Christopher P Crum

Brigham and Women's Hospital , Boston, Massachusetts, United States

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Publications (144)976.76 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The oviducts contain high grade serous cancer (HGSC) precursors (serous tubal intraepithelial neoplasia or STINs), which are γ-H2AXp- and TP53 mutation-positive. Although they express wild type p53, secretory cell outgrowths (SCOUTs) are associated with older age and serous cancer; moreover both STINs and SCOUTs share a loss of PAX2 expression (PAX2n). We evaluated PAX2 expression in proliferating adult and embryonic oviductal cells, normal mucosa, SCOUTs, Walthard cell nests (WCNs), STINs and HGSCs, and the expression of genes chosen empirically or from SCOUT expression arrays. Clones generated in vitro from embryonic gynecologic tract and adult fallopian tube were Krt7p/ PAX2n/EZH2p and underwent ciliated (PAX2n/EZH2n/FOXJ1p) and basal (Krt7n/EZH2n/Krt5p) differentiation. Similarly non-ciliated cells in normal mucosa were PAX2p but became PAX2n in multilayered epithelium undergoing ciliated or basal (Walthard cell nests or WCN) cell differentiation. PAX2n SCOUTs fell into two groups; Type I were secretory or secretory/ciliated with a “tubal” phenotype and were ALDH1n and β-cateninmem (membraneous only). Type II displayed a columnar to pseudostratified (endometrioid) phenotype, with an EZH2p, ALDH1p, β-cateninnc (nuclear and cytoplasmic), stathminp, LEF1p, RCN1p and RUNX2p expression signature. STINs and HGSCs shared the Type I immunophenotype of PAX2n, ALDH1n, β-cateninmem, but highly expressed EZH2p, LEF1p, RCN1p, and stathminp. This study, for the first time, links PAX2n with proliferating fetal and adult oviductal cells undergoing basal and ciliated differentiation and shows that this expression state is maintained in SCOUTs, STINs and HGSCs. All three entities can demonstrate a consistent perturbation of genes involved in potential tumor suppressor gene silencing (EZH2), transcriptional regulation (LEF1), regulation of differentiation (RUNX2), calcium binding (RCN1) and oncogenesis (stathmin). This shared expression signature between benign and neoplastic entities links normal progenitor cell expansion to abnormal and neoplastic outgrowth in the oviduct and exposes a common pathway that could be a target for early prevention.
    The Journal of Pathology 08/2014; · 7.59 Impact Factor
  • M. Herfs, CP. Crum
    International Journal of Cancer 07/2014; · 6.20 Impact Factor
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    ABSTRACT: Recent studies have identified a putative cell of origin for cervical intraepithelial neoplasia (CIN) and cervical cancer at the squamo-columnar junction (SCJ) and suggest that these cells may not regenerate following excision (LEEP). This study addressed the impact of SCJ excision on the temporal dynamics, histologic and viral (HPV) characteristics of recurrent CIN. One hundred thirty one consecutive patients treated by excision and attending follow-up visits were enrolled. We compared recurrent and initial CIN with attention to excision margins, timing of recurrence, CIN grade, HPV types, p16 immunophenotype, and SCJ immunophenotype. During the follow-up period (up to four years), sixteen (12.2%) recurrences were identified. Four (25%) were identified at the first follow-up visit, closely resembled the initial CIN 2/3 in grade and HPV type, and were typically SCJ marker positive [SCJ(+)], suggesting non-excised (residual) disease. Twelve (75%) manifested after the first postoperative visit and all were in the ectocervix or in mature metaplastic epithelium. All of the 12 delayed recurrences were classified as CIN 1 and were SCJ (-). Nine of 11 SCJ (-) recurrences (82%) followed regressed spontaneously. Taken together, these results show that new lesions developing from any HPV infection are delayed and occur within the ectocervix or metaplastic epithelium. This dramatically lower risk of CIN 2/3 following successful SCJ excision suggests that removal of the SCJ could be a critical variable in reducing the risk of subsequent CIN 2/3 and cervical cancer. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 05/2014; · 6.20 Impact Factor
  • Clinical Ovarian and Other Gynecologic Cancer. 01/2014;
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    ABSTRACT: Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. The aetiological role of infection with high-risk human papilloma viruses (HPVs) in cervical carcinomas is well established. Previous studies have also implicated somatic mutations in PIK3CA, PTEN, TP53, STK11 and KRAS as well as several copy-number alterations in the pathogenesis of cervical carcinomas. Here we report whole-exome sequencing analysis of 115 cervical carcinoma-normal paired samples, transcriptome sequencing of 79 cases and whole-genome sequencing of 14 tumour-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas include recurrent E322K substitutions in the MAPK1 gene (8%), inactivating mutations in the HLA-B gene (9%), and mutations in EP300 (16%), FBXW7 (15%), NFE2L2 (4%), TP53 (5%) and ERBB2 (6%). We also observe somatic ELF3 (13%) and CBFB (8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines (Tp*C sites) than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumours with HPV integration compared with expression of the same genes in tumours without viral integration at the same site. These data demonstrate several recurrent genomic alterations in cervical carcinomas that suggest new strategies to combat this disease.
    Nature 12/2013; · 38.60 Impact Factor
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    ABSTRACT: This study computed the risk of clinically silent adnexal neoplasia in women with germ-line BRCA1 or BRCA2 mutations (BRCA(m+)) and determined recurrence risk. Methods: We analyzed risk reduction salpingo-oophorectomies (RRSOs) from 349 BRCA(m+) women processed by the SEE-FIM protocol and addressed recurrence rates for 29 neoplasms from three institutions. Results: Nineteen neoplasms (5.4%) were identified at one institution, 9.2% of BRCA1 and 3.4% of BRCA2 mutation-positive women. Fourteen had a high-grade tubal intraepithelial neoplasm (HGTIN, 74%). Mean age (54.4) was higher than the BRCA(m+) cohort without neoplasia (47.8) and frequency increased with age (p<0.001). Twenty-nine BRCA (m+) patients with neoplasia from three institutions were followed for a median of 5years (1-8yrs.). One of 11 with HGTIN alone (9%) recurred at 4years, in contrast to 3 of 18 with invasion or involvement of other sites (16.7%). All but two, are currently alive. Among the 29 patients in the three institution cohort, mean ages for HGTIN and advanced disease were 49.2 and 57.7 (p=0.027). Conclusions: Adnexal neoplasia is present in 5-6% of RRSOs, is more common in women with BRCA1 mutations, and recurs in 9% of women with HGTIN alone. The lag in time from diagnosis of the HGTIN to pelvic recurrence (4years) and differences in mean age between HGTIN and advanced disease (8.5years) suggest an interval of several years from the onset of HGTIN until pelvic cancer develops. However, some neoplasms occur in the absence of HGTIN.
    Gynecologic Oncology 12/2013; · 3.93 Impact Factor
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    ABSTRACT: High-grade serous ovarian carcinoma presents significant clinical and therapeutic challenges. Although the traditional model of carcinogenesis has focused on the ovary as a tumor initiation site, recent studies suggest that there may be additional sites of origin outside the ovary, namely the secretory cells of the fallopian tube. Our study demonstrates that high-grade serous tumors can originate in fallopian tubal secretory epithelial cells and also establishes serous tubal intraepithelial carcinoma as the precursor lesion to high-grade serous ovarian and peritoneal carcinomas in animal models targeting the Brca, Tp53, and Pten genes. These findings offer an avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 and BRCA2 mutations.
    Cancer cell 12/2013; 24(6):751-765. · 25.29 Impact Factor
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    ABSTRACT: ATP-binding cassette (ABC) transporters in placenta protectively transport drugs and xenobiotics. ABCB5 [subfamily B (MDR/TAP)] is a novel ABC multidrug-resistance transporter that also mediates cell fusion, stem cell function, and vasculogenic plasticity. Immunohistochemistry and double-labeling immunofluorescence staining for ABCB5 and ABCB5/CD200, respectively, was performed on formalin-fixed, paraffin-embedded placental tissue from 5 first trimester, 5 second trimester, and 5 term pregnancies as well as 5 partial moles, and 5 complete moles. In addition, tumor cells from 5 choriocarcinoma and 5 placental site trophoblastic tumor cases were examined. ABCB5 staining was observed in villous trophoblasts in 100% (5/5) of first trimester placentas (with progressive decrease in term placentas); 100% of partial moles (5/5); and 100% of complete moles (5/5). Notably, reactivity was discretely restricted to the inner trophoblast layer, with no staining of overlying syncytiotrophoblast. Antibody specificity and localization was confirmed further by in situ hybridization. ABCB5 expression was retained in 20% of choriocarcinomas (1/5) and 40% of placental site trophoblastic tumors (2/5). Prior studies have localized expression of multidrug-resistance-1, also known as ABCB1, within the syncytiotrophoblast of early placentas, where it serves a protective function as an efflux transporter. Our results show that ABCB5 is preferentially expressed in the cytotrophoblast layer of placental villi. The expression of this novel biomarker at the maternal-fetal interface raises questions on its role in placental structure and function as well as on its potential contribution to the protective efflux provided by other P-glycoprotein transporters.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 12/2013; · 2.07 Impact Factor
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    ABSTRACT: It is currently hoped that deaths from extra-uterine high-grade serous cancer (HGSC) will be reduced via opportunistic salpingectomy in healthy women. Accumulated data implicate the fimbria as a site of origin and descriptive molecular pathology and experimental evidence strongly support a serous carcinogenic sequence in the fallopian tube. Both direct and indirect ("surrogate") precursors suggest the benign tube undergoes important biologic changes after menopause, acquiring abnormalities in gene expression that are often shared with malignancy, including PAX2, ALDH1, LEF1, RCN1, RUNX2, beta catenin, EZH2 and others. However, the tube can be linked to only some HGSCs, recharging arguments that nearby peritoneum/ovarian surface epithelium (POSE) also hosts progenitors to this malignancy. A major sticking point is the difference in immunophenotype between POSE and Müllerian epithelium, essentially requiring mesothelial to Müllerian differentiation prior to or during malignant transformation to HGSC. However, emerging evidence implicates an embryonic or progenitor phenotype in the adult female genital tract with the capacity to differentiate, normally or during neoplastic transformation. Recently, a putative cell of origin to cervical cancer has been identified in the squamo-columnar (SC) junction, projecting a model whereby Krt7+ embryonic progenitors give rise to immuno-phenotypically distinct progeny under stromal influences via "top down" differentiation. Similarly, biphasic cell differentiation can be seen in the endometrium with a parallel in the juxtaposition of mesothelial and mullerian differentiation in the ovary. An abrupt mesothelial-Mullerian transition remains to be proven, but would explain the rapid evolution, short asymptomatic interval, and absence of a defined epithelial starting point in many HGSCs. Resolving this question will require accurately distinguishing progenitor from progeny tumor cells in HGSC and pinpointing where initial transformation and trans-differentiation occurs if the POSE is an origin. Both will be critical to expectations from prophylactic salpingectomy and future approaches to pelvic serous cancer prevention.
    The Journal of Pathology 09/2013; · 7.59 Impact Factor
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    ABSTRACT: The placenta is a transient organ that is necessary for proper fetal development. Its main functional component is the trophoblast, which is derived from extra-embryonic ectoderm. Little is known about early trophoblast differentiation in the human embryo, owing to lack of a proper in vitro model system. Human embryonic stem cells (hESCs) differentiate into functional trophoblast following BMP4 treatment in the presence of feeder-conditioned media; however, this model has not been widely accepted, in part owing to a lack of proof for a trophoblast progenitor population. We have previously shown that p63, a member of the p53 family of nuclear proteins, is expressed in proliferative cytotrophoblast (CTB), precursors to terminally differentiated syncytiotrophoblast (STB) in chorionic villi and extravillous trophoblast (EVT) at the implantation site. Here, we show that BMP4-treated hESCs differentiate into bona fide CTB by direct comparison with primary human placental tissues and isolated CTB through gene expression profiling. We show that, in primary CTB, p63 levels are reduced as cells differentiate into STB, and that forced expression of p63 maintains cyclin B1 and inhibits STB differentiation. We also establish that, similar to in vivo events, hESC differentiation into trophoblast is characterized by a p63(+)/KRT7(+) CTB stem cell state, followed by formation of functional KLF4(+) STB and HLA-G(+) EVT. Finally, we illustrate that downregulation of p63 by shRNA inhibits differentiation of hESCs into functional trophoblast. Taken together, our results establish that BMP4-treated hESCs are an excellent model of human trophoblast differentiation, closely mimicking the in vivo progression from p63(+) CTB stem cells to terminally differentiated trophoblast subtypes.
    Development 09/2013; · 6.60 Impact Factor
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    ABSTRACT: Low-grade cervical squamous abnormalities (low-grade squamous intraepithelial lesions [LSIL, CIN1]) can be confused with or followed by high-grade (HSIL, CIN2/3) lesions, expending considerable resources. Recently, a cell of origin for cervical neoplasia was proposed in the squamocolumnar junction (SCJ); HSILs are almost always SCJ, but LSILs include SCJ and SCJ subsets. Abnormal cervical biopsies from 214 patients were classified by 2 experienced pathologists (panel) as LSIL or HSIL using published criteria. SILs were scored SCJ and SCJ using SCJ-specific antibodies (keratin7, AGR2, MMP7, and GDA). Assessments of interobserver agreement, p16 staining pattern, proliferative index, and outcome were compared. The original diagnostician agreed with the panel diagnosis of HSIL and SCJ LSIL in all cases (100%). However, for SCJ LSIL, panelists disagreed with each other by 15% and with the original diagnostician by 46.2%. Comparing SCJ and SCJ LSILs, 60.2% and 94.9% were p16 positive, 23% and 74.4% showed strong (full-thickness) p16 staining, and 0/54 (0%) and 8/33 (24.2%) with follow-up had an HSIL outcome, respectively. Some SCJ LSILs are more likely to both generate diagnostic disagreement and be associated with HSIL. Conversely, SCJ LSILs generate little observer disagreement and, when followed, have a very low risk of HSIL outcome. Thus, SCJ biomarkers in conjunction with histology may segregate LSILs with very low risk of HSIL outcome and conceivably could be used as a management tool to reduce excess allocation of resources to the follow-up of these lesions.
    The American journal of surgical pathology 09/2013; 37(9):1311-8. · 4.06 Impact Factor
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    ABSTRACT: As life expectancy lengthens, cases of non-viral-associated vulvar squamous cell carcinoma and its precursor lesion, so-called differentiated vulvar intraepithelial neoplasia (VIN), continue to increase in frequency. Differentiated VIN often is difficult to recognize and failure to detect it before invasion results in morbidity and mortality. Thus, identification of a reliable biomarker for this type of lesion would be of great clinical benefit. Our recent studies have identified activation (ser235/236 phosphorylation) of ribosomal protein S6 (p-S6) in basal epithelial cells as an event that precedes and accompanies laminin γ(2) overexpression in most preinvasive oral dysplasias. To test this as a potential biomarker of vulvar dysplasia, we immunostained seven differentiated VINs and nine papillomavirus-related 'classic' VINs, most of which were associated with carcinoma, for p-S6. All carcinomas, all differentiated VINs, and most classic VINs contained regions of p-S6 staining in the basal layer, whereas basal and parabasal cells of normal vulvar epithelium and hyperplastic and inflamed lesions lacking cellular atypia were p-S6 negative. Laminin γ(2) was expressed in a subset of VINs, always occurring within basal p-S6 positive regions, as we had found previously for oral dysplasias. Lichen sclerosus is considered a potential precursor of vulvar carcinoma. Two lichen sclerosus lesions of patients with a concurrent carcinoma and one of six lichen sclerosus lesions without atypia or known concurrent carcinoma were basal p-S6 positive. In summary, there is a distinct difference in p-S6 basal cell layer staining between benign and neoplastic vulvar squamous epithelium, with consistent staining of differentiated VIN and of some lichen sclerosus lesions. These results support further studies to assess the potential of p-S6 as a biomarker to identify vulvar lesions at risk of progressing to invasive cancer.Modern Pathology advance online publication, 14 June 2013; doi:10.1038/modpathol.2013.85.
    Modern Pathology 06/2013; · 5.25 Impact Factor
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    ABSTRACT: PURPOSE/OBJECTIVE(S): To evaluate the effect of margin status and radiation dose in patients treated with radiation therapy (RT) for vulvar cancer. Clinical outcomes included vulvar recurrence (VR), relapse-free (RFS) and overall survival (OS). PATIENTS/METHODS: We retrospectively reviewed the records of 300 patients with Stage I-IVA vulvar cancer treated between 1988 and 2009. Slides were reviewed and margin status was scored as negative (>1 cm), close (<1cm) or positive after formalin fixation. Cox proportional hazards models were constructed to determine significant prognostic factors for vulvar relapse. RESULTS: Of 205 eligible patients, 69 (34%) had negative surgical margins, 116 (56%) had close margins and 20 (10%) had positive margins. Median follow-up time was 49 months. The 4-year RFS rate was 53% and OS was 73%. Of 78 recurrences, 62 had the vulva as the first site of recurrence. The 4-year rates of freedom from vulvar recurrence were 82%, 63% and 37% for those with negative, close and positive margins, respectively (p for trend=0.005). On multivariate analysis, close margins (HR=3.03, 95% CI 1.46-6.26) and positive margins (HR=7.02, 95% CI 266-18.54) were associated with a significantly increased risk of vulvar relapse. Those who received a dose >56 Gy had a lower risk of relapse than those who received <50.4 Gy (p<0.05). Though recurrences were noted with margins up to 9 mm, the highest risk of vulvar recurrence was associated with margins <5 mm (p=0.002). CONCLUSIONS: Close or positive margins were associated with a significantly increased risk of vulvar recurrence. Radiation with a dose >56 Gy may decrease the risk of vulvar recurrence.
    Gynecologic Oncology 06/2013; · 3.93 Impact Factor
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    ABSTRACT: Serous tubal intraepithelial carcinoma (STIC) is a noninvasive phase of pelvic serous cancer at risk for metastasizing. Because of its biologic significance, its accurate distinction from nonmalignant mimics is important. Loss of cell orientation is an important feature of STIC. We sought to determine whether the immunohistochemical localization of cytoskeletal-organizing proteins phospho-ezrin-radaxin-moesin (p-ERM) would be useful in making this distinction. The benign oviductal entities (normal and p53 signatures), premalignant atypias (tubal intraepithelial lesions in transition), serous intraepithelial carcinomas (STICs), and carcinomas were analyzed for 5 staining patterns and compared. Linear or uniform luminal p-ERM staining was strongly associated with benign mucosa in contrast to STICs, in which it was lost and often replaced by nonlinear or nonuniform patterns highlighting individually cell groups or single cells. Premalignant atypias were similar to benign mucosa by p-ERM staining and retained the linear luminal pattern. This study shows, for the first time, that patterns of staining for an immunohistochemical correlate of cell polarity (p-ERM) differ between STICs, their benign counterparts and premalignant atypias that do not fulfill the criteria for STICs. If confirmed, these findings warrant further analysis of indices of cell polarity as objective markers for the diagnosis and mapping of the evolution of pelvic serous precursors.
    International journal of gynecological pathology: official journal of the International Society of Gynecological Pathologists 05/2013; · 2.07 Impact Factor
  • Michael Herfs, Christopher P Crum
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    ABSTRACT: Since the discovery of human papillomavirus (HPV) type 16 in early 80s, the link between HPV and cervical cancer has been established with certainty, a function of the discovery and cloning of a range of HPV types associated with both cancer precursors (cervical intraepithelial neoplasia or CIN) and carcinomas and extensive epidemiologic, clinical, pathologic, and experimental data. These accumulated results have culminated in new paradigms of cancer prevention through screening and triage. Despite this, the management of women with CIN is still suboptimal and the overtreatment of these conditions still occurs, largely due to the lack of clarity regarding which precancerous lesions are most likely to progress in grade. Recently, a discrete population of cuboidal cells was discovered at the cervical squamocolumnar junction, the anatomic site where the large majority of HPV-related (pre)neoplastic lesions develop. These cells seem to be embryonic in nature and participate both in benign metaplasias and the initial phase of precancer development. This review summarizes the historical evolution of precursor management, assesses the potential role of this and other discoveries in segregating lower from higher-risk precursors, and examines their potential impact on the management of women with real or potential cervical cancer precursors.
    Advances in anatomic pathology 03/2013; 20(2):86-94. · 3.22 Impact Factor
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    ABSTRACT: Differentiating ovarian tumors based on developmental pathway may further our understanding of the disease. Traditionally, ovarian cancers were thought to arise from the ovarian surface epithelium; however, recent evidence suggests some tumors originate in the fallopian tube. We classified cases in a population-based case-control study (NECC) and two cohort studies (NHS/NHSII) by tumor dominance, a proxy for tissue of origin. Dominant tumors (likely ovarian origin) are restricted to one ovary or are at least twice as large on one ovary compared to the other. Ovarian cancer risk factors were evaluated in relation to dominant and non-dominant tumors (likely tubal origin) using polytomous logistic regression (NECC) or competing risks Cox models (NHS/NHSII). Results were combined using random-effects meta-analyses. Among 1,771 invasive epithelial ovarian cancer cases, we observed 1,089 tumors with a dominant mass and 682 with no dominant mass. Dominant tumors were more likely to be mucinous, endometrioid, or clear cell, whereas non-dominant tumors were more likely to be serous. Tubal ligation, two or more births, endometriosis, and age were more strongly associated with dominant (RRs = 0.60, 0.83, 1.58, 1.37, respectively) than non-dominant tumors (RRs = 1.03, 0.93, 0.84, 1.14 p-difference = 0.0001, 0.01, 0.0003, 0.01, respectively). These data suggest that risk factors for tumors putatively arising from ovarian versus fallopian tube sites may differ; in particular, reproductive factors may be more important for ovarian-derived tumors. As this is the first study to evaluate ovarian cancer risk factors by tumor dominance, these results need to be validated by other studies.
    International Journal of Cancer 01/2013; · 6.20 Impact Factor
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    ABSTRACT: The potential role of the cell-of-origin in determining the tumor phenotype has been raised, but not adequately examined. We hypothesized that distinct cells-of-origin may play a role in determining ovarian tumor phenotype and outcome. Here we describe a new cell culture medium for in vitro culture of paired normal human ovarian (OV) and fallopian tube (FT) epithelial cells from donors without cancer. While these cells have been cultured individually for short periods of time, to our knowledge this is the first long-term culture of both cell types from the same donors. Through analysis of the gene expression profiles of the cultured OV/FT cells we identified a normal cell-of-origin gene signature that classified primary ovarian cancers into OV-like and FT-like subgroups; this classification correlated with significant differences in clinical outcomes. The identification of a prognostically significant gene expression signature derived solely from normal untransformed cells is consistent with the hypothesis that the normal cell-of-origin may be a source of ovarian tumor heterogeneity and the associated differences in tumor outcome.
    PLoS ONE 01/2013; 8(11):e80314. · 3.53 Impact Factor
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    ABSTRACT: "Giant Condylomas" of the cervix are very uncommon, and have not been fully characterized in the English literature. We report 4 cases of cervical giant condyloma seen in our practice. Patients were predominantly young and presented with a cervical lesion producing bleeding or a mass effect. Biopsy/excision revealed a uniformly bland, exophytic squamous epithelial proliferation with viral cytopathic changes and absence of stromal invasion. Human papilloma virus types 6 and 11 were detected in all cases. Follow-up was uneventful without recurrence or spread. Giant condylomas of the cervix as defined in this report signify a benign albeit extensive variant of low-risk human papilloma virus infection. This term is proposed as a specific descriptor for such lesions and should be considered in the setting of any large well-differentiated exophytic cervical squamous lesion in young or immunosuppressed women. The term "giant condyloma of Buschke and Loewenstein" should be discontinued given the lack of specificity.
    The American journal of surgical pathology 12/2012; · 4.06 Impact Factor
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    ABSTRACT: Mullerian low grade serous carcinoma (LGSC) and high grade serous carcinoma (HGSC) have distinct molecular profiles, clinical behavior and treatment response. This study examines publicly available gene expression profiles of LGSC and HGSC to identify differentially expressed genes and key pathways involved in carcinogenesis and chemotherapy response. Our analysis supports the hypothesis that serous mullerian carcinoma develop through two different pathways yielding two distinct malignancies, namely LGSC and HGSC. Furthermore, genes potentially involved in chemotherapeutic resistance of LGSC were identified. Suppressing the levels of these genes/proteins may increase clinical response to standard chemotherapy in patients with LGSC. In summary, this review shows the molecular profile of LGSC and HGSC through multi-center analysis of gene expression profiles of these tumors. The gene signatures of these neoplasms may potentially be used to develop disease-specific, targeted therapy for LGSC and HGSC.
    Gynecologic Oncology 12/2012; · 3.93 Impact Factor
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    ABSTRACT: A fundamental controversy in using biomarkers to diagnose cervical cancer precursors [ie, squamous intraepithelial lesions (SIL)] is their lack of specificity for high-grade SIL [HSIL; cervical intraepithelial neoplasia grade 2/3 (CIN2/3)]. Stathmin-1 (STMN), a microtubule-destabilizing protein important in mitosis, is overexpressed in a variety of malignancies including those from the Müllerian tract and may be associated with poor outcome. However, the use of STMN as a diagnostic marker in cervical SILs has not been explored. A total of 193 cervical samples, including benign cervix and squamous and glandular lesions, were evaluated for STMN, p27 (a known cell cycle regulator inversely expressed with STMN in normal and many neoplastic tissues), p16, and Ki67 expression by immunohistochemical analysis. SILs were independently scored and classified as benign, low-grade SIL (LSIL/CIN1), and HSIL (separated into CIN2 or CIN3) on the basis of a majority diagnosis. Each diagnosis was correlated with biomarker expression independent of hematoxylin and eosin review. STMN was normally expressed in basal cells of the ectocervix and was absent in benign endocervix;"positive" STMN staining was defined as immunoreactivity in at least two thirds of the epithelial thickness. A majority hematoxylin and eosin diagnosis was obtained in 189/193 cases on initial independent review, with squamous epithelia ultimately classified as benign, CIN1, CIN2, and CIN3 in 25, 56, 11, and 16 cases, respectively. STMN was positive in 5/56 (9%) CIN1, 5/11 (45%) CIN2, 14/15 (93%) CIN3, all adenocarcinoma in situ (19/19), and all invasive squamous cell carcinoma (32/32) and adenocarcinoma (34/34) cases. In contrast, 40/56 (71%) CIN1, 11/11 (100%) CIN2, and 15/16 (94%) CIN3 lesions were p16 positive (defined as diffuse block staining in at least one third of the epithelial thickness). One CIN3 was negative for both p16 and STMN. Ki67 and p27 staining was variable in squamous lesions. These results demonstrate that STMN is overexpressed in virtually all cervical carcinomas and CIN3 lesions. In contrast to p16, which often stains LSIL and a small subset of reactive biopsies, STMN has greater specificity for CIN3 and has the potential to distinguish these latter lesions from the majority of low-grade precursors and negative/reactive cervical biopsies. STMN overexpression appears independent of proliferation, maturation, and human papilloma virus cytopathic effect and may be useful diagnostically in identifying HSIL. Further studies correlating STMN staining with lesion persistence or morphologic progression, in the context of CIN grade, are warranted.
    The American journal of surgical pathology 12/2012; · 4.06 Impact Factor

Publication Stats

5k Citations
976.76 Total Impact Points


  • 2000–2014
    • Brigham and Women's Hospital
      • • Division of Women's and Perinatal Pathology
      • • Department of Medicine
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 2012–2013
    • University of Liège
      Luik, Walloon Region, Belgium
    • St. Francis Medical Center
      Louisiana, United States
  • 2002–2013
    • Harvard Medical School
      • • Department of Radiation Oncology
      • • Department of Pathology
      • • Department of Cell Biology
      Boston, MA, United States
    • Massachusetts Institute of Technology
      • George R. Harrison Spectroscopy Laboratory
      Cambridge, Massachusetts, United States
  • 2011
    • Genome Institute of Singapore
      Tumasik, Singapore
  • 2010–2011
    • University of Michigan
      • Department of Pathology
      Ann Arbor, MI, United States
    • Universidade Federal do Paraná
      • Departamento de Patologia Básica
      Curitiba, Estado do Parana, Brazil
  • 2006–2011
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2007–2010
    • Partners HealthCare
      Boston, Massachusetts, United States
  • 2009
    • University of Utah
      • Department of Pathology
      Salt Lake City, UT, United States
    • Boston Children's Hospital
      • Department of Pathology
      Boston, MA, United States
  • 2006–2009
    • Dana-Farber Cancer Institute
      • • Department of Cancer Biology
      • • Department of Radiation Oncology
      Boston, MA, United States
  • 2008
    • Universitat de Lleida
      • Department of Vegetal Production and Forestry Science
      Lérida, Catalonia, Spain
  • 2003
    • University of Texas MD Anderson Cancer Center
      • Department of Gynecologic Oncology
      Houston, TX, United States