Primary central nervous system lymphoma

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Primary central nervous system lymphoma
Other namesMicroglioma and Primary brain lymphoma [1]
Primary central nervous system B-cell non-Hodgkin lymphoma.jpg
Brain magnetic resonance imaging showing primary central nervous system B-cell non-Hodgkin lymphoma of the sella turcica and hypothalamus, continuing to the tectum (intensely white areas in the middle).
Specialty Hematology and Neuro-oncology

Primary central nervous system lymphoma (PCNSL), also termed primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS), [2] is a primary intracranial tumor appearing mostly in patients with severe immunodeficiency (typically patients with AIDS). It is a subtype and one of the most aggressive of the diffuse large B-cell lymphomas. [3]

Contents

PCNSLs represent around 20% of all cases of lymphomas in HIV infections. (Other types are Burkitt's lymphomas and immunoblastic lymphomas). Primary CNS lymphoma is highly associated with Epstein-Barr virus (EBV) infection (> 90%) in immunodeficient patients (such as those with AIDS and those immunosuppressed), [4] and does not have a predilection for any particular age group. Mean CD4+ count at time of diagnosis is ~50/μL. In immunocompromised patients, prognosis is usually poor. In immunocompetent patients (that is, patients who do not have AIDS or some other acquired or secondary immunodeficiency), there is rarely an association with EBV infection or other DNA viruses. In the immunocompetent population, PCNSLs typically appear in older patients in their 50s and 60s.

Importantly, the incidence of PCNSL in the immunocompetent population has been reported to have increased more than 10-fold from 2.5 cases to 30 cases per 10 million population. [5] [6] The cause for the increase in incidence of this disease in the immunocompetent population is unknown.

Signs and symptoms

A primary CNS lymphoma usually presents with seizure, headache, cranial nerve findings, altered mental status, or other focal neurological deficits typical of a mass effect. [7] [8] Systemic symptoms may include fever, night sweats, or weight loss. Other symptoms include

Diagnosis

Micrograph showing a primary CNS lymphoma with the characteristic perivascular distribution composed of large cells with prominent nucleoli. Brain biopsy. HPS stain. Primary CNS lymphoma - very high mag.jpg
Micrograph showing a primary CNS lymphoma with the characteristic perivascular distribution composed of large cells with prominent nucleoli. Brain biopsy. HPS stain.

The current standard for diagnosis typically includes positive CSF cytology, vitreous biopsy, or brain/leptomeningeal biopsy. [10] Histopathological confirmation is essential for definitive diagnosis. [11]

MRI or contrast enhanced CT classically shows multiple ring-enhancing lesions in the deep white matter. The major differential diagnosis (based on imaging) is cerebral toxoplasmosis, which is also prevalent in AIDS patients and also presents with a ring-enhanced lesion, although toxoplasmosis generally presents with more lesions and the contrast enhancement is typically more pronounced. Imaging techniques cannot distinguish the two conditions with certainty, and cannot exclude other diagnoses. Thus, patients undergo a brain biopsy or vitreous biopsy, if there is intraocular involvement. [10]

Classification

Most PCNSLs are diffuse large B cell non-Hodgkin lymphomas. [12] [13]

Treatment

Surgical resection is usually ineffective because of the depth of the tumour. Treatment with irradiation and corticosteroids often only produces a partial response and tumour recurs in more than 90% of patients. Median survival is 10 to 18 months in immunocompetent patients, and less in those with AIDS. The addition of IV methotrexate and folinic acid (leucovorin) may extend survival to a median of 3.5 years. If radiation is added to methotrexate, median survival time may increase beyond 4 years. However, radiation is not recommended in conjunction with methotrexate because of an increased risk of leukoencephalopathy and dementia in patients older than 60. [14] In AIDS patients, perhaps the most important factor with respect to treatment is the use of highly active anti-retroviral therapy (HAART), which affects the CD4+ lymphocyte population and the level of immunosuppression. [15] The optimal treatment plan for patients with PCNSL has not been determined. Combination chemotherapy and radiotherapy at least doubles survival time, but causes dementia and leukoencephalopathy in at least 50% of patients who undergo it. The most studied chemotherapeutic agent in PCNSL is methotrexate (a folate analogue that interferes with DNA repair). Methotrexate therapy in patients with PCNSL typically requires hospitalization for close monitoring and intravenous fluids. Leucovorin is often given for the duration of the therapy. Standard chemotherapeutic regimens for lymphoma such as CHOP are ineffective in PCNSL, probably due to poor penetration of the agents through the blood brain barrier. [15]

Newer treatments, such as high dose chemotherapy combined with autologous stem cell transplant are proving to increase survival by years. [16] New research to increase permeability of the blood brain barrier with NGR-hTNF followed by CHOP, produced responses in 75% cases. [17]

A phase 1 clinical trial of ibrutinib – an inhibitor of Bruton's tyrosine kinase – in 13 patients reported responses in 10 (77%). [18] Five of the responses were complete.

Prognosis

In immunocompetent patients

The initial response to radiotherapy is often excellent, and may result in a complete remission. However, the duration of response with radiotherapy alone remains short, with median survival after treatment with radiotherapy just 18 months. Methotrexate based chemotherapy markedly improves survival, with some studies showing median survival after methotrexate chemotherapy reaching 48 months. [15]

In AIDS patients

Patients with AIDS and PCNSL have a median survival of only 4 months with radiotherapy alone. Untreated, median survival is only 2.5 months, sometimes due to concurrent opportunistic infections rather than the lymphoma itself. Extended survival has been seen, however, in a subgroup of AIDS patients with CD4 counts of more than 200 and no concurrent opportunistic infections, who can tolerate aggressive therapy consisting of either methotrexate monotherapy or vincristine, procarbazine, or whole brain radiotherapy. These patients have a median survival of 10–18 months. Of course, highly active antiretroviral therapy (HAART) is critical for prolonged survival in any AIDS patient, so compliance with HAART may play a role in survival in patients with concurrent AIDS and PCNSL. [15]

Related Research Articles

<span class="mw-page-title-main">Brain tumor</span> Neoplasm in the brain

A brain tumor occurs when abnormal cells form within the brain. There are two main types of tumors: malignant (cancerous) tumors and benign (non-cancerous) tumors. These can be further classified as primary tumors, which start within the brain, and secondary tumors, which most commonly have spread from tumors located outside the brain, known as brain metastasis tumors. All types of brain tumors may produce symptoms that vary depending on the size of the tumor and the part of the brain that is involved. Where symptoms exist, they may include headaches, seizures, problems with vision, vomiting and mental changes. Other symptoms may include difficulty walking, speaking, with sensations, or unconsciousness.

<span class="mw-page-title-main">Lymphoma</span> Hematologic cancer that affects lymphocytes

Lymphoma is a group of blood and lymph tumors that develop from lymphocytes. The name typically refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enlarged lymph nodes, fever, drenching sweats, unintended weight loss, itching, and constantly feeling tired. The enlarged lymph nodes are usually painless. The sweats are most common at night.

AIDS-related lymphoma describes lymphomas occurring in patients with acquired immunodeficiency syndrome (AIDS).

<span class="mw-page-title-main">Glioblastoma</span> Aggressive type of brain cancer

Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to unconsciousness.

<span class="mw-page-title-main">Primary effusion lymphoma</span> Medical condition

Primary effusion lymphoma (PEL) is classified as a diffuse large B cell lymphoma. It is a rare malignancy of plasmablastic cells that occurs in individuals that are infected with the Kaposi's sarcoma-associated herpesvirus. Plasmablasts are immature plasma cells, i.e. lymphocytes of the B-cell type that have differentiated into plasmablasts but because of their malignant nature do not differentiate into mature plasma cells but rather proliferate excessively and thereby cause life-threatening disease. In PEL, the proliferating plasmablastoid cells commonly accumulate within body cavities to produce effusions, primarily in the pleural, pericardial, or peritoneal cavities, without forming a contiguous tumor mass. In rare cases of these cavitary forms of PEL, the effusions develop in joints, the epidural space surrounding the brain and spinal cord, and underneath the capsule which forms around breast implants. Less frequently, individuals present with extracavitary primary effusion lymphomas, i.e., solid tumor masses not accompanied by effusions. The extracavitary tumors may develop in lymph nodes, bone, bone marrow, the gastrointestinal tract, skin, spleen, liver, lungs, central nervous system, testes, paranasal sinuses, muscle, and, rarely, inside the vasculature and sinuses of lymph nodes. As their disease progresses, however, individuals with the classical effusion-form of PEL may develop extracavitary tumors and individuals with extracavitary PEL may develop cavitary effusions.

<span class="mw-page-title-main">Intravascular lymphomas</span> Medical condition

Intravascular lymphomas (IVL) are rare cancers in which malignant lymphocytes proliferate and accumulate within blood vessels. Almost all other types of lymphoma involve the proliferation and accumulation of malignant lymphocytes in lymph nodes, other parts of the lymphatic system, and various non-lymphatic organs but not in blood vessels.

Lymphomatoid granulomatosis (LYG or LG) is a very rare lymphoproliferative disorder first characterized in 1972. Lymphomatoid means lymphoma-like and granulomatosis denotes the microscopic characteristic of the presence of granulomas with polymorphic lymphoid infiltrates and focal necrosis within it.

Intraocular lymphoma is a rare malignant form of eye cancer. Intraocular lymphoma may affect the eye secondarily from a metastasis from a non-ocular tumor or may arise within the eye primarily. PIOL is a subset of primary central nervous system lymphoma (PCNSL). PCNSL are most commonly a diffuse large B-cell immunohistologic subtype of non-Hodgkin's lymphoma according to the World Health Organization (WHO) classification of lymphomas. The most common symptoms of PIOL include blurred or decreased vision due to tumor cells in the vitreous. Most cases of PIOL eventuate to central nervous system involvement (PCNSL) while only 20% of PCNSL lead to intraocular (PIOL) involvement. PIOL and PCNSL remain enigmas because both structures are immunologically privileged sites and so do not normally have immune cells trafficking through these structures. What is more, while the vast majority of PCNSL in patients with acquired immune deficiency syndrome (AIDS) is related to the Epstein-Barr virus (EBV), the development of PCNSL and PIOL in immunocompetent patients is unknown and shows no general relation to infectious DNAs.

<span class="mw-page-title-main">Atypical teratoid rhabdoid tumor</span> Medical condition

An atypical teratoid rhabdoid tumor (AT/RT) is a rare tumor usually diagnosed in childhood. Although usually a brain tumor, AT/RT can occur anywhere in the central nervous system (CNS), including the spinal cord. About 60% will be in the posterior cranial fossa. One review estimated 52% in the posterior fossa, 39% are supratentorial primitive neuroectodermal tumors (sPNET), 5% are in the pineal, 2% are spinal, and 2% are multifocal.

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<span class="mw-page-title-main">Mantle cell lymphoma</span> Type of blood cancer

Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffeld and Jaffe in 1991.

<span class="mw-page-title-main">Leptomeningeal cancer</span> Medical condition

Leptomeningeal cancer is a rare complication of cancer in which the disease spreads from the original tumor site to the meninges surrounding the brain and spinal cord. This leads to an inflammatory response, hence the alternative names neoplastic meningitis (NM), malignant meningitis, or carcinomatous meningitis. The term leptomeningeal describes the thin meninges, the arachnoid and the pia mater, between which the cerebrospinal fluid is located. The disorder was originally reported by Eberth in 1870. It is also known as leptomeningeal carcinomatosis, leptomeningeal disease (LMD), leptomeningeal metastasis, meningeal metastasis and meningeal carcinomatosis.

<span class="mw-page-title-main">Marginal zone lymphoma</span> Group of lymphomas

Marginal zone lymphomas, also known as marginal zone B-cell lymphomas (MZLs), are a heterogeneous group of lymphomas that derive from the malignant transformation of marginal zone B-cells. Marginal zone B cells are innate lymphoid cells that normally function by rapidly mounting IgM antibody immune responses to antigens such as those presented by infectious agents and damaged tissues. They are lymphocytes of the B-cell line that originate and mature in secondary lymphoid follicles and then move to the marginal zones of mucosa-associated lymphoid tissue (MALT), the spleen, or lymph nodes. Mucosa-associated lymphoid tissue is a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body such as the gastrointestinal tract, mouth, nasal cavity, pharynx, thyroid gland, breast, lung, salivary glands, eye, skin and the human spleen.

<span class="mw-page-title-main">Orbital lymphoma</span> Human disease of the eye

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<span class="mw-page-title-main">Plasmablastic lymphoma</span> Type of large B-cell lymphoma

Plasmablastic lymphoma (PBL) is a type of large B-cell lymphoma recognized by the World Health Organization (WHO) in 2017 as belonging to a subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation. The other lymphoid neoplasms within this subgroup are: plasmablastic plasma cell lymphoma ; primary effusion lymphoma that is Kaposi's sarcoma-associated herpesvirus positive or Kaposi's sarcoma-associated Herpesvirus negative; anaplastic lymphoma kinase-positive large B-cell lymphoma; and human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified. All of these lymphomas are malignancies of plasmablasts, i.e. B-cells that have differentiated into plasmablasts but because of their malignant nature: fail to differentiate further into mature plasma cells; proliferate excessively; and accumulate in and injure various tissues and organs.

A central nervous system tumor is an abnormal growth of cells from the tissues of the brain or spinal cord. CNS tumor is a generic term encompassing over 120 distinct tumor types. Common symptoms of CNS tumors include vomiting, headache, changes in vision, nausea, and seizures. A CNS tumor can be detected and classified via neurological examination, medical imaging, such as x-ray imaging, magnetic resonance imaging (MRI) or computed tomography (CT), or after analysis of a biopsy.

Primary testicular diffuse large B-cell lymphoma (PT-DLBCL), also termed testicular diffuse large B-cell lymphoma and diffuse large B-cell lymphoma of the testes, is a variant of the diffuse large B-cell lymphomas (DLBCL). DLBCL are a large and diverse group of B-cell malignancies with the great majority (-85%) being typed as diffuse large B-cell lymphoma, not otherwise specified. PT-DLBCL is a variant of DLBCL, NOS that involves one or, in uncommon cases, both testicles. Other variants and subtypes of DLBCL may involve the testes by spreading to them from their primary sites of origin in other tissues. PT-DLBCL differs from these other DLBCL in that it begins in the testes and then may spread to other sites.

<span class="mw-page-title-main">T-cell acute lymphoblastic leukemia</span> Type of acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is a type of acute lymphoblastic leukemia characterized by an aggressive malignant neoplasm of the bone marrow. Acute lymphoblastic leukemia (ALL) is a condition where immature white blood cells accumulate in the bone marrow, subsequently crowding out normal white blood cells and creating a build-up in the liver, spleen, and lymph nodes.

Central Nervous System Prophylaxis, or CNS prophylaxis, is a type of chemotherapy for patients at risk of cancer metastasis into the central nervous system (CNS). Prophylaxis originated from the Greek word “phulaxis”, meaning the act of guarding. CNS prophylaxis refers to preventative measures that kill cancer cells potentially in the intrathecal space and the organs of the central nervous system.

References

  1. ↑ "CNS lymphoma, primary information". Diseases Database. Retrieved 17 April 2011.
  2. ↑ Grimm KE, O'Malley DP (February 2019). "Aggressive B cell lymphomas in the 2017 revised WHO classification of tumors of hematopoietic and lymphoid tissues". Annals of Diagnostic Pathology. 38: 6–10. doi:10.1016/j.anndiagpath.2018.09.014. PMID   30380402. S2CID   53196244.
  3. ↑ Sukswai N, Lyapichev K, Khoury JD, Medeiros LJ (January 2020). "Diffuse large B-cell lymphoma variants: an update". Pathology. 52 (1): 53–67. doi: 10.1016/j.pathol.2019.08.013 . PMID   31735345.
  4. ↑ Fine HA, Mayer RJ (December 1993). "Primary central nervous system lymphoma". Annals of Internal Medicine. 119 (11): 1093–1104. doi:10.7326/0003-4819-119-11-199312010-00007. PMID   8239229. S2CID   27535985.
  5. ↑ Eby NL, Grufferman S, Flannelly CM, Schold SC, Vogel FS, Burger PC (December 1988). "Increasing incidence of primary brain lymphoma in the US". Cancer. 62 (11): 2461–2465. doi: 10.1002/1097-0142(19881201)62:11<2461::aid-cncr2820621135>3.0.co;2-m . PMID   3179963.
  6. ↑ Corn BW, Marcus SM, Topham A, Hauck W, Curran WJ (June 1997). "Will primary central nervous system lymphoma be the most frequent brain tumor diagnosed in the year 2000?". Cancer. 79 (12): 2409–2413. doi: 10.1002/(sici)1097-0142(19970615)79:12<2409::aid-cncr17>3.3.co;2-2 . PMID   9191531.
  7. ↑ Bataille B, Delwail V, Menet E, Vandermarcq P, Ingrand P, Wager M, et al. (February 2000). "Primary intracerebral malignant lymphoma: report of 248 cases". Journal of Neurosurgery. 92 (2): 261–266. doi:10.3171/jns.2000.92.2.0261. PMID   10659013.
  8. ↑ Herrlinger U, Schabet M, Bitzer M, Petersen D, Krauseneck P (July 1999). "Primary central nervous system lymphoma: from clinical presentation to diagnosis". Journal of Neuro-Oncology. 43 (3): 219–226. doi:10.1023/A:1006298201101. PMID   10563426. S2CID   5990227.
  9. ↑ Primary CNS Lymphoma at eMedicine
  10. 1 2 Scott BJ, Douglas VC, Tihan T, Rubenstein JL, Josephson SA (March 2013). "A systematic approach to the diagnosis of suspected central nervous system lymphoma". JAMA Neurology. 70 (3): 311–319. doi:10.1001/jamaneurol.2013.606. PMC   4135394 . PMID   23319132.
  11. ↑ von Baumgarten L, Illerhaus G, Korfel A, Schlegel U, Deckert M, Dreyling M (June 2018). "The Diagnosis and Treatment of Primary CNS Lymphoma". Deutsches Ärzteblatt International. 115 (25): 419–426. doi:10.3238/arztebl.2018.0419. PMC   6056710 . PMID   29999484.
  12. ↑ Lukes RJ, Collins RD (October 1974). "Immunologic characterization of human malignant lymphomas". Cancer. 34 (4 Suppl): suppl:1488–suppl:1503. doi: 10.1002/1097-0142(197410)34:8+<1488::aid-cncr2820340822>3.0.co;2-c . PMID   4608683. S2CID   9652828.
  13. ↑ Jellinger K, Radaskiewicz TH, Slowik F (1975). "Primary Malignant Lymphomas of the Central Nervous System in Man". Malignant Lymphomas of the Nervous System. Vol. 6. pp. 95–102. doi:10.1007/978-3-662-08456-4_16. ISBN   978-3-540-07208-9. PMID   1098380.{{cite book}}: |journal= ignored (help)
  14. ↑ Deangelis LM, Hormigo A (October 2004). "Treatment of primary central nervous system lymphoma". Seminars in Oncology. 31 (5): 684–692. doi:10.1053/j.seminoncol.2004.07.011. PMID   15497122.
  15. 1 2 3 4 Primary CNS Lymphoma~treatment at eMedicine
  16. ↑ Omuro A, Correa DD, DeAngelis LM, Moskowitz CH, Matasar MJ, Kaley TJ, et al. (February 2015). "R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma". Blood. 125 (9): 1403–1410. doi:10.1182/blood-2014-10-604561. PMC   4342354 . PMID   25568347.
  17. ↑ Ferreri, Andrés J. M.; Calimeri, Teresa; Conte, Gian Marco; Cattaneo, Dario; Fallanca, Federico; Ponzoni, Maurilio; Scarano, Eloise; Curnis, Flavio; Nonis, Alessandro; Lopedote, Paolo; Citterio, Giovanni (2019-07-18). "R-CHOP preceded by blood-brain barrier permeabilization with engineered tumor necrosis factor-α in primary CNS lymphoma". Blood. 134 (3): 252–262. doi: 10.1182/blood.2019000633 . ISSN   0006-4971. PMID   31118164. S2CID   162182856.
  18. ↑ Grommes C, Pastore A, Palaskas N, Tang SS, Campos C, Schartz D, et al. (September 2017). "Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma". Cancer Discovery. 7 (9): 1018–1029. doi:10.1158/2159-8290.CD-17-0613. PMC   5581705 . PMID   28619981.
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