Primary central nervous system ALK-negative anaplastic large cell lymphoma

Primary central nervous system ALK-negative anaplastic large cell lymphoma

see also Primary central nervous system ALK-positive anaplastic large cell lymphoma


Primary central nervous system anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma (ALCL) is an extremely rare type of primary central nervous system lymphoma (PCNSL).

There are only nine cases reported in the literature to date, most of which have an overall survival time of no more than 8 months. Yuan et al. reported such a rare case that has a good outcome with the longest survival time and performed a literature review 1).


George et al. reported four new cases of primary central nervous system ALCL from the Mayo Clinic and incorporated additional data from five previously published cases. ALK-1 expression was determined in all nine tumors. Patient age was 4-66 years (mean 29 years) with a bimodal distribution: 6 < or = 22 years, 3 > or = 50 years. Six were female. Tumors were mostly supratentorial, five were multifocal, and seven had involvement of dura or leptomeninges. Seven tumors were T cells, two were null cells, and five of nine were ALK-1 immunopositive. Total mortality was six of nine. Three patients, 4-18 years of age (mean 13 years), were alive at 4.8-6.1 years postdiagnosis; these tumors were all ALK-positive. Five patients, 13-66 years of age (mean 43 years), died of tumor 4 days to 11 weeks postdiagnosis; four of five of these tumors were ALK-negative. One 10-year-old child with an ALK-positive tumor died of sepsis, but in remission. The central nervous system ALCL is aggressive. The study suggests that a better outcome may be associated with young age and ALK-1 positivity, prognostic parameters similar to systemic ALCL 2).


A review demonstrated that ALK-negative ALCL exhibits a poor prognosis and is very often fatal. The majority of ALK-negative patients were treated with radiotherapy or supportive care, due to their older age or poor PS. As ALK-negative ALCL tends to occur in older individuals, similar to PCNSL and DLBCL, chemoradiotherapy including HD-MTX should be initiated earlier.

In conclusion, findings indicate that the prognosis of ALCL of the CNS is correlated with ALK positivity and patient age of <40 years. Chemoradiotherapy with MTX is recommended as the standard treatment for ALCL. However, additional multicenter studies including large numbers of cases are required 3).

A 19-year-old male patient was admitted to the hospital complaining of dizzinessCT and MRI imaging showed a heterogeneous enhanced lesion in the left parieto-occipital lobe and the leptomeninges of the occipital lobe and the cerebellum. The lesion was resected and confirmed to be ALK-negative ALCL by pathological examination. Then, the patient received 10 cycles of chemotherapy with high-dose methotrexate (HD-MTX) and whole brain radiotherapy. The patient recovered well and was regularly followed up. He was free of symptoms without recurrence on imaging examination 3 years later. ALCL is a rare type of PCNSL. HD-MTX combined with radiation is an effective therapeutic approach. However, further prospective studies with a large number of patients are needed to identify the biological characteristics of this rare type of PCNSL 4).


1) , 4)

Yuan C, Duan H, Wang Y, Zhang J, Ou J, Wang W, Zhang M. Primary central nervous system ALK-negative anaplastic large cell lymphoma: a case report and literature review. Ann Palliat Med. 2021 Jul 1:apm-21-557. doi: 10.21037/apm-21-557. Epub ahead of print. PMID: 34263607.
2)

George DH, Scheithauer BW, Aker FV, Kurtin PJ, Burger PC, Cameselle-Teijeiro J, McLendon RE, Parisi JE, Paulus W, Roggendorf W, Sotelo C. Primary anaplastic large cell lymphoma of the central nervous system: prognostic effect of ALK-1 expression. Am J Surg Pathol. 2003 Apr;27(4):487-93. doi: 10.1097/00000478-200304000-00008. PMID: 12657933.
3)

Nomura M, Narita Y, Miyakita Y, Ohno M, Fukushima S, Maruyama T, Muragaki Y, Shibui S. Clinical presentation of anaplastic large-cell lymphoma in the central nervous system. Mol Clin Oncol. 2013 Jul;1(4):655-660. doi: 10.3892/mco.2013.110. Epub 2013 Apr 30. PMID: 24649224; PMCID: PMC3915681.

Primary Central Nervous System Angiosarcoma

Primary Central Nervous System Angiosarcoma

Angiosarcoma is an infrequent tumor among sarcomas, especially presenting as a primary tumor within the central nervous system, which can lead to rapid neurological deterioration and death in few months.

Mena et al. reported in 1991 eight patients with primary angiosarcoma of the central nervous system these included five males and three females ranging in age from 2 weeks to 72 years (mean 38 years). Of the eight neoplasms, six were located in the cerebral hemispheres and one was in the meninges; the site was unknown in the other. All patients underwent surgical resection. Five of the eight patients died, four within 4 months after surgery and one after 30 months. Two of the remaining three patients were 17 and 27 years old at the time of diagnosis and were alive at follow-up review 39 and 102 months after surgery, respectively. One patient was lost to follow-up monitoring. Microscopically, all eight tumors demonstrated a well-differentiated pattern with irregular vascular channels and intraluminal papillae; in addition, four showed poorly differentiated solid areas. Immunohistochemical staining of neoplastic cells to factor VIII-related antigen and Ulex europaeus agglutinin I was performed in five tumors and was focally positive in four. No correlation could be shown between the histological features and the growth and biological behavior of the tumors 1)

Valera-Melé et al. presented a 41-year old man with a right frontal enhancing hemorrhagic lesion. Surgery was performed with histopathological findings suggesting a primary central nervous system angiosarcoma. He was discharged uneventfully and received adjuvant chemotherapy and radiotherapy. At 5 months, the follow-up MRI showed two lesions with an acute subdural hematoma, suggesting a relapse. Surgery was again conducted finding tumoral membranes attached to the internal layer of the dura mater around the right hemisphere. The patient died a few days later due to the recurrence of the subdural hematoma. This case report illustrates a rare and lethal complication of an unusual tumor. The literature reviewed shows that gross-total resection with adjuvant radiotherapy seems to be the best treatment of choice 2).


Gao M, Li P, Tan C, Liu J, Tie X, Pang C, Guo Z, Lin Y. Primary Central Nervous System Angiosarcoma. World Neurosurg. 2019 Dec;132:41-46. doi: 10.1016/j.wneu.2019.08.128. Epub 2019 Aug 27. PubMed PMID: 31470162 3).


report a case of intracranial angiosarcoma in a Caucasian male and present a review of the imaging features in the recent literature. The tumor mostly presents as a well-demarcated, heterogeneous, moderately to strongly enhancing lesion with signs of intratumoral bleeding and surrounding vasogenic edema. The differential imaging features of common hemorrhagic intracranial tumors are discussed 4).


Two cases of primary angiosarcoma of the brain are well characterized by imaging, histopathology, and immunohistochemistry. Case 1: The first patient was a 35-year-old woman who developed exophthalmos. Subtotal resection of a left extra-axial retro-orbital mass was performed.

Case 2: our second patient was a 47-year-old man who presented with acute visual loss, word-finding difficulty, and subtle memory loss. A heterogeneously-enhancing left sphenoid wing mass was removed. We also review the literature aiming at developing a rational approach to diagnosis and treatment, given the rarity of this entity.

Gross total resection is the standard of care for primary angiosarcoma of the brain. Adjuvant radiation and chemotherapy are playing increasingly recognized roles in the therapy of these rare tumors 5).


1)

Mena H, Ribas JL, Enzinger FM, Parisi JE. Primary angiosarcoma of the central nervous system. Study of eight cases and review of the literature. J Neurosurg. 1991 Jul;75(1):73-6. doi: 10.3171/jns.1991.75.1.0073. PMID: 2045922.
2)

Valera-Melé M, Darriba Allés JV, Ruiz Juretschke F, Sola Vendrell E, Hernández Poveda JM, Montalvo Afonso A, Casitas Hernando V, García Leal R. Primary central nervous system angiosarcoma with recurrent acute subdural hematoma. Neurocirugia (Astur). 2021 Mar 22:S1130-1473(21)00027-0. English, Spanish. doi: 10.1016/j.neucir.2021.02.002. Epub ahead of print. PMID: 33766476.
3)

Gao M, Li P, Tan C, Liu J, Tie X, Pang C, Guo Z, Lin Y. Primary Central Nervous System Angiosarcoma. World Neurosurg. 2019 Dec;132:41-46. doi: 10.1016/j.wneu.2019.08.128. Epub 2019 Aug 27. PubMed PMID: 31470162.
4)

Jerjir N, Lambert J, Vanwalleghem L, Casselman J. Primary Angiosarcoma of the Central Nervous System: Case Report and Review of the Imaging Features. J Belg Soc Radiol. 2016 Oct 10;100(1):82. doi: 10.5334/jbr-btr.1087. PMID: 30151480; PMCID: PMC6100495.
5)

Hackney JR, Palmer CA, Riley KO, Cure JK, Fathallah-Shaykh HM, Nabors LB. Primary central nervous system angiosarcoma: two case reports. J Med Case Rep. 2012 Aug 21;6:251. doi: 10.1186/1752-1947-6-251. PMID: 22909122; PMCID: PMC3459733.

Methotrexate for Primary central nervous system lymphoma

In neurooncology and onco-hematology, intraventricular injection of chemotherapeutic agents (most typically, methotrexate) is an inevitable part of many protocols for treating patients with malignant tumors of the CNS, neuroleukemia, CNS lymphomas and some other disorders.


High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL 1).


MTX-monotherapy is tolerable in terms of adverse effects and still considered as a treatment option in patients with PCNSL. However, an additional therapeutic option should be prepared for non-CR responders to induction chemotherapy 2).


The addition of intraventricular MTX (rather than just intrathecal via LP) delivered through a Ommaya reservoir (6 doses of 12 mg twice a week, with IV leucovorin rescue) may result in even better survival 3)

In the event of an intrathecal MTX overdose (OD), interventions recommended 4) :

ODs of up to 85 mg can be well tolerated with little sequelae; immediate LP with drainage of CSF can remove a substantial portion of the drug (removing 15 ml of CSF can eliminate ≈ 20–30% of the MTX within 2 hrs of OD). This can be followed by ventriculolumbar perfusion over several hours using 240 ml of warmed isotonic preservative-free saline entering through the ventricular reservoir and exiting through a External lumbar cerebrospinal fluid drainage. For major OD of > 500 mg, add intrathecal administration of 2,000 U of carboxypeptidase G2 (an enzyme that inactivates MTX). In cases of MTX OD, systemic toxicity should be prevented by treating with IV dexamethasone and IV (not IT) leucovorin.


Therapeutic Outcomes and Toxicity of High-Dose Methotrexate-Based Chemotherapy for Elderly Patients with Primary Central Nervous System Lymphoma: A Report on Six Cases. 5).


A study provides Class III evidence that in immunocompetent patients with primary CNS lymphomas (PCNSLs), high-dose methotrexate (HD-MTX) plus rituximab compared with HD-MTX alone improves complete response (CR) and overall survival rates 6).

Case series

Yoon et al. presented the experiences with high-dose methotrexate (HD-MTX) monotherapy for immunocompetent patients with PCNSL at three institutions and investigate factors related to survival.

PCNSL patients, who were histologically confirmed with diffuse large B cells and treated with HD-MTX monotherapy from 2001 to 2016, were retrospectively reviewed. Patients underwent induction chemotherapy with 8 g/m2 of MTX every 10 days (maximum three cycles). Maintenance chemotherapy of 3.5 g/m2 of MTX (maximum six cycles) was selectively performed depending on the response to induction chemotherapy.

A total of 67 patients were included. Although seven patients discontinued induction chemotherapy because of MTX toxicity, 40 (59.7%) patients showed a complete response (CR) to induction chemotherapy. Twenty-six (38.8%) and three (4.5%) patients showed a CR and partial response, respectively, after maintenance chemotherapy. Forty-one patients with recurrence or progression following HD-MTX underwent second-line treatment. Progression-free survival rates were 43% and 24% at 1 and 2 years, respectively. The median overall survival was 40.3 months. In a multivariate analysis, a radiological CR to induction chemotherapy was a significant factor related to prolonged progression-free survival and overall survival (P < 0.05).

MTX-monotherapy is tolerable in terms of adverse effects and still considered as a treatment option in patients with PCNSL. However, an additional therapeutic option should be prepared for non-CR responders to induction chemotherapy 7).


A single-institution retrospective analysis was performed for 12 patients with newly diagnosed PCNSL treated with combined high-dose methotrexate (HD-MTX) and RTX. MTX was administered biweekly at 8 g/m2/dose until a complete response (CR) was achieved or for a maximum of eight doses. RTX was provided for a total of eight weekly doses at 375 mg/m2/dose. Following a median of 11 cycles of MTX, the radiographic overall response rate was 91% and the CR rate was 58%. A CR was achieved after a median 6 cycles of MTX. The median progression-free survival time was 22 months and the median overall survival time has not yet been attained. These results compare favorably to single-agent HD-MTX and suggest a role for immunochemotherapy in the treatment of PCNSL 8).


Zhu et al. studied the response and adverse effects of intravenous high-dose MTX in patients who were 70 or more years of age at the time of diagnosis. They identified 31 patients diagnosed with PCNSL at age > or =70 years (median, 74 years) who were treated with high-dose MTX (3.5-8 g/m(2)) as initial therapy from 1992 through 2006. The best response to MTX was determined by contrast-enhanced MRI. Toxicity was analyzed by chart review. These 31 patients received a total of 303 cycles of MTX (median, eight cycles per patient). Overall, 87.9% of the cycles required dose reduction because of impaired creatinine clearance. In 30 evaluable patients, the overall radiographic response rate was 96.7%, with 18 complete responses (60%) and 11 partial responses (36.7%). Progression-free survival and overall survivals were 7.1 months and 37 months, respectively. Grade I-IV toxicities were observed in 27 of 31 patients and included gastrointestinal disturbances in 58% (3.2% grade III), hematological complications in 80.6% (6.5% grade III), and renal toxicity in 29% (0% grade III/IV). High-dose MTX is associated with a high proportion of radiographic responses and a low proportion of grade III/IV toxicity in patients 70 or more years of age. High-dose MTX should be considered as a feasible treatment option in elderly patients with PCNSL 9).

References

1) , 9)

Zhu JJ, Gerstner ER, Engler DA, Mrugala MM, Nugent W, Nierenberg K, Hochberg FH, Betensky RA, Batchelor TT. High-dose methotrexate for elderly patients with primary CNS lymphoma. Neuro Oncol. 2009 Apr;11(2):211-5. doi: 10.1215/15228517-2008-067. Epub 2008 Aug 29. PMID: 18757775; PMCID: PMC2718993.
2) , 7)

Yoon WS, Park JS, Kim YI, Chung DS, Jeun SS, Hong YK, Yang SH. High-dose methotrexate monotherapy for newly diagnosed primary central nervous system lymphoma: 15-year multicenter experience. Asia Pac J Clin Oncol. 2020 Sep 25. doi: 10.1111/ajco.13427. Epub ahead of print. PMID: 32978898.
3)

DeAngelis LM, Yahalom J, Thaler HT, Kher U. Com- bined Modality Therapy for Primary CNS Lympho- mas.JClinOncol.1992;10:635–643
4)

O’Marcaigh AS, Johnson CM, Smithson WA, et al. Successful Treatment of Intrathecal Methotrexate Overdose by Using Ventriculolumbar Perfusion and Intrathecal Instillation of Carboxypeptidase G2. Mayo Clin Proc. 1996; 71:161–165
5)

Tempaku A, Takahashi Y, Kamada H. Therapeutic Outcomes and Toxicity of High-Dose Methotrexate-Based Chemotherapy for Elderly Patients with Primary Central Nervous System Lymphoma: A Report on Six Cases. Acta Haematol. 2019 May 21:1-2. doi: 10.1159/000499100. [Epub ahead of print] PubMed PMID: 31112947.
6)

Holdhoff M, Ambady P, Abdelaziz A, Sarai G, Bonekamp D, Blakeley J, Grossman SA, Ye X. High-dose methotrexate with or without Rituximab in newly diagnosed primary CNS lymphoma. Neurology. 2014 Jul 15;83(3):235-9. doi: 10.1212/WNL.0000000000000593. Epub 2014 Jun 13. PubMed PMID: 24928128; PubMed Central PMCID: PMC4117362.
8)

Ly KI, Crew LL, Graham CA, Mrugala MM. Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: A single-institution experience. Oncol Lett. 2016 May;11(5):3471-3476. doi: 10.3892/ol.2016.4393. Epub 2016 Mar 30. PMID: 27123138; PMCID: PMC4840907.
WhatsApp WhatsApp us
%d bloggers like this: