Ana Slipicevic, MSca, Geir Frode Øy, MScb, Inger Cecilie Askildt, BSca, Arild Holth, BSca, Ellen Hellesylt, BSca, Vivi Ann Flørenes, PhDa, Ben Davidson, MD, PhD

Division of Pathology, Norwegian Radium Hospital, Rikshospitalet Medical Center, N-0310 Oslo, Norway.

Abstract

We recently reported on higher expression of the insulin-like growth factor pathway genes IGF-II and IGFBP3 in serous ovarian/peritoneal carcinoma compared to malignant peritoneal mesothelioma. The present study analyzed the diagnostic and clinical role of these proteins in serous effusions. Effusions (n = 327), including 294 carcinomas (205 ovarian, 48 breast, 17 cervical/endometrial, 12 lung, 12 gastrointestinal/genitourinary) and 33 malignant mesotheliomas, were immunostained for insulin-like growth factor-II and insulin-like growth factor binding protein-3. Surgical ovarian carcinoma (n = 124) and peritoneal mesothelioma (n = 18) specimens were additionally studied. Insulin-like growth factor binding protein-3 levels were measured in 148 effusion supernatants (114 ovarian carcinomas, 18 breast carcinomas, 16 mesotheliomas) using enzyme-linked immunosorbent assay. Insulin-like growth factor binding protein-3 promoter methylation was analyzed in 11 ovarian carcinoma effusions. Insulin-like growth factor binding protein-3 (P = .002) and insulin-like growth factor-II (P < .001) expression by immunohistochemistry was significantly higher in carcinomas compared to mesotheliomas, with diagnostic sensitivity of 77% and 70% and specificity of 55% and 70%, respectively. In surgical specimens, insulin-like growth factor binding protein-3 expression was higher in ovarian carcinomas compared to peritoneal mesotheliomas (P = .007), whereas insulin-like growth factor-II expression was comparable (P = .505). Insulin-like growth factor binding protein-3 levels by enzyme-linked immunosorbent assay were comparable in the 3 analyzed cancer types. Insulin-like growth factor binding protein-3 promoter methylation was found in 6 of 11 effusions. High insulin-like growth factor binding protein-3 expression in prechemotherapy and high insulin-like growth factor-II expression in postchemotherapy ovarian carcinoma effusions correlated with poor overall survival (P = .031 and P = .024, respectively). Insulin-like growth factor-II expression in postchemotherapy effusions was an independent prognostic factor in Cox multivariate analysis (P = .04). In conclusion, insulin-like growth factor-II and insulin-like growth factor binding protein-3 are more frequently expressed in metastatic carcinomas compared to mesothelioma in effusions but are less specific than currently used markers. Insulin-like growth factor-II and insulin-like growth factor binding protein-3 may be novel prognostic markers in metastatic ovarian carcinoma.

Keywords: Insulin-like growth factor, Effusions, Carcinoma, Mesothelioma, Survival

Glossary

carcinoma

(car-sin-o-ma) a malignant tumor that begins in the lining layer (epithelial cells) of organs. At least 80% of all cancers are carcinomas.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

peritoneal

(pair-uh-tuh-nee-al) the serous membrane that lines the cavity of the abdomen. (More on Peritoneal Mesothelioma.)

Davidson B.

Division of Pathology, Norwegian Radium Hospital, Rikshospitalet University Hospital, Oslo, Norway. ben.davidson@medisin.uio.no

Abstract

Malignant mesothelioma is a primary cancer of the serosal cavities, an anatomic site that is also frequently affected by metastatic disease, predominantly from primary carcinomas of the lung, breast, and ovary. Advances in immunohistochemistry have resulted in improved diagnostic sensitivity and specificity in the differential diagnosis between metastatic adenocarcinoma and malignant mesothelioma in both cytological and histological material. Recently, the author’s group applied high throughput technology to the identification of new markers that may aid in differentiating malignant mesothelioma from ovarian and peritoneal serous carcinoma, tumors with closely related histogenesis and antigenic profile. In addition to the improved tools available for serosal cancer diagnosis, knowledge regarding the biology of malignant mesothelioma has been accumulating in recent years. This review presents current data regarding the diagnostic and biological aspects of malignant mesothelioma.

Glossary

adenocarcinoma

(add-en-o car-sin-o-muh). Cancer that starts in the glandular tissue, such as in the ducts or lobules of the breast.

diagnosis

identifying a disease by its signs or symptoms, and by using imaging procedures and laboratory findings. The earlier a diagnosis of cancer is made, the better the chance for long-term survival.

carcinoma

(car-sin-o-ma) a malignant tumor that begins in the lining layer (epithelial cells) of organs. At least 80% of all cancers are carcinomas.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

peritoneal

(pair-uh-tuh-nee-al) the serous membrane that lines the cavity of the abdomen. (More on Peritoneal Mesothelioma.)

Kalof AN, Cooper K.

Department of Pathology, University of Vermont/Fletcher Allen Health Care, Burlington, VT 05401, USA. alexandra.kalof@vtmednet.org Abstract

D2-40 is a commercially available monoclonal antibody directed against human podoplanin, a transmembrane mucoprotein that is expressed in lymphatic endothelial cells. Since its introduction, D2-40 immunoexpression has been described in a variety of lymphovascular neoplasms including lymphangioma, Kaposi sarcoma, and hemangioendothelioma, as well as nonvascular neoplasms such as epithelioid mesothelioma, seminoma, and hemangioblastoma. More recently, D2-40 immunoexpression has been reported in primary adrenal cortical tumors, schwannomas, and adnexal tumors of the skin. This brief review provides an update on the ever-expanding proposed applications of D2-40 immunohistochemistry in surgical pathology.

Glossary

sarcoma

(sar-co-muh) a malignant tumor growing from connective tissues, such as cartilage, fat, muscle, or bone.

antibody

a protein in the blood that defends against foreign agents, such as bacteria. These agents contain certain substances called antigens. Each antibody works against a specific antigen. (See also antigen.)

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Lee JM, Pou K, Sadow PM, Chen H, Hu B, Hewison M, Adams JS, Sugarbaker DJ, Fisher ND.

Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA. jaymoonlee@mednet.ucla.edu

Abstract

Objective: To report a case of coincident hypercalcemia and Cushing syndrome arising from mesothelioma.

Methods: We describe the clinical, laboratory, imaging, and pathologic findings of a patient with malignant pleural mesothelioma and elucidate the underlying biologic mechanisms resulting in concurrent overexpression of steroid and polypeptide hormones.

Results: A 62-year-old woman presented with chest discomfort and cough. Radiologic imaging revealed a diffuse pleural-based mass encasing the right lung. There was no invasion into the chest wall, diaphragm, or mediastinum, and there was no distant disease. Laboratory analyses documented hypercalcemia and Cushing syndrome, which were due to ectopic overproduction of 1,25-dihydroxyvitamin D (1,25[OH]₂D) and corticotropin. Surgical resection resulted in normocalcemia with normalization of serum 1,25(OH)₂D and reduction in hypercortisolemia. The extrapleural pneumonectomy specimen revealed overexpression of the 1,25(OH)₂D synthetic enzyme 25-hydroxyvitamin-D-1alpha-hydroxylase (1alpha-hydroxylase) and underexpression of the 1,25(OH)₂D catabolic enzyme 24-hydroxylase. Immunohistochemistry and electron microscopy demonstrated corticotropin and secretory granules in the tumor tissue.

Conclusion: These findings support the evidence for a paracrine role of vitamin D in the resistance of the human host to antigen.

Glossary

resection

surgery to remove part or all of an organ or other structure.

imaging

any method used to produce a picture of internal body structures. Some imaging methods used to detect cancer are x-rays (including mammograms and CT scans), magnetic resonance imaging (MRI), scintigraphy, and ultrasound.

antigen

(an-tuh-jen) a substance that causes the body's immune system to react. This reaction often involves production of antibodies. For example, the immune system's response to antigens that are part of bacteria and viruses helps people resist infections. Cancer cells have certain antigens that can be found by laboratory tests. They are important in cancer diagnosis and in watching response to treatment. Other cancer cell antigens play a role in immune reactions that may help the body's resistance against cancer.

tissue

a collection of cells, united to perform a particular function.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

extrapleural pneumonectomy

(EPP) surgery to remove the pleura, diaphragm, pericardium, and entire lung involved with the tumor. You can view a web cast from Brigham and Women's Hospital in Boston of this procedure being done by Dr. David Sugarbaker: see the extrapleural pneumonectomy (EPP) web cast here.

Tamiya M, Yamane H, Terada H, Matsuno O, Yamamoto S.

Respiratory Department, NHO Osakaminami Medical Center.

Abstract

A 62-year-old man with pain in his hip joints and back was admitted to our hospital. His chest radiograph and CT showed a huge mass extending from the left upper pericardium to the left hilum, but no pleural effusion or other lesions. A contrast-enhanced abdominal CT showed multiple metastases to bones and both kidneys. Bronchoscopy revealed obstruction of the left B3 by a visible tumor. The biopsy specimens of the initial immunohistochemical staining were slightly positive for calretinin. However, we diagnosed the condition as sarcomatoid carcinoma of the lung on the basis of the clinical evaluation. Although radiotherapy was administered, his condition rapidly deteriorated and he died due to progression of the disease. Autopsy revealed extensive invasion, suggesting mesothelioma. Therefore, immunohistochemical staining was performed; the findings revealed sarcomatoid malignant mesothelioma. In conclusion, we encountered a rare case of sarcomatoid malignant mesothelioma (stage IV).

Glossary

carcinoma

(car-sin-o-ma) a malignant tumor that begins in the lining layer (epithelial cells) of organs. At least 80% of all cancers are carcinomas.

bronchoscopy

(BRON-kos-ko-pee) examination of the bronchi using a flexible, lighted tube called a bronchoscope.

biopsy

(buy-op-see) the removal of a sample of tissue to see whether cancer cells are present. There are several kinds of biopsies. In some, a very thin needle is used to draw fluid and cells from a lump. In a core biopsy, a larger needle is used to remove more tissue.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

pleural effusion

an abnormal accumulation of fluid, usually caused by trauma or disease, in the pleural space.

Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M.

Laboratory of Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.

Abstract

Ovarian cancer and malignant mesothelioma frequently express both mesothelin and CA125 (also known as MUC16) at high levels on the cell surface. The interaction between mesothelin and CA125 may facilitate the implantation and peritoneal spread of tumors by cell adhesion, whereas the detailed nature of this interaction is still unknown. Here, we used truncated mutagenesis and alanine replacement techniques to identify a binding site on mesothelin for CA125. We examined the molecular interaction by Western blot overlay assays and further quantitatively analyzed by enzyme-linked immunosorbent assay. We also evaluated the binding on cancer cells by flow cytometry. We identified the region (296-359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin as the minimum fragment for complete binding activity to CA125. We found that substitution of tyrosine 318 with an alanine abolished CA125 binding. Replacement of tryptophan 321 and glutamic acid 324 with alanine could partially decrease binding to CA125, whereas mutation of histidine 354 had no effect. These results indicate that a conformation-sensitive structure of the region (296-359) is required and sufficient for the binding of mesothelin to CA125. In addition, we have shown that a single chain monoclonal antibody (SS1) recognizes this CA125-binding domain and blocks the mesothelin-CA125 interaction on cancer cells. The identified CA125-binding domain significantly inhibits cancer cell adhesion and merits evaluation as a new therapeutic agent for preventing or treating peritoneal malignant tumors.

Glossary

mutation

a change; a change in a gene.

flow cytometry

(flow cy-tom-uh-tree) a test of tumor tissue to see how fast the tumor cells are reproducing and whether the tumor cells contain a normal or abnormal amount of DNA. This test is used to help predict how aggressive a cancer is likely to be. (See also ploidy, DNA, S-phase fraction.)

cell

the basic unit of which all living things are made. Cells replace themselves by splitting and forming new cells (mitosis). The processes that control the formation of new cells and the death of old cells are disrupted in cancer.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

antibody

a protein in the blood that defends against foreign agents, such as bacteria. These agents contain certain substances called antigens. Each antibody works against a specific antigen. (See also antigen.)

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

peritoneal

(pair-uh-tuh-nee-al) the serous membrane that lines the cavity of the abdomen. (More on Peritoneal Mesothelioma.)

Addis B, Roche H.

Department of Cellular Pathology, Southampton University Hospitals NHS Trust, Southampton, UK. bruce.addis@suht.swest.nhs.uk

Abstract

Many centres are now seeing increasing numbers of patients with malignant mesothelioma. This presents pathologists involved in making the diagnosis with a number of problems, which can be divided into those encountered in making the distinction between mesothelioma and benign changes and those experienced in separating mesotheliomas from other types of epithelial and connective tissue tumours. Immunohistochemistry plays a major role in helping to make the diagnosis, but it should be interpreted with due regard to the clinical setting and radiological features, and with a knowledge of the wide morphological variations seen in mesothelioma. This review identifies some of these problems and addresses the uses and limitations of immunohistochemistry in different situations. It includes a discussion of some of the less common variants of mesothelioma and other pleural-based tumours that enter into the differential diagnosis.

Glossary

diagnosis

identifying a disease by its signs or symptoms, and by using imaging procedures and laboratory findings. The earlier a diagnosis of cancer is made, the better the chance for long-term survival.

benign

(be-nine) not cancer; not malignant.

tissue

a collection of cells, united to perform a particular function.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

Expression of GATA-6 transcription factor in pleural malignant mesothelioma and metastatic pulmonary adenocarcinoma.

Lindholm PM, Soini Y, Myllärniemi M, Knuutila S, Heikinheimo M, Kinnula VL, Salmenkivi K.

Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Finland.

Abstract

Background: Malignant mesothelioma (MM) is a highly aggressive tumour with poor prognosis and limited response to therapy. New markers for the prediction of prognosis in MM and in pulmonary adenocarcinoma of the pleura are valuable. GATA-6 belongs to a six member zinc finger transcription factor family named after their recognition motif W-GATA-R. AIM: To clarify the distribution and possible function of GATA-6 transcription factor in MM and in pleural metastasis of lung adenocarcinomas.

Methods: 63 pleural MM and 36 pleural metastatic pulmonary adenocarcinomas were studied for GATA-6 expression by immunohistochemistry using tissue microarrays. Expression of GATA-6 was examined in relation to thyroid transcription factor-1 expression, survival, proliferation and apoptosis.

Results: Nuclear immunoreactivity for GATA-6 was stronger and more frequent in MM than in metastatic pleural adenocarcinoma. Prognosis was better in patients with GATA-6 expression when compared to those with no GATA-6 expression (p = 0.002); in the subgroup analysis the difference was significant in epithelial and sarcomatous mesothelioma. GATA-6 was not associated with spontaneous proliferation or apoptosis of the tumour cells in situ.

Conclusion: Results suggest that GATA-6 plays a role in pleural malignancies, predicting longer survival in subgroups of MM.

Glossary

adenocarcinoma

(add-en-o car-sin-o-muh). Cancer that starts in the glandular tissue, such as in the ducts or lobules of the breast.

therapy

any of the measures taken to treat a disease. Unproven therapy is any therapy that has not been scientifically tested and approved. Use of an unproven therapy instead of standard (proven) therapy is called alternative therapy. Some alternative therapies have dangerous or even life-threatening side effects. For others, the main danger is that a patient may lose the opportunity to benefit from standard therapy. Complementary therapy, on the other hand, refers to therapies used in addition to standard therapy. Some complementary therapies may help relieve certain symptoms of cancer, relieve side effects of standard cancer therapy, or improve a patient's sense of well-being. The ACS recommends that patients considering use of any alternative or complementary therapy discuss this with their health care team.

prognosis

(prog-no-sis) a prediction of the course of disease; the outlook for the cure of the patient. For example, women with breast cancer that was detected early and who received prompt treatment have a good prognosis.

pleura

(pler-uh) the membrane around the lungs and lining of the chest cavity. (Pleural mesothelioma.)

metastasis

(meh-tas-teh-sis) the spread of cancer cells to distant areas of the body by way of the lymph system or bloodstream.

in situ

in place; localized and confined to one area. A very early stage of cancer.

tissue

a collection of cells, united to perform a particular function.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

apoptosis

a type of cell death in which the cell basically commits suicide; scientists believe some types of cancer may originate from an interruption of this programmed cell death, allowing cells to grow out of control.

Ismail HM, Moneer M, El-Baradie M, Khorshid O, Touny A.

The Department of Pathology , National Cancer Institute, Cairo University. Hodanci@hotmail.com

Abstract

Background: The aim of the study was to verify the frequency of the immunohistochemical overexpression of her-2/neu and p53 in gastric carcinoma and their relation to the other clinico-pathological features and the impact on survival rates.

Patients and Methods: A total of 93 patients of gastric carcinoma, who had a potential curative surgery in the period from 2001-2007 and with representative paraffin blocks, and sufficient follow-up data were included in this study. They were arrayed and evaluated for protein marker overexpression using tissue microarray (TMA). Patients, tumor and treatment characteristics were collected from the patients’ files. The possible prognostic significance of p53 and her-2/neu over expression and different clinico-pathological features on survival rates were explored.

Results: Twenty four (25.8%) cases were her-2/neu and p53 positive. None of the examined clinico-pathologic factors had a significant relation to her-2/neu overexpression. p53 was overexpressed in intestinal type, 14/34 (41.2%), more than in diffuse type, 10/59 (16.9%), (p= 0.01). There was no relation between the overexpression of p53 and her-2/neu. The median survival period was 17.7 months. The survival rates at 12 months were 64.2%, 52.2%, 55.6% and 45.0% for overall (OS), local control (LC), metastasis free survival (MFS) and disease free survival (DFS) rates, respectively. Patients with advanced stages had a significantly lower OS and MFS. Age above 57 years was associated with significantly lower OS, LC, MFS and DFS. Patients who received radiotherapy had significantly higher OS, LC, MFS and DFS. None of the survival rates had been affected by the overexpression of p53, or her-2/neu.

Conclusion: Although, this study failed to show any prognostic effect of p53 and her-2/neu on survival rates, we may suggest that p53 overexpression may play a role in the pathogenesis of intestinal gastric adenocarcinoma. It could also demonstrate the significantly improved survival rates with adjuvant chemoradiation. Also, TMA is a useful technique for rapid identification of protein expression profiles using minimal samples from archived tissues.

Keywords: Her-2/neu, p53, Gastric carcinoma, Tissue microarray, Prognostic factors.

Glossary

adenocarcinoma

(add-en-o car-sin-o-muh). Cancer that starts in the glandular tissue, such as in the ducts or lobules of the breast.

metastasis

(meh-tas-teh-sis) the spread of cancer cells to distant areas of the body by way of the lymph system or bloodstream.

carcinoma

(car-sin-o-ma) a malignant tumor that begins in the lining layer (epithelial cells) of organs. At least 80% of all cancers are carcinomas.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

tissue

a collection of cells, united to perform a particular function.

tumor

an abnormal lump or mass of tissue. Tumors can be benign (not cancerous) or malignant (cancerous).

Hu JC, Brookings W, Aldridge MC.

Department of Surgery, Queen Elizabeth II Hospital, Howlands, Welwyn Garden City, Hertfordshire, AL7 4HQ, UK.

Abstract

Introduction: A 59-year-old man with previous exposure to asbestos presented with dyspnoea and pleuritic chest pain, had a pleural effusion and was treated for pneumonia. His symptom recurred and was found to have an abdominal mass.

Discussion: An abdominal computerised tomogram revealed pancreatic body mass arising. Pleural fluid cytology and a pleural biopsy failed to demonstrate malignancy. The pancreatic tumour was resected by distal pancreatectomy, segmental colectomy and splenectomy. The tumour was a solid pseudopapillary pancreatic tumour (SPT) with a high metastatic potential. The patient deteriorated and a repeat biopsy of the thickened pleura confirmed malignancy which was initially thought to be metastases from the SPT. Immunohistochemical staining confirmed malignant mesothelioma. The patient developed liver metastases and died 2 years from the diagnosis of metastatic disease.

Glossary

pleura

(pler-uh) the membrane around the lungs and lining of the chest cavity. (Pleural mesothelioma.)

diagnosis

identifying a disease by its signs or symptoms, and by using imaging procedures and laboratory findings. The earlier a diagnosis of cancer is made, the better the chance for long-term survival.

cytology

(cy-tahl-uh-gee) the branch of science that deals with the structure and function of cells.

cancer

malignancy; a group of diseases typified by abnormal, generally out-of-control, cell growth.

biopsy

(buy-op-see) the removal of a sample of tissue to see whether cancer cells are present. There are several kinds of biopsies. In some, a very thin needle is used to draw fluid and cells from a lump. In a core biopsy, a larger needle is used to remove more tissue.

mesothelioma

a tumor derived from mesothelial tissue, such as the peritoneum (lining the abdomen) or pleura (lining the lungs). More on mesothelioma.

pleural effusion

an abnormal accumulation of fluid, usually caused by trauma or disease, in the pleural space.