Hematolymphoid and Hematopoietic Tumors

Main Text

Preamble

This chapter focuses on hematopoietic tumors and tumor-like conditions. We begin with an increasingly common group of neoplasms, lymphomas and related disorders, then turn our attention briefly to histiocytic tumors, such as Langerhans cell histiocytosis and Erdheim-Chester disease.

Plasma cell myeloma and solitary plasmacytoma affecting the skull and brain are usually secondary to extracranial disease, but they are a form of mature B-cell neoplasms and hence are included here rather than in Chapter 31 on metastases. We conclude the chapter with a brief discussion of extramedullary hematopoiesis—benign, nonneoplastic proliferations of blood-forming elements—which can appear virtually identical to malignant hematopoietic neoplasms.

Lymphomas and Related Disorders

Preamble

The 2021 WHO divides primary CNS lymphoma (PCNSL) into primary diffuse large B-cell lymphoma of the CNS (CNS-DLBCL) (> 95% of lesions), immunodeficiency-associated CNS lymphomas, intravascular large B-cell lymphoma, anaplastic large cell lymphoma [ALK(+)/ALK(-)], T-cell and NK/T-cell lymphomas, and “other low-grade B-cell lymphomas of the CNS, which includes extranodal marginal zone lymphoma,” as well as mucosa-associated lymphoid tissue (MALT) lymphoma of the dura.

We begin this chapter by focusing on CNS-DLBCL. We then consider the fascinating spectrum of immunodeficiency-associated CNS lymphomas and other lymphoproliferative disorders, including lymphomatoid granulomatosis (LG) and posttransplant lymphoproliferative disorder (PTLD).

We follow with a discussion of intravascular large B-cell lymphoma, an uncommon but increasingly well-recognized cause of unexplained cognitive decline in older adult patients. Uncommon PCNSLs, such as MALT lymphoma of the dura, are then briefly discussed. We close the section with a brief review of CNS metastatic lymphoma.

Diffuse Large B-Cell Lymphoma of CNS

Terminology

CNS-DLBCL is an extranodal B-cell lymphoma that arises exclusively inside the CNS. The vast majority of PCNSLs are diffuse large B-cell lymphomas (DLBCLs). For purposes of discussion, in this text, the terms PCNSL and DLBCL are used interchangeably.

Etiology

The brain parenchyma normally contains very few lymphocytes. So how and why lymphomas arise as primary CNS neoplasms in immunocompetent individuals is unknown. To date, no genetic predispositions to PCNSL have been identified. No viral associations have been identified.

What is clear is that lymphoma cells—regardless of whether they originate within or outside the brain—exhibit a distinct, highly selective neurotropism for the CNS microenvironment and its vasculature. Intra- and perivascular tumor spread is common.

Pathology

Location

CNS-DLBCL can affect any part of the neuraxis. Up to 75% all PCNSLs contact a CSF surface, either the ventricular ependyma or pia (29-1). Lesions are often deep seated with a predilection for the periventricular white matter, especially the corpus callosum (29-5A). The basal ganglia and thalami are the next most common locations (29-2).

The hypothalamus, infundibulum, and pituitary gland are less common sites. Primary DLBCL may also develop in the leptomeninges, calvarial vault, and central skull base, although these areas are more commonly involved by metastatic spread from extracranial primary tumors. Ocular manifestations may occur in ~ 20% of patients and spinal cord involvement is rare, < 1%.

Gross Pathology

DLBCL lesions vary in size from microscopic implants to large bulky masses. Up to 2/3 are solitary lesions.

Single or multiple hemispheric masses that appear relatively well demarcated rather than diffusely infiltrating lesions are typical. Large confluent areas of frank necrosis and gross intratumoral hemorrhage are more common in AIDS-related PCNSLs (29-8).

Rarely, DLBCL diffusely infiltrates the brain, involving both gray and white matter structures. So-called lymphomatosis cerebri, like “gliomatosis cerebri,” is an anatomic pattern, not a distinct disease entity. Lymphomatosis cerebri often presents as patchy or confluent T2/FLAIR hyperintensities in the deep white matter and basal ganglia with variable enhancement.

Microscopic Features

PCNSLs are highly cellular tumors. MIB-1 is high, often exceeding 50% (significantly higher than with glioblastoma). The WHO does not assign a grade to PCNSL.

Clinical Issues

Lymphomas of the CNS are the second most frequent primary brain malignancy in adults after gliomas, accounting for 7% of all malignant tumors. Although PCNSLs account for only 3% of all malignant CNS neoplasms, worldwide prevalence is increasing as a result of the HIV/AIDS epidemic and the use of immunosuppressive therapies. PCNSLs are generally tumors of middle-aged and older adults. Peak age (in immunocompetent patients) is 60 years. CNS-DLBCL is typically EBV(-).

Most patients present with focal neurologic deficits, altered mental status, and neuropsychiatric disturbances. Seizures are less common than in patients with other primary brain tumors.

CNS-DLBCL is an aggressive tumor with a median survival of only a few months in untreated patients. In general, immunocompetent patients younger than 60 years fare slightly better than older patients and patients with acquired immunodeficiency syndromes.

Early diagnosis is crucial for proper management of PCNSLs. Stereotactic biopsy is typically performed for diagnostic confirmation and histologic tumor typing. Treatment options include corticosteroids, high-dose methotrexate-based polychemotherapy, and radiation. Newer therapies include consolidative high-dose chemotherapy and autologous stem cell transplantation after methotrexate-based chemotherapy with prolonged survival.

Approximately 70% of patients initially respond to treatment, but relapse is very common. Progression-free survival is approximately one year, and overall survival is approximately three years. Only 20-40% of patients experience prolonged progression-free survival.

Imaging

General Features

Contrast-enhanced cranial MR is the modality of choice in evaluating patients with suspected PCNSL. CECT of the chest, abdomen, and pelvis or PET/CT is generally recommended in patients with suspected PCNSL to look for an extracranial source of disease. Occult systemic lymphomas are found in 5-8% of patients with putative PCNSL.

CT Findings

All PCNSLs are highly cellular tumors. White matter or basal ganglia lesions in contact with a CSF surface are typical. Most lesions appear hyperdense compared with normal brain on NECT scans (29-3A)(29-4). Marked peritumoral edema is common, but gross necrosis, hemorrhage, and calcification are rare (2-5%) unless the patient is immunocompromised (29-9A).

DLBCLs in immunocompetent patients show mild to moderate, relatively homogeneous enhancement on CECT. Irregular ring enhancement is rare unless the patient is immunocompromised.

MR Findings

Over 3/4 of DLBCLs in immunocompetent patients are iso- or slightly hypointense compared with gray matter on T1WI and isointense on T2WI (29-3B) (29-6A).

FLAIR signal is variable but usually iso- or hyperintense (29-5A). Microhemorrhages with intratumoral “blooming” on T2* are present in 5-8% of cases, but gross hemorrhage is uncommon unless the patient is immunocompromised.

Nearly all PCNSLs in immunocompetent patients enhance (29-3C). Solid homogeneous (29-3C) (29-5C)or mildly heterogeneous enhancement is common (29-6B); ring enhancement is much less common (10-15%) (29-7). MRS typically demonstrates elevated choline and high lipids.

Because of their high cellularity, > 95% of PCNSLs show mild to moderate diffusion restriction with low ADC values (29-5B). MRS is nonspecific with elevated choline, reduced NAA and myoinositol, and prominent lipids. Tumor neovascularization is absent in PCNSLs; therefore, rCBV is relatively low, and permeability is not increased on DCE pMR even though the tumor is highly malignant.

Lymphomatosis cerebri mimics diffuse white matter disease with confluent T2/FLAIR hyperintensities. Enhancement can be subtle, patchy, or even absent.

Steroid administration significantly alters the imaging findings of PCNSLs. Cell lysis with tumor regression and normalization of the blood-brain barrier occurs in 40-85% of patients with corticosteroid-treated PCNSLs. Tumors typically diminish in size. Contrast enhancement also decreases or even disappears completely (“ghost tumor”), although some T2 and FLAIR signal abnormalities may persist.

Differential Diagnosis

The major differential diagnosis of PCNSL is glioblastoma (GBM). Although both tumors often cross the corpus callosum, hemorrhage and necrosis are rare in PCNSL. Enhancement in immunocompetent patients with PCNSL is strong and relatively homogeneous, whereas a peripheral ring pattern is more typical of GBM. Advanced MR techniques, such as DWI, MRS, and DCE pMR are helpful in distinguishing PCNSLs from other highly aggressive primary brain tumors.

The second most common differential diagnosis of PCNSL is metastasis. Dura-based PCNSLs may resemble meningioma or—due to their hyperdensity—even look like an acute epi- or subdural hematoma.

In the setting of solid organ or hematopoietic stem cell transplants, LG and PTLD may closely resemble PCNSL. Biopsy is necessary for confirmation and patient management.

Immunodeficiency-Associated CNS Lymphomas

Lymphomas associated with either inherited or acquired immunodeficiency are grouped together as immunodeficiency-associated CNS lymphomas. The immunodeficiency-associated CNS lymphomas include AIDS-related DLBCL and EBV(+) DLBCL in older adult patients (> 50 years) with no known immunodeficiency.

PCNSLs associated with EBV account for 10-15% of all cases. Congenital immunodeficiency syndromes increase the risk of lymphoma, as do severe acquired immunosuppression and autoimmune diseases, such as Sjögren syndrome and systemic lupus erythematosus.

AIDS-Related Diffuse Large B-Cell Lymphoma

Although HIV-associated PCNSL has become rarer with the introduction of highly active antiretroviral therapy (HAART), between 2-12% of HIV/AIDS patients eventually develop CNS lymphoma, generally during the later stages of their disease.

Pathology

Multiple lesions are common, as are larger, more confluent necrotic areas and intratumoral hemorrhages (29-8).

Clinical Issues

Mean age at onset in HIV/AIDS patients is 40 years, two decades younger than immunocompetent patients. Lymphomas in transplant recipients occur even earlier, generally between 35-40 years of age. Mean age of onset in children with inherited immunodeficiencies is 10 years.

Imaging

Multiple lesions are common, as are more frequent and larger confluent areas of necrosis (29-9A). Intratumoral hemorrhage with T1 shortening (29-9B)and “blooming” on T2* scans is common. Enhancement is variable but often mild. Ring enhancement surrounding a nonenhancing core of necrotic tissue is typical.

Differential Diagnosis

In immunocompromised patients, the major differential diagnosis of PCNSL is toxoplasmosis. A solitary ring-enhancing lesion in an HIV/AIDS patient is most often lymphoma, whereas multiple lesions are more characteristic of toxoplasmosis. An eccentric target sign is suggestive of toxoplasmosis, although necrotic lymphomas occasionally show an enhancing ring with a nodule pattern. Additional differential considerations for immunodeficiency-associated CNS lymphomas include glioblastoma or metastases.These two entities often present as ring-enhancing lesions with marked surrounding T2/FLAIR signal abnormality.

Lymphomatoid Granulomatosis

LG is an angiocentric and angiodestructive lymphoproliferative disorder characterized by polymorphous lymphoid infiltrates with EBV(+) atypical B cells in a T-cell-rich inflammatory background.

Etiology

LG is an EBV-driven disease and is present in the majority of cases. Immunodeficiency, such as HIV/AIDS and patients on immunosuppression for solid organ transplants, increases the risk of LG.

Pathology

The lung is the most common location for LG followed by the skin. The CNS is involved in ~ 25% of cases. Macroscopically, the lesions may resemble tumor or infarct-like areas of necrosis.

LG is characterized histologically by polymorphous lymphoid infiltrates, primarily lymphocytes and plasma cells, angiitis and granulomatosis with central necrosis. LG may be graded as grade 1, grade 2, or grade 3 based on the proportion of EBV-expressing CD20(+) B cells. The majority of CNS LG is grade 2 or grade 3.

Clinical Issues

LG is a rare disease that usually occurs in adults in the fifth and sixth decades with a male predilection. The typical patient is a middle-aged man with fever, dry cough, and weight loss. Patients with CNS LG often present with focal neurologic symptoms, headaches, &/or cognitive impairment. CNS LG is often aggressive and has similar treatment to DLBCL, including steroids, radiation, &/or chemotherapy.

Imaging

LG may occur in the brain parenchyma, leptomeninges, or cranial nerves. Spinal cord involvement is rare. Imaging is often nonspecific with multifocal T2/FLAIR nodular hyperintensities as well as solid and ring-like enhancement patterns (29-10).

Other imaging patterns described include multifocal punctate, nodular, linear enhancing foci. Leptomeningeal and cranial nerve enhancement has also been described. Dural-based enhancing masses and choroid plexus lesions have been reported.

Differential Diagnosis

The major differential diagnosis of LG is vasculitis and lymphoma, particularly intravascular lymphoma (IVL). Vasculitis is typically characterized by multifocal T2 hyperintensities, often with restricted diffusion, and blood products on MR. IVL typically shows small ischemic foci with infarct-like lesions and microhemorrhages, as well as linear or punctate enhancement along perivascular spaces. Other imaging considerations include CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids), which often shows enhancing punctate or curvilinear lesions “peppering” the pons. Other regions of involvement in CLIPPERS include the cerebellar hemispheres, basal ganglia, and cerebral white matter.

Posttransplant Lymphoproliferative Disorder

Posttransplant lymphoproliferative disorder (PTLD) is a potentially life-threatening complication of immunosuppressive therapy in patients with solid organ or hematopoietic cell transplantation.

The PTLD clinical spectrum can range from an infectious mononucleosis-like illness with reactive lymph node hyperplasia to malignant lymphoma. PTLD is related to EBV.

Pathology

PTLD may be monomorphic or polymorphic. Monomorphic resembles aggressive DLBCL with a predisposition for growth in perivascular spaces. Polymorphic PTLD has a heterogeneous cell population.

Clinical Issues

PTLD often presents several years following the transplant and symptoms vary with tumor location. Treatment is variable but often includes discontinuing immunosuppressive medications. Surgery, chemotherapy, and radiation therapy are sometimes required.

Epidemiology

The overall prevalence of PTLD following solid organ transplantation is 0.5-2.5%. Up to 15-20% of patients who develop PTLD have CNS involvement. Isolated CNS PTLD is rare, occurring in < 0.5% of transplant patients.

Demographics

Pediatric transplant patients develop PTLD more often than adult patients, as children are less likely to have EBV-specific immunity at the time of transplantation. The frequency varies with the type of transplant. The highest prevalence is seen with multiple organ transplant or intestinal (20%), lung or heart (8-20%), liver (4-15%), and kidney (1-8%). PTLD after bone marrow transplant is rare.

Imaging

Imaging features of CNS PTLD often resemble those of AIDS-related lymphoma or metastatic disease (29-11). Most lesions are single masses, hypointense to cortex on T1WI and heterogeneous on T2WI (29-12A). Solid or ring enhancement is common following contrast administration (29-12B). Moderate restriction is often present on DWI/DTI. Hemorrhage is not a typical feature of PTLD. Perfusion parameters, rCBV are lower than lymphoma or metastatic disease.

Extracranial head and neck PTLD results in a bilateral cervical lymphadenopathy in 75% of cases. Necrosis may be present. Other manifestations include orbital or sinonasal involvement.

Differential Diagnosis

The major differential diagnosis of PTLD is CNS-DLBCL, especially AIDS-related lymphoma. Other considerations include opportunistic infections, such as toxoplasmosis and metastatic disease.Toxoplasmosis typically involves the basal ganglia and corticomedullary junctions. Multiple lesions are more common with toxoplasmosis. Toxoplasmosis often shows an eccentric target on postcontrast images. Metastatic disease often has multiple lesions and marked FLAIR hyperintensity related to vasogenic edema.

Intravascular Large B-Cell Lymphoma

IVL is a distinctive type of aggressive B-cell lymphoma characterized by proliferating malignant cells within small and medium-sized vessels (29-15). Although it can involve any organ, IVL typically affects the skin and the CNS. The brain is nearly always involved. Spinal cord involvement is rare.

Terminology

IVL was formerly called angiocentric or angioendotheliotropic lymphoma, angiotropic large cell lymphoma, endovascular lymphoma, and malignant angioendotheliomatosis. The WHO 2021 term is intravascular large B-cell lymphoma.

Etiology

IVL is an aggressive malignant lymphoma that usually arises from B cells. T cells or NK cells may occasionally be the cell of origin. A possible association of IVL (especially the NK type) with EBV has been reported.

Pathology

The gross macroscopic appearance varies from normal to small multifocal infarcts of varying ages scattered throughout the cortex and subcortical white matter (29-15). Focal cerebral masses are rare. Petechial microhemorrhages may be present and are more common than confluent macroscopic bleeds.

At histologic examination, markedly atypical cells with large round nuclei and prominent nucleoli are found in small and medium-sized vessels. Extension into the adjacent perivascular spaces is minimal or absent. CD20 staining is helpful in identifying tumor cells, especially when they are sparse and widely scattered.

Clinical Issues

Epidemiology

IVL is rare. CNS involvement occurs in 75-85% of patients.

Demographics

IVL is typically a tumor of middle-aged and older adult patients. Mean age at presentation is 60-65 years.

Presentation

Sensory and motor deficits, neuropathies, and multiple stroke-like episodes are common symptoms. Some patients present with progressive neurologic deterioration and cognitive decline characterized by confusion and memory loss. Skin changes with elevated plaques or nodules are present in 1/2 of all cases.

Natural History

Outcome is generally poor. By the time of initial presentation, most patients have advanced disseminated disease. IVL is a relentless, rapidly progressive disease with a high mortality rate. Mean survival is 7-12 months.

Treatment Options

Because IVL is a widely disseminated disease, systemic chemotherapy is the recommended treatment. High-dose chemotherapy with autologous stem cell transplantation is often used in younger patients.

Imaging

There are no pathognomonic neuroimaging findings for IVL. Ischemic foci with infarct-like lesions are the most common imaging finding (29-13C). CT may be normal or nonspecific, demonstrating only scattered white matter hypodensities. MR shows multiple T2/FLAIR hyperintensities (29-13A). Both macro- and microhemorrhages are common, so “blooming” foci on T2* (GRE, SWI) are often present (29-13B). Linear/punctate enhancement oriented along penetrating arteries and perivascular spaces is suggestive of IVL (29-14). Multifocal areas of diffusion restriction may be present (29-16).

Differential Diagnosis

IVL is a “great imitator,” both clinically and on imaging studies. Stereotactic biopsy is thus necessary to establish the definitive diagnosis . Vasculitis with punctate and linear enhancing foci may be virtually indistinguishable from IVL on imaging studies alone (29-17).

PCNSL, especially in the setting of immunodeficiency syndromes, may mimic IVL. IVL is most often multifocal, whereas 2/3 of PCNSLs are solitary lesions. Diffuse multifocal PCNSL, especially when it occurs in the form of lymphomatosis cerebri, may be difficult to distinguish from IVL. Lymphomatosis cerebri often shows little or no enhancement.

Rapidly progressive leukoencephalopathy with confluent nonenhancing white matter lesions is a rare presentation of diffusely infiltrating CNS IVL and may mimic a cerebral demyelinating disorder.

Diffuse subacute viral encephalitis can likewise mimic IVL, especially on biopsy. Parenchymal neurosarcoid with perivascular nodular spread may also resemble IVL on imaging studies.

Miscellaneous Rare CNS Lymphomas

Other than DLBCL, PCNSLs are rare. These lymphomas include anaplastic large cell lymphoma [ALK(+)/ALK(-)], T-cell and NK/T-cell lymphomas and “other low-grade B-cell lymphomas of the CNS,” which includes extranodal marginal zone lymphoma.

Low-grade lymphomas, most of which are B cell, account for ~ 3% of all CNS lymphomas and almost exclusively affect immunocompetent adults. Primary CNS T-cell lymphomas and NK/T-cell lymphomas are very rare, accounting for ~ 2% of all PCNSLs (29-18). Most reported cases are associated with prior EBV infection. Imaging findings are generally indistinguishable from parenchymal DLBCL.

MALT Lymphoma of Dura

Extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT lymphomas)in the head and neck are most often ocular adnexal tumors, occurring in the conjunctiva, lacrimal glands, orbit, and eyelids. The cranial meninges, especially the dura, are occasional intracranial sites. Diffuse dura-arachnoid thickening with one or more meningioma-like masses is the most typical imaging finding (29-19). Parenchymal lesions are rare. Prognosis is excellent with a five-year survival rate of 85%.

Metastatic Intracranial Lymphoma

Metastatic intracranial lymphoma is also called secondary CNS lymphoma (SCNSL). Between 5-10% of patients with diffuse large B-cell systemic lymphomas eventually develop CNS involvement.

Metastatic lymphoma rarely presents as a parenchymal mass. In contrast with PCNSL, skull and dural involvement is much more frequent. Both calvarial vault and skull base metastases are common. More recent studies suggest brain parenchymal involvement is more common than leptomeningeal disease and both are present in 10% of cases.

Calvarial lesions often involve the adjacent scalp and epidural space (29-20). Dural “tails” are common. Involvement of the leptomeninges and underlying brain parenchyma may occur as late complications. Parenchymal lesions in the absence of skull and dural disease are uncommon. Leptomeningeal and CSF spread with cranial nerve, choroid plexus, and spine “drop” metastases occur but are rare (29-21).

Histiocytic Tumors

Preamble

Histiocytic CNS neoplasms are a heterogeneous group of tumors that are histologically and immunologically identical to their extracranial counterparts. The 2021 WHO classification recognizes five histiocytic tumors that affect the CNS: Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), Rosai-Dorfman disease (RDD), juvenile xanthogranuloma, and histiocytic sarcoma.

Langerhans Cell Histiocytosis

LCH is a clonal neoplastic proliferation of immature, partially activated dendritic Langerhans cells. Between 50-60% of patients with LCH have BRAF V600E mutations, but the RAF-MEK-ERK pathway is activated in all patients. MAP2K1, which encodes MEK1, is mutated in 25% of cases.

LCH is now classified on the basis of disease extent as unifocal, multifocal (usually polyostotic), and disseminated disease. Most cases with isolated lesions present in young children under two years of age. Multifocal disease onset is generally between 2-5 years of age.

Geographic destructive bone lesions with “beveled edges” are the most common manifestation of LCH (80-95% of cases) (29-22). The craniofacial bones and skull base are the most commonly affected sites (55%) (29-23A). 1/2 of LCH cases affect the hypothalamic-pituitary region, often with absence of the posterior pituitary “bright spot” and a thickened, enhancing nontapering infundibular stalk (29-23B). Nearly 1/3 of cases involve the cranial meninges.

Approximately 1/3 of patients exhibit parenchymal lesions. A leukoencephalopathy-like pattern, often with degenerative changes in the dentate nuclei &/or basal ganglia, occurs in nearly 1/3 of all LCH cases (29-23C).

LANGERHANS CELL HISTIOCYTOSIS: IMAGING

CT

• > 50% have lytic craniofacial lesion(s)

• “Beveled” lesion > geographic destruction

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