​Clinical History: A 33-year-old male with underlying retroviral disease presented with altered behavior. Biopsy of the brain lesion. One representative section.

Educational notes:
1. The brain tissue fragments show necrotizing cerebritis with large areas of necrosis containing eosinophilic cellular debris. There are foci of mixed acute and chronic inflammatory infiltrates and perivascular inflammatory infiltrates. Extracellular microorganisms and rare pseudocysts are observed, morphologically consistent with free tachyzoites and bradyzoites of Toxoplasma gondii.
2. Most common differential diagnoses for intracranial lesions of AIDS patients are primary central nervous system lymphoma, progressive multifocal leukoencephalopathy, cerebral toxoplasmosis and HIV encephalitis. In this brain tissue biopsy, microorganisms with the size less than a lymphocyte are identified. Histoplasma capsulatum and Toxoplasma gondii are the main differentials. Morphologically, the former is distinguished from the latter by presence of fungal cell wall in the form of halo in H&E stain. This could be highlighted by GMS and PAS special stains. Toxoplasma gondii may be difficult to be recognized due to resemblance to cellular debris. Immunohistochemistry against Toxoplasma gondii is helpful.

​Reference 1. Lee, Ashley M., et al. "Safety and diagnostic value of brain biopsy in HIV patients: a case series and metaanalysis of 1209 patients." Journal of Neurology, Neurosurgery & Psychiatry 87.7 (2016): 722-733. 2. Kradin, Richard L. Diagnostic Pathology of Infectious Disease. Elsevier Health Sciences, 2017.

Educational notes:
1. Section shows tumor tissue fragments composed of bizarre malignant cells with angulated hyperchromatic nuclei and abundant cytoplasm. Numerous multinucleated tumor giant cells are admixed. Mitoses are easily observed. The adjacent glial tissue is focally infiltrated by malignant
cells. Immunohistochemistry shows the malignant cells are positive for GFAP and negative for pan-cytokeratin and HMB-45. Histological findings are consistent with giant cell glioblastoma, WHO grade IV. (Note: Without IDH evaluation, a diagnosis of glioblastoma, NOS, is more appropriate, vide infra)
2. The 2016 World Health Organization Classification of Tumors of the Central Nervous System employs integrated phenotypic and genotypic parameters for tumor classification. Glioblastomas are classified into (1) glioblastoma, IDH-wildtype (about 90 %), which corresponds to the clinically defined primary or de novo glioblastoma in older patients; (2) glioblastoma, IDH-mutant (about 10%), which corresponds to secondary glioblastoma with a history of prior lower grade diffuse glioma in younger patients, and (3) glioblastoma, NOS, a diagnosis for those tumors that IDH
evaluation cannot be performed.
3. Along with gliosarcoma and epithelioid glioblastoma, giant cell glioblastoma is a variant under the umbrella of glioblastoma, IDH-wildtype. Histologically, it is characterized by bizarre, multinucleated giant cells and an occasionally abundant reticulin network. Palisading and large
ischaemic necroses are observed. Atypical mitoses are frequent. Microvascular proliferation is not common. Giant cell glioblastoma has a somewhat better prognosis than ordinary glioblastoma.
Reference:
1. World Health Organization. (2016). WHO Classification of Tumours of the Central Nervous System Revised 4th Edition. David N. Louis, (Ed.). Internat. Agency for Research on Cancer.

​HISTORY: 68/Male/Presented with patches and plaques at trunk, UL, LL with tumour-like lesion at thigh

1) Section from the left thigh punch biopsy shows diffuse dermal infiltration by large neoplastic lymphoid cells arranged in solid sheets. The cells display moderate to markedly pleomorphic vesicular nuclei with prominent multiple nucleoli. The cytoplasm is eosinophilic and ample in amount. Mitotic figures are frequently seen.
Occasional histiocytes and small reactive lymphocytes are appreciated in the background.
The overlying epidermis shows marked acanthosis and parakeratosis with prominent lymphocyte epidermotropism and Pautrier microabscesses. No angio-invasion or angio-destruction is seen.
2) Immunohistochemistry study shows the neoplastic lymphoid cells are immunoreactive (+) for CD2, CD3 and CD5, with aberrant loss in CD7 and CD8. CD4 is positive (+) in a significant number of cells. CD30, ALK-1 and CD20 are negative (-). The proliferative index as estimated by Ki67 is high (>90%).
3) The evolution of patches and plaques followed by tumoral stage further supports the diagnosis of large cell transformation Mycosis fungoides (MF).
Transformation MF is defined by: -
1. Presence of 25% blastic cells (large cells, 4x reactive lymphocytes).
2. Discrete tumour cell nodule. CD30 positive cells are only seen in ~ 30-50% of cases and is not required in making the diagnosis.
4) MF is defined as epidermotropic PCTCL of small to medium-sized T lymphocytes with cerebriform nuclei. The term should only be used for classical cases (i.e evolution of patches, plaques, and tumours + variants with a similar clinical course).
5) MF is the most common subtype of CTCL, accounting for approximately half of all cutaneous lymphomas. Patients with MF most often experience a protracted clinical course in which disease patches, plaques, and tumors develop over several years or even decades.
6) Some patients, however, undergo a process of large-cell transformation (LCT) which may be characterized by a more aggressive disease course and shortened survival. Early recognition of the clinical clues associated with LCT allows the dermatologist to diagnose this entity earlier and offer patients more aggressive treatment regimens.
7) The prognosis of LCT is reportedly worse than classic MF, and the median survival from diagnosis of LCT has been cited as 37 months for patients with LCT compared with 163 months for those with more classic MF without LCT.
Other studies have reported median survivals as low as 1 month.
REFERENCES:
• Mc Kee’s Pathology of The Skin
• E. Olsen et al. Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC). Blood (2007)
• B. Vergier et al. Transformation of mycosis fungoides: clinicopathological and prognostic features of 45 cases. French Study Group of Cutaneous Lymphomas. Blood (2000)
• WHO Classification of Skin Tumours. WHO Classification of Tumours, 4th Edition, Volume 11. Edited by Elder DE, Massi D, Scolyer RA, Willemze R