2020 NPA-06

This case was originally published in 2020. The information provided in this case 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 case.

This 52-year-old man was found on the floor by co-workers, confused and aphasic. He was diagnosed with HIV infection roughly 10 years previously, and, at the time, treatment was deferred. Since then, he was lost to follow-up. Over the past three years, he noted a gradual, unplanned, 20-pound weight loss and near-daily nausea, with frequent vomiting. The patient was admitted to the hospital where lab studies revealed a CD4 count of 73. MR imaging showed a 2.5 x 1.5-cm rim-enhancing left temporal lobe mass felt to be suspicious for lymphoma or high-grade glioma. A resection of the lesion was performed, and the intraoperative frozen section diagnosis rendered was "atypical lymphoid infiltrate, highly suspicious for lymphoma."

Tissue Site
brain, temporal lobe

The whole slide image provided is an H&E-stained image of the brain from the left temporal lobe resection specimen.

The final diagnosis was toxoplasmosis based on the presence of detectable free tachyzoites (Image F, Image G, and Image H). However, the presence of well-preserved organisms was only a focal finding (Image H), and it was difficult to distinguish partially-degraded tachyzoites from nuclear debris in areas of necrotic brain and/or blood vessels (Image F and Image G); as such, IHC confirmation of toxoplasmosis was highly valuable (Image I). Encysted bradyzoites were not readily found in this specimen but are often encountered in severe infections (see Image J for example in different case). Other histologic clues to the diagnosis included the admixture of several histologic patterns: 1) infarct-like coagulative necrosis (Image C and Image D) with occasional abscess-like neutrophilic infiltrates; 2) an encephalitis-like inflammatory pattern including perivascular lymphocytes (Image E) and microglial nodules (see Image K for example in different case); and 3) vasculitis (Image C, Image D, and Image E). Given the single ring-enhancing mass identified on MR imaging (Image A), a neoplasm such as glioblastoma or CNS lymphoma was initially favored. This clinical mimicry of a neoplasm was further exacerbated by a frozen section misdiagnosis favoring lymphoma due to cytologic atypia in scattered reactive lymphoid and histiocytic cells (Image B). Nevertheless, the correct diagnosis became evident on permanent sections. The patient was subsequently treated with antimicrobial therapy, and follow-up MRI showed no evidence of residual infection one year after his brain biopsy (Image L).

Toxoplasmosis is caused by the obligate, intracellular, protozoal parasite, Toxoplasma gondii. Estimates of incidence suggest that over one-third of the world’s population has been infected, with seroprevalence at roughly 13% in the USA and up to 75% in other parts of the globe. The definitive host is the cat, with infection of the human intermediate host potentially occurring from exposure to oocysts in cat feces. More commonly, however, infection occurs from ingestion of undercooked meat that contains oocysts in the skeletal muscle of other intermediate hosts, such as cattle, sheep, and pigs. In the gut, the organism converts from encysted bradyzoites to rapidly dividing, free tachyzoites which then spread throughout the body, mostly to skeletal muscle, the eye, and the CNS. This acute primary infection is asymptomatic in most immunocompetent hosts but may also produce a self-limited infection clinically resembling mononucleosis. Nevertheless, acute infection is particularly harmful to the developing CNS of a fetus if transmitted by the mother during pregnancy (eg, congenital toxoplasmosis), constituting the first part of the commonly utilized “TORCH infections” acronym for serious congenital infections (Toxoplasmosis, Other such as syphilis, Rubella, CMV, HSV). TORCH infections often lead to tissue destruction with secondary microcephaly, hydrocephalus, and other developmental abnormalities. With an intact cellular immune system, the tachyzoites are mostly eliminated by the end of infection, although small subsets convert back to the more slowly dividing bradyzoite cysts which then hide from the immune system due to poorly-understood mechanisms, including shielding protozoal antigens behind the highly-glycosylated cyst wall. In the CNS, they can infect any cell type but are thought to mostly persist in a dormant state within neurons.

Reactivation disease or the latent infection form is often encountered many years after primary infection and typically afflicts severely-immunocompromised hosts; HIV-positive patients with low CD4 counts are particularly predisposed. Patients are at risk with CD4 counts below 200 and reach extremely high risk when they dip below 50. In the latent disease, bradyzoites once again convert into rapidly-dividing tachyzoites which then infect many different surrounding cell types, including blood vessels. The latter leads to characteristic necrotizing vasculitis, thrombosis, and secondary brain tissue necrosis seen histologically; this also explains the common ring-enhancing pattern on neuroimaging, and the term “toxoplasma abscess” is sometimes utilized. Perivascular lymphocytes, macrophages, activated microglia, and microglial nodules are other common inflammatory components, explaining the alternate terminology of “toxoplasma encephalitis.” Both tachyzoites and bradyzoites are easily recognized in tissue sections when well-preserved but are occasionally scarce or degenerated; IHC can therefore be extremely valuable for confirmation of the diagnosis in such cases. In patients treated with antibiotics prior to biopsy, organisms may be absent altogether. Also, rare examples of immune reconstitution inflammatory syndrome (IRIS) (eg, an HIV-positive toxoplasmosis patient that has not been previously compliant but then restarts antiretroviral therapy) show intense perivascular inflammatory infiltrates rich in CD8-positive T-cells.

Toxoplasmosis is one of the most common opportunistic infections in HIV-positive patients and is one of the disease-defining manifestations of AIDS. The typical MRI study reveals multiple ring-enhancing lesions with sites of greatest predilection being the basal ganglia, thalamus, and cerebral gray-white junctions. With a classic presentation, empiric antimicrobial therapy (combination of pyrimethamine and sulfadiazine, or co‑trimoxazole if sulfadiazine is not available) is typically instituted. A brain biopsy is usually only considered if the patient doesn’t respond to this therapy or presents with atypical features, one example being the presence of a solitary lesion as in the current case. The differential often includes neoplasia, especially an Epstein-Barr virus-driven, primary CNS diffuse large B-cell lymphoma, since, unlike their typically homogenously-enhancing counterparts in immunocompetent hosts, immunosuppression-associated lymphomas feature centrally necrotic ring-enhancing masses. Besides toxoplasmosis and CNS lymphoma, another common diagnosis on brain biopsy in AIDS patients is progressive multifocal leukoencephalopathy (PML), although most lack contrast enhancement on MR imaging unless there is superimposed IRIS. Histologically, PML is characterized by active demyelination with pale white matter, sheets of foamy macrophages, enlarged bizarre appearing astrocytic nuclei, and plum-colored intranuclear inclusions within large rounded oligodendrocyte nuclei, the latter corresponding to viral inclusions from the JC papovavirus. PML represents another opportunistic infection due to reactivation disease, and the virus is detectable in tissue sections using immunohistochemical or in situ hybridization stains.

Rare and unusual presentations of toxoplasmosis include diffuse encephalitis and ventriculitis/periventriculitis patterns. Despite diagnostic advances in neuroimaging and cerebral spinal fluid polymerase chain reaction detection, brain biopsy remains a relatively safe and sensitive diagnostic method, even in the current era of highly active antiretroviral therapy (HAART), which began in 1996. Both surgical and autopsy series have shown that cerebral toxoplasmosis has become far less common than in the pre-HAART era, but it still remains a relatively frequent finding even in the post-HAART era. Antimicrobial therapy is effective in 70% to 80% of patients, but, as with the innate immune response, this cannot completely eradicate the relatively resistant bradyzoite cysts.

• Cerebral toxoplasmosis can appear on MRI as a solitary, ring-enhancing mass that mimics a tumor, such as lymphoma or glioblastoma.
• Although toxoplasmosis is encountered much less often in the post-HAART era than during the pre-1996 AIDS epidemic, it remains one of the more common diagnostic considerations in neurosurgical specimens from HIV-positive patients, particularly those with CD4 counts below 200.
• The combination of infarct-like CNS necrosis, abscess, encephalitis, and/or vasculitis in an immunocompromised patient should always raise suspicion of cerebral toxoplasmosis.
• In some toxoplasmosis cases, intact organisms are only found focally or not at all on H&E-stained sections; therefore, IHC should be applied in all cases where it remains a diagnostic possibility.

1. Bowen LN, Smith B, Reich D, Quezado M, Nath A. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nat Rev Neurol. 2016;12(11):662-74.
2. Lee AM, Bai HX, Zou Y, et al. Safety and diagnostic value of brain biopsy in HIV patients: a case series and meta-analysis of 1209 patients. J Neurol Neurosurg Psychiatry. 2016;87(7):722-33.
3. Lummus S, Kleinschmidt-DeMasters BK. Predominantly periventricular necrotizing encephalitis due to toxoplasmosis: two unusual cases and review of literature. Clin Neuropathol. 2014;33(1):29-37.
4. Pittella JE. Pathology of CNS parasitic infections. Handb Clin Neurol. 2013;114:65-88.
5. Silva AC, Rodrigues BS, Micheletti AM, et al. Neuropathology of AIDS: an autopsy review of 284 cases from brazil comparing the findings pre- and post-HAART (highly active antiretroviral therapy) and pre- and postmortem correlation. AIDS Res Treat. 2012;2012:186850. doi:10.1155/2012/186850.
6. Wohlfert EA, Blader IJ, Wilson EH. Brains and brawn: toxoplasma infections of the central nervous system and skeletal muscle. Trends Parasitol. 2017;33(7):519-31.
7. Zhang J, Liu X, Fu K, et al. Diagnostic value and safety of stereotactic biopsy in acquired immune deficiency syndrome patients with intracranial lesions: systematic review and meta-analysis. World Neurosurg. 2017;98:790-9.