Section 5 -

If It Looks Like A Tumor, But It Isn't... Paul Van der Valk

With the striking progress of imaging of brain lesions diagnostic accuracy has gone up remarkably; for some diseases, for instance multiple sclerosis, imaging has revolutionized the diagnostic process. However, occasionally the radiology (or the radiologist) is wrong by suggesting a tumorous process and subsequent biopsy shows a benign or reactive lesion. So great is the trust in the imaging that considerable forces of persuasion of the pathologist may be required to convince the clinician. Also, often the pathologist him- or herself needs to be convinced. Therefore, it is good to call attention to those lesions the surgical neuropathologist is confronted with that are clinical mimics of tumors. Any attempt to be complete in this area is futile, but in general there are several groups of conditions that should be considered here, 1) infectious diseases, 2) demyelinating diseases, and 3) other conditions. Each of these categories will be discussed, with diagnostic pointers and techniques, again without attempting to be exhaustive. 1) Infectious diseases . The array of infectious diseases in the CNS is huge, but relatively few will be biopsied (with any frequency) under suspicion of a neoplastic process. Bacterial inflammation/abcesses can look deceptively like tumors on imaging. Some newer imaging modalities (diffusion-weighted MRI) can help in distinguishing between these two entities, but nevertheless, this may be difficult. Biopsies often easily reveals the true nature of the lesion, but in longer-standing abcesses the brain tissue surrounding the necrotic center can cause difficulties, in that neutrophils can be scarce and the reactive gliosis can exhibit some degree of cytonuclear atypia. However, reactive astrocytes are usually relatively regularly distributed in the tissue (a fact best appreciated on low magnification), in contrast to the haphazard localization of tumorous astrocytes. Granulocytes are occasionally present in necrotizing tumors, but this is relatively unusual, so any lesion with more than a few granulocytes should trigger the consideration of an inflammatory lesion. Viral infections, especially herpesviruses, can cause a densely cellular picture, due to increase of lymphoid and activated microglial cells. Though lymphocytes resemble oligodendrocytes the rather wild histology (caused by the many rod-like microglial cells) will immediately suggest an inflammatory process, not the more histologically "quiet" oligodendroglioma. The viral infection progressive multifocal leukoencephalopathy (PML) is more of a demyelinating disease (see under 2)) Parasitic infections with necrosis can be bothersome when a biopsy specimen shows predominantly necrosis (toxoplasmosis!); as was mentioned, a few tumors have infiltrates with granulocytes. Of course, a necrotizing tumor is a glioblastoma that mostly will show marked nuclear atypia, in excess of that seen in inflammation. It is important to think of the possibility of an infectious disease early and reserve some tissue for microbiology and, on the paraffin sections, to look for micro-organisms and perform the appropriate stains or PCR's to demonstrate them.. 2) Demyelinating diseases Any demyelinating disease causes accumulations of foamy macrophages, that are usually quickly recognized, but occasionally can look like astrocytic cells. Also, in any demyelinating disease, astrocytes can show even marked atypia and mitotic figures, including atypical mitoses. Together with the increased cellularity a glioma becomes a serious consideration. However, in gliomas large numbers of foam cells are (very) unusual, so demonstration of the macrophage origin with special stains (Oil red O, CD68, other macrophage markers) will argue for a benign, demyelinating condition. If there is a sharp drop in cellularity, suggesting the edge of the lesion a myelin stain can be helpful: a sharp border of demyelination strongly suggests a demyelinating disease. Again, it is important to be aware of this possibility and to consider it, even when the clinicians are convinced this is a tumor (the radiological picture can really closely resemble a glioblastoma!). Of course, in multiple sclerosis the MRI usually shows many more, smaller "white" lesions, but a solitary MRI lesion does not rule out multiple sclerosis and there are solitary demyelinating lesions, of unknown origin. Classification of such demyelinating lesions on histology alone is not possible. PML, mentioned earlier can be demonstrated with immunohistochemistry and/or molecular biology and of course presents in a typical clinical background of immune suppression. But, under circumstances, the immunesuppression may be mild and have gone unnoticed. 3) Others There is a number of diseases that may present with cerebral lesions; especially hypercellular conditions can be troublesome. In many cases the offending cell type is a histiocyte (sarcoidosis, Erdheim-Chester disease, malakoplakia, a.o.) and most of the consideration mentioned under 2) can be cited here as well, including astrocytic atypia. Demonstration of the involved cell type is vital. In summary, a number of important remarks can be made; Consider a non-neoplastic disease if you cannot easily classify the lesion as a tumor, or if something is not quite right (the atypia is limited to scattered cells, the degree of atypia does not match with the cellularity, and so on) Always keep the consideration of an inflammatory lesion in the back of the mind Look for micro-organisms and stain for them. Some excellent antibodies are available Do a myelin stain when an "edge" presents itself If there is any doubt about the predominant cell type characterize them using immunohistochemistry (GFAP, CD68, MIB-1). A high number of histiocytic cells argue for a reactive lesion. Large numbers of granulocytes usually also argue for a benign lesions, though exceptions occur! A few references on this subject: The Brain: Inflammatory disorders. Chapter 3 from Surgical Pathology of the nervous system and its coverings. P. C. Burger, B. W. Scheithauer, F. S. Vogel. Churchill Livingstone, Philadelphia, 2002 Jain D, Rajesh LS, Vasishta RK, Radotra BD, Banerjee AK. Demyelinating disease simulating brain tumours: a histopathologic assessment of seven cases. Indian J. Med. Sci. 2006; 60: 47-52 Comi G. Multiple sclerosis: pseudotumoral forms. Neurol. Sci. 2004; 25 suppl.4: S374-9 Chang SC, Lai PH, Chen WL, Weng HH, Ho JT, Wang JS, Chang CY, Pan HB, Yang CF. Diffusion-weighted MRI features of brain abscess and cystic or necrotic tumors: comparison with conventional MRI. Clin. Imaging 2002; 26: 227-36