Pitfalls in Surgical Neuropathology
Moderators: Dr. Arie Perry and Dr. Richard A. Prayson
Case 5 -
If It Looks Like a Tumor, But It Isn't...
Paul van der Valk, M.D, Ph.D.
VU Medical Center
Amsterdam, The Netherlands
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.
Case 5 - Figure 1
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.
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..
- 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
- 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
- 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.
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.
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.
Diagnosis: Active inflammatory demyelinating disease
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
- 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