https://orcid.org/0000-0002-7054-8624
Abstract
Primary central nervous system anaplastic large cell lymphoma, anaplastic lymphoma kinase positive (primary CNS ALCL, ALK+) is a rare CNS lymphoma whose description is limited to case reports. These tumors have a variable clinical course, and prognosis is primarily determined by age. We present the largest case series to date of primary CNS ALCL, ALK+, with observational data.
A retrospective search of multiple academic centers was performed to identify cases of primary CNS ALCL, ALK+. We also performed a review of published cases of primary CNS ALCL, ALK+. Clinical history, radiography, pathology, and genetic testing data were obtained to determine the prognostic implications in the context of clinical course.
We identified three cases of primary CNS ALCL, ALK+ from our databases. A literature review identified 30 published reports of 31 individual cases. Clinical features for the combined 34 cases included a median age of 18.5 years, with a male to female ratio of 4.7:1, and the most common symptom was headache. Genetic studies demonstrated an ALK rearrangement by fluorescence in situ hybridization, and a gene fusion assay confirmed an NPM1-ALK gene fusion in one case.
We present the largest case series to date of a rare primary CNS lymphoma with additional diagnostic and clinical information.
Primary central nervous system anaplastic large cell lymphoma, anaplastic lymphoma kinase positive (CNS ALCL, ALK+) is a rare CNS lymphoma that is much more common in young male patients with outcomes strongly associated with age.
In histologically challenging cases of CNS lymphoma that are negative for B-cell markers, CD30 can serve as an important immunohistochemical marker.
Primary CNS ALCL, ALK+ may be a distinct entity, and due to the limited number of cases reported, further genetic analysis would be prudent to discern a relationship to non-CNS ALCL, ALK+.
Introduction
Primary central nervous system lymphoma (PCNSL), defined as a lymphoma confined to the brain, spinal cord, and/or eye, represents approximately 4% of all primary brain tumors and 1% to 2% of non-Hodgkin lymphoma.1 Greater than 95% of PCNSL cases are diffuse large B-cell lymphomas.2 Other types of PCNSL, including anaplastic large cell lymphoma, ALK positive (ALCL, ALK+), are extremely rare, with only case reports and a single small case series currently published in the literature.3-32
Anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma that was first described in 1985 by Stein et al33 and is characterized by large, pleomorphic to anaplastic lymphocytes that often contain horseshoe-shaped nuclei, termed “hallmark cells.” 33,34 By definition, ALCL displays strong surface expression of CD30, often with loss of one or more T-cell antigens, and occasionally of all T-cell markers, giving rise to the null-cell phenotype.35 Within ALCL, there are two primary categories recognized by the World Health Organization (WHO): those that express anaplastic lymphoma kinase (ALK) and those that lack expression of ALK.36 These entities differ in presentation and overall survival, with ALCL, ALK+ having a better prognosis.
ALK is a tyrosine kinase that is part of the insulin receptor superfamily.37 ALK has three regions, including the extracellular ligand binding region, transmembrane region, and a cytoplasmic domain, which is the site of catalytic activity. The cytoplasmic domain forms homodimers with other molecules, thus undergoing activation by phosphorylation and downstream signaling. The normal expression of ALK is limited to the central and peripheral nervous system; however, the physiologic function of ALK is unclear at this time.
Most cases of ALCL, ALK+ are characterized by a translocation resulting in a fusion between ALK and NPM1 genes38; however, other partner genes have been identified.36 ALK immunohistochemistry often results in nuclear and cytoplasmic expression of ALK, but various patterns have been reported.39-41
Due to primary CNS ALCL, ALK+ being limited largely to single case reports, a comprehensive histologic, immunophenotypic, and molecular characterization of primary CNS ALCL, ALK+ has not been previously reported. Similarly, the clinical and prognostic features of primary CNS ALCL, ALK+ are poorly understood. Herein, we searched the electronic databases of three large pathology departments at major academic centers for cases of primary CNS ALCL, ALK+. We discovered three cases from these institutions and provide detailed clinical, histologic, immunophenotypic, and molecular descriptions of these cases. We also performed a literature review and summarize the findings from 31 previously reported cases.
MATERIALS AND METHODS
H&E
Fresh tissue was sent to a frozen section laboratory for confirmation of lesional tissue (via frozen section and smear). The remainder of the fresh tissue was placed in formalin to produce formalin-fixed tissue sections by standard laboratory protocols, cut into 5-μm sections, and stained to produce H&E-stained slides.
Immunohistochemistry
Antibodies, clone information, and manufacturers for immunohistochemistry performed are provided in Supplemental Table 1 (all supplemental materials can be found at American Journal of Clinical Pathology online). In brief, the following antibodies were used: CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD79a, PAX5, CD25, CD30, CD43, CD45, CD56, CD57, CD138, ALK-1, TdT, TIA-1, perforin, granzyme B, and EMA. In situ hybridization for Epstein-Barr virus encoded RNA (EBER ISH) was also performed.
Next-Generation Sequencing Panel
The next-generation sequencing (NGS) platform used to analyze case 3 included a hybrid capture sequencing assay, which interrogates the exons of 447 genes and 191 introns across 60 genes. Structural rearrangements were evaluated with BreaKmer analysis as previously described.42
Karyotype
For karyotype analysis, GTG-banded metaphase chromosomes were captured and processed using Cytovision Ultra Workstations (Leica Microsystems, version 4.5.2). Twenty metaphases from across two cultures were analyzed. Chromosomal abnormalities were described according to the International System for Human Cytogenetic Nomenclature.43
Fluorescence In Situ Hybridization (FISH)
We prepared 5-μm sections of formalin-fixed, paraffin-embedded (FFPE) tumor material for fluorescence in situ hybridization (FISH) analysis on cases 1 and 2. An H&E section was reviewed to select regions for hybridization that contained a majority of tumor cells. The probes used included a Kreatech ALK dual-color break-apart probe set or a Vysis LSI ALK (2p23) dual-color, break-apart probe set by Abbott Molecular. This probe combination detects rearrangements of the ALK gene seen in some cases of ALCL, lung adenocarcinoma, and other tumors. It also detects copy number abnormalities of ALK. Approximately 100 interphase nuclei were examined with the ALK break-apart probe set and fluorescence microscopy. An ALK rearrangement is reported if more than 9% or 15% of tumor cells show split signals, respectively, with the two probe sets.
Gene Fusion Assay
As previously described, anchored multiplex polymerase chain reaction (PCR) assay for targeted fusion transcript detection by NGS44 was performed. Total nucleic acid was isolated from FFPE tissue and reverse transcribed with random hexamers, followed by second-strand synthesis to create double-stranded complementary DNA (cDNA). The double-stranded cDNA was end-repaired, adenylated, and ligated with a half-functional adapter. Two hemi-nested PCR reactions using the ArcherDx Heme Fusion kit primers were performed to create a fully functional sequencing library that targets specific exons of genes. Illumina NextSeq 2 × 150 base paired-end sequencing results were aligned to the hg19 human genome reference using bwa-mem.45 A laboratory-developed algorithm was used for fusion transcript detection and annotation. The assay is validated for samples showing 6% or higher tumor cellularity.
Literature Review
A literature review was performed by searching the PubMed database from years 1980 to 2021 according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.46 Globally, our study included human patients of any age reported in the English literature published after 1980 to cover all reports in the era of modern imaging. The MEDLINE database was searched with the PubMed search engine with the following Boolean phrase: (“anaplastic large cell lymphoma” OR “ALCL”) AND (“primary CNS” OR “brain” OR “central nervous system”) AND “ALK.” After applying an English-language filter, the search returned 64 results. First, article titles and abstracts were screened for applicability/availability, and suitable abstracts were reviewed in detail. Then a detailed review of the full article was performed for applicability. This review resulted in selection of 20 articles outlining 21 separate cases of primary CNS ALK-positive ALCL.3-32 Each article was reviewed in its entirety, and an additional 10 articles outlining 10 separate cases were identified from cited references. In total, 30 articles describing 31 cases of CNS ALCL, ALK+ were identified. A symptom or finding was deemed present if mentioned in the article at least once and not available if not mentioned. Data were tabulated.
Statistical Analysis
Statistical analyses were performed using GraphPad Prism software (GraphPad Software). For Kaplan-Meier analysis, the log-rank test was used to test for statistical significance, with a P value of less than .01 considered statistically significant.
RESULTS
Case 1
A 36-year-old right-handed woman presented with a 1-month history of fatigue, unintentional 10-pound weight loss, and left facial droop. Magnetic resonance imaging (MRI) of the brain revealed a 2.1-cm heterogeneously contrast-enhancing lesion in the right basal ganglia with surrounding vasogenic edema causing a leftward midline shift Figure 1A. A smaller left basal ganglia lesion was also observed. Computed tomography (CT) scan of the chest, abdomen, and pelvis did not show radiographic abnormalities. She was started on broad-spectrum antibiotics for presumed infection, but subsequent infectious workup was negative, including serum human immunodeficiency virus antibody and Cryptococcus antigen, as well as blood cultures. Dexamethasone was started, resulting in improvement of neurologic symptoms. Follow-up brain MRI 1 week after presentation showed decrease in size of both lesions.
Imaging and histologic characteristics of primary central nervous system anaplastic large cell lymphoma, anaplastic lymphoma kinase positive. Magnetic resonance imaging, H&E-stained section, CD30 and ALK-1 immunostains for case 1 (A, C, E, G, respectively) and case 2 (B, D, F, H). Magnification for C-F: ×200.
Following cessation of dexamethasone, the lesions increased in size, and a stereotactic brain biopsy was performed to obtain a tissue diagnosis. Histologic examination revealed brain tissue with a patchy but prominent infiltrate of large lymphoid cells with moderate amounts of cytoplasm, irregular nuclear contours, and multiple small nucleoli Figure 1C. By immunohistochemistry, the large atypical lymphoid cells were diffusely positive for CD45, and a minor subset was weakly positive for CD3, CD2, and CD7. The neoplastic cells were positive for CD30 and displayed nuclear ALK-1 reactivity Figure 1E and Figure 1G. The neoplastic cells were also positive for CD4, granzyme B, and TIA-1. Cytogenetic testing revealed an ALK rearrangement by FISH, and an NGS heme fusion panel revealed a NPM1-ALK gene fusion. Together, the morphologic, immunophenotypic, and cytogenetic features were diagnostic of primary CNS ALCL, ALK+.
Following her diagnosis, positron emission tomography (PET)/CT was performed and revealed no evidence of disease outside of the right basal ganglia. Ultimately, she was started on high-dose methotrexate, which she tolerated well. She was then treated with alectinib, a next-generation ALK inhibitor. Autologous stem cell transplant was performed, complicated by mucositis, typhlitis, tonsillar abscess, bacteremia, and severe epidermal necrolysis. Subsequent MRI was concerning for disease progression, but the biopsy specimen revealed only reactive gliosis with no evidence of lymphoma. At the time of writing, she is without disease recurrence for 19 months and continues on alectinib.
Case 2
A 33-year-old right-handed man had persistent, progressive right retro-orbital headache, right ptosis, and fever. MRI demonstrated a contrast-enhancing region of the right frontal lobe Figure 1B with opacification of the left sphenoid sinus and ethmoid air cells. Lumbar puncture was notable for an elevated WBC count, and cerebrospinal fluid cytology revealed large mononuclear cells with azurophilic cytoplasm and prominent nucleoli. Extensive infectious disease workup was negative. Bone marrow biopsy specimen showed no evidence of involvement by lymphoma.
The patient underwent a right frontal craniotomy to biopsy the frontal brain lesion. Histologic examination revealed a mixture of medium-sized to large atypical cells with relatively abundant amphophilic cytoplasm and nuclei that were eccentrically placed and occasionally multilobated Figure 1D. By immunohistochemistry, the tumor cells were positive for CD30 and ALK-1 (cytoplasmic only) Figure 1F and Figure 1H. The tumor cells were additionally positive for CD2, CD3, Cd7, CD43, perforin, and granzyme B. A subset of the lymphoma population was positive for CD8. The tumor cells were negative for TdT, CD4, CD5, CD56, CD57, CD20, and PAX-5. In situ hybridization for EBER ISH was negative. FISH analysis revealed ALK gene rearrangement using an ALK break-apart probe set. Additional molecular genetic studies were not performed.
Following the diagnosis, imaging of the chest and abdomen by PET/CT revealed no evidence of disease outside of the CNS, thus confirming the diagnosis of primary CNS ALCL, ALK+. The patient was subsequently treated with high-dose methotrexate for a total of eight cycles followed by two consolidation cycles. He also received monthly temozolomide for a total of 12 cycles. He was then treated with monthly high-dose methotrexate for a total of 10 months. At last follow-up, 76 months after initial presentation, he was disease free without evidence of recurrence.
Case 3
A 37-year-old right-handed man presented with 1 week of headaches, decreased appetite, weight loss, fevers, night sweats, and dysarthria. Brain MRI showed multiple contrast-enhancing lesions in the supratentorial and infratentorial compartments with leptomeningeal and parenchymal involvement.
Biopsy specimen of a cerebellar lesion showed cerebellum infiltrated by markedly atypical cells predominantly in the molecular layer and leptomeninges. The neoplastic cells were large, with irregular nuclei, prominent nucleoli, coarse chromatin, and abundant basophilic to clear cytoplasm. Immunohistochemical studies showed that the cells were positive for CD30 (diffuse, strong), ALK-1, CD45, CD25, and TIA-1 (focal) and negative for CD2, CD3, CD4, CD5, CD8, CD20, CD79a, CD138, EMA, and EBER ISH, establishing a diagnosis of primary CNS ALCL, ALK+. Cytogenetic studies demonstrated a normal male karyotype, and an NGS panel did not identify pathogenic genetic alterations.
Staging CT scans showed no splenomegaly or intrathoracic or intra-abdominal adenopathy. Bone marrow biopsy specimen did not show involvement by lymphoma, and chromosomal analysis revealed a normal male karyotype. The peripheral blood smear showed granulocytosis with occasional circulating myelocytes and occasional reactive lymphocytes without evidence of circulating lymphoma cells.
The patient was treated with local tumor resection and intrathecal methotrexate. Follow-up MRI study 9 months after the initial presentation showed persistent T2 abnormalities in the margin of the frontal lobe resection cavity. He was seen by his primary oncologist 12 months after initial presentation and was in clinical remission but subsequently lost to follow-up.
Literature Review
We systematically searched the PubMed database from the years 1980 to 2021 and found 30 articles describing 31 cases of primary CNS ALCL, ALK+.3-32 All of these articles except for one are single case reports. The only previous case series described five cases of primary CNS ALCL, ALK+,7 three of which had been published previously as individual case reports,3-5 which expanded upon the description by George et al.7 Including the three new cases presented above, we reviewed the clinical, radiologic, histologic, cytogenetic, and molecular profiles of 34 total cases of primary CNS ALCL, ALK+ Table 1.
Summary of Characteristics of Reported Primary Central Nervous System Anaplastic Large Cell Lymphoma, Anaplastic Lymphoma Kinase Positive
| Case No. | Authors | Age, y | Sex | Location | Meningeal Involvement | Phenotype | ALK staining Pattern | Cytogenetics/Molecular | Chemotherapy | Radiation | Methotrexate | Outcome (Interval From Diagnosis) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Havlioglu et al, 19953 | 4.5 | F | Multiple cerebral lobes, brainstem, spinal cord | + | Null | N + C | NA | + | + | – | Alive, NED (6.1 years) |
| 2 | Buxton et al, 19984 | 10 | M | Parietal lobe and falx | + | T cell | N + C | NA | + | – | + | Dead (6 months) |
| 3 | Abdulkader et al, 19995 | 13 | M | Frontal and parietal lobes | – | T cell | N + C | NA | + | – | + | Dead (NA) |
| 4 | Ponzoni et al, 20026 | 29 | M | Frontotemporal lobe | + | T cell | N | NA | + | + | + | Alive, NED (19 months) |
| 5 | George et al, 20037 | 17 | M | Parietal dura | + | T cell | N + C | NA | – | + | – | Alive, NED (4.8 years) |
| 6 | George et al, 20037 | 18 | F | Temporal lobe and dura | + | T cell | N + C | NA | + | + | – | Alive, NED (5.2 years) |
| 7 | Rupani et al, 20058 | 17 | M | Frontoparietal dura | + | T cell | C | NA | + | + | – | Dead (4 months) |
| 8 | Cooper et al, 20069 | 39 | M | Parieto-occipital lobe | – | T cell | N + C | NA | + | + | + | Alive, NED (9 months) |
| 9 | Karikari et al, 200710 | 4 | M | Frontal and parietal lobes, pineal | + | T cell | N + C | Karyotype t(2;5)(p23;q35) | + | + | – | Alive, NED (1 month) |
| 10 | Carmichael, 200711 | 38 | M | Parieto-occipital lobe | – | T cell | NA | NA | + | + | + | Alive, NED (15 months) |
| 11 | Merlin et al, 200812 | 13 | M | Frontal leptomeninges | + | T cell | N + C | TCR gene rearrangement NPM1-ALK gene fusion | + | + | + | Dead after second relapse (27 months) |
| 12 | Ozkaynak, 200913 | 9 | M | Bilateral frontal lobes | + | T cell | NA | NA | + | + | + | Alive, NED (26 months) |
| 13 | Shah et al, 201014 | 2 | M | Right hemisphere leptomeninges | + | T cell | N + C | NA | + | – | + | Alive, NED (9 years) |
| 14 | Vivekanandan et al, 201115 | 20 | M | Temporal leptomeninges | + | T cell | NA | NA | + | + | + | Alive, NED (8 years) |
| 15 | Nomura et al, 201316 | 20 | M | Frontal lobe | – | T cell | N + C | NA | + | – | + | Alive, NED (5 years) |
| 16 | Park et al, 201317 | 31 | M | Temporal leptomeninges | + | T cell | N + C | ALK rearrangement (FISH) | + | – | + | Alive, NED (18 months) |
| 17 | Kim et al, 201318 | 30 | M | Parieto-occipital dura | + | T cell | N + C | ALK rearrangement (FISH) | + | + | + | Alive, NED (16 months) |
| 18 | Geetha et al, 201419 | 19 | M | Cerebellum | – | Null | C | NA | + | – | + | Dead (10 months) |
| 19 | Kim et al, 201420 | 10 | F | Left hemisphere leptomeninges | + | NA | N + C | NA | + | – | + | Alive, NED (2 months) |
| 20 | Furuya et al, 201421 | 11 | M | Parietal lobe | + | Null | N + C | NA | + | + | + | Alive, NED (8 years) |
| 21 | Menon et al, 201522 | 43 | M | Multiple falx dura lesions | + | Null | N + C | TCR gene rearrangement NGS analysis: wild type | NA | NA | NA | Dead (NA) |
| 22 | Dunbar et al, 201523 | 10 | M | Frontal lobe, basal ganglia | + | T cell | N + C | ALK rearrangement (FISH) | + | + | + | Alive, NED (3 years) |
| 23 | Kuntegowdenahalli et al, 201524 | 18 | M | Parieto-occipital dura | + | T cell | N + C | NA | + | + | + | Alive, NED (NA) |
| 24 | Splavski et al, 201625 | 26 | M | Lateral ventricle | – | T cell | NA | NA | + | + | + | Alive, NED (2 years) |
| 25 | Dong et al, 201626 | 34 | M | Spinal dura and cauda equina | + | Null | N + C | NA | + | + | + | Alive, NED (23 months) |
| 26 | Kaku et al, 201727 | 21 | M | Frontoparietal dura | + | Null | N + C | NA | + | + | + | Alive, NED (2 years) |
| 27 | Feng et al, 202028 | 8 | M | Occipital lobe | + | T cell | N + C | TCR gene rearrangement | NA | NA | NA | Dead (8 weeks) |
| 28 | Hirano et al, 202029 | 26 | M | Occipital dura | + | T cell | N + C | NA | + | – | + | Alive (5 months) with recurrence (2 months) |
| 29 | Lee et al, 202030 | 12 | M | Parietal dura | + | NA | N + C | NA | + | – | + | Alive, NED (16 months) |
| 30 | Liu et al, 202031 | 12 | M | Occipital dura | – | Null | N + C | ALK rearrangement (FISH) TCR gene rearrangement | – | – | – | Dead (1 month) |
| 31 | Strosberg and Sagatys, 202132 | 29 | F | Frontal lobe, basal ganglia, brainstem | – | T cell | N + C | NA | + | – | + | Dead (39 months) |
| 32 | Current study case 1 | 36 | F | Basal ganglia | – | T cell | N | ALK rearrangement (FISH) NPM1-ALK gene fusion | + | – | + | Alive, NED (19 months) |
| 33 | Current study case 2 | 33 | M | Frontal lobe | – | T cell | C | ALK rearrangement (FISH) | + | – | + | Alive, NED (6 years) |
| 34 | Current study case 3 | 37 | M | Multiple supra- and infratentorial lesions | + | Null | NA | NGS analysis: wild type | + | – | + | Alive, NED (12 months) |
| Case No. | Authors | Age, y | Sex | Location | Meningeal Involvement | Phenotype | ALK staining Pattern | Cytogenetics/Molecular | Chemotherapy | Radiation | Methotrexate | Outcome (Interval From Diagnosis) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Havlioglu et al, 19953 | 4.5 | F | Multiple cerebral lobes, brainstem, spinal cord | + | Null | N + C | NA | + | + | – | Alive, NED (6.1 years) |
| 2 | Buxton et al, 19984 | 10 | M | Parietal lobe and falx | + | T cell | N + C | NA | + | – | + | Dead (6 months) |
| 3 | Abdulkader et al, 19995 | 13 | M | Frontal and parietal lobes | – | T cell | N + C | NA | + | – | + | Dead (NA) |
| 4 | Ponzoni et al, 20026 | 29 | M | Frontotemporal lobe | + | T cell | N | NA | + | + | + | Alive, NED (19 months) |
| 5 | George et al, 20037 | 17 | M | Parietal dura | + | T cell | N + C | NA | – | + | – | Alive, NED (4.8 years) |
| 6 | George et al, 20037 | 18 | F | Temporal lobe and dura | + | T cell | N + C | NA | + | + | – | Alive, NED (5.2 years) |
| 7 | Rupani et al, 20058 | 17 | M | Frontoparietal dura | + | T cell | C | NA | + | + | – | Dead (4 months) |
| 8 | Cooper et al, 20069 | 39 | M | Parieto-occipital lobe | – | T cell | N + C | NA | + | + | + | Alive, NED (9 months) |
| 9 | Karikari et al, 200710 | 4 | M | Frontal and parietal lobes, pineal | + | T cell | N + C | Karyotype t(2;5)(p23;q35) | + | + | – | Alive, NED (1 month) |
| 10 | Carmichael, 200711 | 38 | M | Parieto-occipital lobe | – | T cell | NA | NA | + | + | + | Alive, NED (15 months) |
| 11 | Merlin et al, 200812 | 13 | M | Frontal leptomeninges | + | T cell | N + C | TCR gene rearrangement NPM1-ALK gene fusion | + | + | + | Dead after second relapse (27 months) |
| 12 | Ozkaynak, 200913 | 9 | M | Bilateral frontal lobes | + | T cell | NA | NA | + | + | + | Alive, NED (26 months) |
| 13 | Shah et al, 201014 | 2 | M | Right hemisphere leptomeninges | + | T cell | N + C | NA | + | – | + | Alive, NED (9 years) |
| 14 | Vivekanandan et al, 201115 | 20 | M | Temporal leptomeninges | + | T cell | NA | NA | + | + | + | Alive, NED (8 years) |
| 15 | Nomura et al, 201316 | 20 | M | Frontal lobe | – | T cell | N + C | NA | + | – | + | Alive, NED (5 years) |
| 16 | Park et al, 201317 | 31 | M | Temporal leptomeninges | + | T cell | N + C | ALK rearrangement (FISH) | + | – | + | Alive, NED (18 months) |
| 17 | Kim et al, 201318 | 30 | M | Parieto-occipital dura | + | T cell | N + C | ALK rearrangement (FISH) | + | + | + | Alive, NED (16 months) |
| 18 | Geetha et al, 201419 | 19 | M | Cerebellum | – | Null | C | NA | + | – | + | Dead (10 months) |
| 19 | Kim et al, 201420 | 10 | F | Left hemisphere leptomeninges | + | NA | N + C | NA | + | – | + | Alive, NED (2 months) |
| 20 | Furuya et al, 201421 | 11 | M | Parietal lobe | + | Null | N + C | NA | + | + | + | Alive, NED (8 years) |
| 21 | Menon et al, 201522 | 43 | M | Multiple falx dura lesions | + | Null | N + C | TCR gene rearrangement NGS analysis: wild type | NA | NA | NA | Dead (NA) |
| 22 | Dunbar et al, 201523 | 10 | M | Frontal lobe, basal ganglia | + | T cell | N + C | ALK rearrangement (FISH) | + | + | + | Alive, NED (3 years) |
| 23 | Kuntegowdenahalli et al, 201524 | 18 | M | Parieto-occipital dura | + | T cell | N + C | NA | + | + | + | Alive, NED (NA) |
| 24 | Splavski et al, 201625 | 26 | M | Lateral ventricle | – | T cell | NA | NA | + | + | + | Alive, NED (2 years) |
| 25 | Dong et al, 201626 | 34 | M | Spinal dura and cauda equina | + | Null | N + C | NA | + | + | + | Alive, NED (23 months) |
| 26 | Kaku et al, 201727 | 21 | M | Frontoparietal dura | + | Null | N + C | NA | + | + | + | Alive, NED (2 years) |
| 27 | Feng et al, 202028 | 8 | M | Occipital lobe | + | T cell | N + C | TCR gene rearrangement | NA | NA | NA | Dead (8 weeks) |
| 28 | Hirano et al, 202029 | 26 | M | Occipital dura | + | T cell | N + C | NA | + | – | + | Alive (5 months) with recurrence (2 months) |
| 29 | Lee et al, 202030 | 12 | M | Parietal dura | + | NA | N + C | NA | + | – | + | Alive, NED (16 months) |
| 30 | Liu et al, 202031 | 12 | M | Occipital dura | – | Null | N + C | ALK rearrangement (FISH) TCR gene rearrangement | – | – | – | Dead (1 month) |
| 31 | Strosberg and Sagatys, 202132 | 29 | F | Frontal lobe, basal ganglia, brainstem | – | T cell | N + C | NA | + | – | + | Dead (39 months) |
| 32 | Current study case 1 | 36 | F | Basal ganglia | – | T cell | N | ALK rearrangement (FISH) NPM1-ALK gene fusion | + | – | + | Alive, NED (19 months) |
| 33 | Current study case 2 | 33 | M | Frontal lobe | – | T cell | C | ALK rearrangement (FISH) | + | – | + | Alive, NED (6 years) |
| 34 | Current study case 3 | 37 | M | Multiple supra- and infratentorial lesions | + | Null | NA | NGS analysis: wild type | + | – | + | Alive, NED (12 months) |
C, cytoplasmic immunostaining; FISH, fluorescence in situ hybridization; N, nuclear immunostaining; NA, not available; N + C, nuclear and cytoplasmic immunostaining; NED, no evidence of disease; NGS, next-generation sequencing; TCR, T-cell receptor; +, given; –, not given.
aT-cell phenotype includes at least one positive T-cell marker (ie, CD2, CD3, CD4, CD5, CD8, etc).
Summary of Characteristics of Reported Primary Central Nervous System Anaplastic Large Cell Lymphoma, Anaplastic Lymphoma Kinase Positive
| Case No. | Authors | Age, y | Sex | Location | Meningeal Involvement | Phenotype | ALK staining Pattern | Cytogenetics/Molecular | Chemotherapy | Radiation | Methotrexate | Outcome (Interval From Diagnosis) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Havlioglu et al, 19953 | 4.5 | F | Multiple cerebral lobes, brainstem, spinal cord | + | Null | N + C | NA | + | + | – | Alive, NED (6.1 years) |
| 2 | Buxton et al, 19984 | 10 | M | Parietal lobe and falx | + | T cell | N + C | NA | + | – | + | Dead (6 months) |
| 3 | Abdulkader et al, 19995 | 13 | M | Frontal and parietal lobes | – | T cell | N + C | NA | + | – | + | Dead (NA) |
| 4 | Ponzoni et al, 20026 | 29 | M | Frontotemporal lobe | + | T cell | N | NA | + | + | + | Alive, NED (19 months) |
| 5 | George et al, 20037 | 17 | M | Parietal dura | + | T cell | N + C | NA | – | + | – | Alive, NED (4.8 years) |
| 6 | George et al, 20037 | 18 | F | Temporal lobe and dura | + | T cell | N + C | NA | + | + | – | Alive, NED (5.2 years) |
| 7 | Rupani et al, 20058 | 17 | M | Frontoparietal dura | + | T cell | C | NA | + | + | – | Dead (4 months) |
| 8 | Cooper et al, 20069 | 39 | M | Parieto-occipital lobe | – | T cell | N + C | NA | + | + | + | Alive, NED (9 months) |
| 9 | Karikari et al, 200710 | 4 | M | Frontal and parietal lobes, pineal | + | T cell | N + C | Karyotype t(2;5)(p23;q35) | + | + | – | Alive, NED (1 month) |
| 10 | Carmichael, 200711 | 38 | M | Parieto-occipital lobe | – | T cell | NA | NA | + | + | + | Alive, NED (15 months) |
| 11 | Merlin et al, 200812 | 13 | M | Frontal leptomeninges | + | T cell | N + C | TCR gene rearrangement NPM1-ALK gene fusion | + | + | + | Dead after second relapse (27 months) |
| 12 | Ozkaynak, 200913 | 9 | M | Bilateral frontal lobes | + | T cell | NA | NA | + | + | + | Alive, NED (26 months) |
| 13 | Shah et al, 201014 | 2 | M | Right hemisphere leptomeninges | + | T cell | N + C | NA | + | – | + | Alive, NED (9 years) |
| 14 | Vivekanandan et al, 201115 | 20 | M | Temporal leptomeninges | + | T cell | NA | NA | + | + | + | Alive, NED (8 years) |
| 15 | Nomura et al, 201316 | 20 | M | Frontal lobe | – | T cell | N + C | NA | + | – | + | Alive, NED (5 years) |
| 16 | Park et al, 201317 | 31 | M | Temporal leptomeninges | + | T cell | N + C | ALK rearrangement (FISH) | + | – | + | Alive, NED (18 months) |
| 17 | Kim et al, 201318 | 30 | M | Parieto-occipital dura | + | T cell | N + C | ALK rearrangement (FISH) | + | + | + | Alive, NED (16 months) |
| 18 | Geetha et al, 201419 | 19 | M | Cerebellum | – | Null | C | NA | + | – | + | Dead (10 months) |
| 19 | Kim et al, 201420 | 10 | F | Left hemisphere leptomeninges | + | NA | N + C | NA | + | – | + | Alive, NED (2 months) |
| 20 | Furuya et al, 201421 | 11 | M | Parietal lobe | + | Null | N + C | NA | + | + | + | Alive, NED (8 years) |
| 21 | Menon et al, 201522 | 43 | M | Multiple falx dura lesions | + | Null | N + C | TCR gene rearrangement NGS analysis: wild type | NA | NA | NA | Dead (NA) |
| 22 | Dunbar et al, 201523 | 10 | M | Frontal lobe, basal ganglia | + | T cell | N + C | ALK rearrangement (FISH) | + | + | + | Alive, NED (3 years) |
| 23 | Kuntegowdenahalli et al, 201524 | 18 | M | Parieto-occipital dura | + | T cell | N + C | NA | + | + | + | Alive, NED (NA) |
| 24 | Splavski et al, 201625 | 26 | M | Lateral ventricle | – | T cell | NA | NA | + | + | + | Alive, NED (2 years) |
| 25 | Dong et al, 201626 | 34 | M | Spinal dura and cauda equina | + | Null | N + C | NA | + | + | + | Alive, NED (23 months) |
| 26 | Kaku et al, 201727 | 21 | M | Frontoparietal dura | + | Null | N + C | NA | + | + | + | Alive, NED (2 years) |
| 27 | Feng et al, 202028 | 8 | M | Occipital lobe | + | T cell | N + C | TCR gene rearrangement | NA | NA | NA | Dead (8 weeks) |
| 28 | Hirano et al, 202029 | 26 | M | Occipital dura | + | T cell | N + C | NA | + | – | + | Alive (5 months) with recurrence (2 months) |
| 29 | Lee et al, 202030 | 12 | M | Parietal dura | + | NA | N + C | NA | + | – | + | Alive, NED (16 months) |
| 30 | Liu et al, 202031 | 12 | M | Occipital dura | – | Null | N + C | ALK rearrangement (FISH) TCR gene rearrangement | – | – | – | Dead (1 month) |
| 31 | Strosberg and Sagatys, 202132 | 29 | F | Frontal lobe, basal ganglia, brainstem | – | T cell | N + C | NA | + | – | + | Dead (39 months) |
| 32 | Current study case 1 | 36 | F | Basal ganglia | – | T cell | N | ALK rearrangement (FISH) NPM1-ALK gene fusion | + | – | + | Alive, NED (19 months) |
| 33 | Current study case 2 | 33 | M | Frontal lobe | – | T cell | C | ALK rearrangement (FISH) | + | – | + | Alive, NED (6 years) |
| 34 | Current study case 3 | 37 | M | Multiple supra- and infratentorial lesions | + | Null | NA | NGS analysis: wild type | + | – | + | Alive, NED (12 months) |
| Case No. | Authors | Age, y | Sex | Location | Meningeal Involvement | Phenotype | ALK staining Pattern | Cytogenetics/Molecular | Chemotherapy | Radiation | Methotrexate | Outcome (Interval From Diagnosis) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Havlioglu et al, 19953 | 4.5 | F | Multiple cerebral lobes, brainstem, spinal cord | + | Null | N + C | NA | + | + | – | Alive, NED (6.1 years) |
| 2 | Buxton et al, 19984 | 10 | M | Parietal lobe and falx | + | T cell | N + C | NA | + | – | + | Dead (6 months) |
| 3 | Abdulkader et al, 19995 | 13 | M | Frontal and parietal lobes | – | T cell | N + C | NA | + | – | + | Dead (NA) |
| 4 | Ponzoni et al, 20026 | 29 | M | Frontotemporal lobe | + | T cell | N | NA | + | + | + | Alive, NED (19 months) |
| 5 | George et al, 20037 | 17 | M | Parietal dura | + | T cell | N + C | NA | – | + | – | Alive, NED (4.8 years) |
| 6 | George et al, 20037 | 18 | F | Temporal lobe and dura | + | T cell | N + C | NA | + | + | – | Alive, NED (5.2 years) |
| 7 | Rupani et al, 20058 | 17 | M | Frontoparietal dura | + | T cell | C | NA | + | + | – | Dead (4 months) |
| 8 | Cooper et al, 20069 | 39 | M | Parieto-occipital lobe | – | T cell | N + C | NA | + | + | + | Alive, NED (9 months) |
| 9 | Karikari et al, 200710 | 4 | M | Frontal and parietal lobes, pineal | + | T cell | N + C | Karyotype t(2;5)(p23;q35) | + | + | – | Alive, NED (1 month) |
| 10 | Carmichael, 200711 | 38 | M | Parieto-occipital lobe | – | T cell | NA | NA | + | + | + | Alive, NED (15 months) |
| 11 | Merlin et al, 200812 | 13 | M | Frontal leptomeninges | + | T cell | N + C | TCR gene rearrangement NPM1-ALK gene fusion | + | + | + | Dead after second relapse (27 months) |
| 12 | Ozkaynak, 200913 | 9 | M | Bilateral frontal lobes | + | T cell | NA | NA | + | + | + | Alive, NED (26 months) |
| 13 | Shah et al, 201014 | 2 | M | Right hemisphere leptomeninges | + | T cell | N + C | NA | + | – | + | Alive, NED (9 years) |
| 14 | Vivekanandan et al, 201115 | 20 | M | Temporal leptomeninges | + | T cell | NA | NA | + | + | + | Alive, NED (8 years) |
| 15 | Nomura et al, 201316 | 20 | M | Frontal lobe | – | T cell | N + C | NA | + | – | + | Alive, NED (5 years) |
| 16 | Park et al, 201317 | 31 | M | Temporal leptomeninges | + | T cell | N + C | ALK rearrangement (FISH) | + | – | + | Alive, NED (18 months) |
| 17 | Kim et al, 201318 | 30 | M | Parieto-occipital dura | + | T cell | N + C | ALK rearrangement (FISH) | + | + | + | Alive, NED (16 months) |
| 18 | Geetha et al, 201419 | 19 | M | Cerebellum | – | Null | C | NA | + | – | + | Dead (10 months) |
| 19 | Kim et al, 201420 | 10 | F | Left hemisphere leptomeninges | + | NA | N + C | NA | + | – | + | Alive, NED (2 months) |
| 20 | Furuya et al, 201421 | 11 | M | Parietal lobe | + | Null | N + C | NA | + | + | + | Alive, NED (8 years) |
| 21 | Menon et al, 201522 | 43 | M | Multiple falx dura lesions | + | Null | N + C | TCR gene rearrangement NGS analysis: wild type | NA | NA | NA | Dead (NA) |
| 22 | Dunbar et al, 201523 | 10 | M | Frontal lobe, basal ganglia | + | T cell | N + C | ALK rearrangement (FISH) | + | + | + | Alive, NED (3 years) |
| 23 | Kuntegowdenahalli et al, 201524 | 18 | M | Parieto-occipital dura | + | T cell | N + C | NA | + | + | + | Alive, NED (NA) |
| 24 | Splavski et al, 201625 | 26 | M | Lateral ventricle | – | T cell | NA | NA | + | + | + | Alive, NED (2 years) |
| 25 | Dong et al, 201626 | 34 | M | Spinal dura and cauda equina | + | Null | N + C | NA | + | + | + | Alive, NED (23 months) |
| 26 | Kaku et al, 201727 | 21 | M | Frontoparietal dura | + | Null | N + C | NA | + | + | + | Alive, NED (2 years) |
| 27 | Feng et al, 202028 | 8 | M | Occipital lobe | + | T cell | N + C | TCR gene rearrangement | NA | NA | NA | Dead (8 weeks) |
| 28 | Hirano et al, 202029 | 26 | M | Occipital dura | + | T cell | N + C | NA | + | – | + | Alive (5 months) with recurrence (2 months) |
| 29 | Lee et al, 202030 | 12 | M | Parietal dura | + | NA | N + C | NA | + | – | + | Alive, NED (16 months) |
| 30 | Liu et al, 202031 | 12 | M | Occipital dura | – | Null | N + C | ALK rearrangement (FISH) TCR gene rearrangement | – | – | – | Dead (1 month) |
| 31 | Strosberg and Sagatys, 202132 | 29 | F | Frontal lobe, basal ganglia, brainstem | – | T cell | N + C | NA | + | – | + | Dead (39 months) |
| 32 | Current study case 1 | 36 | F | Basal ganglia | – | T cell | N | ALK rearrangement (FISH) NPM1-ALK gene fusion | + | – | + | Alive, NED (19 months) |
| 33 | Current study case 2 | 33 | M | Frontal lobe | – | T cell | C | ALK rearrangement (FISH) | + | – | + | Alive, NED (6 years) |
| 34 | Current study case 3 | 37 | M | Multiple supra- and infratentorial lesions | + | Null | NA | NGS analysis: wild type | + | – | + | Alive, NED (12 months) |
C, cytoplasmic immunostaining; FISH, fluorescence in situ hybridization; N, nuclear immunostaining; NA, not available; N + C, nuclear and cytoplasmic immunostaining; NED, no evidence of disease; NGS, next-generation sequencing; TCR, T-cell receptor; +, given; –, not given.
aT-cell phenotype includes at least one positive T-cell marker (ie, CD2, CD3, CD4, CD5, CD8, etc).
The median and mean (SD) ages at diagnosis were 18.5 and 20.6 (11.4) years, respectively (range, 2-43 years). Fifteen (44.1%) patients were younger than 18 years, and 19 (55.9%) were 18 years old or older. There were 28 male patients and 6 female patients, with a male-to-female ratio of 4.7:1. The most common presenting symptoms included headache (21 cases, 61.8%), seizure (15 cases, 44.1%), vomiting (10 cases, 29.4%), focal motor deficit (10 cases, 29.4%), and fever (8 cases, 23.5%). Other, less common, presenting symptoms included altered mental status/confusion (6 cases, 17.6%), dizziness/ataxia (5 cases, 14.7%), and visual deficit (5 cases, 14.7%). Uncommon presenting symptoms included generalized weakness, weight loss, focal sensory deficit, and aphasia (two cases each, 5.4%) and neck stiffness, syncope, and fatigue (one case each, 2.9%).
Tumors were most commonly solitary (25 cases, 73.5%), whereas 9 (26.5%) patients had multifocal disease within the CNS at presentation. Tumors were isolated to the supratentorial compartment in 32 (94.1%) cases, the infratentorial compartment in 5 (14.7%) cases, and both the supra- and infratentorial compartments in 2 (5.9%) cases. Interestingly, in one case, the tumor was located within the lateral ventricle.25 Involvement limited to the dura/leptomeninges was reported in 13 (38.2%) cases, while dural/leptomeningeal involvement in addition to parenchymal involvement was reported in 25 (73.5%) cases.
Treatment details were available for all but two cases. Thirty (93.8%) of 32 patients received chemotherapy, with 26 (81.3%) patients receiving methotrexate at some point during their treatment course. Eighteen (56.3%) patients received radiation therapy, 3 (9.4%) patients received autologous stem cell transplant, and 1 patient received no specific lymphoma therapy. Overall, 25 (73.5%) patients were alive at the time of report (only one of whom experienced disease recurrence), while 9 (26.5%) patients had died of their disease. Among the seven patients who died with available data, the median overall survival was 6 months (range, 1-39 months). Kaplan-Meier analysis revealed significantly better overall survival in patients younger than 18 years compared with those 18 years or older old (P = .005) Figure 2A. There was no statistically significant difference in overall survival based on tumor focality (unifocal vs multifocal), immunophenotype (T cell vs null cell), or treatment (chemotherapy only vs chemotherapy and radiation) Figure 2B, Figure 2C, and Figure 2D.
Survival analysis of primary central nervous system anaplastic large cell lymphoma, anaplastic lymphoma kinase positive. Kaplan-Meier analysis to assess overall survival based on age (P = .0048) (A), tumor focality (P = .5298) (B), immunophenotype (P = .8556) (C), and treatment (P = .5944) (D). Log-rank test for significance.
The immunohistochemical characteristics reported in each study varied greatly. A summary of the most commonly reported immunostains is provided in Figure 3. As expected, CD30 was specifically reported as positive in all but one case (Nomura et al16 did not report CD30 results). Similarly, CD45 was positive in 24 of 26 cases. All 34 cases describe ALK positivity in tumor cells, although the staining pattern was reported or displayed for only 28 (82.4%) cases. Nuclear and cytoplasmic ALK staining was observed in 23 (82.1%) of 28 cases, nucleus-restricted staining was observed in 2 (7.1%) cases, and staining restricted to the cytoplasm was reported in 3 (10.7%) cases. For cases in which sufficient data were available, most (24 of 32, 75.0%) displayed a T-cell immunophenotype, whereas 8 (25.0%) cases displayed a null-cell phenotype. Insufficient data were presented in two reports,20,30 thereby precluding classification of those tumors as T cell or null cell. Of the cases in which T-cell markers were reported, 14 (53.8%) of 26 were CD3 positive, 7 (77.8%) of 9 were CD43 positive, 6 (50.0%) of 12 were CD4 positive, 4 (36.4%) of 11 were CD8 positive, 4 (57.1%) of 7 were CD7 positive, and 3 (37.5%) of 8 were CD2 positive. B-cell markers were negative in all 27 cases in which the stains were reported. Granzyme B was positive in 7 (100%) of 7 cases, and TIA-1 was positive in 6 (75.0%) of 8 cases. CD5 was reported positive in only 2 (18.2%) of 11 cases. Finally, Ki-67 was reported in 15 cases, with a median reported proliferation index of 85% (range, 50%-95%).
Immunohistochemical profile of primary central nervous system anaplastic large cell lymphoma, anaplastic lymphoma kinase positive. The immunohistochemical staining profile for prior reported cases and the current cases is summarized.
Cytogenetic and/or molecular studies were infrequently reported (12 of 34 cases, 35.3%). T-cell receptor gamma (TRG) gene rearrangement studies identified a clonal T-cell population in four cases. FISH using ALK gene break-apart probes was positive for an ALK rearrangement in all six cases in which the results were reported. In one case, NPM1-ALK gene fusion was detected by reverse transcriptase–PCR.12 Similarly, case 1 was also shown to harbor the NPM1-ALK gene rearrangement by a gene fusion assay. One case described a balanced reciprocal translocation between chromosomes 2p23 and 5q35,10 potentially supporting an NPM1-ALK fusion, but was not assessed further or confirmed. Finally, case 3 demonstrated a normal karyotype and no mutations by an NGS panel of 447 genes associated with cancer.
Discussion
We present three new cases of primary CNS ALCL, ALK+, comprising the largest case series to date. We also review the literature from 31 prior cases of primary CNS ALCL, ALK+. This tumor tends to occur in children and young adults, predominantly male patients, and patients commonly have headache and/or seizure. Most tumors are unifocal and often involve the dura and/or leptomeninges. Reported treatments commonly include chemotherapy, and overall survival varies considerably, with most patients experiencing favorable long-term outcomes while others died of their disease relatively quickly.
Overall, the clinical characteristics of primary CNS ALCL, ALK+ are similar to those of systemic ALCL, ALK+, in that younger male patients are predominantly affected with relatively good clinical outcome.47 Other primary CNS T-cell lymphomas, such as ALCL, ALK– and peripheral T-cell lymphoma, not otherwise specified, also tend to have leptomeningeal involvement, similar to primary CNS ALCL, ALK+. However, other varieties of primary CNS T-cell lymphoma tend to occur in older patients and act more aggressively, with a worse clinical outcome.22
Primary CNS ALCL, ALK+ presents as a diagnostic challenge, both radiographically and histologically. The radiographic differential diagnosis for primary CNS ALCL, ALK+ is broad and includes infection, an autoimmune process, and other parenchymal tumors. Clinically, patients often have signs/symptoms of meningitis. Similarly, the radiologic finding of leptomeningeal involvement can support a clinical suspicion of meningitis, and indeed, many of the patients summarized here were first treated with antibiotics and/or antituberculous agents. In addition, inflammatory/autoimmune pachymeningitis can present with nonspecific signs and radiologic evidence of leptomeningeal thickening/enhancement, as was observed in several cases summarized here. Interestingly, primary diffuse large B-cell lymphoma of the CNS rarely presents with leptomeningeal involvement, unlike primary CNS ALCL, ALK+ and other primary CNS T-cell lymphomas, thus providing a diagnostic clue when evaluating for CNS lymphomas.48 For parenchymal tumors, one must also consider glial/glioneuronal tumors and embryonal tumors in children and young adults.
In the published literature, more aggressive diagnostic techniques, such as brain biopsy, were used only when symptoms worsened or did not improve. However, the histologic and immunohistochemical heterogeneity of CNS lymphomas as well as the extreme rarity of primary CNS ALCL, ALK+ may contribute to diagnostic challenges. Thus, CD30 immunostaining can serve as a useful screening tool for any primary CNS lymphoma that lacks expression of B-cell markers.
Several questions remain regarding primary CNS ALCL, ALK+. In particular, only a minority of publications report on this tumor’s molecular/cytogenetic features. ALK FISH was reported in only six cases, and an NPM1-ALK gene rearrangement was only reported twice. There were several cases with cytoplasmic ALK staining that suggest a noncanonical ALK fusion (including one case in our series), but most of these cases were not analyzed further. As such, potential novel gene fusions may not be reported, thus creating a gap in the knowledge of ALCL, ALK+ disease biology. However, as brain biopsies are limited in nature, further molecular analysis may not be always feasible, and this continues to be a challenge in the diagnostic evaluation of primary CNS lymphomas. To illustrate this particular limitation, case 3 failed to reveal genomic changes by karyotype and NGS, and this may be the result of limited tumor cellularity, genetic changes below the validated limit of detection, or sampling bias, especially in relation to the karyotype result. As such, tissue stewardship may be necessary when evaluating potential CNS lymphomas, especially given the rarity of these tumors.
Also, given the rarity of primary CNS ALCL, ALK+, there are no consistent treatment guidelines to follow, and treatment modalities reported in the literature vary considerably. With the advancement of personalized medicine, and ALK-specific inhibitors in particular, the molecular drivers controlling tumorigenesis can be targeted for more rationalized and, ideally, more efficacious therapies.
Last, ALCL, ALK+; ALCL, ALK–; primary cutaneous ALCL; and breast implant–associated ALCL are all recognized as unique (or provisional) entities in the most recent WHO classification.36 It is not currently clear whether primary CNS ALCL, ALK+ represents a unique pathologic entity or a rare, localized manifestation of ALCL, ALK+. Further studies, such as targeted NGS panels, gene fusion analysis, or optical genome mapping, may be necessary to demonstrate features that underscore its pathobiology while allowing for a better understanding of the relationship of this tumor to the far more common non-CNS ALCL, ALK+.
In conclusion, we present the largest case series to date of primary CNS ALCL, ALK+. We also review the literature regarding primary CNS ALCL, ALK+ and show that this rare tumor is more common in young male patients and often shows leptomeningeal enhancement as a presenting radiographic feature. Young age could be associated with better overall survival. We also summarize the clinical, histologic, and immunophenotypic profile of these tumors in order to aid in making this challenging diagnosis. Primary CNS ALCL, ALK+ should be considered in any patient with a CNS lymphoma that does not morphologically or immunohistochemically resemble a B-cell lymphoma, particularly in young male patients with leptomeningeal involvement.
References
Author notes
First authors.
