William L. Marsh

Multi-Institutional Phase II Study of Selumetinib in Patients With Metastatic Biliary Cancers

PURPOSE Biliary cancers (BCs) carry a poor prognosis, but targeting the RAS/RAF/mitogen-activated protein kinase kinase (MEK)/extracellular signal-related kinase (ERK) pathway is of significance. Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC. PATIENTS AND METHODS This was a multi-institutional phase II study of selumetinib at 100 mg given orally twice per day to patients with advanced BC. The primary end point was response rate. All patients were required to provide tissue before enrolling. The levels of phosphorylated ERK (pERK) and AKT (pAKT) were assessed by immunohistochemistry. Tumors were genotyped for the presence of BRAF- and/or RAS-activating mutations. RESULTS Twenty-eight eligible patients with a median age of 55.6 years were enrolled. Thirty-nine percent of patients had received one prior systemic therapy. Three patients (12%) had a confirmed objective response. Another 17 patients (68%) experienced stable disease (SD), 14 of whom (56%) experienced prolonged SD (> 16 weeks). Patients gained an average nonfluid weight of 8.6 pounds. Median progression-free survival was 3.7 months (95% CI, 3.5 to 4.9) and median overall survival was 9.8 months (95% CI, 5.97 to not available). Toxicities were mild, with rash (90%) and xerostomia (54%) being most frequent. Only one patient experienced grade 4 toxicity (fatigue). All patients had tissue available for analysis. No BRAF V600E mutations were found. Two patients with short-lived SD had KRAS mutations. Absence of pERK staining was associated with lack of response. CONCLUSION Selumetinib displays interesting activity and acceptable tolerability in patients with metastatic BC. Our results warrant further evaluation of selumetinib in patients with metastatic BC.

A Comparison of CD10 to pCEA, MOC-31, and Hepatocyte for the Distinction of Malignant Tumors in the Liver

The distinction of hepatocellular carcinoma (HCC) from metastatic adenocarcinoma (MA) and cholangiocarcinoma (CC) in some cases requires the use of immunohistochemistry. CD10 has recently been suggested as a useful stain for HCC. We directly compared CD10 with other immunohistochemical markers, Hepatocyte, pCEA, and MOC31, that have previously shown to be useful for the distinction between tumors in the liver to help define the current panel of stains that most readily distinguishes HCC from CC and MA. One hundred previously well-characterized tumors in the liver were evaluated and included 25 HCC, 15 CC, and 60 MAs (15 each from breast, esophageal/gastric, pancreatic, and colorectal origin). Tumors were immunostained with the commercially available antibodies Hepatocyte, pCEA, MOC31, and CD10. CD10 stained 13 of 25 HCC and was rarely positive in MA and CC (3/75). Hepatocyte stained 24 of 25 HCC and was negative in all 75 MA and CC. pCEA stained 24 of 25 HCC and 71 of 75 MA and CC with the proper pattern of immunoreactivity, but the pattern of staining was difficult to interpret in several cases. MOC31 stained 1 of 25 HCC and 65 of 75 MA and CC. Hepatocyte was the most sensitive and specific single marker for HCC. CD10 is not a useful addition or substitution to the panel of Hepatocyte, MOC31, and pCEA. The combination of Hepatocyte, MOC31, and pCEA correctly classified 99 of 100 tumors in this study and is our proposed panel of immunostains for the initial workup of malignant tumors in the liver.

Pathologic Findings in Reduction Mammaplasty Specimens

Reduction mammaplasty (RM) is a common surgical procedure that yields a variable amount of tissue for pathologic examination. Occult breast carcinomas are detected rarely in these specimens. We evaluated the pathologic findings in RM specimens performed in our institution during an 11.5-year period (July 1989 to December 2000). A total of 560 patients who had undergone RM were identified, 503 bilateral and 57 unilateral. The average number of blocks submitted per breast was 3.9 (range, 1-23). Pathologic changes were present in 338 cases (60.4%). Unsuspected carcinomas (small invasive carcinomas, 3; ductal carcinoma in situ, 1) were found in 4 cases (0.7%). Atypical ductal and/or atypical lobular hyperplasia were identified in 8 cases (1.4%). Lesions associated with a mildly increased carcinoma risk (moderate/florid ductal hyperplasia, sclerosing adenosis, and papilloma) were identified in 52 cases (9.3%). Other findings included fibrocystic changes, fibrosis, mild ductal hyperplasia, fibroadenoma, and adenosis. Pathologic examination of RM specimens provides important clinical information and should be performed routinely.

Ectomesenchymal chondromyxoid tumor of the anterior tongue: a report of three cases

Ectomesenchymal chondromyxoid tumor is a newly described benign neoplasm that presents clinically as a firm, painless, slow-growing mass that typically involves the anterior dorsal tongue. It has been reported to occur over a wide age range (9 to 78 years) and has no apparent sex predilection. Histologically, the tumor is composed of a well-circumscribed, unencapsulated lobular proliferation of fusiform and polygonal cells in a chondromyxoid matrix. Features such as multilobulated nuclei, foci of cellular atypia, and infiltration may be present. Though disturbing, these do not appear to indicate malignant behavior. We report three cases of ectomesenchymal chondromyxoid tumors that confirm the previously described clinical, histologic, and immunohistochemical features. In addition, we describe the ultrastructural features of one of the cases.

Leiomyosarcoma metastatic to the oral region: Report of three cases

Leiomyosarcoma, a malignant lesion of smooth muscle origin, is rare in the oral region. Metastatic leiomyosarcoma may originate from several potential primary sites, and the lung is the most common target tissue for metastatic deposits. This article describes three cases of leiomyosarcoma that were metastatic to the oral cavity and discusses the clinical and histopathologic differential diagnosis.

Serous Cystadenoma of the Pancreas: Clinical and Pathological Features in 33 Patients

Aim: To report the clinicopathological features of patients with serous cystadenomas of the pancreas. Methods: Thirty-three cases of serous cystadenoma diagnosed between 1977 and 2006 were retrieved from the files of the Ohio State University Medical Center. Clinical data and microscopic slides were reviewed. Results: The patients included 27 women and 6 men with an age range of 38–83 (mean 64.3) years. The clinical presentation included 13 patients with abdominal pain and 8 patients with abdominal mass; 9 tumors were found incidentally. Abdominal CT scans in 25 patients were interpreted as suspicious for carcinoma in 8 (32%), suspicious for serous cystadenoma in 8, neoplasm not otherwise specified in 8, and suspicious for a pseudocyst in 1. Only 7 patients underwent a preoperative biopsy, and 5 of these were diagnosed as having a serous cystadenoma. All but 2 of the patients underwent surgical resection of the tumor. The serous cystadenomas varied in size from 1.0 to up to 13 cm in maximum dimension, and all but one had a multicystic appearance. Of the 33 serous cystadenomas, 20 (61%) were located in the pancreatic tail, 4 (12%) in the pancreatic body, 4 in the pancreatic body and tail, and 5 (15%) in the head of the pancreas. Follow-up in 17 patients (median 3 years, range from 1 month to 11 years) showed no recurrence of serous cystadenomas. One patient had von Hippel-Lindau syndrome, 4 patients had diabetes mellitus, 3 patients had metastatic cancer, and 2 patients had ovarian tumors. Conclusions: Serous cystadenoma is an uncommon neoplasm that can be confused with malignancy both clinically and radiologically; a correct diagnosis is important in order to provide an accurate prognosis.

Double Immunohistochemical Staining With MUC4/p53 Is Useful in the Distinction of Pancreatic Adenocarcinoma From Chronic Pancreatitis: A Tissue Microarray-Based Study

CONTEXT Immunohistochemical stains have been used for the distinction of pancreatic adenocarcinoma from chronic pancreatitis. OBJECTIVE To determine if a double stain for MUC/p53 improved specificity and sensitivity for distinction of pancreatic adenocarcinoma from chronic pancreatitis by comparing maspin, mucin 4 (MUC4), p53, Smad4, and the double stain MUC4/p53. DESIGN Seventy-four pancreatic adenocarcinomas and 19 chronic pancreatitis cases were retrieved from archival files. Tissue cores were arrayed to create a tissue microarray of 2-mm cores. Sections were stained with antibodies against maspin, MUC4, p53, and Smad4. Additionally, a 2-color, double stain for MUC4 and p53 was developed and evaluated. Five percent or greater staining in either of the cores was considered positive. Intensity (0, 1, 2) and extent (%) of tumor cells staining was also determined. RESULTS The sensitivity for distinction of pancreatic adenocarcinoma from chronic pancreatitis with maspin, MUC4, p53, and Smad4 was 90%, 77%, 60%, and 63%, respectively; the specificity was 67%, 78%, 88%, and 88%, respectively. When MUC4 and p53 were combined in a double stain, and positive staining for either considered a positive result, the sensitivity increased to 96% but specificity was 73%. When immunoreactivity for both antibodies was necessary for a positive result, sensitivity fell to 39% but specificity was 100%. No correlation was found between intensity or extent of staining with any of the individual stains and tumor differentiation. CONCLUSION The double immunohistochemical stain for MUC4/p53 can be a useful diagnostic tool in conjunction with the hematoxylin-eosin-stained section for pancreatic adenocarcinoma, particularly when limited tumor is available for multiple stains.

A modified Lynch syndrome screening algorithm in colon cancer: BRAF immunohistochemistry is efficacious and cost beneficial.

OBJECTIVES Somatic BRAF mutation in colon cancer essentially excludes Lynch syndrome. We compared BRAF V600E immunohistochemistry (IHC) with BRAF mutation in core, biopsy, and whole-section slides to determine whether IHC is similar and to assess the cost-benefit of IHC. METHODS Resection cases (2009-2013) with absent MLH1 and PMS2 and prior BRAF mutation polymerase chain reaction results were chosen (n = 57). To mimic biopsy specimens, tissue microarrays (TMAs) were constructed. In addition, available biopsies performed prior to the resection were available in 15 cases. BRAF V600E IHC was performed and graded on TMAs, available biopsy specimens, and whole-section slides. Mutation status was compared with IHC, and cost-benefit analysis was performed. RESULTS BRAF V600E IHC was similar in TMAs, biopsy specimens, and whole-section slides, with only four (7%) showing discordance between IHC and mutation status. Using BRAF V600E IHC in our Lynch syndrome screening algorithm, we found a 10% cost savings compared with mutational analysis. CONCLUSIONS BRAF V600E IHC was concordant between TMAs, biopsy specimens, and whole-section slides, suggesting biopsy specimens are as useful as whole sections. IHC remained cost beneficial compared with mutational analysis, even though more patients needed additional molecular testing to exclude Lynch syndrome.

Management of a patient with multiple recurrences of fibromatosis (desmoid tumor) of the breast involving the chest wall musculature

BackgroundFibromatosis or desmoid tumor is a rare soft tissue tumor that lacks a metastatic potential, but is characterized by a locally aggressive and infiltrating growth pattern and a high propensity toward local recurrence if incompletely excised.Case presentationWe report a patient with three post-surgical recurrences of fibromatosis of the breast over a seven year period. The fibromatosis was found to be involving the chest wall musculature and causing persistent and worsening pain. An aggressive operative strategy was undertaken, consisting of mastectomy with en bloc resection of the underlying chest wall musculature, ribs, and parietal pleura.ConclusionAggressive surgical management of fibromatosis of the breast with suspected chest wall involvement is appropriate to attempt to obtain a long-term durable cure.

Adenoma of the common bile duct: endoscopic diagnosis and resection

Adenomas of the common bile duct are a rare and unusual cause of bile duct obstruction, with only a few cases recorded in the medicalliterature.s Since the advent of endoscopy, adenomas of the duodenum and ampulla of Vater presenting with cholestasis have been commonly documented.11 However, recorded cases of adenomas arising within the common bile duct are still rare, and largely confined to the surgical literature.s We present, what is to our knowledge, the first case in the English language literature of an adenoma of the common bile duct presenting with biliary obstruction as diagnosed by endoscopic retrograde cholangiography (ERe) and endoscopically resected.