2020 NPA Minisymposium

This minisymposium was originally published in 2020. The information provided in this minisymposium was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this minisymposium.

While brain neoplasms are the most common diagnoses in the practice of surgical neuropathology, occasionally patients present with lesions radiographically suggestive of neoplasm which turn out to be nonneoplastic. These include mass-forming lesions of vascular, inflammatory, demyelinating and infectious etiologies, and accurate diagnosis is crucial for adequate treatment and prognostic evaluation. Many of these entities represent a challenge to the pathologist, in part because they tend to be uncommon, making them less likely to encounter during one’s clinical practice and thus harder to recognize. Imaging advances, however, have been increasingly effective at identifying specific characteristics for some of these mimickers, and in many cases biopsies can be avoided. Being familiar with the most frequent pseudoneoplastic disorders of the CNS and their clinical, radiological, and histopathological features will benefit the pathologist confronted with one of these challenging differential diagnoses.

Vascular Mimickers of Neoplasms in the CNS

In the era of advanced imaging technologies, vascular-related lesions only rarely are mistaken for CNS neoplasms. Diagnostic biopsies, however, do occur for entities like CNS infarcts or vascular malformations. Vasculitis and amyloidomas are more difficult to assess on imaging and also sometimes get biopsied to establish a diagnosis. The pathologist must be on-guard at all times, and especially at intraoperative consultation, for nonneoplastic conditions in submitted biopsies/resections.

CNS infarcts can have a wide variety of appearances on imaging studies depending on age and presence or absence of necrosis or hemorrhage. MRI can generally distinguish an infarct from a high-grade neoplasm based on different sequences and radiographic characteristics. However, infarcts can show significant mass effect and variable enhancement on imaging, similar to neoplasms. When an infarct does get biopsied the pathologist should first rule out neoplastic, autoimmune, or infectious disease based on architectural and cytopathological characteristics with aid of IHC/special stain techniques. The findings of hypoxic-ischemic change to neurons (shrunken with eosinophilic cytoplasm and pyknotic nuclei), edema, mixed inflammation, and/or necrosis/hemorrhage in the absence of neoplasm or infection should prompt consideration for infarct. Vascular amyloid deposition, hyalinization, or thrombosis could support an infarct. Often the differential is with glioblastoma, which can have significant hemorrhage, necrosis, and mixed acute and chronic inflammation. Vascular proliferation may be present in infarct as growth of multiple capillaries, which typically differs from the multilayered endothelial proliferation seen in glioblastoma. The presence of macrophages in a biopsy without overtly neoplastic cells raises the possibility of infarct rather than neoplasm. If only necrotic tissue is present in the biopsy/resection, that should be stated and accompanied by a differential diagnosis discussion within the comment.

Vascular lesions, such as arteriovenous malformations (AVMs), capillary/cavernous hemangiomas, and aneurysms, can present clinically like neoplasms with focal or diffuse neurological signs/symptoms and, rarely, may mimic neoplasms on CT/MRI. They can be partially thrombosed and may show enhancement and surrounding vasogenic edema on imaging studies. Vascular lesions may occur in the skull, meninges, CNS parenchyma, and occasionally intraventricularly. They also can produce infarcts, hemorrhage, and gliosis in the vicinity. Fairly characteristic histopathological changes to the vessels (such as “arterialized” veins with thickened walls which may be highlighted by an elastin stain) and surrounding tissue may help to establish the diagnosis and distinguish vascular lesions from neoplasm.

Vasculitis (or angiitis) of the CNS is often associated with systemic rheumatologic disease such as systemic lupus erythematosus (SLE) and can be focal or diffuse in the brain and spinal cord. Ischemic and hemorrhagic strokes may accompany the vasculitis. Imaging studies may show mass-like lesions with varying degrees of edema, hemorrhage, and enhancement. Granulomatous angiitis can be seen in severe forms of primary angiitis of the CNS (PACNS) and may also present with mass lesions. In some cases, vasculitis may be associated with amyloid deposition (Aβ-related angiitis). Biopsy may be necessary to distinguish vasculitis from CNS lymphoma which can have similar appearance on imaging studies. On biopsy of vasculitis, infiltration and damage of blood vessels are hallmarks. Perivascular accumulation of lymphoid cells can also occur and can mimic CNS lymphoma angiocentricity. IHC, molecular studies, and/or flow cytometry should be employed to rule in/out diagnosis of lymphoma. If granulomatous inflammation is present, special stains (GMS, AFB, Warthin-Starry) may be used to investigate for organisms, and Congo red or beta-amyloid IHC should be employed to rule out amyloid.

Amyloidoma can present in the brain or spinal cord parenchyma or surrounding meningeal tissues. It may present with clinical symptoms/signs associated with a mass lesion in the given location. It is often associated with light chain deposition and should prompt investigation for an underlying hematologic malignancy. Amyloidoma can be difficult to diagnose on CT or MRI and may or may not have evidence of surrounding hemorrhage and edema. Biopsy/resection reveals extracellular accumulation of amyloid that can be confirmed by IHC or Congo red.

Infectious Mimickers of Neoplasms in the CNS

Abscesses of the CNS can present as space-occupying lesions focally or multifocally and may mimic many features of primary or metastatic neoplasia. A wide variety of organisms can infect the CNS and result in abscess formation. Diffusion-weighted MR images (DWI) may show hyperintense signals within abscesses due to the high viscosity of pus compared to necrotic tissue which is less viscous and shows hypointensity. Spectroscopy may also help to distinguish tumor from pus. Unfortunately, overlapping radiologic findings exist between infectious abscesses and glioblastoma or metastatic disease; all can show ring-enhancement. Based on clinical features, empirical treatment may be initiated without CNS surgical intervention. However, surgery may be necessary to decompress a lesion, to obtain tissue for culture, or to establish a diagnosis. Pyogenic abscesses can occur in the setting of chronic obstructive pulmonary disease, congenital heart defects, sepsis, direct inoculation after trauma, or endocarditis, as examples. Pyogenic abscesses can occur in all clinical settings and not just with immunocompromised patients. Biopsies of abscesses typically show acute and chronic inflammation, necrotic tissue, and a gliotic/fibrous wall depending on age of the abscess.

Individuals who are immunocompromised due to age, cancer, treatment with a variety of anti-cancer or rheumatologic therapies, or due to congenital or acquired immune compromising diseases are particularly susceptible to CNS infections (meningitis, encephalitis, abscesses). Immunocompromised patients are more susceptible to CNS lymphoma and opportunistic organisms such as toxoplasmosis or fungal diseases that can be difficult to differentiate on imaging and may require biopsy. Similarly, fungal infections from species like Cryptococcus and Aspergillus or parasites like Taenia solium causing cerebral cysticercosis can develop into abscesses with inflammation, hemorrhage, necrosis, and mass effect. Granulomatous masses caused by mycobacterial infections (tuberculoma/tuberculous abscess) or spirochetes (syphilitic cerebral gumma) can also be seen in immunocompromised patients and be mistaken for CNS neoplasms.

Viral encephalitis can mimic CNS neoplasms, particularly lymphoma. Progressive multifocal leukoencephalopathy (PML), a condition caused by reactivation of JC virus with inflammation and demyelination, is a common mass-forming CNS viral infection. PML lesions tend to show mild-to-moderate mass effect and can demonstrate irregular peripheral enhancement in the context of IRIS (immune reconstitution inflammatory syndrome). Immunostaining can identify the JC virus within infected glial cells and readily distinguishes PML from other demyelinating diseases such as acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) or neoplasms such as lymphoma or glioma. Herpes simplex virus and cytomegalovirus infections, especially when focal, can appear similar to lymphoma by imaging and clinical symptoms. As with vasculitis, there can be variable mixed inflammation, hemorrhage, and necrosis.

Demyelinating and Inflammatory Mimickers of Neoplasms in the CNS

An entity frequently misdiagnosed as glioma is tumefactive demyelination, which presents as a mass-forming lesion, usually large (>2 cm), involving a cerebral hemisphere with concerning radiological qualities. It is characterized by contrast enhancement with mass effect out of proportion to the size of the lesion. A pattern of incomplete ring-enhancement with the opening oriented towards the cortex (“horseshoe ring”) is relatively specific in differentiating this entity from high-grade glioma. Additional MRI sequences, such as DWI and spectroscopy, can also be helpful in distinguishing the two by suggesting increased cellularity and showing neoplastic metabolic spectra in gliomas. Microscopic hallmarks of active demyelination include abundant foamy macrophages containing myelin debris (demonstrated with myelin stains), sharp lesional demarcation, variable lymphocytic infiltrates, and relative preservation of axons (using neurofilament IHC or silver techniques). If the inflammatory component is exuberant, the diagnosis of CNS lymphoma may be entertained, but IHC to exclude a neoplastic B-cell population is sufficient in most cases. Astrocytes typically admixed with the inflammatory cells can be numerous and show significant nuclear atypia, and caution should be used when considering the diagnosis of astrocytoma in a lesion with frequent macrophages. Creutzfeldt cells, astrocytes with abundant cytoplasm and fragmented nuclei, and granular mitoses are frequently seen in demyelinating lesions. Thus, smears or touch preparations showing foamy macrophages should lead the pathologist to entertain the possibility of demyelination or infarct and caution against a diagnosis of tumor intraoperatively despite the presence of astrocytic atypia. Of note, a steroid-treated lymphoma may resemble demyelinating disease.

Sarcoidosis should be entertained when assessing CNS masses in any location, particularly cranial nerves, meninges, and sellar region (hypothalamus and neurohypophysis). In patients with isolated neurosarcoidosis, biopsy can prove essential for an adequate diagnosis and establishing therapy. Nonnecrotizing granulomas with multinucleated giant cells associated with gliosis are the characteristic histopathological features. By definition, sarcoidosis is a diagnosis of exclusion, and other causes should be ruled out.

Lymphocytic hypophysitis is an autoimmune disorder that can mimic pituitary adenoma clinically and radiologically, so encountering this on a biopsy is possible. Microscopic features include infiltration of the adenohypophysis by T-cell predominant lymphocytes with occasional formation of germinal centers and scattered plasma cells and macrophages. Importantly, pathologists considering a diagnosis of lymphocytic hypophysitis should first rule out a germ cell tumor (using IHC for OCT3/4 or SALL4, for example), given that germinoma in this location can show florid inflammation with few neoplastic cells, and the therapeutic approach is radically different. Granulomatous inflammation in the pituitary may also be seen in association with germinomas or as the main pathology in granulomatous hypophysitis.

A number of inflammatory mimickers of neoplasia show a predilection for the meninges, including vasculitides and autoimmune disorders. Clinical presentations include headaches, cranial neuropathies, and increased intracranial pressure for most cases. Rheumatoid arthritis can present with leptomeningeal or dural-enhancing lesions which histopathologically demonstrate the typical rheumatoid nodules characterized by lymphoplasmacytic inflammation, collagen necrobiosis with neutrophilic cellular debris, and palisading histiocytes with occasional multinucleated giant cells. A substantial proportion of so-called idiopathic pachymeningitis is now better understood as IgG4-related hypertrophic pachymeningitis, which may or may not be associated with involvement of other organs. Morphologically, the findings in the meninges are similar to those seen in systemic IgG4-related sclerosing disorders, including storiform fibrosis and prominent IgG4-positive plasma cells; obliterative phlebitis is typically not seen in these lesions in the CNS. Other heterogeneous inflammatory mass-forming lesions in the meninges have been named inflammatory pseudotumor and plasma cell granuloma, sometimes interchangeably. These must be differentiated from low-grade lymphoma and inflammatory myofibroblastic tumor, a spindle cell lesion that is rare in the CNS and typically associated with ALK-1 abnormalities. Additional lymphocyte- and histocyte-rich conditions involving the meninges include Castleman disease and histiocytoses such as Rosai-Dorfman disease, Langerhans cell histiocytosis, and Erdheim-Chester disease which frequently carry somatic MAPK pathway mutations and are now considered neoplastic entities.

Miscellaneous Mimickers of Neoplasms in the CNS

One of the most frequent, relevant, and challenging differential diagnoses in patients with a history of CNS neoplasm is the distinction between tumor recurrence and radiation injury. Unsurprisingly, these processes have radically different treatment approaches. Pseudoprogression is typically self-limited and occurs within three to six months posttherapy, while late delayed radiation necrosis arises months to years posttherapy. Both can present as space-occupying lesions, frequently centered in the surgical tumor bed, with contrast enhancement. New MRI modalities, including spectroscopy, can contribute to the presurgical distinction, but often tissue diagnosis is required. More often than not, a mixture of radiation-induced (treatment-related) changes and variable amounts of cellular tumor are present. It may be relevant for clinical management to know what the proportions of each are in a surgical sample. Classic radiation-induced histology includes large areas of geographic coagulative-type necrosis, dystrophic calcifications, prominent vascular injury with hyalinization and fibrinoid necrosis, rarefied and gliotic surrounding white matter, histiocytic infiltrates, and low proliferation index. Cytologic atypia can occur with bizarre nuclei and abundant cytoplasm, but frequent mitoses, high cellularity, high nuclear:cytoplasmic ratios, microvascular proliferation, and palisading necrosis are all features only seen in recurrent glioma.

Malformative and hamartomatous conditions in the CNS may present as mass lesions and frequently are associated with seizures when located in the cortex. The most common problem is differentiating these from low-grade glial or glioneuronal tumors, such as ganglioglioma or diffuse astrocytoma. Isolated, sporadic, epilepsy-associated lesions of the cortex include the classic malformation of cortical development known as focal cortical dysplasia (FCD), which may expand the cortex and blur the gray-white junction. Histological characteristics can be subtle and include cortical architectural disarray and cytologic abnormalities. By contrast, ganglioglioma demonstrates higher cellularity, binucleate dysmorphic neurons, a low-grade neoplastic glial component, and frequent BRAF V600E mutations. Most diffuse astrocytomas will demonstrate IDH mutations, and the residual cortical neurons should not be dysmorphic. It is important, however, to note that FCD can coexist with neoplastic and other localized lesions. Cortical tubers, a main feature of tuberous sclerosis, are histologically indistinguishable from FCD but they are usually multiple and associated with other CNS and non-CNS lesions or a family history of the disorder. In Cowden syndrome, a characteristic cerebellar lesion called Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum) can represent a diagnostic challenge, particularly when arising as an isolated lesion in an adult patient. MRI demonstrates characteristic focal expansion of a cerebellar hemisphere with alternating high and low signal. Histologically, enlarged and dysmorphic ganglion cells replace the internal granular layer, and there is relative preservation of the foliar architecture (which would be lost in neoplastic conditions such as ganglioglioma). Although listed in the World Health Organization classification, it is still unclear whether this should be considered a neoplastic or hamartomatous lesion. Meningioangiomatosis is a plaque-like cortical and leptomeningeal well-circumscribed lesion with a variably-cellular meningothelial and fibroblastic proliferation intertwined with prominent abnormal sclerotic vessels growing into the cortex with underlying gliosis, neurofibrillary tangles, and calcifications. Morphologic variation may account for this lesion resembling a vascular malformation or mimicking a meningioma. Most cases are sporadic, but meningioangiomatosis can arise in the context of neurofibromatosis type 2, and, in that case, it can be multifocal and associated with small glial microhamartomas (hamartia) in the surrounding cortex.

An unusual mass-forming process of uncertain etiology, calcifying pseudoneoplasm of the neuraxis (CAPNON) is a densely-calcified to ossified lesion usually associated with the leptomeninges and/or adjacent bone. CAPNON can be lobulated and show peripheral ring enhancement on MRI. Histologically, there are confluent, densely-calcified, relatively acellular amorphous basophilic nodules with surrounding radially-arranged epithelioid cells, occasionally adjacent inflammation including multinucleated giant cells, and piloid gliosis. The prognosis is excellent with surgical excision considered curative.

Since primary CNS tumors can display prominent cystic change, it is worth mentioning some of the cystic nonneoplastic lesions that fall into the differential diagnosis. Readily identifiable by location, pineal cyst is a common finding in autopsy cases. It can also come to clinical attention when identified in the setting of neurological symptoms such as headache. The cyst wall is characteristically formed by compressed gliotic parenchyma with Rosenthal fibers and hemosiderin deposition, occasionally adjacent to residual pineal parenchyma. The most common diagnostic errors in this setting are pilocytic astrocytoma and pineocytoma. Lack of microcysts and characteristic glomeruloid vessels argue against pilocytic astrocytoma, and lack of pineocytomatous rosettes and sharp demarcation of pineal tissue from the cyst argue against pineocytoma. Epidermoid and dermoid cysts, frequently arising in the posterior fossa, can rarely be mistaken for papillary craniopharyngioma, given the shared presence of squamous epithelium. They, however, display mature keratinizing epithelium (epidermoid) with adjacent adnexal structures (dermoid) and lack BRAF V600E mutations typical of papillary craniopharyngioma. In the sellar region, Rathke’s cleft cyst is lined by ciliated, mucus-producing cuboidal to columnar epithelium with variable degrees of squamous metaplasia and must be differentiated from craniopharyngioma. Similar histologically to Rathke’s cleft cyst is neuroenteric (endodermal) cyst, most commonly seen along the spine or in the posterior fossa, which should be differentiated from true cystic teratoma (with more than one ectodermal/mesodermal/endodermal lineage tissue) and metastatic adenocarcinoma.

• Familiarity with potential mimickers in the diagnosis of tumor-like lesions of the CNS is essential for the pathologist to avoid diagnostic errors with significant consequences.
• Radiological, epidemiological, and clinical characteristics are useful in the diagnosis of these entities.
• Vascular etiologies (infarct) and infections are the most common causes of CNS tumor mimickers.
• Inflammatory conditions can present with intra-axial or meningeal-based lesions.
• Tumefactive demyelination is a commonly unrecognized and misdiagnosed entity.
• Intraoperative assessment of smear preparation can contribute to prevent diagnostic error: when foamy macrophages are present the diagnosis of glioma should be deferred.

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