none of the IPs recurred during the follow-up period. Four IMTs had either ALK protein overexpression or 2p23 rearrangement, and 1 case demonstrated both. None of the IPs were positive for ALK. Neither IMT nor IP cases demonstrated HHV-8 expression. We suggest that IMT in the CNS is distinct from the nonneoplastic IP, and distinguishing IMT from nonneoplastic lesions should enable better decisions for patient management.
    Human Pathlogy 04/2008; 39(3):410-9. · 2.84 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This case describes a young girl with Graves' disease, who presented with fulminant hepatic failure 9 months into propylthiouracil (PTU) therapy. Her clinical presentation was consistent with 'probable autoimmune hepatitis,' as defined by the International Autoimmune Hepatitis Group scoring system. Despite discontinuation of PTU and high-dose steroid therapy, she required liver transplantation. Subsequent pathology could not definitively rule out autoimmune hepatitis. PTU is an important cause of drug-related liver failure in children, and clinicians should be mindful that it is frequently used in patients who already have an underlying risk of autoimmune liver disease.
    Pediatric Transplantation 07/2006; 10(4):525-8. · 1.50 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mucinous colorectal cancer (CRC) has been reported to have distinct clinicopathological and genetic characteristics. However, the incidence and the relationship among microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and BRAF and KRAS mutations in mucinous and non-mucinous CRC are not known. Activating mutations of BRAF and KRAS and their relationship with MSI and CIMP were examined in 83 sporadic CRC specimens (26 mucinous and 57 non-mucinous CRC). MSI, CIMP, BRAF and KRAS mutation were observed in 17, 24, 25 and 36% of the tumors, respectively. BRAF mutation was highly correlated with MSI (p < 0.001) and CIMP (p < 0.001). A higher incidence of MSI (27% vs. 12%), CIMP (38% vs. 18%, p < 0.05) and BRAF mutation (46% vs. 16%, p < 0.01) was observed in mucinous CRC. KRAS mutation (27% vs. 40%) was observed more frequently in non-mucinous CRC. Significantly higher percentages of mucinous CRC (54%, p < 0.05) had MSI or CIMP or BRAF mutations. Concordant occurrence of 2 or more of these alterations was observed in 39% of mucinous CRC and only 11% of non-mucinous CRC (p < 0.01). The more frequent occurrence and closer association among MSI, CIMP and BRAF mutation in mucinous CRC observed in our study further supports the idea that its pathogenesis may involve distinct genetic and epigenetic changes.
    International Journal of Cancer 06/2006; 118(11):2765-71. · 6.20 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cavernous hemangiomas (CH) are typically described as solitary, well-circumscribed lesions and are reported to have a distinct fibrous interface. This study describes underrecognized histological changes of large hepatic hemangiomas that contradict this long-standing view. Nineteen cases of hepatic resections for CH were reviewed. Stains for estrogen and progesterone receptors (ER/PR), MIB-1, alpha-smooth muscle actin, collagen IV, and elastic Van Gieson stains were applied to the lesions. The CHs measured 5-31 cm (mean 16.6 cm). Sixteen (84%) CHs had an irregular interface with the liver parenchyma while only three had the well-defined fibrous capsule typically described for CH. Fifteen (79%) CHs had dilated vascular spaces filled with blood 0.1-2.0 cm beyond the confines of the main CH, which we have designated hemangioma-like vessels (HLVs). The histochemical and immunohistochemical stains in both CH and HLVs were similar, with the walls of the vessels composed predominantly of collagen with some faint elastic fibers and smooth muscle, endothelium underlined by collagen IV, negative ER/PR in all components, and a proliferation rate of <5/100 endothelial cells. Irregular edges of CH and HLVs in the liver parenchyma adjacent to CH have been underrecognized. No significant differences in staining or proliferative rate were present between CHs and HLVs, suggesting the HLVs are within the spectrum of CH.
    Liver international: official journal of the International Association for the Study of the Liver 05/2006; 26(3):334-8. · 3.87 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mucin core proteins are expressed in a tissue and cell type specific manner in the normal gastrointestinal tract. Aberrant expression of mucin core proteins have been reported in colorectal neoplasms. To examine the relationship between subsets of colorectal polyps and non-mucinous and mucinous adenocarcinomas of the colorectum, we evaluated the frequency of the expression of cell lineage associated mucin core proteins (MUC5AC and MUC2), trefoil factors (TFF1 and TFF3), and APC and p21 in these tissues. An immunohistochemical study was performed in 10 normal rectal mucosa samples (NM) 21 hyperplastic polyps (HP), 20 serrated adenomas (SA), 25 tubular adenomas (TA), 13 tubulovillous adenomas (TVA), 7 villous adenomas (VA), 42 non-mucinous colorectal cancers (NMC), and 19 mucinous colorectal cancers (MC). A higher frequency of ectopic expression of gastric foveolar mucin, MUC5AC, and the expression of intestinal goblet cell mucins, MUC2, was observed respectively in HP (100%, 100%), SA (85%, 85%), TVA (85%, 85%), and VA (100%, 100%), compared to TA (32%, p<0.002; 36%, p<0.01). MC (68%, 100%) also showed a higher frequency of the expression of MUC5AC and MUC2 compared to NMC (31%, p=0.001; 38%, p<0.001), and TFF1 showed similar patterns of expression. APC protein and p21 were also expressed at a higher frequency in HP (100%, 100%), and SA (67%, 83%), than in TA (29%, p<0.03; 46%, p<0.05). MC (68%, 100%) showed a higher frequency of expression of APC protein and p21 than NMC (19%, p<0.001; 45%, p<0.01). Our results showed that MUC2 expression and de novo ectopic expression of MUC5AC and TFF1 are more frequent in HP, SA, TVA, VA, and MC than in TA and NMC. These results suggest that simultaneous activation of differentiation pathways of goblet cells and gastric foveolar cells may occur predominantly in the pathogenesis of HP, SA, TVA, VA, and MC, while the pathogenesis of TA and NMC are less likely to involve these processes.
    International Journal of Oncology 11/2005; 27(4):957-64. · 2.66 Impact Factor

Publication Stats

505 Citations
145.11 Total Impact Points

Institutions

  • 2005–2014
    • University of California, San Francisco
      • • Department of Pathology
      • • Division of Hospital Medicine
      • • Veterans Affairs Medical Center
      San Francisco, California, United States