Case 2 -

Minimal Bulk Malignant Mesothelioma (Mesothelioma in Situ/early Mesothelioma) Claire W. Michael University of Michigan Ann Arbor, MI

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Clinical History: Thocacocentesis fluid submitted from a 63 years old man presenting with recurrent effusion. Chest x-ray and CT Scan with and without contrast showed large left pleural effusion. the lungs were clear and no pleural thickening or nodularities were noted. Case 2 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 2 - Figure 1 Pleural effusion exhibiting high cellularity and wide range of cellular size. Some cells are gigantic with enlaged nuclei, prominent nucleoli and have moderate to abundant cytoplasm. Case 2 - Figure 2 Notice the varaiation in size and the large single or multinucleated cells approaching the size of adjacent morules. Case 2 - Figure 3 Histologic section of the pleura showing surface mesothelium changes Case 2 - Figure 4 Histologic section showing microscopic submesothelial foci of invasion. Case 2 - Figure 5 Histologic section showing microscopic foci of invading mesothelial cords. Introduction: Body cavity effusions are among the most commonly received specimens in the cytology laboratory. They also are the most commonly referred specimens for consultation. Accurate diagnosis of effusions is very important as it saves the patient further morbidity resulting from more invasive diagnostic tests. In mesothlioma, cyologic diagnosis can save the patient from undergoing a VATS with core biobpy since it is well documented that mesothlioma have a tendecy to spread along the biopsy tract. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: 63 years old man who presented in December of 1993 with dyspnea and productive cough. Chest x-ray and CT scan with and without contrast showed a large left pleural effusion. The lungs were clear and no pleural thickening or nodularities were noted. Thoracocentesis was performed and the pleural fluid was interpreted by cytology as reactive mesothelial cells. In April of 1994 he was admitted to the hospital for persistent effusion. Thoracocentesis at that time was interpreted as malignant cells consistent with mesothelioma. Consequently, fluoroscope with peeling of the pleura and talc pleurodesis were performed. The surgeon noted the presence of nodular reaction across the pleura. Pleural biopsies were interpreted as fibrotic thickening indicative of early plaque formation and atypical mesothelial proliferation. In September 1994, he presented with a huge left effusion. Thoracocentesis resulted in 2000 cc of fluid interpreted as malignant mesothelioma. Patient was referred for chemotherapy treatment with Alimta. Past medical history is significant for coronary artery disease. He does not smoke and drinks only on occasions. He worked as engineering technician/designer and has used various materials and chemical building models (methylene chloride, benzene glues, spray paint, lead etc.) He has used fiberglass to finish boats on a few occasions. He also worked in the shipyard industry and had history of asbestos exposure. Differential Diagnoses: Metastatic adenocarcinoma Reactive esothelium Malignant mesothelioma Final Diagnosis: Minimal Bulk Malignant Mesothelioma (Mesothelioma in Situ/early Mesothelioma). Case Discussion: Diagnostic difficulties in effusion cytology include the following: Recognizing a reactive effusion Distinguishing reactive from malignant mesothelial cells Distinguishing mesothelioma from adenocarcinoma Benign mesothelium Quiescent mesothelium: A monolayer of flattened sheets with epithelial features (classic example are sheets seen in pelvic washes) Cells break off as single cells or in few small groups Round to oval cells, 15-20 µm in diameter Cytoplasm is moderate in amount, translucent, and contain peripheral vacuoles containing glycogen Long slender microvilli under light microscopy appear as a pale zone at the periphery causing a fuzzy or a brush like appearance. The central portion of the cytoplasm is denser and darker due to the perinuclear intermediate filaments resulting in a two- tone or endo-ectoplasmic demarcation. Cells may be single or binucleated Nuclei are monotonous, centrally located, and oval to round, with evenly distributed chromatin. Nucleoli are indistinct Occasional cells exhibit the characteristic "window" and "cellular clasping" appearance Reactive/hyperplastic/hypertrophic mesothelium Shed as doublets or triplets with windows between them. Few papillary groups may be formed Connections by clasp-like articulations are more obvious Cells are round to oval, 20-40µm in diameter Abundant cytoplasm with endo-ectoplasmic demarcation and peripheral submembranous vacuoles Cytoplasmic protrusions distal to cellular connection Nuclei are round to oval with some variation in size and chromatin distribution. The cell size may vary slightly, however, within a small range and only few cells will appear out of proportion. Nucleoli may become prominent Multinucleated cells increase Occasionally intranuclear inclusions are noted Causes of mesothelial hyperplasia Heart failure Infection (pneumonia, lung abscess) Infarction (may shed in sheets) Liver disease such as hepatitis or cirrhosis (may cause pronounced hyperplasia) Collagen disease Renal disease such as uremia or peritoneal dialysis Pancreatic disease Radiation (split field, tandom ovoids) Chemotherapy (bleomycin, cytoxan) Traumatic irritation (hemodialysis, surgery) Chronic inflammation (PID, pleuritis) Underlying neoplasm causing irritation of the mesothelium (fibroid) Foreign substance (talc, asbestos) Note: Hyperplasia and hypertrophy with papillary formation may be so pronounced and may mimic malignancy (mesothelioma or adenocarcinoma). Malignant mesothelioma Malignant mesothelioma is a rare disease with an average incidence of 2 cases per 1 million people per year in the United States. However it is extremely important to recognize it since mesothelioma has different therapeutic implications from other tumors. In addition, its recognition will spare the patients repeated procedures such as core biopsies that frequently carries the risk of seeding along the needle tract. Malignant mesothelioma may result into a very cellular fluid; however it is not unusual to obtain a fluid with low or scant cellularity. The increase in cell size is one of the most prominent features in mesothelioma (attain a gigantic size). Gross appearance: Early stage: appears as hundreds of tiny nodules on the serous membrane. Pleural thickening and plaques are noted when associated with asbestos exposure. Late stage: nodules become confluent and the serosal membrane becomes thick and gradually the parietal and visceral membranes become fused together, with disappearance of any fluid. Types of mesothelioma: Epithelioid (tubulopapillary, well differential papillary, epithelioid, transitional, deciduoid, clear variant, microcystic, and small cell) Sarcomatous Biphasic Anaplastic Epithelioid variant is the most common type seen in effusion cytology particularly the first three patterns. The correct diagnosis involves two steps: First, recognize the mesothelial origin Second: recognize their malignant features How to recognize a mesothelioma Highly cellular smears All cells look alike, i.e. no evidence of two cell population Cellular spheres with smooth borders (morules) Tight and loose clusters with scalloped borders High number of cells within the clusters Individual cells show a wide variation in size and shape ranging from small to gigantic. Large multinucleated cells with abundant cytoplasm, some of these cells approach the size of small morules Mesothelial cell features are easily recognized and exaggerated Yellow glycogen is frequently detected Nuclei are usually bland or slightly atypical (nuclear irregularity, coarse chromatin and hyperchromasia). Very prominent nucleoli Background of numerous lymphocytes or abundant blood Thick extracellular matrix (hyaluronic acid) is frequently present causing a grossly recognized thick consistency described as "Tar-like" or Honey-like". This matrix can sometimes interfere with smear preparation particularly Liquid based Preps. Notes to remember Not all malignant mesothelioma fluids are cellular Although highly associated with asbestos exposure, one third of the cases are not, and in many the history is not given to us. Mesothelioma effusions are large, unilateral and recur fast and frequently A low cellularity on a repeated tap within a short interval does not exclude mesothelioma Some mesotheliomas manifest mainly as single large cells. These cells exhibit all the features described above Differential diagnosis usually involves one of two patterns: Atypical cells mostly presenting as single cells with few groups Atypical cells mostly presenting as cellular spheres Differential diagnosis of effusions with papillary clusters or balls: Breast carcinoma Ovarian carcinoma Lung adenocarcinoma Prostatic adenocarcinoma (very rare) Poorly differentiated squamous cell carcinoma Malignant mesothelioma Florid reactive mesothelium Differential diagnosis of effusions with large single cells: Lung adenocarcinoma Breast carcinoma Pancreatic adenocarcinoma Renal cell carcinoma Malignant melanoma Malignant mesothelioma Reactive mesothelium How to approach the diagnosis: Is there one or two cell population? Are the cells monotonous in appearance (look-alike) or pleomorphic (wide variation in shape and atypia)? Are the atypical cells within a small size range or is there a wide variation in size? Do the cells exhibit a two tone cytoplasm, vacuolated, dense, etc..? Are the nuclei highly atypical or not? Features favoring a reactive mesothelium: One cell population with monotonous appearance Atypia is not very pronounced Cellular clusters may be present but not as tight as spheres Little variation in size or shape of cells Classic features of mesothelium including cytoplasmic glycogen Features favoring adenocarcinoma: Pleomorphic population of cells with obvious atypia Little variation in size of cells Two cell population (background reactive mesothelium) may be detected Lack of two tone cytoplasm Cytoplasmic glycogen rarely seen (lung adenocarcinoma) True gland formation may be seen in some clusters Features favoring malignant mesothelioma: Monotonous cell population with mild to moderate atypia Morules and numerous discohesive cells Numerous multinucleated giant mesothelial cells Markedly enlarged cells (5-10 times that of normal mesothelium) Background cells show a wide range of size Features indicative of mesothelial origin Review of the Literature/Treatment Options: The concept of mesothelioma in situ was introduced by Witaker et al. in 1992. They describe its diagnostic feature as follows: Diagnosis of malignant mesothelioma proven at some stage of the development of the disease. No gross tumor at time of open thoracotomy or pleuroscopy (sand spots or nondescript pleural thickening was acceptable). No tumor identified radiologically. Of the seven cases they describes six underwent thoracocentesis, four of which were diagnosed as malignant mesothelioma and two as reactive. Microscopically this entity was characterized by: Papillary and tubulopapilary arrangements with surface extensions projecting towards the serosal cavity. Large mesothelial cells with atypical nuclei, i.e. mesothelioma in situ Disease largely localized to the surface with foci of invasion into the submesothelial surface. In 1998 Henderson et al further defined this entity as a minimal bulk mesothelioma. The defined mesothelioma in situ as: a) replacement of benign surface mesothlium by cells that have cyto-architectural features of malignancy, and b) all but one case had areas of microscopic invasion. Diagnostic criteria for minimal bulk mesothelioma: Abnormal architecture at the surface msothelium cytologic atyia Absence of exudative inflammation. Conclusion(s): The diagnosis of malignant mesothelioma can be rendered by cytologic examination of the fluid utilizing both morphologic features and immunostains. In rare cases malignant mesothelioma can still be diagnosed on fluids despite the absence of radiologic findings. References: Tao LC. Cytopathology of Malignant Effusions. In ASCP Theory and Practice of Cytopathology 6, Edited by W.W. Johnston, 1996, American Society of Clinical Pathologists. Bedrossian CWM. Malignant Effusions: A Multimodal Approach to Cytologic Diagnosis. 1994. Igaku-Shoin Medical Publishers Inc. New York, NY. Whitaker D, Maims F, Henderson D, Shilkin K. The concept of mesothelioma in situ: Implications for diagnosis and histogenesis. Seminars of Diagnostic Pathology1994;9:151-161. Henderson D, shilkin K, Whitaker D. Reactive mesothelial hyperplasia vs mesothelioma, including mesothelioma in situ. Am J Clin Path 1998;110: 397-404. Cury PM, Butcher DN, Corrin B, Nicholson. The use of histological and immunohistochemical markers to distinguish pleural malignant mesothelioma and in situ mesothelioma from reactive mesothelial hyperplasia and reactive pleural fibrosis. Journal of Pathology;189:251- 257. Simon F, Jobmen G, Krismann M, Muller K-M. Chromosomal alterations in early stages of malignant mesothelioma. Virchows Arch 2005;447:762-767.