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REVIEW ARTICLE Imaging of Lymphomas Involving the CNS: An Update-Review of the Full Spectrum of Disease with an Emphasis on the World Health Organization Classifications of CNS Tumors 2021 and Hematolymphoid Tumors 2022 A. Pons-Escoda, P. Naval-Baudin, R. Velasco, N. Vidal, and C. Majós ABSTRACT SUMMARY: Lymphomas of the CNS are the second most frequent primary brain malignancy in adults after gliomas. Presurgical sus- picion of lymphoma greatly impacts patient management. The radiologic features of this tumor have been widely covered in the literature for decades, but under current classifications, mainly corresponding to the most common presentations of the most fre- quent type: primary diffuse large B-cell lymphoma of the CNS. Nevertheless, rarer presentations of this specific lymphoma and of other World Health Organization lymphoma subtypes with different imaging features are rarely treated. Moreover, important advances in imaging techniques, changing epidemiologic factors with relevant impact on these tumors (eg, immunodeficiency/dys- regulation), and recent updates of the World Health Organization Classification of CNS Tumors 2021 and Hematolymphoid Tumors 2022 may have rendered some accepted concepts outdated. In this article, the authors aim to fulfill a critical need by providing a complete update-review, emphasizing the latest clinical-radiologic features of the full spectrum of lymphomas involving the CNS. ABBREVIATIONS: ALK1/ALK¼ anaplastic lymphoma kinase positive and negative; CLIPPERS ¼ chronic lymphocytic inflammation with pontine perivascu- lar enhancement responsive to steroids; DLBCL ¼ diffuse large B-cell lymphoma; EBV ¼ Epstein-Barr virus; MALT ¼ mucosa-associated lymphoid tissue; NK ¼ natural killer; PSR ¼ percentage of signal recovery; WHO ¼ World Health Organization ymphomas of the CNS are the second most frequent primary the mostfrequenttype: primary diffuse large B-cell lymphoma Lbrain malignancy in adults after gliomas, accounting for 7% of (DLBCL) of the CNS, negative for Epstein-Barr virus (EBV). If rarer all malignant tumors. A presurgical suspicion of this tumor will presentations of this specific lymphoma or other specific subtypes greatly impact patient management. Corticoids should be avoided with different characteristic imaging features are considered, the before a definitive diagnosis is made, and prompt biopsy is recom- complexity increases, and it becomes a great mimicker with a chal- mended to prioritize chemoradiotherapy instead of tumor resec- lenging differential diagnosis. Also, important advances in imaging 2,3 tion, such as in the case of suspected glioblastoma. techniques, dynamic changes in epidemiologic factors with relevant The radiologic features of these tumors have been widely cov- impact on these tumors (eg, immunodeficiency/dysregulation), and ered in the literature in recent decades. Imaging characteristics of recent changes in the World Health Organization (WHO) classifi- 2 4 lymphomas may be considered typical, leading to a potential mis- cations of CNS and hematolymphoid tumors may have rendered 5-8 understanding of this tumor as a straightforward presurgical sus- some well-accepted concepts of the disease outdated. picion. Nevertheless, this is often far from the reality in daily The Research Ethics Committee of the Hospital Universitari practice. In fact, the typical appearance of lymphomas is currently de Bellvitge approved this article for publication (PR348/22). almost exclusively related to the most common presentations of WHO Classification of Tumors, 5th Edition Received December 6, 2022; accepted after revision January 19, 2023. Insights. Some basic concepts regarding WHO classifications need From the Radiology (A.P.-E., P.N.-B., C.M.) Pathology Departments (N.V.), Hospital Universitari de Bellvitge, Barcelona, Spain; Neurooncology Unit (A.P.-E., R.V., N.V., C.M.), to be understood for an optimally up-to-date comprehension of Institut d’Investigació Biomèdica de Bellvitge, Barcelona, Spain; and Institute of lymphomas in the CNS. First, these tumors fall between two 5th Neurosciences and Department of Cell Biology, Physiology and Immunology (R.V.), 2 4 Universitat Autònoma de Barcelona, Barcelona, Spain. edition WHO classifications: the CNS and the hematolymphoid. This work was partially supported by a grant from the Instituto de Salud Carlos III Second, despite impressive advances in molecular pathology, the (PI20/00360) to Carles Majós and Albert Pons-Escoda. mainstay in lymphomas remains histology of biopsy specimens; Please address correspondence to Albert Pons-Escoda, MD, Radiology Department, this differs greatly from other brain tumors such as gliomas, for Institut de Diagnòstic per la Imatge, Hospital Universitari de Bellvitge, C/Feixa Llarga SN, L’Hospitalet de Llobregat, 08907, Barcelona, Spain; e-mail: albert.pons.idi@gencat.cat; which molecular pathology is vital. Nevertheless, clinically rele- @PonsEscoda vant pathogenesis, mutation profiles, and genetic drivers have Indicates open access to non-subscribers at www.ajnr.org http://dx.doi.org/10.3174/ajnr.A7795 been characterized in recent years. Recurrent mutations frequently 358 Pons-Escoda Apr 2023 www.ajnr.org activate the B-cell receptor, toll-like receptor, and NF-kBpath- barriers (eg, the blood-brain barrier). However, large B-cell lym- ways, and alterations in genes involved in chromatin structure phomas occurring in the dura (dural lymphoma) or inside the brain and modification, cell-cycle regulation, and immune recognition vessels (intravascular lymphoma) escape these immune privileges 2,4 are common. MYD88 and CD79B mutations may be of clinical in- and are, therefore, classified separately. terest because they can be detected in several body fluids (plasma With all these upgraded concepts in mind, the authors aim to and CSF), potentially assisting in disease-monitoring under treat- provide a complete update-review of imaging features of the full ment and in minimally-invasive initial diagnosis. Also, knowledge spectrum of lymphomas involving the CNS, mainly based on those entities included in the 5th edition WHO Classification of Tumors of genetically activated pathways, tumor immune microenviron- ment, and expression of immune-response biomarkers may point of the CNS 2021. Primary DLBCL of the CNS, immunodeficiency- to specific treatment targets. Finally, lymphoma classifications associated CNS lymphoma, lymphomatoid granulomatosis, intra- include clinical factors, especially regarding the immune status of vascular large B-cell lymphoma of the CNS, mucosa-associated patients, which plays an essential role in tumor classification with lymphoid tissue (MALT) lymphoma of the dura, other low-grade 2,4 important treatment implications. B-cell lymphomas of the CNS, anaplastic large-cell lymphoma (ana- plastic lymphoma kinase positive and negative [ALK1/ALK–]), Updates. Thus, some changes may be identified in the updated and T-cell and natural killer (NK)/T-cell lymphoma are discussed. WHO Classifications of CNS Tumors 2021 and Hematolymphoid Finally, the clinical-radiologic entity “lymphomatosis cerebri” and Tumors 2022, first in CNS immunodeficiency-associated lym- secondary lymphomas are also reviewed. phoma. Whereas the prior CNS classification included a hetero- geneous group of diseases primarily defined by the patient Imaging of CNS Lymphomas immunodeficiency setting, currently, it is exclusively defined as Primary DLBCL of the CNS. Primary DLBCL of the CNS corre- DLBCL and EBV positive (both essential criteria) lymphoma. sponds to 80%–85% of all CNS lymphomas, occurs almost always Moreover, the current spectrum of immunodeficiency includes in immunocompetent patients, is EBV-negative, and is of unknown immune-dysregulation according to the hematolymphoid classi- etiology. The term primary CNS lymphoma may be considered fication, in which immunocompromised settings without a fully imprecise, and it is no longer recommended by the WHO classifi- demonstrable immunodeficiency, such as immunosenescence cation of hematolymphoid tumors for referring specifically to pri- 2,4 2,4 (among others), are included. mary DLBCL of the CNS, which is the currently preferred term. Next, a change in terminology is recommended in the upcom- It usually appears as single or multiple (30%–35%) parenchy- ing hematolymphoid classification, representing a paradigm shift. mal lesions, located supratentorially (.80%), with a particular af- Currently, the type of immunodeficiency-associated lymphoma is finity for the basal ganglia, periventricular regions, midline, and not first determined by the immunodeficiency/dysregulation set- corpus callosum (45%). It is also frequent in brain hemispheres ting, as in the previous classification (eg, AIDS-related DLBCL). (40%), rarely found in the posterior fossa, and exceptionally in Instead, it is defined primarily by the tumor histology with the the spinal cord (Fig 1). Associated leptomeningeal or subependy- so-called 3-part nomenclature, composed of the following: 1) his- mal enhancement is characteristic, but an exclusive presentation tologic lesion, 2) oncogenic virus status, and 3) immunodefi- of the disease in this location may raise suspicion of secondary ciency background of the patient (eg, DLBCL, EBV-positive, and lymphoma. The typical perivascular histologic pattern also carries autoimmune setting). This integrated nomenclature allows the a characteristic perivascular enhancement on imaging (Fig 1). grouping of specific types of immunodeficiency-associated lym- Parenchymal lesions are most frequently solid and homogeneous, phomas (such as DLBCL EBV-positive), despite the underlying but their presentation can range from well-defined expansive to 2,5-7,11 immunodeficiency/dysregulation, to better define the unique ill-defined infiltrative lesions. 4,9,10 Notably, these lesions are frequently hyperattenuating on shared pathogenetic mechanisms. 2,5-7,11 On the other hand, lymphomatoid granulomatosis is no lon- NCCT, which is important to keep in mind because CT is ger considered an immunodeficiency-associated entity. It occurs the first-line radiologic examination and suspicion at this point exclusively in immunocompetent patients, and in the case of an may lead to corticoid avoidance (Fig 1). If administered, corticoids 2,3,12 underlying immunodeficiency, it should be considered a subtype can complicate subsequent imaging and histologic diagnosis. of a polymorphic lymphoproliferative disorder. Regarding specific tumor MR imaging features, lymphoma typi- Also, according to the WHO classification of hematolym- cally appears hypointense on T2WI with marked diffusion restric- phoid tumors, the term primary CNS lymphoma may be consid- tion on DWI. Nevertheless, a T2-blackout effect consisting of a ered imprecise, and it is no longer recommended for referring persistent hypointensity on b ¼ 1000 images due to very low T2 sig- specifically to primary DLBCL of the CNS, which is the currently nal may lead to misinterpretation. Thus, ADC map hypointensity 2,4 preferred term. mightbemorereliable than b ¼ 1000 hyperintensity in assessing 2,5-7,11 Finally, some tumors do not differ in their specific histology but actual diffusion restriction. NCCT hyperattenuation, low T2 rather in their precise location. This is because in the new WHO signal, and diffusion restriction correlate with high cellularity on his- hematolymphoid classification, primary DLBCL of the CNS is clas- tology, with Ki-67 proliferation indexes usually above 90% (Fig 1). sified together with DLBCL of the vitreoretina and of the testes of Historically, the presence of hemorrhage or signs of necrosis immunocompetent patients as primary DLBCL of immune-privi- on preoperative imaging in immunocompetent patients have leged sites. All these entities arise in so-called immune sanctuaries been considered a factor arguing strongly against a diagnosis of created by their anatomic and functional immune regulatory lymphoma. However, the histologic appearance of tumor AJNR Am J Neuroradiol 44:358–66 Apr 2023 www.ajnr.org 359 tumor shows low-to-intermediate CBV, a high percentage of signal recov- ery (PSR), and characteristic time-in- 7,17,18 tensity curve morphology. Lower CBV values in lymphomas have para- doxically been related to a worse prog- 19 1 nosis of survival. H-MR spectroscopy can also reinforce a presurgical suspi- cion in basically 2 ways: Short TE depicts much lower mIns (described as a glial marker) than that associated with enhancing non-necrotic astrocytoma (ie, grade 3), and long TE shows much lower mobile lipids (associated with ne- crosis) than glioblastoma or metastasis (Fig 2). Brain FDG-PET may play a role in the presurgical differentiation of lym- phoma and other malignant brain tumors such as glioblastoma and metas- tasis because most lymphoma lesions are highly FDG-avid, with homogene- ous uptake. As an additional comment on pri- mary DLBCL of the CNS, it has been reported that “sentinel” inflammatory lesions, which may disappear after anti- inflammatory treatment, can precede the diagnosis of lymphoma by up to 2 years, so attention must be paid to the patient’s history of prior inflammatory brain lesions (Fig 3). FIG 1. Primary DLBCLs of the CNS, EBV-negative. A–C: Usual deep, periventricular, corpus callosum, Immunodeficiency-Associated CNS and midline location (A); a rare location in the posterior fossa (B); and exceptional in the spinal cord Lymphoma. According to the latest (C). D–G: Parenchymal lesions with associated characteristic leptomeningeal (D), subependymal (E), WHO classification, the immunodefi- and perivascular (arrow, F) enhancement patterns. Histologic hematoxylin-eosin stain (original mag- ciency-associated CNS lymphoma sub- nification 20) shows highly cellular, perivascular accumulation of lymphoma cells (G). H–J:Mass type specifically corresponds to primary lesion with ill-defined infiltrative (H) or well-defined expansive (I) margins. Hyperattenuated lesions on NCCT (J). K–N: Deep T2 hypointensity of a lesion (K) with a T2-blackout effect at b ¼ 1000 image DLBCL of the CNS, EBV-positive. (L) but a low signal of actual diffusion restriction on the ADC map (M). Ki-67 proliferation index by Indeed, large B-cell histology and lym- immunohistochemistry (original magnification 20) exceeding 90% (N). photropic EBV tissue–positivity are cur- rently the essential diagnostic criteria for immunodeficiency-associated lymphoma of the CNS. It repre- samples frequently includes hemorrhagic tumors with central ne- crosis. Accordingly, recent literature reports the presence of hem- sents 8%–10% of all primary CNS lymphomas. Despite being con- orrhage on imaging in up to 50% of patients evaluated with SWI sidered an infrequent entity, this is the second most frequent type (20% with T2WI) and heterogeneous or ring enhancement (usually of primary lymphoma of the CNS. Its clinical context has changed 3,15 associated with necrosis) in up to 10%–15% of cases. Therefore, during recent decades. Whereas in the 1990s, AIDS due to HIV the authors discourage this classic assumption and believe that a was the leading cause, currently and especially in more developed certain degree of hemorrhage and heterogeneous or ring enhance- countries, other causes predominate, such as post transplant status, 22-28 ments does not rule out suspicion of lymphoma, considering other autoimmune disease, and iatrogenesis. This shift in the mech- imaging features as well (Fig 2). anisms of immunodeficiency and other developments in patient Regarding quantitative imaging techniques beyond DWI, H- monitoring as well as in imaging techniques have also resulted in a MR spectroscopy and DSC-PWI, included in consensus recom- change in the main differential diagnoses to consider. Currently, mendations for imaging CNS lymphoma, have shown promis- therefore, glioblastoma or metastases are more likely than oppor- 8,29,30 ing results for presurgical diagnosis. Attention must be paid to tunistic infections, in contrast to previous decades. pulse-sequence parameters (TE, TR, flip angle), prebolus usage, Morphologic imaging of this lymphoma is quite characteristic, and leakage corrections for DSC-PWI, but in general terms, this and the opposite of that of the “typical” CNS lymphoma. It can 360 Pons-Escoda Apr 2023 www.ajnr.org the perfusion features of this lymphoma follow those of low-to-intermediate CBV, high PSR, and the characteristic time-intensity curve morphology when depicting an ROI in the solid parts of 8 1 tumors (Fig 4). Finally, the H-MR spectroscopy pattern seems of low value for presurgical characterization as lym- phoma because this tumor has promi- nent mobile lipids overlapping with necrotic glioblastomas or metastasis. In conclusion, wesuggestthatin dealing with a necrohemorrhagic tumor, potential immunodeficiency/dysregula- tion of the patient must be thoroughly examined. If this cannot be ruled out, DLBCL EBV-positive should be consid- ered, and careful DSC-PWI assessment can provide a presurgical diagnostic clue. Lymphomatoid Granulomatosis. Ac- cording to the new WHO classification FIG 2. A–C: Primary DLBCLs of the CNS, EBV-negative, with imaging signs of central necrosis (A) and tumoral hemorrhage (B and C). D–G: DSC-PWI features of a left frontal primary DLBCL of the of hematolymphoid tumors, lympho- CNS, EBV-negative (D). Low-to-intermediate CBV on noncorrected (E) and corrected (F)color matoid granulomatosis is a lymphopro- maps. Characteristic lymphoma DSC-PWI time-intensity curve morphology with ascending-part liferative disorder with large atypical of the curve recovering signal intensity far above the baseline (high PSR) (G). EBV-positive B-cells, T-cell infiltration, and tissue necrosis occurring exclu- sively in immunocompetent patients. Previously, it was included in the group of immunodeficiency-associated enti- ties, but currently, the identification of an underlying immunocompromised status rules out lymphomatoid granulo- matosis, and it should instead be con- sidered a subtype of a polymorphic FIG 3. Sentinel inflammatory lesions preceding primary DLBCL of the CNS. Two enhancing peri- lymphoproliferative disorder in the ventricular temporal lesions were detected in a patient (A). A biopsy was obtained, and histopa- setting of immunodeficiency/dysre- thology showed an inflammatory infiltrate without evidence of neoplasia. The lesions disappeared gulation. Lymphomatoid granulo- on further imaging controls during the following 2 years (B). In a subsequent MR imaging control, new masslike lesions reappeared (C and D). A biopsy of the new lesions yielded the final histopa- matosis is a very rare entity that thologic diagnosis of primary DLBCL of the CNS. exceptionally occurs primarily in the CNS, though CNS involvement is be deep or hemispheric, with a slightly greater tendency to multi- usually secondary. It represents a spectrum of lymphoid dis- plicity. It is almost constantly highly necrotic with ring enhance- ease graded from 1 to 3, with corresponding degrees of aggres- 2,4 ment and intermediate-to-prominent signs of hemorrhage. T2WI siveness from indolent to very aggressive. and DWI signal patterns are both variable and inconsistent. In On imaging, typical findings are those of secondary lymphoma summary, it is a tumor that differs from the typical appearance of with frequent subependymal or leptomeningeal involvement and perivascular enhancement. Occasionally, it may be angiocentric lymphoma and, rather, presents more like the main differential 8,29,30 diagnoses, which are glioblastoma and metastasis. Acharac- and angiodestructive, resembling intravascular lymphoma. When teristic T2WI heterogeneous hypointensity of the nonenhancing there is isolated CNS involvement, it usually corresponds to grade 2,4 “necrosis,” not corresponding to blood products or mineralization, 3 disease, and brain biopsy demonstrates DLBCL EBV-positive, has recently been suggested in these tumors, in contrast to the in which case imaging findings may consist of masslike lesions 2,4,31,32 usual hyperintense T2 signal of nonhemorrhagic necrosis in other with hemorrhage and necrosis. tumors (Fig 4). In the recent literature, lymphomatoid granulomatosis has While conventional imaging is often insufficient to reach a been correlated with chronic lymphocytic inflammation with pon- tine perivascular enhancement responsive to steroids (CLIPPERS). presurgical diagnosis of this challenging entity, quantitative imag- ing, especially DSC-PWI, can provide diagnostic clues. Indeed, Some authors hypothesize that this entity is a kind of a sentinel AJNR Am J Neuroradiol 44:358–66 Apr 2023 www.ajnr.org 361 lesion, while others postulate that CLIPPERS may be an inflammatory response to lymphomatous tumor cells, responding to corticosteroids preceding 33,34 the definitive tumor recurrence. Intravascular Large B-Cell Lymphoma of the CNS. Intravascular large B-cell lymphoma of the CNS is defined by the selective proliferation of malignant B large-tumor cells within the brain ves- sels, particularly small- to medium-sized blood vessels, without or with minimal parenchymal extension. The tumor cells may occlude vessels causing patched bleeding and ischemia. Also, it is not exceptional for some tumor cells to extravasate beyond the vessels, focally reaching brain parenchyma. Regarding clinical presentation, strokelike symptoms are typical, though not always present. The main phenomena detected on imaging are ischemic and hemorrhagic lesions, which usually suggest the dif- ferential with vasculitis, emboli, or hypercoagulability. The ischemia-like lesions appear dynamic and evanescent between near-in-time imaging follow- ups. Furthermore, those possible tumor cells that extravasate beyond the vessels may focally reach the brain parenchyma, forming tumor islands that can appear as enlarging areas of parenchymal 2,36 enhancement. Morphologic imaging features on these enhancing islands may be helpful for presurgical suspicion because they can express the signal char- acteristics of typical lymphoma. In addi- tion, ependymal and leptomeningeal 36,37 enhancement may also be present. Advanced imaging features may include atumoral pattern on H-MR spectros- copy with high Cho to NAA ratios, as well as a characteristic DSC-PWI pat- tern with shortened MTT (differing from ischemic lesions), low-to-interme- diate CBV,high PSR,and the character- istic time-intensity curve morphology of 7,18,20 lymphomas in the CNS. In summary, this entity should be kept in mind whenever encountering MR imaging with hemorrhage and FIG 4. Primary DLBCLs of the CNS, EBV-positive (immunodeficiency/dysregulation-associ- multiple dynamic ischemic lesions on ated). Single (A)and multiple (B) lesions with prominent necrosis (C and E) and tumoral hemor- T2WI and DWI, enlarging parenchy- rhage (D and F). Heterogeneous deep T2 hypointensity (H) of the nonenhancing central mal enhancement, and possible associ- content (G) of lesions, so-called necrosis. Low-intermediate CBV on the corrected color map ated leptomeningeal or subependymal (I) and DSC-PWI time-intensity curve with high PSR ( J), also very characteristic of this lym- 36,37 phoma subtype. disease (Fig 5). 362 Pons-Escoda Apr 2023 www.ajnr.org FIG 5. Intravascular lymphoma (A–D). Acute patched ischemia-like lesions on DWI (A), hemorrhages (B), and an area of enhancement (C), which grows on the subsequent few days of imaging control (D). Dashed arrow in C–D indicatesthe growth of thesameenhancing-lesion in few days. DLBCL fol- lowing a lymphomatosis cerebri pattern (E–J): extensive, patched, bilateral, and diffuse FLAIR hyperintensity on the basal ganglia (E) and white matter (F), with an area of enhancement in the left cerebellum (H) and associated leptomeningeal disease (arrow in H). Intermediate CBV in DSC-PWI color maps (I) and characteristic high PSR and time-intensity curve morphology (J). Tumoral pattern on H-MR spectroscopy at long TE with a high Cho-to-NAA ra- tio (H) and absent mIns at the short TE (not shown), helpful in the differential diagnosis with nontumoral entities and gliomatosis cerebri, respectively. MALT Lymphoma of the Dura. Lymphomas arising primarily in On conventional imaging, they appear as extra-axial lesions the dura are rare (1%) and usually correspond to MALT lym- with a wide dural base, soft attachment angles, and a possible phoma. Occasionally, large B-cell lymphoma may also be primar- CSF cleft between the lesion and brain parenchyma. In addition, 2,38 edema or brain tissue infiltration can occur. They usually appear ily dural. Etiology and underlying associations are unknown. AJNR Am J Neuroradiol 44:358–66 Apr 2023 www.ajnr.org 363 A clue for the presurgical suspicion of this tumor is provided by a characteristic pattern of bone infiltration or transdiploic extension. Characteristically, lymphoma presents as an extensive soft-tissue mass without bone destruction (normal bone to subtle permeative patterns) (Fig 6). This pattern is explained by the extension of tumor cells through Haversian canals. It differs from what is seen in meningiomas with hyperostosis or in plasmacy- toma or metastasis with aggressive lytic destruction. Other Low-Grade B-Cell Lymphomas of the CNS, Anaplastic Large Cell Lymphoma ALK+/ALK, T-Cell and Natural Killer (NK)/T-Cell Lymphoma. The CNS WHO classification 2021 includes low-grade B-cell lymphoma of the CNS, ALK1/ALK, T-Cell, and NK/T-cell lymphoma classified as miscellaneous, rare lymphomas in the CNS. They represent a heterogeneous group of tumors with scarce evidence of concrete imaging findings. While low-grade B-cell lymphomas may occasionally appear as lymphoma-like lesions, other very different radiologic appearan- ces are described, such as resembling edema, glial tumor, meningi- oma, and gliosis. Regarding anaplastic large-cell and T-cell or NK/T-cell lymphomas, some authors postulate that they may resemble lymphoma or lymphomatosis cerebri on imaging, with other nonspecific presentations also possible (Fig 7). In summary, very heterogeneous imaging presentations, occasionally resem- bling lymphoma, can be seen in this heterogeneous group of 41-43 exceptional entities. FIG 6. Dural lymphomas. MALT dural lymphoma (A–D)with extra- Lymphomatosis Cerebri. Lymphomatosis cerebri corresponds to axial lesion features such as a CSF cleft (A) and a wide-implantation a clinical-radiologic pattern that is not included as a concrete his- duralbase with soft marginalangles (C), as well as T2-hypointensity topathologic WHO entity. It may be observed in the context of (A) and diffusion restriction (B). Almost normal calvarial bone; only different histologic lymphoma subtypes, but in most cases, it cor- subtle sclerosis seen (D), despite the great soft-tissue component on responds to primary DLBCL of the CNS. The typical clinical pre- both sides of the diploe (A–C). Similar imaging features with minimal sentation is a subacute onset of dementia, cognitive impairment, bone destruction and a subtle permeative pattern (F) in comparison 44,45 and personality changes. with the prominent soft-tissue component (E) in another diffuse large B-cell dural lymphoma (E and F). It consists of a nonenhancing or scarcely-enhancing (30%) T2-FLAIR hyperintense infiltration of brain tissue. It is usually located in white matter regions, with different distributions rang- ing from focal to patched or diffuse. The main differential includes gliomatosis cerebri (also considered a radiologic pattern and not a WHO entity) and inflammatory and toxic-metabolic diseases. Of note, in this form of CNS lymphoma, brain lesions may be highly variable and change between near-in-time follow- 44-47 up scans. In line with what was detailed in the intravascular lymphoma section, the detection of a tumoral pattern on H-MR spectros- copy without relevant amount of mIns (potential glial marker FIG 7. NK/T-cell lymphoma presenting with a lymphomatosis cerebri radiologic pattern (A–C). Patched and diffuse, bilateral and asymmet- present in gliomatosis) in abnormal areas of T2-FLAIR hyperin- ric, deep and subcortical, hyperintense lesions on FLAIR (A and B) tensity, as well as the above-described characteristic DSC-PWI without contrast enhancement (C). pattern in the possible enhancing lesions, supports presurgical 46,47 suspicion (Fig 5). homogeneous, NCCT hyperattenuated, T2WI hypointense, and with restricted diffusion; however, these features overlap with Secondary Lymphomas of the CNS. Secondary lymphoma refers those of the most frequent extra-axial tumor in adults, meningi- to the CNS spread of lymphoma that originated elsewhere. It may 39,40 oma (Fig 6). be as an isolated recurrence or as a synchronic systemic disease Regarding advanced imaging, H-MR spectroscopy can be of with an overall incidence of around 5%–10% in patients with sys- help for the differential diagnosis because meningiomas charac- temic lymphomas, usually non-Hodgkins. Its occurrence is teristically present with alanine, metastases present abundant mo- directly correlated with pathologic aggressiveness and ranges bile lipids, and the rarer solitary fibrous tumors (formerly termed from ,3% in the indolent, less-aggressive histologies to as high 39 48 hemangiopericytoma) show a high myo-inositol peak. as 50% in the very aggressive ones such as Burkitt lymphoma. 364 Pons-Escoda Apr 2023 www.ajnr.org 1) Primary DLBCLs of the CNS present as homogeneous lesions, hyperdense on NECT, T2 hypointense, and with restricted dif- fusion. The presence of a certain degree of hemorrhage or signs of necrosis should not rule out their presurgical diagnosis. 2) Immunodeficiency-associated lymphomas (primary DLBCLs of the CNS, EBV-positive) appear as necrohemorrhagic tumors in potentially immunocompromised hosts. Special attention must be paid to the features of DSC-PWI, which may provide findings that suggest lymphoma. 3) Dural lymphoma should be suspected when a disproportion- ate soft-tissue mass without relevant bone destruction is iden- tified in an extra-axial transdiploic tumor. 4) Intravascular lymphoma and lymphomatosis cerebri may be evolutive diagnoses of suspicion when dynamically changing T2-FLAIR areas of signal abnormality (and hemorrhage in intravascular lymphoma) are found. Also, attention must be paid to leptomeningeal and subependymal enhancement. 5) DSC-PWI and H-MRS provide clues of great help in the dif- ferential diagnosis for each lymphoma subtype. 6) Secondary lymphomas often appear as parenchymal lesions. Isolated leptomeningeal or subependymal disease is charac- teristic but apparently less prevalent than formerly assumed. ACKNOWLEDGMENTS We thank CERCA Programme/Generalitat de Catalunya for FIG 8. Imaging findings in secondary lymphomas of the CNS. A–B: Thin subtle linear (arrow in A) and nodular (B) subependymal enhance- institutional support. ments. C–D: Prominent leptomeningeal disease along the superior ver- mian and cerebellar folia and third cranial nerve (arrow in C)as well as Disclosure forms provided by the authors are available with the full text and inside the right internal auditory canal—cranial nerves VII and VIII— PDF of this article at www.ajnr.org. and along the trigeminal nerve in the right Meckel cave and the left cisternal segment (arrows in D). Associated parenchymal mass in the left temporal lobe (C). E–F: Secondary lymphomas presenting as pre- dominant intraparenchymal lesions with associated adjacent subepen- REFERENCES dymal (E) and leptomeningeal (F) disease. 1. Miller KD, Ostrom QT, Kruchko C, et al. Brain and other central nervous system tumor statistics, 2021. CA Cancer J Clin 2021;71:381– 406 CrossRef Medline Although historically, it has been thought that secondary lym- 2. 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American Journal of Neuroradiology – American Journal of Neuroradiology
Published: Apr 1, 2023
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