Background: Primary central nervous system lymphoma (PCNSL) is an uncommon tumor in the brain. Although most PCNSL are readily diagnosed as diffuse large B cell lymphoma (DLBCL) on the first biopsy, very rare cases have been described in which the first detected intracerebral lesions are non-neoplastic, and are composed mostly of perivascular T cells, not B cells. This phenomenon is known as “sentinel lesions.” Keywords: Primary CNS lymphoma, Diffuse large B cell lymphoma, Sentinel lesion Case presentation We describe a case of a patient who Background presented with dysarthria and blurry vision, and was Primary central nervous system lymphoma (PCNSL) is found to have abnormal T2 hyperintensity and contrast very rare, with an age-adjusted incidence rate of only 0.44/ enhancement along both internal capsules and basal 100,000, less than 2% of all non-Hodgkin lymphomas ganglia. Biopsy of the right basal ganglia showed an ex- throughout the body . The vast majority of PCNSL is tensive intracerebral perivascular infiltrate with abun- diffuse large B cell lymphoma (DLBCL) that is CD20/ dant small, mature-appearing B cells that showed no MUM1 positive. CD10 may be present in some cases, and evidence of clonality. After four months of monitoring, a many tumors show Bcl6 expression, even if only focally new expansile lesion developed in the left middle cere- . Unlike most systemic DLBCL, PCNSL often expresses bellar peduncle; biopsy of the new lesion showed un- high levels of Myc, yet typically lacks MYC rearrangement equivocal DLBCL, including clonal immunoglobulin . Most PCNSL cases are sporadic, and are not linked to heavy chain rearrangement. anything other than advanced age and male gender [2, 4]. Radiologically, PCNSL tends to be rather symmetrical, with involvement of the bilateral white matter and corpus Conclusions To the best of our knowledge, this is the callosum by T2 iso-to-hyperintense, contrast-enhancing first indication that pre-PCNSL sentinel lesions, previ- lesions that fluctuate over time . Epstein-Barr virus in- ously reported to only show T cell predominance, can fection is associated with DLBCL in immunocomprom- also contain large amounts of non-neoplastic B cells. ised patients, is not considered to be part of PCNSL This underscores the importance of considering PCNSL pathology, and has decreased in frequency in the era of ef- as the underlying disease when abnormally high levels of fective anti-HIV therapies . B cells are found within a brain biopsy, even when there Whereas most PCNSL present as DLBCL histologi- is no flow cytometric, immunohistochemical, or molecu- cally, rare examples of non-neoplastic perivascular T lar evidence of clonality. cell-rich sentinel lesions have been described that pre- * Correspondence: firstname.lastname@example.org cede the onset of frank PCNSL. Herein we describe a Departments of Neurological Surgery, Feinberg School of Medicine, unique PCNSL case where the sentinel lesion within the Northwestern University, Tarry 2-705, 300 East Superior Street, Chicago, IL cerebrum contained large amounts of non-neoplastic B 60611, USA Departments of Pathology, Feinberg School of Medicine, Northwestern cells. University, Chicago, IL 60611, USA Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Javier et al. Diagnostic Pathology (2018) 13:37 Page 2 of 6 Case presentation The patient was a 60 year-old previously healthy man who presented to an outside institution with a rapid on- set of dysarthria without aphasia, as well as blurred vi- sion in his right eye without ptosis. The patient had a history of high blood pressure (controlled with losartan) and acid reflux, but no recurring infections, headaches, abnormal clotting or bleeding, night sweats, dysphagia, or weakness. At the outside institution, a full battery of laboratory testing, including complete blood count, complete metabolic profile (CMP), erythrocyte sedimen- tation rate, vasculitis panel, autoimmune panel, and my- asthenia gravis panel, was negative. A stroke was therefore initially suspected, but magnetic resonance im- aging (MRI) showed T2 hyperintensity tracking along both corticospinal tracts from the corona radiata through the posterior limb of both internal capsules and cerebral peduncles, as well as some matching contrast enhancement (Fig. 1a-b). Although nonspecific, this was originally felt to be most consistent with a neurodegen- erative disease such as amyotrophic lateral sclerosis (ALS) or other metabolic disorder. At a second external institution, electromyography was obtained that ruled out ALS. The patient remained fairly stable for the next several months, and declined follow-up appointments and im- aging. Four months after initial presentation, he devel- oped bilateral blurry vision and leg weakness, yet still declined follow-up care until arriving at our institution 8 months after his initial presentation. An MRI at that time showed new enhancing lesions in the bilateral basal ganglia (Fig. 1c-d), raising concern for CNS vasculitis. Yet aside from a mild elevation of antinuclear anti- bodies, his serum protein electrophoresis, vitamin B12, vitamin D, folate, and repeat autoimmune and CMP panels were all within normal limits. Computerized tom- ography of the patient’s chest, abdomen, and pelvis were Fig. 1 Serial MRIs. The initial set of MRIs showed T2 hyperintensity all negative for lymphadenopathy. Flow cytometry on a and some contrast enhancement in the bilateral internal capsules (a, cerebrospinal fluid sample was negative for atypical lym- b). Eight months later, a second set of MRIs showed new enhancing phocytes; only 1% of the lymphocytes present in the lesions in the bilateral basal ganglia (c, d). Eleven months after initial cerebrospinal fluid were CD19+ B cells. presentation, the right basal ganglia lesion appeared to grow, whereas the lesion in the left basal ganglia diminished (e, f). In the Up to this point, the comprehensive workup had been final set of MRI, 15 months after initial presentation, the right basal inconclusive, so no treatment had yet been administered, ganglia lesion was unchanged (not shown), and a new enhancing including steroids. But when another MRI showed fur- mass appeared in the left middle cerebellar peduncle ther progression of the right basal ganglia lesion (h). c = contrast 3 months later (11 months after initial presentation, Fig. 1e-f), a stereotactic biopsy of the right basal ganglia was taken in an effort to establish a diagnosis. The tissue in inflammatory diseases of the brain, as well as large showed brisk perivascular and parenchymal lymphocytic numbers of admixed CD3/5-positive T cells, the Ki67 infiltration (Fig. 2), but no evidence of vessel wall dam- proliferation index was only 5% (Fig. 3). Other stains, in- age. All the lymphocytes appeared small and mature, cluding CD10 and EBV-encoded RNA (EBER) in-situ with no mitoses anywhere in the biopsy. While immuno- hybridization were negative (Fig. 3), as was Bcl1 (not histochemical studies showed a strikingly high number shown). Luxol fast blue showed no lipid-laden macro- of CD20-positive B cells, relative to what is typically seen phages or other evidence of demyelination (not shown). Javier et al. Diagnostic Pathology (2018) 13:37 Page 3 of 6 Fig. 2 Hematoxylin and eosin (H & E) features of both biopsies. In the first biopsy of the right basal ganglia lesion (a,e), abundant mature- appearing lymphocytes were present in a mostly perivascular distribution. In the second biopsy of the left middle cerebellar peduncle lesion (f-j), there were sheets of neoplastic cells with large nuclei and numerous mitoses (j, arrowheads). Scale bar = 2 mm in a & f, 200 μm in b-d and g-i, and 50 μmine&j Flow cytometry performed on an unfixed portion of the with dexamethasone, with no clinical improvement. Pa- biopsy was negative for abnormal clonal subpopulations, tient adherence to the medication was uncertain, and sub- and molecular analysis was negative for immunoglobulin sequent appointments and imaging were delayed. heavy chain gene rearrangement. The biopsy was then Four months after the first biopsy (15 months post initial sent for external review by additional neuropathology and presentation), the patient developed unsteady walk, cheek hematopathology experts, who concurred that a neoplastic and tongue numbness, post-meal emesis, slurred speech, process could not be proven. and worsening bilateral leg weakness. A fourth MRI Despite the lack of any definitive evidence of a B cell showed a new enhancing region in the left middle cerebel- neoplasm on the initial biopsy, the high number of B cells lar peduncle (Fig. 1g-h), prompting a biopsy of the pedun- still raised concern for a lymphoproliferative process. A cular lesion. This time, the tissue showed an obvious working diagnosis of low grade B cell lymphoma was malignancy, composed of cells with large, highly atypical therefore discussed, with a differential including demyelin- nuclei and clumped chromatin, scant cytoplasm, and abun- ating disease with B cell infiltrates. Thereafter, the patient dant mitoses (Fig. 2). Unlike the prior biopsy, the repeat bi- was prescribed 4 doses of rituximab over 4 weeks, along opsy showed a clear preponderance of CD20-positive B Fig. 3 Comparative immunohistochemistry between the first and second biopsies. See “Case presentation” section for description. Of note, the vessel shown in the CD20/3/5/10 panels from the first biopsy was adjacent to the vessel shown in the Ki67/EBER panels, due to the original vessel diminishing on deeper sectioning. Scale bar = 200 μm Javier et al. Diagnostic Pathology (2018) 13:37 Page 4 of 6 cells, as well as an extremely high Ki67 proliferation index to be more likely in females. None of the sentinel lesions approaching 100% (Fig. 3). MUM1 and cMYC were positive have occurred in patients with prior immunocomprom- in 80 and 40% of the tumor cells, respectively, while Bcl2 ised conditions, and none of the cases in which EBV was was present in 80% of cells and Bcl6 was expressed by only tested have been positive. All sentinel lesions have shown 10–15% of the cells overall (Fig. 4). CD5, CD10, and EBER T2 hyperintensity and various degrees of contrast en- were all negative in the neoplasm (Fig. 3). Immunoglobu- hancement that usually fluctuated over time prior to the lin heavy chain gene PCR showed clonal rearrangement, onset of frank PCNSL. In reports including detailed hist- whereas a fluorescent in situ hybridization test for MYC ology, all found a perivascular pattern of lymphocyte-rich rearrangement was negative (not shown). No flow cytom- inflammation, often accompanied by demyelination. In all etry was done on the second biopsy. Subsequent comput- such cases, inflammation was mostly composed of T cells, erized tomography showed no evidence of systemic with only rare mature B cells and variable macrophages. lymphadenopathy. The median time between sentinel lesion biopsy and a Based on the new diagnosis of a primary CNS diffuse diagnosis of PCNSL was 9 months, although three pa- large B cell lymphoma, the patient was administered tients had extended intervals of 2–4 years before PCNSL. high-dose methotrexate, temozolomide, and rituximab. With one exception , none of the PCNSL biopsies were This regimen failed, and the patient continued to progress taken from the same site as the sentinel lesions. To the such that, 19 months after his initial symptoms, he was suf- best of our knowledge, the current case is the first ex- fering from dysphagia, aspiration pneumonia, and hypoxia. ample of a PCNSL-associated sentinel lesion containing large numbers of mature B cells, yet with no evidence of Discussion and conclusions clonality. The term “sentinel lesion” was first coined in 1996 to de- In general, inflammatory processes within the brain scribe extremely rare cases in which a non-neoplastic in- are composed predominately of T cells, and at most con- tracerebral perivascular inflammation occurs before the tain only a few scattered B cells. Even very florid cases of onset of clinically overt PCNSL . Prior to the current intracerebral inflammation, as seen in tumefactive mul- case, 12 examples of sentinel lesions had been described tiple sclerosis or acute disseminated encephalomyelitis, in the literature, revealing an emergence of distinctive contain far more T cells than B cells, although the latter clinical, histologic, and radiologic patterns (Table 1). Like do contribute to autoimmune diseases within the brain PCNSL in general, patients with PCNSL-associated senti- [7, 8]. Therefore, when abnormally large numbers of B nel lesions have a median age of 57. Although the male:fe- cells are found in a brain biopsy, exceeding T cells, a male ratio for all PCNSL is 3:2 , sentinel lesions appear lymphoid neoplasm is the most likely cause. Yet in the current case, the first biopsy only showed mature-appearing B cells, raising the possibility of a low-grade B cell neoplasm. Intracranial low-grade B cell lymphoproliferative disorders and lymphomas are very rare, and when they do occur, they are far more com- mon in the meninges than in the cerebral parenchyma  and show some sign of clonality, e.g. light chain re- striction on flow cytometry or heavy chain gene re- arrangement via PCR [9–12]. The first biopsy from this patient produced no such evidence. Lymphomatoid granulomatosis (LG) is an angiocentric lymphoprolifera- tive disorder that contains varying amounts of B cells, can progress to DLBCL, and rarely can originate in the brain rather than the more common sites, skin and lungs [13, 14]. Yet LG is defined by the presence of EBV and overt vasculitis with necrosis , whereas both bi- opsies from the current patient were EBER-negative and showed no sign of vessel wall damage or necrosis. The pathophysiology of pre-PCNSL sentinel lesions remains unclear, though several hypotheses have been Fig. 4 Additional immunohistochemistry from the second biopsy. advanced. First, the non-neoplastic inflammatory cells See “Case presentation” section for description. Of note, most of the may represent an immune response against clinically oc- neoplastic cells in the biopsy were Bcl6 negative; the image shows cult PCNSL, which only manifests when a subclone de- the most positive region. Scale bar = 200 μm velops that can better evade the immune system . For Javier et al. Diagnostic Pathology (2018) 13:37 Page 5 of 6 Table 1 Reported PCNSL cases preceded by sentinel lesions Reference Age Sex Immune Steroids prior to first Demyelinating? Predominant Time between sentinel lesion biopsy and status biopsy? lymphocyte PCNSL diagnosis Alderson et al. 58 F Competent Yes Yes T cell 7 months 1996  49 F Competent No No None (no 11 months inflammation) 54 F Competent Yes No T cell 9 months 57 F Competent Yes Yes T cell 9 months Kuhlmann et al. 65 M Competent Yes Yes T cell 9 months 2001  Ng et al. 2007  29 F Competent Yes Yes not available 48 months Husseini et al. 2012 59 F Competent No Yes T cell 30 months  Yamamoto et al. 70 M Competent No Yes not available 3 months 2014  Taieb et al. 2014 58 M Competent No No T cell 24 months  Lu et al. 2016  44 F Competent No Yes T cell 5 months Kvarta et al. 2016 57 F Competent Yes Yes T cell 6 months  Current case 60 M Competent No No B cells > T cells 4 months example, a young woman with presumptive demyelinat- In summary, although it is not yet clear what causes ing disease only developed overt PCNSL after giving rare PCNSL patients to develop non-neoplastic inflam- birth, suggesting that pregnancy-related changes in her matory sentinel lesions, this case expands the histologic immune system allowed the PCNSL to finally emerge range of such lesions to include large numbers of . Second, the sentinel inflammatory lesions could non-neoplastic B cells. PCNSL must therefore be represent paraneoplastic autoimmune disease caused by retained in the differential diagnosis of older patients PCNSL, as has been described in systemic non-Hodgkin with T2 hyperintense, contrast-enhancing lesions, even lymphomas and carcinomas from such sites as ovary, when such lesions show a relapsing-remitting course lung, breast, and thymus [6, 17]. To date, no data exist and the initial biopsies show no sign of malignancy. on the presence of well-known paraneoplastic antibodies like anti-Hu, -Yo, or -Ri in any patient with PCNSL and Abbreviations CMP: Complete metabolic profile; DLBCL: Diffuse large B cell lymphoma; sentinel lesions. A third hypothesis is that, in rare in- EBER: EBV-encoded RNA; LG: Lymphomatoid granulomatosis; MRI: Magnetic stances of an intracerebral autoimmune disease, a resonance imaging; PCNSL: Primary central nervous system lymphoma pre-neoplastic B cell subclone may develop and eventu- ally transform into full-blown PCNSL [6, 18]. Some Availability of data and materials lymphomas may develop from chronic autoimmune dis- Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. eases in this manner, though the evidence for this is lim- ited to systemic lymphomas, not PCNSL . However, Authors’ contributions in all but one previously reported example of sentinel le- RJ and CH each contributed portions of the manuscript text and figures; NS, sions and PCNSL, the overt malignancy appeared to de- AB, RS, ML, and AS revised it for content. All authors have read and approve velop at a completely different location within the brain the final manuscript. from the sentinel lesions, as was the case in our current patient; one postmortem study even showed no evidence Ethics approval and consent to participate Not applicable. of PCNSL at the site from which the sentinel lesion was identified [6, 20]. Finally, some patients may have had Consent for publication PCNSL right from the beginning of their symptoms, but Written informed consent for publication of their clinical details and clinical pre-biopsy corticosteroids caused selective apoptosis in images was obtained from the patient. A copy of the consent form is PCNSL cells, leaving behind only the non-neoplastic im- available for review by the Editor of this journal. mune components [2, 6]. However, as the current case demonstrates, there is no link between sentinel lesions Competing interests and pretreatment with steroids (Table 1). 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