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Primary Central Nervous System ALK-Negative Anaplastic Large Cell Lymphoma: A Case Report and Literature Review

Yujie Zhang, Fatemeh Fekrmandi, Jingxin Qiu
American Journal of Medical Case Reports. 2022, 10(3), 77-83. DOI: 10.12691/ajmcr-10-3-9
Received February 20, 2022; Revised March 22, 2022; Accepted March 29, 2022

Abstract

Primary central nervous system (CNS) lymphoma represents approximately 4% of CNS tumors, among which majority are originated from B-cells and only 2% from T-cells. Anaplastic large cell lymphoma (ALCL), a subtype of T-cell lymphoma, is classified into anaplastic lymphoma kinase (ALK)-positive and -negative subtypes. While the former accounts for 70-80% of cases, ALK-negative ALCL represents only a minority of cases. Here we present a case of primary CNS ALK-negative ALCL in a 73-year-old black male. He initially presented with significant fatigue and was treated for malaria with minimal improvement. He was subsequently found to have leukocytosis and developed left-sided weakness and facial droop. MRI showed a large temporoparietal intra-axial mass with vasogenic edema and mass effect. Initial brain biopsy was non-diagnostic. He was placed on steroids and pursued further workup in our institution. Upon tapering steroid, he developed left leg weakness. Repeat MRI revealed multiple intracranial lesions with one showing progression after steroid tapering. Repeat biopsy was performed and a diagnosis of primary CNS ALK-negative ALCL was rendered 47 days after the initial nondiagnostic biopsy. Literature review showed 39 reported cases of primary CNS ALCL, among which only 11 cases were ALK-negative. We present this case to demonstrate; a. the non- specific clinical presentation poses a diagnostic challenge. b. multiple intracranial lesions, along with waxing and waning clinical course with steroid administration, could be a sign of CNS lymphoma and c. biopsy prior to start of steroids is preferred for diagnosis.

1. Introduction

Primary central nervous system (CNS) lymphoma refers to a lymphoma in the eye, brain, and spinal cord with no evidence of systemic disease. Among CNS tumors, primary CNS lymphoma represents approximately 4% of central nervous system tumors 1. While majority of primary CNS lymphomas are B-cell lymphomas and approximately 95% are diffuse large B cell lymphoma 2, 3, 4, only approximately 2% of primary CNS lymphomas are T-cell lymphomas 5.

Anaplastic large cell lymphoma (ALCL), a subtype of T-cell lymphoma, is characterized by the CD30 positive large lymphocytes. This was initially introduced by using CD30 (Ki-1 clone) antibody to strongly highlight all or nearly all neoplastic cells in ALCL. Over 50% of CD30 positive lymphomas were also immunoreactive to T cell-associated antigen in the absence of B cell antigen 6. Based on the expression of anaplastic lymphoma kinase (ALK), ALCL is further subclassified into ALK-positive and ALK-negative subtypes. ALK-positive ALCL represents approximately 70-80% of cases and is well characterized by translocation of t (2; 5) (p23; q35) resulting in a fusion of nucleolar phosphoprotein 1 gene and the ALK tyrosine kinase gene 7 and is often associated with better prognosis. However, multiple layers of facts make primary CNS ALK-negative ALCL an extremely rare entity 8. It has been reported that DUSP22 rearrangements were associated with favorable outcomes TP63 rearrangements encoding p63 fusion proteins were associated with aggressive clinical behavior and poor outcomes 9, 10. Here we present a case of primary CNS ALK-negative ALCL.

2. Case Report

A 73-year-old African man with past medical history of prostate cancer status post radical prostatectomy in 2013, presented with significant fatigue in January 2021. Further infectious workup was negative including COVID-19 but his clinical presentation was consistent with active malaria infection. He was treated for malaria twice with minimal relief of symptoms and was hospitalized during the second treatment where he was found to have leukocytosis. He also developed left-sided weakness with facial drop and MRI demonstrated a large, temporoparietal intra-axial mass with vasogenic edema, mass effect, and midline shift with patchy contrast enhancement. Imaging studies including the thyroid, abdomen and pelvic did not reveal any primary site for malignancy. Initial stereotactic brain biopsy was nondiagnostic. He was placed on steroids and pursued further workup of right intracranial lesion at our institution. An outside MRI was reviewed at our institution demonstrating large area of ill-defined hyperintensity in the right cerebral hemisphere involving subcortical white matter on the right basal ganglia with increased mass effect. He was started dexamethasone taper, and repeat MRI showed the amount of enhancement is decreased compared to the previous MRI. PET scan was negative for disease outside the brain. Infectious disease studies including SARS-CoV-2, nocardia, Epstein-Barr virus (EBV), syphilis, cryptococcus, mycobacteria, and toxoplasma gondii were negative. He later developed left leg weakness and repeat MRI showed newly developed increased size of multiple enhancing nodules in the right periventricular region (Figure 1A) with the largest lesion measuring 15 mm in diameter and additional new punctate enhancing lesion in the left periventricular white matter. He was referred for repeat brain biopsy. This second brain biopsy demonstrated anaplastic large cell lymphoma, ALK-negative. Due to lack of evidence for a systemic disease and multiple socio-economic factors such as age, insurance coverage, immigration status, and available treatment options, whole-body irradiation followed by brentuximab vedotin, cyclophosphamide, hydroxydaunorubicin (doxorubicin), and prednisone was considered. He completed whole-body irradiation. On the most recent follow-up, the patient reported that he felt stronger after radiation but more recently weaker using a wheelchair with one episode of dizziness, with no residual toxicities noted. Review of MRI and laboratory findings did not reveal evidence of lymphoma (Figure 1B); therefore, patient was placed on surveillance. The patient has been doing relatively well, now at approximately 7 months post-diagnosis and 6 months post-irradiation.

Microscopic evaluation of the resected brain lesion as demonstrated in Figure 2 shows fragments of brain tissue with multifocal and perivascular infiltrates of malignant cells which are medium to large-sized with some containing multilobate/multiple nuclei. The tumor cells are positive for CD30 (strong and diffuse with membranous and Golgi staining patterns), CD2, CD4, CD25, MUM1, TIA1 (subset) and granzyme B (subset); negative for CD45, CD43, B-cell markers (CD19, CD20, PAX5, and CD79a), CD3, CD5, CD7, CD8, CD10, CD56, perforin, EMA, CD138, and CD68. ALK is negative. EBV is negative. Cytokeratin marker AE1/3, melanoma markers including Melan-A and S100 are negative. The Ki67 proliferation index is up to 80%. FISH studies of DUSP22 or TP63 gene rearrangement are negative.

  • Figure 2. Images of primary CNS ALK-negative anaplastic large cell lymphoma. Brain lesion resection shows fragments of brain tissue with multifocal and perivascular infiltrates of medium to large-sized malignant cells, some with multilobate/multiple nuclei (A and B). They are mitotically active highlighted by Ki67(C), positive for CD30 (D), CD4 (E), MUM1 (F), TIA1 (G), and Granzyme B (H), and negative for ALK (I), EBV (J), CD19 (K), and CD79a (L). TIA1: T-cell intranuclear antigen 1

3. Discussion

Primary CNS ALCL is a rare entity, literature review showed only 39 reported cases in the current literature [11-46] (Table 1) with 28 cases ALK-positive ALCL, and 11 cases ALK-negative ALCL. These patients’ age ranged from 22 to 82 with median of 63-year-old. Based on the reported 11 cases, CNS ALK-negative ALCL exhibited a male propensity (8/11, 72.7%); usually multifocal (6/11, 54.5%); and displayed a diverse prognosis with 8 patients passed away after 11 days to 8-month of follow-up, and 3 cases with no evidence of residual disease after 2 courses of chemotherapy, at 18- and 25-month follow-up.

Here we presented the 12th CNS ALK-negative ALCL case from a 73-year-old male patient from Africa. Rendering such a diagnosis is challenging and it took 47 days from the initial nondiagnostic brain biopsy to the repeat brain biopsy in the US, not to mention if the time required for diagnosis were calculated from the onset of early symptoms presented months earlier. The reported time required to make the diagnosis of this rare entity is an average of approximately 40 days 46. One reason for such a challenging diagnosis may be due to the nonspecific symptoms like fatigue that our patient presented with initially, followed by left-sided weakness and facial drop. The nonspecific presentation is in line with the reported clinical symptoms from patients with final diagnosis of CNS ALK-negative ALCL including headache, blurry vision, hemiparesis, ataxia, leg weakness, memory loss, and dementia-like symptoms [11-46].

Chart review of this current case revealed that patient was started on steroids and the initial brain biopsy was nondiagnostic. He was referred to our institution for further workup. His steroids were tapered after which he developed left leg weakness and repeat MRI showed progression of one of the intracranial lesions. A repeat brain biopsy was performed and a diagnosis of ALK- negative ALCL was confirmed. The similar clinical temporal course was also reported by Lannon et al 46. In that report, patient was discontinued on steroids and developed new onset of tingling in both hands and feet and the return of multiple intracranial abnormalities. After re- administration of steroids, MRI showed near-complete resolution of intracranial enhancement. However, patient’s clinical symptoms aggravated, and MRI showed spinal disease with significant mass effect after two weeks of discontinuation of steroids. Then the patient underwent surgery of laminectomy and resection of the lesion from which a diagnosis was reached.

In terms of the location of the intracranial lesions, this current patient was initially found to have lesions located at temporoparietal and frontal regions. This is in accordance with previously reported parietal/frontal/occipital (6/11, 54.5%) lobes of the cerebrum 15, 37, 39, 40, 41, 42, 43, 44, 45, 46. Our current case did not show meningeal involvement, which may add inflammatory processes such as meningitis or sarcoidosis, meningioma into the differential diagnoses. It has been reported that two cases with CNS ALK-negative ALCL had dura involvement 15 and majority of cases with CNS ALK- positive ALCL had meningeal involvement and some were treated with antibiotic and anti-tuberculosis regiments 12, 13, 14, 16, 19, 21, 22, 28, 30, 31, 36. And the current patient was treated with anti- malaria therapy initially in Africa.

While the correlation of EBV with B-cell lymphoma has been documented, the convincing evidence of correlation between infection of EBV or human T-cell leukemia virus and the development of ALCL is lacking and pathogenesis of ALCL is not fully elucidated. The fusion of ALK, initially identified in 1994, with nucleolar phosphoprotein 1 gene in the t (2;5) (p23; q35) is associated with majority of ALK-positive ALCL 7. This fusion results in activation of diverse pathogenic signaling pathways including RAS-extracellular signal regulated kinase pathway, Janus kinase 3-STAT3 intracellular pathway, and phosphoinositide 3-kinase-Akt pathway to facilitate cell survival, proliferation, cell cycle progression, and tumorigenesis 47. However, on the other hand, the molecular basis of ALK-negative ALCL has been unclear. Studies have demonstrated that rearrangement phosphatase gene DUSP22 due to t (6;7) (p25.3; q32.3) resulting in down-regulation of DUSP22, the function of which in ALK-negative ALCL is poorly understood, and it has been proposed that it is worthwhile to investigate if DUSP22 serves as a putative tumor suppressor 48. In addition, rearrangement of TP63 leads to inhibition of the p53 pathway and tumorigenesis 10. And the rearrangement of DUSP22 and TP63 are mutually exclusive and are absent in ALK-positive ALCL with DUSP22 having as favorable outcome as ALK-positive ALCL, and TP63 rearrangement having inferior outcomes. Similarly, DUSP22 has been reported to be associated with better outcome of ALK-negative ALCL. But TP63 rearrangements has been reported to be associated with worse outcome of ALK-negative ALCL 9. Furthermore, constitutive activation of Janus kinase 3-STAT3 pathway is also implicated in the oncogenesis of ALK-negative ALCL 49. These rearrangements suggest that ALK-negative ALCL is a heterogeneous disease genetically and shows wide range of outcome clinically and may be utilized as predicative biomarkers to guide management decision making 50. Rearrangement of DUSP22 and rearrangement of TP63 were performed for this case and were both negative. The patient is relatively doing well at 6 months post-diagnosis.

4. Conclusion

The current case, to our best knowledge, is the 12th case diagnosed with this rare entity of primary CNS ALK-negative ALCL. There are only 39 cases of primary CNS ALCL in the literatures with 28 cases of ALK-positive ALCL and 11 cases of ALK-negative ALCL. This case is in line with the previous reports in several aspects including the age, gender, location, focality, the time required to render the final diagnosis, and the effect of steroids on the lesions posing diagnostic challenges. It is suggested that when encountering patients with multiple intracranial lesions, waxing and waning clinical course after steroids administration and cessation, ALCL needs to be considered in the differential diagnosis. If clinically appropriate, biopsy/prior to steroids treatment is recommended to make earlier diagnosis.

Abbreviations

CNS: Central nervous system

ALK: Anaplastic lymphoma kinase

ALCL: Anaplastic large cell lymphoma

COVID-19: Coronavirus disease 2019

TIA1: T-cell intranuclear antigen 1

MUM1: Multiple myeloma oncogene 1

EMA: Epithelial membrane antigen

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Published with license by Science and Education Publishing, Copyright © 2022 Yujie Zhang, Fatemeh Fekrmandi and Jingxin Qiu

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Normal Style
Yujie Zhang, Fatemeh Fekrmandi, Jingxin Qiu. Primary Central Nervous System ALK-Negative Anaplastic Large Cell Lymphoma: A Case Report and Literature Review. American Journal of Medical Case Reports. Vol. 10, No. 3, 2022, pp 77-83. http://pubs.sciepub.com/ajmcr/10/3/9
MLA Style
Zhang, Yujie, Fatemeh Fekrmandi, and Jingxin Qiu. "Primary Central Nervous System ALK-Negative Anaplastic Large Cell Lymphoma: A Case Report and Literature Review." American Journal of Medical Case Reports 10.3 (2022): 77-83.
APA Style
Zhang, Y. , Fekrmandi, F. , & Qiu, J. (2022). Primary Central Nervous System ALK-Negative Anaplastic Large Cell Lymphoma: A Case Report and Literature Review. American Journal of Medical Case Reports, 10(3), 77-83.
Chicago Style
Zhang, Yujie, Fatemeh Fekrmandi, and Jingxin Qiu. "Primary Central Nervous System ALK-Negative Anaplastic Large Cell Lymphoma: A Case Report and Literature Review." American Journal of Medical Case Reports 10, no. 3 (2022): 77-83.
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  • Figure 1. MRI Images of primary CNS ALK-negative anaplastic large cell lymphoma. A. Repeat MRI after steroid tapering shows multifocal contrast enhancing lesions involving the right periventricular region. B. Repeat MRI two month after radiation shows no evidence of residual/recurrent contrast enhancing lesions
  • Figure 2. Images of primary CNS ALK-negative anaplastic large cell lymphoma. Brain lesion resection shows fragments of brain tissue with multifocal and perivascular infiltrates of medium to large-sized malignant cells, some with multilobate/multiple nuclei (A and B). They are mitotically active highlighted by Ki67(C), positive for CD30 (D), CD4 (E), MUM1 (F), TIA1 (G), and Granzyme B (H), and negative for ALK (I), EBV (J), CD19 (K), and CD79a (L). TIA1: T-cell intranuclear antigen 1
[1]  Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ. Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer. 2011; 105(9): 1414-1418.
In article      View Article  PubMed
 
[2]  Bhagavathi S, Wilson JD. Primary central nervous system lymphoma. Arch Pathol Lab Med. 2008; 132(11): 1830-1834.
In article      View Article  PubMed
 
[3]  Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011; 117(19): 5019-5032.
In article      View Article  PubMed
 
[4]  Batchelor TT, Thye LS, Habermann TM. Current Management Concepts: Primary Central Nervous System Lymphoma, Natural Killer T-Cell Lymphoma Nasal Type, and Post-transplant Lymphoproliferative Disorder. Am Soc Clin Oncol Educ Book. 2016; 35: e354-366.
In article      View Article  PubMed
 
[5]  Ferreri AJ, Reni M, Pasini F, et al. A multicenter study of treatment of primary CNS lymphoma. Neurology. 2002; 58(10): 1513-1520.
In article      View Article  PubMed
 
[6]  Stein H, Mason DY, Gerdes J, et al. The expression of the Hodgkin's disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that Reed-Sternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood. 1985; 66(4): 848-858.
In article      View Article  PubMed
 
[7]  Morris SW, Kirstein MN, Valentine MB, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. Science. 1994; 263(5151): 1281-1284.
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