Monoclonal CEA Research Articles

Do You Know the Details of Your PAX8 Antibody? Monoclonal PAX8 (MRQ-50) Is Not Expressed in a Series of 45 Medullary Thyroid Carcinomas.

Medullary thyroid carcinomas display cytologic and architectural features that can simulate various primary and metastatic neoplasms. PAX8 immunoexpression in neuroendocrine neoplasms yielded antibody-dependent findings. Since the data regarding the expression profile of monoclonal PAX8 (MRQ-50) antibody is limited in large series of medullary thyroid carcinomas, this study investigated the expression profile of PAX8 (MRQ-50) in a series of 45 medullary thyroid carcinomas. PAX8 (MRQ-50) expression was noted in the thyroid follicular epithelial cells surrounding the tumor and was negative in all medullary thyroid carcinomas. In addition, twenty medullary thyroid carcinomas showed scattered entrapped thyroid follicular epithelial cells at the periphery of the tumor. Entrapped follicular epithelial cells were positive for PAX8 and thyroglobulin, and were negative for monoclonal CEA and calcitonin. A panel approach combining monoclonal antibodies to transcription factors, hormones and cell-specific peptides often assist diagnosticians in the workup of the cellular origin of a neuroendocrine neoplasm. Since PAX8 immunostaining is dependent on the antibody characteristics in neuroendocrine neoplasms, pathologists should be aware of the details of the PAX8 antibody used in a particular case.

A Report of Submucosal Intravascular Paraganglioma of the Gallbladder and Review of the Literature

Abstract Objectives The purpose of this case study and review of the literature is to allow pathologists to recall an appropriate differential diagnosis for submucosal epithelial tumors of the gallbladder. It is also important to note the immunohistochemical evaluation of a paraganglioma. Methods Intraoperative findings were multiple adhesions of the omentum to the gallbladder itself, with a mildly dilated cystic duct measuring 6 to 7 mm externally. The intraoperative cholangiogram was normal with no evidence of retained stones. The gallbladder was 9.5 cm and essentially unremarkable with no stones upon gross examination. Palpation revealed a 5 × 4 × 4-mm gray-tan cystic duct lymph node that was microscopically unremarkable. Microscopically, there was a 2.7-mm submucosal intravascular epithelioid tumor. Cytologically, the cellular infiltrate was cohesive, filled, and expanded a single submucosal vessel. A broad panel of immunohistochemical stains was performed, with the results listed below. Results Carbonic anhydrase IX: Negative; Monoclonal CEA: Negative; CK7: Negative; CK 20: Negative; Gata-3: Positive; Mart-1: Negative; OCT3/4: Strong diffuse positive; P 63: Negative; Pancytokeratin: Negative; PAX-8: Negative; S-100: Negative; WT1: Negative; PLAP: Negative; Hep par 1: Negative; AFP: Negative; CD117: Negative; CD 30: Negative; CDX2: Negative; Glypican 3: Negative; SALL4: Negative; Inhibin: Negative ERG: Negative; CD34: Negative; CD56: Strong diffuse positive; Synaptophysin: Strong diffuse positive; Chromogranin: Strong diffuse positive. Conclusion Expert opinion was requested to confirm the presumed diagnosis on this case. The consulting pathologist was in agreement that this was best classified as an intravascular paraganglioma. The patient was seen in follow-up and a CT of the chest, abdomen, and pelvis was ordered. Interestingly, a 1.9-cm enhancing upper pole right renal mass was identified. The patient was sent to urologic surgical consultation in which they believed this tumor to represent a stage 1a primary renal cell carcinoma and subsequently sent for radiofrequency ablation.

Primary Hepatic Mixed Acinar-Neuroendocrine Tumor: A Rare Case of a Liver Mass

Extra-pancreatic primary acinar cell carcinomas (ACC) are rare and have been reported in the stomach, jejunum, colon and liver. Of the seven hepatic cases reported, most presented with abdominal pain, a liver mass and no pancreatic involvement. This case is one among the unusual cases reported. A 67-year-old lady with past history of chronic hepatitis B infection presented with progressively worsening abdominal pain. Lab workup revealed an elevated lipase (3532 U/L), a normal liver function test, AFP and CA19-9. Abdominal ultrasound and CT showed an 11cm by 8cm heterogeneously enhancing mass in the right hepatic lobe with central enhancement [Figure 1] and no involvement of the pancreas or the biliary tree. Histopathology of the mass revealed atypical proliferation of neoplastic cells with pseudo-glandular formation and occasional prominent nucleoli [Figure 2a]. The cells stained positive for pancytokeratin, CK7, chromogranin, synaptophysin [Figure 2b] and trypsin; and negative for Hep-Par 1 [Figure 3], monoclonal CEA and CA19-9. The histologic features and immunophenotype were consistent with mixed acinar-neuroendocrine tumor. Surveillance MRI and endoscopic ultrasound (EUS) did not demonstrate a pancreatic mass leading to a diagnosis of primary hepatic ACC. It was determined that the tumor was not surgically resectable due to vascular proximity and the patient was referred to an oncologist for systemic chemotherapy. Patients with rare primary hepatic ACC usually present with abdominal pain with normal to low elevations of AFP and CA19-9. A para-neoplastic syndrome causing lipase hyper-secretion as seen in this patient has been mentioned in the literature. CT scan usually shows a single large hypo-enhancing lesion with areas of necrosis or multiple smaller solid lesions. Histopathology reveals typical tumor cells with immmuno-histochemistry demonstrating positivity for trypsin and chymotrypsin for acinar differentiation; synaptophysin for neuroendocrine differentiation. Multiple theories including presence of common progenitor cells showing aberrant pancreatic differentiation or occurrence of heterotopic or metaplastic pancreatic tissue among liver tissue has been implicated in the etio-pathogenesis. This case highlights the occurrence of a rare tumor and that it should be considered in the differential when a vascular tumor is detected in an otherwise healthy liver with normal tumor markers.2320_A Figure 1. shows axial and sagittal sections of Abdominal CT scan demonstrating the extent of the tumor2320_B Figure 2. (a) shows pseudo-glandular formation and prominent nucleoli on H and E stain and Figure 2 (b) shows tumor cells staining positive for synaptophysin2320_C Figure 3. Figure 3 shows islands of normal hepatic tissue with negative staining for Hep-Par 1

Positivity for GATA3 and TTF-1 (SPT24), and Negativity for Monoclonal PAX8 Expand the Biomarker Profile of the Solid Cell Nests of the Thyroid Gland.

Solid cell nests (SCNs) are usually distinguished on conventional H&E-stained sections; however, the morphological heterogeneity in SCNs and hyperplasia of these ultimobranchial body remnants can mimic other diagnostic entities including but not limited to papillary microcarcinoma. In order to confirm the thyroid follicular epithelial origin and exclude the possibility of SCNs, most diagnosticians use immunohistochemical biomarkers of thyroid follicular epithelial cells and/or those of SCNs. While the expression profile of monoclonal PAX8 has not been reported previously in SCNs, the status of TTF-1 expression using the 8G7G3/1 clone has been inconsistent among several studies. Given the potential diagnostic pitfalls, this series investigated the expression profile of GATA3, monoclonal PAX8, and TTF-1 (SPT24), along with p63, p40, monoclonal calcitonin, monoclonal CEA, and HBME-1 in a tissue microarray (TMA) of 56 SCNs. SCNs were all diffusely and strongly positive for TTF-1 (SPT24), p63, and p40, and were negative for monoclonal PAX8 and calcitonin. Positivity for GATA3 and monoclonal CEA was identified in 41 (73.2%) and 36 (64.3%) of SCNs. In addition, 18 (32.1%) SCNs displayed HBME-1 reactivity. These findings expand the immunohistochemical correlates of SCNs by demonstrating positivity for GATA3 and TTF-1 (SPT24), and negativity for monoclonal PAX8. The identification of monoclonal CEA expression and HBME-1 in SCNs also underscores the limitations of these select biomarkers in the distinction of C cell proliferations and papillary microcarcinoma, respectively. The findings of this series also suggest that positivity for TTF-1 (SPT24) alone should not be used to confirm the thyroid follicular epithelial origin. Therefore, the combined use of TTF-1 (SPT24) and monoclonal PAX8 in association with p63 or p40 provides an accurate distinction of SCNs.

Hepatoid Adenocarcinoma of the Rectum With Liver Metastasis in Patient With Ulcerative Colitis

Hepatoid adenocarcinoma (HA) is a rare malignant tumor of extrahepatic origin that morphologically and immunophenotypically resembles hepatocellular carcinoma. We report a case of a 38-year-old Caucasian male with 13 year history of ulcerative colitis who initially presented to an outside facility with three months of diarrhea, mild abdominal pain, and ten-pound weight loss. Outpatient colonoscopy revealed severely ulcerated rectosigmoid mucosa with necrotic features and he was transferred to our facility for further workup of presumed ischemic colitis. CT abdomen showed a large, 8.1 x 9.4 x 6.6 cm hepatic mass with portal vein thrombus and rectosigmoid thickening. Liver protocol MRI did not demonstrate characteristic contrast washout seen in hepatocellular carcinoma (HCC). Alpha-feto protein (AFP; 15,523 ng/mL) and carcinoembryonic antigen (CEA; 20.3 ng/mL) were elevated. The patient subsequently underwent triple phase CT which was also not consistent with HCC. Scrotal ultrasound to rule out a primary testicular malignancy was negative; however, human chorionic gonadotropin (beta hCG) was elevated, increasing the concern for extragonadal yolk sac tumor. The patient underwent liver biopsy and repeat colonoscopy with rectal biopsies. Histologic morphology and immunophenotype from both specimens were consistent with hepatoid adenocarcinoma. Given these findings a diagnosis of hepatoid adenocarcinoma of the rectum with hepatic metastasis was made. The patient was subsequently started on palliative FOLFOX chemotherapy. Hepatoid adenocarcinoma is a rare malignant tumor of extrahepatic origin whose features mimic those of hepatocellular carcinoma. Most cases have been reported as arising in the stomach, though HA has also been described in the small and large intestines, lung, ovary, uterus, bladder, pancreas, and gallbladder. HA is often metastatic at time of diagnosis and carries a poor prognosis. Most cases of HA arising in the intestines have been described in patients with inflammatory bowel disease, who are known to be at increased risk of developing adenocarcinoma of the GI tract. Hepatoid adenocarcinoma should be considered in the differential diagnosis of malignant lesions in the IBD patient.Figure: A. A liver core biopsy low power image depicting diffuse infiltration of the tissue by carcinoma. B &C. High power images reveal a mixed hepatocellular/trabecular and glandular architecture composed of cytologically atypical eosinophilic cells vaguely resembling atypical hepatocytes. Immunohistochemistry (not shown) exhibits positive staining for pankeratin, cdx-2, polyclonal CEA, monoclonal CEA, alpha-fetoprotein, glypican-3, SALL-4, and focal positivity for CK20, and is negative for CK7, HepPar-1, Vimentin, CD31, and CD34.

Infarcted neuroendocrine tumor following endobronchial ultrasound guided fine needle aspiration of a pulmonary nodule: Typical versus atypical carcinoid a pathological diagnostic dilemma

IntroductionPulmonary Neuroendocrine tumors have been categorized into high, intermediate and low grade. The distinction between low grade typical carcinoid from atypical carcinoid depends on mitotic count and presence of punctate necrosis. Case presentationThe patient is a 60year old female with past medical history of diabetes mellitus, hyperlipidemia, gastrointestinal reflux disease and cervical myelopathy. An incidental right upper lobe nodule was discovered during hospitalization for post-total knee arthroplasty sepsis. Follow-up CT and PET scans demonstrated size stability with mild hypermetabolic activity. The tumor was excised by a robotic thoracoscopic right upper lobectomy and mediastinal lymph node dissection. A lobulated, tan-yellow, well demarcated firm mass, measuring 1.2×1×1cm was grossly identified. Microscopically, the well circumscribed mass demonstrated near complete infarct-like central necrosis with a peripheral viable cellular rim consisting of nests of tumor cells that stained positively with TTF-1, Synaptophysin, Chromogranin, and CD56; and was negative for calcitonin and monoclonal CEA. The mitotic figure count was negligible and met the WHO criteria for typical carcinoid. The proliferative index (Ki-67) was slightly high at 9.29%. DiscussionThe unusual central necrosis seen in the tumor and the relatively high proliferative index created a pathological diagnostic dilemma discussed in this report.

Immunohistochemical profile of ductal adenocarcinoma of the prostate.

Ductal adenocarcinoma of the prostate (DAC) is considered to be an aggressive subtype of prostate cancer with greater risk of progression than acinar adenocarcinoma (AC). It has been debated whether DAC is a distinct subtype or a morphological variant of AC. Our aim was to examine the protein expression of DAC and to compare the results with AC. A tissue microarray was constructed from 60 DAC and 46 AC matched by Gleason score. The slides were stained for 28 immunomarkers (estrogen, progesterone and androgen receptor, prolactin, PSA, prostein, PSMA, PSAP, CDX2, lysozyme, villin, monoclonal CEA, CK7, CK20, HMWCK, p63, p504s, c-myc, EGFR, Ki-67, p16, p21, p27, p53, PTEN, ERG, PAX-2, and PAX-8). HMWCK was positive in 8.5 % of DAC, but negative in all cases of AC (p = 0.045). p16 was positive in 53.3 % of DAC and in 26.1 % of AC (p = 0.005). p53 was positive in 42.4 % of DAC and 26.7 % of AC (p = 0.031). A distinct patchy positivity of CK20 was seen in 23.7 % of DAC, and this pattern was also seen in 9.1 % of AC (p = 0.047). Villin was positive in 3.4 % of DAC while expression was negative in AC. Ki-67 labeling index was significantly higher in DAC than in AC (mean 9.2 % [95 % CI 6.4-12.0] and 2.6 % [1.9-3.4], p < 0.001). While there is some overlap in the immunohistochemical expression of DAC and AC, the differences between these two morphotypes of prostatic carcinoma are consistent with DAC having a more aggressive phenotype than AC.

Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature

The current diagnostic criteria for hepatoid adenocarcinoma of lung include typical acinar or papillary adenocarcinoma and a component resembling hepatocellular carcinoma and expressing α-fetoprotein (AFP). Distinguishing hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung is difficult in patients with both lung and liver masses and in patients at risk for lung and liver cancer because of smoking and viral hepatitis, respectively. We studied morphologic features of hepatoid adenocarcinoma of lung and established an immunohistochemical panel to facilitate distinction of hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung. Five cases of hepatoid adenocarcinoma of lung were stained with hematoxylin and eosin and mucicarmine for histomorphologic evaluation. The 14-marker immunohistochemical profile was established for hepatoid adenocarcinoma of lung and compared with that of hepatocellular carcinoma. Two cases of hepatoid adenocarcinoma of lung had signet-ring cell components. Three cases were pure hepatoid adenocarcinoma without components of acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma. Like hepatocellular carcinoma, hepatoid adenocarcinoma of lung expresses CK8 (5/5), CK18 (5/5), AFP (3/5) and HepPar1 (5/5), shows cytoplasmic staining with TTF-1 (5/5) and does not express CK14 (0/5). Unlike hepatocellular carcinoma, it expresses CK5/6 (1/5), CK7 (3/5), CK19 (4/5), CK20 (1/5), HEA125 (5/5), MOC31 (5/5), monoclonal CEA (3/5) and napsin A (1/5). An immunohistochemical panel that includes a variety of cytokeratins, monoclonal CEA and EpCAM markers (HEA125 and MOC31) facilitates distinction of hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung, especially when correlated with clinical and radiologic findings. We propose modification of the current diagnostic criteria for hepatoid adenocarcinoma of lung. Tumor composition can be either pure hepatoid adenocarcinoma or hepatoid adenocarcinoma with components of typical acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma. AFP expression is not requisite for diagnosis as long as other markers of hepatic differentiation are expressed.

Pancreatic Metastasis of Papillary Thyroid Carcinoma Diagnosed by Endoscopic Ultrasound and Fine-Needle Aspiration

Introduction: The National Cancer Institute estimates that in 2012 the new number of new thyroid cancer cases reported will be approximately 56,000 with 1,780 expected deaths. There are four distinct subtypes of thyroid cancer: papillary, follicular, medullary, and anaplastic, with papillary being the most common subtype. Associated metastatic disease appears in about 5% of these patients with the most common site of metastasis being the lung and bone. Metastatic disease to the pancreas is extremely rare, with only a few cases reported. Case Report: A 61-year-old female, with a history of papillary thyroid carcinoma treated by thyroidectomy and radioiodine ablation (RAI), presents for evaluation for persistent elevation of her thyroglobulin level. A positron emission tomography scan revealed a 3-cm heterogeneously enhancing lesion in the body of the pancreas. At time of presentation the patient denied any jaundice, abdominal pain, nausea, vomiting, back pain, or weight loss. On physical examination the patient was anicteric, with no abdominal tenderness or masses. Patient underwent an endoscopic ultrasound (EUS) for further evaluation revealing a round, hypoechoic well-defined mass in the pancreatic body, approximately 3.6 x 3.4 cm. The pancreatic duct, upstream from the lesion, was dilated to 5 mm. Fine needle aspiration of the mass using a trans-gastric approach was performed. Immunohistochemical staining showed the neoplastic cells to be positive for TTF-1, thyroglobulin, CK19, and CK7. CK20, monoclonal CEA, and the neuroendocrine markers were negative. CA 19-9 was focally positive. Cytology was positive for the presence of malignant cells and findings were consistent with metastatic thyroid carcinoma to the pancreas. Discussion: This case illustrates a very rare presentation of metastatic disease. For diagnosis, EUS is now recognized as the most sensitive tests for the detection of both primary and metastatic lesions of the pancreas. Also observed in our case is the utilization of EUS-FNA with sensitivity for detecting malignancy ranging from 75-90%. This technique is superior to that of CT-guided FNA as well as endoscopic retrograde pancreatography (ERP). Our case highlights the utility of EUS, EUS-FNA, and immunohistochemical staining to obtain a tissue diagnosis in suspected pancreatic metastasis.

Sensitive electrochemical immunoassay of a biomarker based on biotin-avidin conjugated DNAzyme concatamer with signal tagging

This work reports a new electrochemical immunoassay protocol with signal amplification for the sensitive detection of a biomarker (carcinoembryonic antigen, CEA, used in this case) by coupling hemin/G-quadruplex-constructed DNAzyme concatamer with the biotin-avidin amplification system. Initially, polyclonal rabbit anti-human CEA antibody (pAb1) was immobilized onto a gold nanoparticle-modified glassy carbon electrode, which was used for the capture of target CEA, and biotin-labeled mouse anti-human monoclonal CEA antibody (bio-mAb2) was then used as a secondary antibody for the formation of the sandwiched immunocomplex in the presence of target CEA on the pAb1-modified electrode. The carried biotin could react with streptavidin and a biotin-labeled initiator strand (S0) in sequence. Two auxiliary DNA strands (S1 and S2) were designed for the concatamer reaction with the S0. The DNA initiator stand (S0) could propagate a chain reaction of hybridization events between alternating S1 and S2 to form a nicked double-helix. Upon addition of hemin, the hemin-binding aptamers can be bound to form the hemin/G-quadruplex-based DNAzymes on the S1 probe. Meanwhile, the formed double-helix DNA polymers could also cause the numerous intercalation of electroactive methylene blue. During the electrochemical measurements, the DNAzymes could catalyze the reduction of H2O2 in a detection solution with the aid of the intercalated methylene blue. Under the optimal conditions, the electrochemical immunosensor exhibited a dynamic working range of 1.0 pg mL−1–50 ng mL−1 toward CEA standards with a detection limit of 0.5 pg mL−1. The reproducibility and selectivity of the developed immunoassay were acceptable (CV <10%). In addition, 6 spiked CEA samples with various concentrations were assayed by using the developed immunoassay, and the recovery was 92–120%.

A Case of Primary Papillary Serous Carcinoma of the Peritoneum in a Man

Purpose: Immunohistological and electron microscopic examinations at autopsy were performed to confirm a diagnosis of a patient, who was clinically diagnosed as poorly differentiated adenocarcinoma by percutaneous biopsy of thickening part of peritoneum. Methods: Enhanced CT scan showed distended stomach and rectum, broad intestinal wall thickening, thickening peritoneum, enlarged mesenteric lymph nodes, small amount of ascites, mild hydronephrosis and thrombosis of innominate and jugular vein. The echo-guided biopsy of the thickening part in the peritoneum was performed, and the lesion was diagnosed as poorly-differentiated adenocarcinoma. However, immunohistological analysis and additional imaging studies could not determine a primary lesion. At autopsy, immunohistochemical studies were performed using primary antibodies for pancytokeratin, epithelial membrane antigen, carcinoembryonic antigen, CA125, neuron-specific enolase, calretinin, D2-40, WT1, cytokeratin 7, cytokeratin 20, BerEP4, LeuM1, CA19-9, chromogranin, synaptophysin, and thyroglobulin. Electron microscopic examination was further performed. Results: Histological examination revealed invasive growth of neoplastic cuboidal or columnar cells with eccentric nuclei forming papillary and glandular structures. Psammoma bodies were found. These microscopic features were highly reminiscent of ovarian/peritoneal serous adenocarcinoma of women. Tumor invasion was observed in subcutaneous tissue of the abdominal wall. The tumor also invaded the right ureter, resulting in hydronephrosis of the right kidney. No tumor was found in paratesticular regions. Metastasis of the tumor was found in lymph nodes (mesenteric, paraaortic, and paratracheal), left adrenal gland, and bilateral lungs. The lungs showed marked lymphangitis carcinomatosa and tumor emboli in the pulmonary artery branches. Venous thrombi containing metastatic tumor cells filled the lumina of the left jugular vein and left renal vein. No primary tumor was found in the visceral organs. The tumor cells were positive for pancytokeratin, EMA, monoclonal CEA, CA125, and NSE. They were negative for calretinin, D2–40, WT1, cytokeratin 7, cytokeratin 20, BerEP4, LeuM1 (CD15), CA19-9, chromogranin, synaptophysin, and thyroglobulin. In electron microscopic examination of the tumor cells, no apparent microvillus was found, although a small number of irregular short cytoplasmic processes were observed. Bundles of intermediate filaments were not seen in these cells. These findings indicated that the tumor was papillary serous adenocarcinoma of the peritoneum in a man. The diagnosis of peritoneal malignant mesothelioma was unlikely. Conclusion: This report is the third case of PSCP in male.

WT1, monoclonal CEA, TTF1, and CA125 antibodies in the differential diagnosis of lung, breast, and ovarian adenocarcinomas in serous effusions

The distinction between metastatic adenocarcinomas of lung (LAC), breast (BAC), and ovary (OAC) in serous effusions can be very difficult since they all can present as tight cell clusters. This is particularly challenging when the malignant effusion is the patient's initial presentation or when the patient has a history of more than one primary. The aim of this study is to evaluate the usefulness of WT1, monoclonal CEA (mCEA), TTF1, and CA125 antibodies in the differential diagnosis of metastatic adenocarcinoma from the lung, breast and ovary in serous effusions. Forty-six samples of serous effusions with their corresponding cell blocks were retrieved from our hospital computer system, including 13 BACs, 13 LACs, and 20 OACs. The diagnoses were confirmed by the surgical resection. Formalin-fixed and paraffin-embedded cell block sections were immunostained for WT1, mCEA, TTF1, and CA125. Two observers blindly reviewed the immunostained slides without knowledge of the previous clinical or histologic diagnoses. The staining intensity was graded semiquantitatively as negative, 0; weak, 1+; moderate, 2+; and strong, 3+. The percentage of positively staining cells was estimated. The distribution patterns of reactivity for WT1 and TTF1 were recorded as nuclear, and mCEA and CA125 as membranous stain. Metastatic OACs showed positive immunoreactivity to WT1 in 19/20 (95%) cases, CA125 in 20/20 (100%), and all showed negative reaction for both mCEA (0/20, 0%) and TTF1 (0/20, 0%). BAC showed positive reaction in 6/13 (46%) cases to CA125 and mCEA. Staining pattern was diffuse for CA125 and focal for mCEA. Only 2/13 (15%) were positive for WT1, while all of 13 BAC cases (0/13, 0%) were negative for TTF1. LAC showed positive immunoreactivity for TTF1 in 9/13 (69%) with a characteristic nuclear staining pattern, but only 3/13 (23%) were focally stained for WT1. In addition, 8/13 (62%) of LAC cases were positive for both CA125 and mCEA. Our results demonstrate that the WT1 stain is specific for metastatic carcinoma of ovarian primary, showing a high sensitivity. In addition, CA125 stain is very sensitive for OACs, but could be positive in about a half of LAC and BAC cases. An immunostaining pattern of positive mCEA as well as negative WT1 rules out OACs, raising the possibility of LACs and BACs. A positive TTF1 staining supports the diagnosis of metastatic carcinoma originating from lung rather than breast, while a negative TTF1 favors the diagnosis of a breast primary. Immunohistochemical studies with WT1, TTF1, and mCEA antibodies are useful in the differential diagnosis of metastatic adenocarcinomas of lung, breast, and ovary.

Nodular hyperplasia of Bartholin’s gland

There has been very little mention of benign solid lesions of the Bartholin's gland (BG) in pathology and gynaecology textbooks, and very few cases have been reported in the literature. Among these lesions, the distinction between nodular hyperplasia (NH) and adenoma has not been well defined. We report ten cases of NH of the BG, describe their clinicopathological, immunohistochemical and ultrastructural findings, and review the literature. We examined retrospectively all lesions involving BGs from our surgical pathology records from 1990 to 2004 with emphasis on NH. To separate NH from adenoma, we applied the criteria proposed by Koenig and Tavassoli. Special stains (PAS with and without prior digestion, Mayer's mucicarmine and Alcian blue with and without hyaluronidase) and immunohistochemistry (CAM5.2, AE1/AE3, HMWK, monoclonal CEA, EMA, ER, PR, ALA, SMA, Ki-67, p53 and polyclonal CEA) were performed on NHs. Two cases were examined ultrastructurally. Using specific criteria, ten cases (age range 23-45 years; mean 36.1) of NH were identified, two of which were diagnosed previously as adenoma, but re-classified as NH. Clinically, these lesions were described either as Bartholin's duct cysts (BDCs) or vulvar lumps. Grossly, NHs were solid, tan and unencapsulated, measuring 12.5-45.0 mm in maximum dimension (mean 23.8). Histologically, the NHs were composed of a proliferation of mucus-secreting acini with preservation of the normal duct-to-acinar relationship. Chronic inflammation and squamous metaplasia were present. Eight lesions focally involved the surgical margins. Intracytoplasmic and intra-luminal secretions were positive for PAS with and without digestion, Alcian blue with and without hyaluronidase and mucicarmine. All lesions showed positive staining for CAM5.2, AE1/AE3, HMWK, EMA, and polyclonal CEA. There was negative staining for Ki-67, ER, PR, ALA, p53 and monoclonal CEA. Periacinar myoepithelial cells stained for SMA. Ultrastructurally, the findings included abundant intracytoplasmic secretory granules, granulofibrillar bodies, prominent Golgi and ribosomes. Myoepithelial cells were identified. There was no tumour recurrence or malignant transformation in eight patients with clinical follow-up. NH of the BG is a rare lesion with benign behaviour. It is a distinct entity and can be separated histologically from an adenoma.

HepPar1, MOC-31, pCEA, mCEA and CD10 for Distinguishing Hepatocellular Carcinoma vs. Metastatic Adenocarcinoma in Liver Fine Needle Aspirates

To investigate immunohistochemical staining of hepatocyte paraffin-1 (HepPar1), alpha-fetoprotein (AFP), polyclonal carcinoembryonic antigen (pCEA), monoclonal CEA (mCEA), MOC-31 and CD10 for differential diagnosis of hepatocellular carcinoma (HCC) from metastatic adenocarcinoma (MA) on fine needle aspiration biopsy (FNAB).Fifty-one archival, paraffin-embedded FNAB cell blocks, representing 18 HCCs and 33 MAs, were immunostained with antibodies for AFP, CD10, pCEA, mCEA, HepPar1 and MOC-31.HepPar1, AFP, canalicular pCEA and CD10 were positive in 78% (14 of 18), 28% (5 of 18), 72% (13 of 18) and 35% (6 of 17) of cases of HCC, respectively. The 33 MAs were negative for immunostaining of the above antibodies except for one AFP-positive MA. Ninety-seven percent (31 of 32) of the MAs and 6% (1 of 17) of the HCCs were positive for MOC-31. Monoclonal CEA was immunoreactive on 82% (27 of 33) of the MAs and negative on all the HCCs.HepPar1 was the most sensitive marker for HCC, followed by canalicular staining for pCEA. For MA, MOC-31 was the most sensitive marker; mCEA was slightly less sensitive but more specific. We suggest using HepPar1, pCEA, CD10, MOC-31 and mCEA as a panel for distinguishing HCC from MA in liver FNAB.

Sensitivity and specificity of immunohistochemical markers used in the diagnosis of epithelioid mesothelioma: a detailed systematic analysis using published data

Immunohistochemistry is frequently employed to aid the distinction between mesothelioma and pulmonary adenocarcinoma metastatic to the pleura, but there is uncertainty as to which antibodies are most useful. We analysed published data in order to establish sensitivity and specificity of antibodies used to distinguish between these tumours with a view to defining the most appropriate immunohistochemical panel to use when faced with this diagnostic problem. A systematic analysis of the results of 88 published papers comparing immunohistochemical staining of a panel of antibodies in mesothelioma with epithelioid areas, and pulmonary adenocarcinoma metastatic to the pleura. Results for a total of 15 antibodies were analysed and expressed in terms of sensitivity and specificity. The most sensitive antibodies for identifying pulmonary adenocarcinoma were MOC-31 and BG8 (both 93%), whilst the most specific were monoclonal CEA (97%) and TTF-1 (100%). The most sensitive antibodies to identify epithelioid mesothelioma were CK5/6 (83%) and HBME-1 (85%). The most specific antibodies were CK5/6 (85%) and WT1 (96%). No single antibody is able to differentiate reliably between these two tumours. The use of a small panel of antibodies with a high combined sensitivity and specificity is recommended.

Immunohistochemistry Can Help Distinguish Metastatic Pancreatic Adenocarcinomas From Bile Duct Adenomas and Hamartomas of the Liver

Not uncommonly, bile duct adenomas (BDAs) and hamartomas (BDHs) of the liver may be difficult to distinguish from metastatic well-differentiated ductal adenocarcinoma of the pancreas. However, this distinction is critical for proper staging and patient management. The primary purpose of this study was to determine if a panel of immunohistochemical stains can help distinguish BDA or BDH from metastatic pancreatic adenocarcinoma in the liver. Routinely processed tissue sections from 25 BDA, 10 BDH, 25 metastatic pancreatic adenocarcinomas to the liver and 6 cases each of metastatic colorectal, breast, and lung adenocarcinomas were immunohistochemically stained for CK7, CK8/CK18, CK19, CK20, p53, p63, TAG-72, monoclonal CEA (mCEA), polyclonal CEA (pCEA), HER-2/neu, AMACR (alpha-methylacyl-CoA racemase), Dpc4 (Smad4), and mesothelin. The slides were evaluated in a blinded fashion, and the results were compared between the benign and malignant lesions. Significantly more (P < 0.05) metastatic pancreatic adenocarcinomas were positive for CK20 (76%), p53 (60%), TAG-72 (88%), mCEA (92%), HER2/neu (40%), and mesothelin (64%) and showed loss of Dpc4 (44%), in comparison to BDA (CK20, 40%; p53, 0%; TAG-72, 0%; mCEA, 0%; HER2/neu, 12%; mesothelin, 0%; loss of Dpc4, 0%) or BDH (CK20, 10%; p53, 0%; TAG-72, 0%; mCEA, 10%; HER2/neu, 0%; mesothelin, 0%; loss of Dpc4, 0%). Of these antibodies, p53, TAG-72, mCEA, loss of Dpc4, and mesothelin had the highest specificity for pancreatic adenocarcinoma, with mCEA having the highest sensitivity (92%). No significant differences were observed in the degree of CK7, CK8/CK18, CK19, or pCEA expression between the three types of lesions. Although none of the BDA or BDH was positive for either p63 or AMACR, two of the metastatic pancreatic adenocarcinomas (8%) were positive for each of these peptides (P > 0.05). For nonpancreatic adenocarcinomas, mCEA showed a reasonably high sensitivity and 100% specificity in the differential diagnosis versus BDA. Immunohistochemical expression of p53, TAG-72, mCEA, mesothelin, and loss of Dpc4 can help distinguish metastatic pancreatic adenocarcinoma in the liver from BDA or BDH. Although p63 and AMACR are also specific for pancreatic adenocarcinoma, their low sensitivity limits their use in clinical practice.

Symptomatic Nephrogenic Metaplasia of Ureter: a Morphologic and Immunohistochemical Study of Four Cases

Nephrogenic metaplasia of the bladder and urethra has been the subject of extensive studies in recent years. However, information about ureteral involvement is still limited because of the rarity of the lesion. We described four cases of nephrogenic metaplasia of the ureter. They occurred in two men and two women whose ages ranged from 46 to 69 years. Three patients had stones, and one had multiple episodes of cystitis and chronic pyelonephritis. The lesions led to ureteral obstruction that in two patients was radiographically suspicious for carcinoma. Microscopically, three lesions were composed of tiny mucin-containing microcysts and medium-sized tubular structures lined by cuboidal cells that showed cytologic atypia characterized by enlarged vesicular nuclei and prominent nucleoli. However, there were no mitotic figures. Two lesions invaded the full thickness of the wall of the ureter and exhibited an infiltrative growth pattern highlighted by cytokeratin stains. The remaining two lesions were confined to the lamina propria. The cells of nephrogenic metaplasia were immunoreactive to cytokeratin 7 and AE1–AE3. They lacked reactivity for monoclonal and polyclonal CEA and p53. The MIB-1-labeling index was <5%. The cytologic atypia and infiltrative growth pattern of ureteral nephrogenic metaplasia should not be misinterpreted as evidence of malignancy. All four patients are alive and symptom free 8 months to 7 years after diagnosis.

Value of mesothelial and epithelial antibodies in distinguishing diffuse peritoneal mesothelioma in females from serous papillary carcinoma of the ovary and peritoneum.

To evaluate the role of mesothelial markers (calretinin, thrombomodulin, cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal carcinoembryonic antigen, Leu-M1, CA-125 and Ber-EP4) in distinguishing diffuse peritoneal malignant mesothelioma from primary serous papillary adenocarcinoma of the ovary and peritoneum. Paraffin-embedded formalin-fixed blocks from 32 diffuse peritoneal mesotheliomas of epithelial subtype (all females), 20 serous papillary ovarian carcinomas and three primary peritoneal serous papillary carcinomas were studied. Calretinin and Ber-EP4 appeared to be the best positive mesothelial and carcinoma marker, respectively. Nuclear calretinin expression was identified in 28 of 32 malignant mesotheliomas with no nuclear immunoreactivity in the cohorts of serous papillary ovarian and peritoneal carcinomas, thus yielding 88% sensitivity and 100% specificity. Ber-EP4 showed 95% sensitivity and 91% specificity for serous papillary ovarian carcinoma. Thrombomodulin, cytokeratin 5/6 and CD44H immunoreactivities were seen in 18 (56%), 17 (53%) and 15 (47%) of peritoneal mesotheliomas, respectively, and in six (30%), five (25%) and five (25%) of the ovarian tumours, respectively. None of the three primary peritoneal serous papillary carcinomas expressed calretinin, thrombomodulin, cytokeratin 5/6 or CD44H. Polyclonal and monoclonal CEA, and Leu-M1 were expressed by two (10%), one (5%) and seven (35%) serous papillary ovarian carcinomas, respectively. None of the serous papillary peritoneal carcinomas expressed polyclonal CEA, monoclonal CEA or Leu-M1. CA-125 was positive in 19 (95%) and two (67%) ovarian and peritoneal carcinomas, respectively, and in eight (25%) peritoneal mesotheliomas. Calretinin and Ber-EP4 are useful discriminant markers in distinguishing peritoneal mesothelioma in women from serous papillary ovarian and peritoneal carcinoma. The other mesothelial markers (thrombomodulin, cytokeratin 5/6, and CD44H) and carcinoma markers (polyclonal and monoclonal CEA, and Leu-M1) yielded a too low sensitivity for practical use.

Florid Endocervical Glandular Hyperplasia with Intestinal and Pyloric Gland Metaplasia: Worrisome Benign Mimic of “Adenoma Malignum”

We describe three cases of florid endocervical glandular hyperplasia with intestinal and pyloric gland metaplasia, which can be a benign mimic of adenoma malignum. In two cases, adenoma malignum was seriously considered preoperatively because of watery vaginal discharge and the results of imaging studies. The three cases shared common histopathological features, i.e., (i) proliferating endocervical glands surrounded by clusters of smaller glands, resembling the pyloric glands of the stomach; (ii) occasional intestinal metaplasia; (iii) bland nuclear features; and (iv) predominantly PAS-positive neutral mucin in the glandular epithelium. In two cases, glands were densely and irregularly arranged in some areas. Immunohistochemistry disclosed that the intracytoplasmic mucin of the metaplastic epithelium was positive for M-GGMC-1 (HIK1083), which reacts with mucin of pyloric glands. Monoclonal CEA was negative in all cases. This pseudoneoplastic benign condition should be recognized by both gynecologists and pathologists, although it might be difficult to establish a definite diagnosis preoperatively even with deep cone biopsy.

Breast Carcinoma versus Lung Adenocarcinoma: The Immunohistochemical Discrimination of Breast Carcinoma Metastatic in Lung

Abstract: Breast and lung adenocarcinomas are the two neoplasms with the highest incidence in women, and as a result, these tumors are some of the most frequently seen tumors in surgical pathology and fine-needle aspiration biopsies. The number of patients having both tumors is on the rise. For therapeutic purposes, it is important to be able to distinguish the two in tissues and in fine-needle aspirates (FNA). Formalin-fixed, paraffin-embedded archival tissue from ductal and lobular breast carcinomas metastatic to lung (29 cases), ductal breast carcinomas (18 cases), and pulmonary adenocarcinomas (15 cases) were examined by light microscopy and by a battery of antibodies, including monoclonal CEA, monoclonal CEA-D14, GCDFP-15, alphalactalbumin, vimentin, S-100 protein, and estrogen-receptor protein. The avidin-biotin immunoperoxidase method was used. Sensitivity and specificity were analyzed and compared with each other using Youden's J statistic. In the lung, CEA-D14 was the single best antibody for identifying lung tumors while GCDFP-15 and estrogen receptor (ER) were the antibodies that best identify metastatic breast carcinoma in the lung. Because of the focal nature of GCDFP-15 staining in many metastatic tumors, this antibody may be less useful for discrimination of breast carcinomas in small biopsies and FNA specimens.