Elizabeth Montgomery

Combinatorial chemoprevention of intestinal neoplasia

A combination of two drugs afforded remarkable protection from intestinal neoplasia in APCMin/+ mice, a murine model of human familial adenomatous polyposis (FAP). One of the drugs was sulindac, a prototypical non-steroidal anti-inflammatory drug with established chemopreventative activity. The second drug was EKI-569, a newly developed, irreversible inhibitor of the epidermal growth factor receptor kinase. Although 100% of the untreated APCMin/+ mice developed ∼20 polyps, nearly half the mice treated with these two agents developed no polyps at all. These results suggest a powerful strategy for the chemoprevention of human colonic neoplasia.

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive “grungy” calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

β-Catenin immunohistochemistry separates mesenteric fibromatosis from gastrointestinal stromal tumor and sclerosing mesenteritis

Although separating gastrointestinal stromal tumor (GIST) from mesenteric fibromatosis and sclerosing mesenteritis is clinically important, this distinction sometimes poses problems for practicing pathologists. In the STI571 (Gleevec, Imatinib) era, the problem may be further compounded when protocol-driven staining for CD117 (c-kit) is performed on spindle cell proliferations presenting in the bowel wall and mesentery using an antibody known to react with the majority of mesenteric fibromatoses when other antibodies are more specific. Because most mesenteric fibromatoses have mutations in the APC/&bgr;-catenin pathway and hence have abnormal nuclear accumulation of &bgr;-catenin protein, we studied &bgr;-catenin expression among a panel of other immunohistochemical stains to distinguish mesenteric fibromatosis, GIST, and sclerosing mesenteritis. Examples of gastrointestinal stromal tumors (GIST, 11), sclerosing mesenteritis (5), and mesenteric fibromatosis (10) were retrieved from the archives of our institutions. Cases were studied with an immunohistochemical panel consisting of CD117, &bgr;-catenin, CD34, smooth muscle actin, desmin, keratin, and S-100 protein. Cases were scored as “negative,” “focally positive,” or “diffusely positive.” In evaluating &bgr;-catenin, nuclear accumulation was required. GIST all had CD117 (11 of 11, diffuse) and CD34 (11 of 11, diffuse) with variable actin (5 of 11, focal) and negative desmin, keratin, S-100 protein. All GIST lacked &bgr;-catenin (0 of 11). Mesenteric fibromatosis had CD117 (6 of 10, 3 focal, 3 diffuse), typically expressed more weakly than in GIST, actin (5 of 9, focal), and desmin (3 of 8, focal) in keeping with myofibroblastic differentiation but lacked CD34, S-100, and keratin. CD117 staining was not eliminated by use of a non-avidin-biotin technique. Nuclear &bgr;-catenin was detected in 9 of 10 fibromatoses, including one case associated with familial adenomatous polyposis. Two of five sclerosing mesenteritis cases focally expressed CD117. None of the sclerosing mesenteritis cases had nuclear &bgr;-catenin. Sclerosing mesenteritis cases were otherwise fibroblastic and myofibroblastic with focal actin in 5 of 5 and negative desmin, keratin, and S-100 protein but one had CD34 (1 of 5, focal). With increasing protocol-driven interest in evaluating bowel wall and mesenteric spindle cell lesions using CD117 (c-kit) antibodies, it is important for practicing pathologists to be aware that lesions other than GISTs are likely to express this antigen using certain antibodies. &bgr;-Catenin staining identifies lesions that are, instead, mesenteric fibromatoses.

Sessile serrated adenomas with low- and high-grade dysplasia and early carcinomas: an immunohistochemical study of serrated lesions "caught in the act".

Sessile serrated adenomas (SSAs) show serrations typical of hyperplastic polyps but display architectural differences and lack traditional dysplasia. SSAs with foci of low- (LGD) or high-grade dysplasia (HGD) or early invasive carcinoma are seldom biopsied and, thus, are not well studied. Immunohistochemical analysis for MLH1, MSH2, MSH6, and PMS2 (mismatch repair gene products) was performed on colon biopsy specimens from 11 patients (age range, 54-87 years; 4 men and 7 women) showing SSA with LGD (n = 1), HGD (n = 5), or focal invasive carcinoma (n = 5). All 11 cases showed intact nuclear staining for MSH2 and MSH6 in the SSA component; in foci of LGD, HGD, or carcinoma; and in background normal mucosa. In contrast, there was tandem loss of MLH1 and PMS2 in zones of LGD (1/1) or HGD (3/5) and early carcinoma (2/4; with concordant loss in associated HGD) but retention in SSA areas (11/11) and normal mucosa (11/11). No patient was known to have hereditary nonpolyposis colorectal cancer/Lynch syndrome. This study offers additional strong evidence that SSA is truly a precursor to at least a subset of sporadic microsatellite-unstable colorectal cancer.

Myofibrosarcoma : A clinicopathologic study

The concept of soft tissue sarcomas composed predominantly of myofibroblasts has been controversial. We examined a series of such lesions of low-and intermediate-grade malignancy to further define their clinical and pathologic features. Histologic appearances of four cases diagnosed as myofibrosarcoma by electron microscopy were reviewed. Eleven additional cases with similar morphology were then identified from 249 tumors originally indexed as fibrosarcoma. Electron microscopy was performed on five of these, and immunohistochemistry was carried out on all cases for which material was available. There were 11 men and 4 women aged 33 to 73 years (median, 54 yrs; mean, 53 yrs). Lesions mainly involved the head and neck, extremities, and trunk and ranged in size from 1.5 to 12 cm. The tumors were composed of bland or pleomorphic stellate to spindled cells with eosinophilic cytoplasm and tapered nuclei in a collagenous stroma; 10 were grade 1 and five were grade 2. All sarcomas displayed fascicular or storiform patterns, and some of the grade 1 lesions superficially mimicked nodular fasciitis. Electron microscopy of nine cases showed myofibroblastic differentiation, and immunohistochemistry showed smooth muscle actin in 13 of 15 cases, muscle-specific actin in 7 of 9, desmin in 6 of 14, and cytokeratin in 0 of 11. Four of nine grade 1 and three of four grade 2 tumors recurred (one twice), and one grade 2 tumor metastasized to the lungs. Myofibrosarcomas are indolent low-grade or occasionally aggressive intermediate-grade sarcomas which can be recognized by light microscopy. Their clinical importance lies in the resemblance, particularly of low-grade examples, to reactive or pseudosarcomatous conditions.

ACVR1B (ALK4, activin receptor type 1B) gene mutations in pancreatic carcinoma

DPC4 is known to mediate signals initiated by type β transforming growth factor (TGFβ) as well as by other TGFβ superfamily ligands such as activin and BMP (bone morphogenic proteins), but mutational surveys of such non-TGFβ receptors have been negative to date. Here we describe the gene structure and novel somatic mutations of the activin type I receptor, ACVR1B, in pancreatic cancer. ACVR1B has not been described previously as a mutated tumor-suppressor gene.

In vivo endomicroscopy improves detection of Barrett's esophagus–related neoplasia: a multicenter international randomized controlled trial (with video)

BACKGROUND Confocal laser endomicroscopy (CLE) enables in vivo microscopic imaging of the GI tract mucosa. However, there are limited data on endoscope-based CLE (eCLE) for imaging Barretts esophagus (BE). OBJECTIVE To compare high-definition white-light endoscopy (HDWLE) alone with random biopsy (RB) and HDWLE + eCLE and targeted biopsy (TB) for diagnosis of BE neoplasia. DESIGN Multicenter, randomized, controlled trial. SETTING Academic medical centers. PATIENTS Adult patients with BE undergoing routine surveillance or referred for early neoplasia. INTERVENTION Patients were randomized to HDWLE + RB (group 1) or HDWLE + eCLE + TB (group 2). Real-time diagnoses and management plans were recorded after HDWLE in both groups and after eCLE in group 2. Blinded expert pathology diagnosis was the reference standard. MAIN OUTCOME MEASUREMENTS Diagnostic yield, performance characteristics, clinical impact. RESULTS A total of 192 patients with BE were studied. HDWLE + eCLE + TB led to a lower number of mucosal biopsies and higher diagnostic yield for neoplasia (34% vs 7%; P < .0001), compared with HDWLE + RB but with comparable accuracy. HDWLE + eCLE + TB tripled the diagnostic yield for neoplasia (22% vs 6%; P = .002) and would have obviated the need for any biopsy in 65% of patients. The addition of eCLE to HDWLE increased the sensitivity for neoplasia detection to 96% from 40% (P < .0001) without significant reduction in specificity. In vivo CLE changed the treatment plan in 36% of patients. LIMITATIONS Tertiary-care referral centers and expert endoscopists limit generalizability. CONCLUSION Real-time eCLE and TB after HDWLE can improve the diagnostic yield and accuracy for neoplasia and significantly impact in vivo decision making by altering the diagnosis and guiding therapy. ( CLINICAL TRIAL REGISTRATION NUMBER NCT01124214.).

Survival after gastric adenocarcinoma resection: eighteen-year experience at a single institution.

Gastric adenocarcinoma is the second leading cause of cancer death worldwide. In Western series, survival rates vary widely and are generally lower than those reported from Eastern series. We performed a retrospective analysis of cases operated on at the Johns Hopkins Hospital over the past 18 years and collected data on demographics, tumor characteristics, pathologic stage, treatment methods, complications, survival time, and other relevant factors. Survival according to stage of disease, Lauren tumor type, tumorlocation,time period, andadministration of adjuvant therapy wasanalyzed, andresultswerecompared with those of other Western series. During this period, 436 patients with gastric adenocarcinoma underwent resection. We have shown a statistically significant association between survival and margin status, stage of disease, and Lauren tumor type. Overall 5-year survival was 26%, and 5-year survival after R0 resection was 33%. No significant difference was detected between survival and tumor location, time period of treatment, or administration of adjuvant therapy. Analysis of various Western series reveals major differences between the cohorts under study, such as stage of disease, extent of resection, tumor type, and tumor location. Many of the reported differences among Western series may be due to cohort differences, such as stage of disease, extent of resection, tumor type, and tumor location.

Histopathology of Ulcerative Colitis in Initial Rectal Biopsy in Children

Definitive histologic diagnosis of ulcerative colitis relies upon mucosal architectural distortion and inflammation in the appropriate clinical setting. Although crypt branching, atrophy, and loss are usually present in first biopsies from adults with ulcerative colitis, it has been our impression that features of chronicity are often lacking in first biopsies from children. To test this hypothesis, initial rectal biopsies and follow-up biopsies and/or colonic resections from 53 children (age 15 months to 17 years) and 38 adults (age 21–76 years) with ulcerative colitis were examined in a blinded fashion for villiform surface, crypt atrophy, branching crypts, lamina propria inflammation, crypt abscesses, cryptitis, and basal plasma cells. Mucosal architecture was classified as normal, focally abnormal, or diffusely abnormal. Medical records were reviewed for confirmatory evidence of ulcerative colitis and for duration of symptoms before biopsy. In 87 of 91 biopsies, the lamina propria contained a mixed inflammatory infiltrate. Crypt abscesses and cryptitis were common in both groups. Initial biopsies from children were less likely to show diffuse architectural abnormalities (17 of 53, 32.1%) compared with biopsies from adults (22 of 38, 57.9% p <0.05). Duration of symptoms before diagnosis was significantly shorter in children (mean 17.5 weeks) compared with adults (mean 54.9 weeks). In summary, initial rectal biopsies from children with ulcerative colitis are less likely to show diagnostic mucosal architectural distortion than biopsies from adults. This difference may be related to a shorter duration of symptoms before biopsy.

Spindle cell lesions of the adult prostate

Prostatic spindle cell lesions are diagnostically challenging and encompass a broad array of benign and malignant processes. A subset of these lesions arises only within the prostate and generally represents entities that originate from the prostate epithelium or stroma, such as sclerosing adenosis, sarcomatoid carcinoma, stromal tumors of uncertain malignant potential (STUMP), and stromal sarcoma. Another subset of spindle cell tumors that involve the prostate are also found at other sites and include solitary fibrous tumor, leiomyosarcoma, and neural lesions among others. Finally, tumors may secondarily involve the prostate yet present as primary prostatic processes, as is evident with several cases of gastrointestinal stromal tumors (GIST). The utility of ancillary studies, including immunohistochemistry, is often limited and the main criteria for diagnosis are the morphologic findings by routine H&E stain. This review addresses the various entities that may present as spindle cell tumors within the adult prostate and discusses the functional aspects of the differential diagnosis of these lesions.