Diagnosis of Lymphoma in Extranodal Sites Other Than Skin

Epidemiology and Etiology

PCNSL may develop in either immunocompetent or immunosuppressed patients. PCNSL makes up 2% to 4% of all primary brain tumors. Patients are predominantly older adults (median age, 55 to 65 years), with a slight male preponderance. Most immunodeficient patients who develop PCNSL are human immunodeficiency virus (HIV) positive, with an estimated risk 1000 times that of immunocompetent individuals. Overall, patients in this group are younger, with a more striking male preponderance. There is also an increased incidence of PCNSL in those with iatrogenic and congenital immunodeficiency. The increased risk in allograft recipients occurred mainly with the use of older azathioprine-based regimens; the risk is much less with more recent cyclosporine-based therapy. There was a sharp increase in PCNSL in recent decades, largely because of the acquired immunodeficiency syndrome (AIDS) epidemic, which has since stabilized. The introduction of highly active antiretroviral therapy (HAART) for HIV-positive patients has dramatically decreased the occurrence of PCNSL in this group. Thus, immunologic abnormalities are important in the pathogenesis of a subset of PCNSL. The cause is unknown in sporadic cases.

Clinical Features

Symptoms are usually of short duration and, depending on the site of the lesion, include speech disturbances, vertigo, weakness, hypothalamic dysfunction, ocular abnormalities, or disturbances of mobility such as ataxia, hemiparesis, hemiplegia, or abnormal gait. Patients may also have seizures or signs or symptoms related to increased intracranial pressure such as headache, papilledema, nausea, or vomiting. Some present with personality changes, confusion, or dementia, mimicking a non-neoplastic disorder.

PCNSL usually presents as a supratentorial mass; presentation in the cerebellum or spinal cord is unusual. PCNSL in the brain or spinal cord may involve the leptomeninges secondarily, but it rarely arises in the leptomeninges. The most common sites are the frontal, temporal, and parietal lobes and the basal ganglia. Rare cases present in the pituitary gland ( Fig. 61-1 ). Lesions may be single or multiple; they are often periventricular, so seeding of the cerebrospinal fluid may occur. Imaging studies typically show irregular, contrast-enhancing lesions with central hypodense areas, consistent with necrosis.

Diagnosis is best established by stereotactic biopsy of the tumor. Cerebrospinal fluid for cytologic examination is insensitive. If fresh material is available, performing touch preparations or smears in addition to routine sections can be helpful in establishing a diagnosis. Resection of the tumor does not improve survival and may lead to a greater neurologic deficit. For immunosuppressed patients, whose lymphomas are almost always Epstein-Barr virus (EBV) positive, the presence of EBV DNA in the cerebrospinal fluid detected by polymerase chain reaction may be a sensitive and specific technique for diagnosing PCNSL and can be used as an alternative to biopsy in selected cases.

Morphologic Features

Autopsy examination typically reveals poorly circumscribed mass lesions with replacement or displacement of normal structures. The lesions often show areas of necrosis or hemorrhage. Some patients have diffuse meningeal involvement, resembling meningitis; rarely, there is diffuse subependymal periventricular involvement by tumor.

The characteristic microscopic appearance is a diffuse proliferation of atypical cells with areas of perivascular growth and often necrosis. If steroids were administered before biopsy, the neoplastic cells may undergo a remarkable degree of apoptosis, and the tumor may temporarily shrink or even disappear, making diagnosis difficult. More than 80% of cases are diffuse large B-cell lymphoma (DLBCL) composed of immunoblasts or centroblasts. The remainder are somewhat poorly characterized low-grade B-cell lymphomas classified as small-lymphocytic or small-lymphocytic plasmacytoid type, Burkitt's lymphoma, and peripheral T-cell lymphomas, including rare cases of anaplastic large-cell lymphoma. Virtually all cases in immunocompromised patients are DLBCLs. One percent to 2% of cases are intravascular large B-cell lymphoma.

Immunophenotype

The DLBCLs are typically CD45 ⁺ , CD20 ⁺ , CD10 ⁻ , BCL-6 ^{+ / −} , BCL-2 ⁺ , MUM1/IRF4 ⁺ , and monotypic immunoglobulin ⁺ (usually IgM). Thus, most cases have a non–germinal-center immunophenotype. A subset of HIV-associated PCNS DLBCL is latent membrane protein (LMP) positive or Epstein-Barr nuclear antigen positive. Loss of human leukocyte antigen (HLA) class I and II molecules is reported frequently.

Genetic Features

Molecular genetic analysis shows monoclonal immunoglobulin gene rearrangements in DLBCL. Virtually all cases of PCNS DLBCL in immunosuppressed patients are positive for EBV-encoded small RNA (EBER) by in situ hybridization, whereas such tumors in immunocompetent patients are EBER negative. About half of cases show mutations of the BCL6 gene, consistent with transition through the germinal center. Aberrant somatic hypermutation of proto-oncogenes such as MYC and PAX5 and deletions in 6q are found in some cases. Multiple genes are differentially expressed; it is possible to predict prognosis on the basis of gene-expression signature. There appears to be preferential use of certain VH families, as well as a high load of somatic mutations, in some cases accompanied by intraclonal diversity. The pattern suggests that the neoplastic cells are derived from antigen-selected B cells of the germinal center. Nearly half of primary CNS DLBCLs are reported to have mutations in the B-cell receptor signaling pathway, potentially leading to constitutive activation of the NFκB pathway.

Postulated Normal Counterpart

Immunophenotypic and genetic features suggest that PCNS DLBCL is derived from a late germinal-center or post–germinal-center B cell. Some investigators have suggested that the cell of origin is a B cell in peripheral lymphoid tissue that crosses the blood-brain barrier and then proliferates to form a tumor in that immunologically protected environment. In such a scenario, it is unclear whether neoplastic transformation takes place before or after entry into the CNS or whether the immunoglobulin genes of tumor cells can continue to mutate outside the germinal center. The loss of HLA molecules may be related in some way to the survival of lymphomas in immune-privileged sites such as the CNS and testis.

Staging, Treatment, and Outcome

Staging should be performed to exclude systemic lymphoma with secondary involvement of the CNS, but staging is usually negative in patients with the findings described earlier. PCNS DLBCL is an aggressive neoplasm requiring prompt diagnosis and therapy. Survival is only a few months without therapy. In contrast to systemic lymphomas, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy is not efficacious in PCNS DLBCL. In the past, traditional therapy was whole-brain radiation combined with steroids. This resulted in complete remission in 90% of cases, but the lymphoma usually relapsed within 1 year, with a median survival of 12 to 18 months and a 5-year survival rate of only 3% to 4%. More recently, survival has improved with the addition of high-dose methotrexate, an agent that can penetrate the blood-brain barrier, to radiation. Unfortunately, long-term survivors who received radiation therapy were at high risk for the development of leukoencephalopathy, manifested by severe progressive dementia, ataxia, and urinary incontinence. For this complication to be avoided, regimens without radiation or with low-dose radiation are used. The standard treatment is currently high-dose methotrexate-based chemotherapy. Relatively good outcomes without cognitive loss have been achieved with intensive chemotherapy-based regimens.

When patients with PCNS DLBCL relapse, the CNS is involved in the vast majority of cases. In a small proportion of cases, lymphoma spreads outside the CNS; sites of spread are usually extranodal, with frequent testicular involvement. The prognosis is better for patients who are younger than 60 years and immunocompetent. Expression of the BRCA1 protein is associated with a significantly poorer outcome. The low-grade B-cell lymphomas appear to have a relatively favorable prognosis, although this topic has not been well studied.

Differential Diagnosis

Sampling artifact or prior steroid therapy can result in a biopsy that shows a predominance of small reactive T cells, mimicking a chronic inflammatory process. Avoiding prebiopsy steroids and obtaining intraoperative frozen sections to ensure that the tissue is representative in any case of suspected PCNSL are helpful in establishing a diagnosis. There may be a surrounding glial reaction that mimics astrocytoma. Other neoplasms, including primitive neuroectodermal tumor, undifferentiated carcinoma, melanoma, anaplastic oligodendroglioma, and rare astrocytomas, can grow in sheets and mimic lymphoma. Arteritis can mimic areas of lymphoma with perivascular growth.

Clinical Features

Primary ocular lymphoma or intraocular lymphoma—lymphoma involving the eye itself—also known as primary vitreoretinal lymphoma, is uncommon. Intraocular DLBCL is considered part of the spectrum of PCNS DLBCL. It occurs predominantly in middle-aged and older adults, with a mean age in the sixties, although occasionally young adults and rarely children are affected. There is a female preponderance. Most patients have no known predisposing conditions, but cases have been described in HIV-infected patients and in iatrogenically immunosuppressed allograft recipients.

Patients typically complain of blurred or reduced vision or floating spots, or both. Although symptoms are often unilateral, ophthalmologic examination reveals involvement of both eyes in the majority of cases. Translucent gray cells appear in sheets and clumps suspended in the vitreous. The majority of cases affect the vitreous and retina. The vitreous typically shows opacification. Whitish, yellow-white, or gray-white infiltrates; plaquelike lesions; or large masses may be seen beneath the retinal pigment epithelium, sometimes with edema, hemorrhage, necrosis, or retinal detachment. Invasion of the optic nerve may occur. Extension to involve the uvea may be seen, but generally involvement centered on the uveal tract (choroid, iris, and ciliary body) is more commonly seen when the eye is secondarily involved by systemic lymphoma. Other manifestations include increased intraocular pressure, keratic precipitates (deposits of cells on the posterior surface of the cornea), and anterior chamber cells and flare (the presence of increased protein causes the normally clear fluid of the anterior chamber to become cloudy [flare] with tiny particles [cells] suspended in the fluid).

Ocular lymphoma can mimic non-neoplastic conditions, including chronic idiopathic uveitis, retinal vasculitis, optic neuritis, amyloidosis, sarcoidosis, and infections such as toxoplasmosis, syphilis, tuberculosis, Whipple's disease, and cytomegalovirus infection. The possibility of lymphoma may be raised when there is a poor response to steroids or antimicrobial therapy or the onset of neurologic symptoms due to CNS involvement.

Techniques used to establish a diagnosis include vitreous aspirate, vitrectomy, retinal or chorioretinal biopsy, or, in patients with a blind, painful eye, ocular enucleation. The most common method is microscopic examination of the vitreous, but the sensitivity of this procedure may be limited by admixed inflammatory cells, by tendency of neoplastic cells to degenerate, or by prior steroid therapy, which may eliminate many of the tumor cells. Diagnostic yield may be improved by combining routine light microscopy with flow cytometry and molecular genetic analysis for B-cell clonality. An elevated interleukin-10 (IL-10) level or an IL-10 to IL-6 ratio greater than 1.0 in the vitreous is strongly associated with intraocular lymphoma and may prompt repeat biopsy if the initial specimen is non-diagnostic.

Pathologic Features

Nearly all intraocular lymphomas are DLBCLs. The pathologic features are virtually identical to PCNS DLBCL presenting in the brain. Rare cases of peripheral T-cell lymphoma presenting with ocular involvement have also been described.

Staging, Treatment, and Outcome

The majority of cases of intraocular DLBCL are associated with CNS DLBCL either at presentation or during follow-up; a minority are associated with systemic lymphoma or remain confined to the eye. Aggressive treatment of isolated intraocular lymphoma can decrease the risk for progression.

Isolated intraocular lymphoma frequently responds well to local therapy (ocular radiation, intravitreal methotrexate, or intravitreal rituximab), but restoration of sight is not guaranteed because the retina may already be irreversibly damaged, and radiation may be associated with retinopathy and cataracts. In addition, relapse and progression to CNS involvement are common. For patients with disease that has spread beyond the eye, high-dose methotrexate-based chemotherapy can be effective, although relapse may occur. For patients with relapsed or refractory disease, the best therapy is uncertain, but treatment with other aggressive combination chemotherapeutic regimens, with or without autologous stem cell transplantation or low-dose whole brain radiation, has been used.

Clinical Features

Patients are usually adults; males and females are equally affected. They typically have a subacute onset of neuritic pain, often accompanied by sensory and motor deficits. Physical examination or magnetic resonance imaging reveals a tumor expanding the nerves, sometimes imparting a fusiform contour. When a single nerve is involved, it is usually the sciatic nerve. Lymphoma infiltrates the nerve, resulting in segmental demyelination and axonal degeneration. Patients may respond to chemotherapy, but most develop relapses in other nerves, the CNS, or a variety of extranodal sites, and the majority succumb to their lymphoma.

Pathologic Features

The lymphomas are most often DLBCLs, but low-grade B-cell lymphomas and T-cell lymphomas have been described.

Differential Diagnosis

On clinical grounds, the differential diagnosis includes paraneoplastic syndrome, degenerative disease, Guillain-Barré syndrome, and schwannoma. On histologic examination, early involvement by low-grade lymphoma can be difficult to distinguish from an inflammatory process.

Clinical Features

Lymphoma arising in the dura mater is uncommon, but well-documented cases have been described. Patients are mostly middle-aged and older adults with a female preponderance. There are no known specific risk factors. They present with seizures, headaches, cranial nerve abnormalities, radicular pain, syncope, or a combination of these findings. Radiologic evaluation usually reveals a localized, expansile mass or plaquelike thickening of the dura over the brain ; preoperatively, this is most often thought to be a meningioma or, less often, a nerve sheath tumor or subdural hematoma.

Pathologic Features

Rare primary dural DLBCLs and follicular lymphomas are reported, but most primary dural lymphomas are extranodal marginal-zone (MALT) lymphomas. The MALT lymphomas have histologic and immunohistologic features similar to those seen in other sites, although sclerosis is more common in the dura. They are composed of small lymphocytes and marginal-zone cells, usually with plasmacytic differentiation and admixed reactive follicles ( Fig. 61-2 ). Entrapped meningothelial cells may be seen. Dural marginal-zone lymphomas may arise in association with meningothelium, just as marginal-zone lymphomas arise in association with epithelium in other sites. Associated amyloid deposition has been described. An unexpectedly high proportion of dural MALT lymphomas have a component of monotypic IgG4-positive plasma cells. A subset of the MALT lymphomas harbor trisomies, with chromosomes 3 and 18 most commonly affected among the small number of case studies. MALT-specific translocations are rare, although a case with IGH /MALT1 fusion has been described. The lymphomas are typically localized. Therapy varies from case to case, but almost all recently reported patients who have undergone thorough staging and received optimal therapy have done well.

Differential Diagnosis

Other low-grade B-cell lymphomas, such as lymphoplasmacytic lymphoma and chronic lymphocytic leukemia, can have histologic features mimicking those of marginal-zone lymphoma, but the immunophenotype and localized nature of the dural MALT lymphomas can be used to exclude other low-grade lymphomas. Some cases previously interpreted as dural plasmacytoma may actually represent MALT lymphoma with marked plasmacytic differentiation. Some cases may raise the question of inflammatory pseudotumor, a chronic inflammatory process, or lymphoplasmacyte-rich meningioma, but immunophenotyping or genotyping can help establish the diagnosis.

Clinical Features

Primary ocular adnexal lymphomas are defined as lymphomas arising in the orbital soft tissue (including extraocular muscles), lacrimal gland, conjunctiva, eyelids, and lacrimal sac. The orbital soft tissue is the most common site, followed by the conjunctiva (bulbar or palpebral), lacrimal gland, and then the lacrimal sac. One percent to 2% of all lymphomas and approximately 8% of all extranodal lymphomas arise in the ocular adnexa. Lymphoid tumors constitute 10% of orbital mass lesions, and lymphoma is the most common orbital malignancy. Lymphomas in this site affect predominantly older adults, and there is a slight female preponderance, with a median age in the sixties and a male-to-female ratio of 3 : 4. Children are only rarely affected. Occasionally patients have a history of an autoimmune disorder, IgG4-related disease, another malignancy, HIV infection, or contact lens wear. An association of a subset of MALT lymphomas with Chlamydophila (formerly Chlamydia ) psittaci infection has been reported in certain countries.

Patients have proptosis, ptosis, a palpable or visible mass, diplopia, tearing, or discomfort. Systemic symptoms are rare. Conjunctival lymphoma usually produces a salmon-colored plaque that is mobile over the surface of the eye. The orbital soft tissue is involved in the majority of cases, sometimes accompanied by lacrimal gland involvement; the conjunctiva is involved in up to approximately one third of cases. In 10% to 25% of cases, there is bilateral involvement.

Pathologic Features

Lymphomas of all types can present with ocular adnexal involvement, but most (60% to 75%) are MALT lymphomas. Most of the remainder are follicular lymphomas, followed by DLBCLs. The DLBCLs include both centroblastic and immunoblastic variants. Rare cases of chronic lymphocytic leukemia, mantle cell lymphoma, Burkitt's lymphoma, and B-lymphoblastic lymphoma present with ocular adnexal involvement. The few primary ocular adnexal lymphomas encountered in HIV-positive patients are usually high-grade B-cell lymphomas, either DLBCL or Burkitt's lymphoma. Rare cases of T-cell lymphoma and natural killer (NK)–cell lymphoma have ocular adnexal involvement at presentation.

The immunophenotypic and genetic features are generally similar to those of the same lymphomas arising elsewhere, although ocular adnexal MALT lymphomas show a tendency for site-specific genetic changes. Approximately one quarter of ocular adnexal MALT lymphomas harbor t(14;18)(q32;q21), a translocation involving IGH and MALT1; this translocation has also been found in MALT lymphomas arising in the liver, skin, and salivary glands but is rare in other sites. Conversely, t(11;18)(q21;q21), a translocation involving API2 and MALT1, is relatively common in gastric and pulmonary MALT lymphoma but is only rarely encountered in ocular adnexa. In patients with bilateral ocular adnexal marginal-zone lymphomas, the morphologic, immunophenotypic, and molecular genetic features are typically identical, consistent with a single neoplastic clone involving both sites, rather than two distinct, unrelated primary tumors. The majority of DLBCLs have a non–GC-B-like immunophenotype, whereas nearly 40% have a GC-B-like phenotype.

Staging, Treatment, and Outcome

Approximately 80% of patients have disease confined to the ocular adnexa, unilaterally or bilaterally. Localized low-grade lymphomas are usually treated with radiation. In about half of patients with MALT lymphoma harboring C. psittaci and in slightly fewer without C. psittaci, the lymphomas showed partial or complete response with antibiotic therapy. Cases of high-grade lymphomas, whether localized or widespread, are usually treated more aggressively. Radiation therapy achieves excellent local control of disease, and freedom from local recurrence is close to 100%. The overall prognosis of ocular adnexal lymphoma is good. Overall survival at 5 years is approximately 90%, and the 5-year disease-free survival rate is approximately 70%. One study of MALT lymphoma showed complete remission in 95% of cases, with 3-year overall survival of 100% and event-free survival of 97%. In another study of 83 ocular adnexal lymphomas of all histologic types, only one death occurred, in a patient with mantle cell lymphoma. Local recurrence is very uncommon among patients treated with optimal radiation therapy. When relapses occur, they may be in lymph nodes, the opposite orbit, or other extranodal sites.

Patients who have disease localized to the ocular adnexa have a much more favorable prognosis than those with more widespread disease. However, isolated bilateral ocular adnexal disease does not have a poorer prognosis than unilateral disease. The histologic type of lymphoma is also important in defining outcome. In most reports, patients with high-grade lymphoma have a poorer outcome.

Differential Diagnosis

Because most ocular adnexal lymphomas are low-grade lymphomas, the main differential diagnosis is a reactive process, including inflammatory pseudotumor and reactive lymphoid hyperplasia. Inflammatory pseudotumor is a lesion with a variably cellular, polymorphic infiltrate of small lymphocytes, plasma cells, immunoblasts, histiocytes, and sometimes eosinophils or neutrophils, in a stroma with areas that are hyalinized or edematous, or both. Vascularity can be prominent, and endothelial cells may appear hyperplastic. Immunohistochemical studies in such cases show a mixture of T cells, B cells, and polytypic plasma cells. In some cases, the plasma cells are predominantly IgG4 positive, suggesting that some inflammatory pseudotumors may be part of the spectrum of IgG4-related disease. A few cases of lymphoma (usually MALT lymphoma) arising in a background of IgG4-related sclerosing dacryoadenitis or IgG4-related sclerosing orbital inflammation have been described, emphasizing the importance of careful histologic and immunophenotypic study of orbital lymphoid infiltrates. Reactive lymphoid hyperplasia usually consists of follicular hyperplasia without a prominent diffuse lymphoid proliferation and without cytologic atypia. A dense, diffuse infiltrate composed predominantly of B cells favors a diagnosis of lymphoma. Such lesions usually express monotypic immunoglobulin and contain clonal B cells on molecular genetic analysis.

Clinical Features

Most patients are adults, with a median age in the fifties and a male-to-female ratio of 1 : 1 to 1 : 1.5. Children may also develop lymphomas in this site. A few patients are HIV positive or iatrogenically immunosuppressed. Patients have dysphagia, dyspnea, snoring, or a neck mass due to cervical lymphadenopathy. A minority of patients have systemic symptoms.

The tonsil is the most frequently involved site, accounting for more than half of Waldeyer's ring lymphomas, followed by the nasopharynx and base of the tongue. Physical examination reveals a mass that is unilateral and exophytic in most cases and may be polypoid, fungating, or ulcerated. The lymphoma is localized (stage I or II) in approximately three quarters of cases; stage II disease, with cervical lymph node involvement, is more common than stage I disease.

Pathologic Features

Sixty percent to 84% of cases are DLBCLs ( Fig. 61-3 ). Other types are uncommon; they include follicular lymphoma, Burkitt's lymphoma, mantle cell lymphoma, marginal-zone lymphoma, extranodal NK/T-cell lymphoma, nasal type, and peripheral T-cell lymphoma. Mantle cell lymphoma can present with involvement of Waldeyer's ring, but in contrast to DLBCL, mantle cell lymphoma is usually widespread at the time of diagnosis. Among children with Waldeyer's ring lymphoma, Burkitt's lymphoma is much more frequent than it is among adults ( Fig. 61-4 ). A distinctive large B-cell lymphoma with a translocation involving IRF4 preferentially involves Waldeyer's ring in children; these lymphomas are DLBCLs or follicular lymphoma, grade 3B that are CD5 ^{− / +} , CD10 ^{+ / −} , BCL6 ⁺ , BCL2 ^{+ / −} , and MUM1 ⁺ . IRF4-translocated large B-cell lymphomas are typically localized and have a favorable prognosis. Extranodal NK/T-cell lymphoma, nasal type, rarely arises in Waldeyer's ring, but in contrast to DLBCL, which usually arises in the tonsil, NK/T-cell lymphoma most often affects the nasopharynx. Patients are younger than those with DLBCL, with a higher proportion of males. The lymphoepithelioid cell type of peripheral T-cell lymphoma, NOS (Lennert's lymphoma), has a predilection for Waldeyer's ring. These lymphomas have pathologic features similar to those seen in other sites.

Hodgkin's lymphoma, almost always of the classical type, rarely presents with involvement of Waldeyer's ring. However, Waldeyer's ring is the most common extranodal site within the head and neck for involvement by Hodgkin's lymphoma. In most cases, staging reveals Hodgkin's lymphoma involving lymph nodes as well. The most common histologic types are nodular sclerosis and mixed cellularity. In one study, among those cases confined to Waldeyer's ring, lymphocyte-rich classical Hodgkin's lymphoma was the most common type. The presence of EBV may be more prevalent in Hodgkin's lymphoma in this anatomic site than elsewhere, possibly because Waldeyer's ring is a reservoir for EBV.

Treatment and Outcome

Patients respond well to therapy, with a high proportion achieving complete remission. However, there is a high rate of distant relapse, particularly in those treated with radiation alone. Although relapses may occur in any lymph node and in a variety of extranodal sites, there is a predilection for spread to the gastrointestinal tract. One recent study reported 5-year OS and PFS rates of 74% and 67%, respectively, for patients with DLBCL and 68% and 59%, respectively, for patients with extranodal NK/T-cell lymphoma. A more favorable prognosis is associated with a tonsillar primary tumor, favorable International Prognostic Index score, localized disease, and, among stage II patients, cervical lymphadenopathy that is unilateral and non-bulky.

Differential Diagnosis

Reactive lymphoid hyperplasia often causes enlargement of one or more of the components of Waldeyer's ring, sometimes forming mass lesions mimicking a neoplasm. Preservation of reactive follicles and crypts favors a reactive process. Infectious mononucleosis due to acute EBV infection can mimic DLBCL or classical Hodgkin's lymphoma, but some architectural preservation, polymorphic composition, positive in situ hybridization for EBER, and clinical features (particularly age) can be helpful in the differential diagnosis. Before making a diagnosis of DLBCL or classical Hodgkin's lymphoma in Waldeyer's ring in a child or adolescent, evaluation for evidence of acute EBV infection is essential. Infiltration of crypt epithelium by lymphoid cells is normal and does not suggest marginal-zone lymphoma. Reactive hyperplasia with monotypic immunoglobulin light-chain expression in marginal-zone B cells that are polyclonal by molecular genetic analysis (“atypical marginal-zone hyperplasia of MALT”) has been reported in Waldeyer's ring in children, representing a pitfall in the diagnosis of MALT lymphoma in this site. The pleomorphic variant of mantle cell lymphoma may mimic DLBCL, and assessment for CD5 and cyclin D1 expression should be considered in cases of what appear to be DLBCL in this area. Undifferentiated nasopharyngeal carcinoma and DLBCL may be difficult to distinguish on routine sections, but immunophenotyping readily establishes a diagnosis.

Clinical Features

Paranasal sinus lymphomas affect men more often than women (male-to-female ratio of 1.5-2 : 1). They affect predominantly middle-aged to older adults and occasionally children. A few patients have been HIV positive or iatrogenically immunosuppressed. Symptoms include nasal obstruction or discharge, facial swelling, pain or numbness, epistaxis, sinus pressure, toothache, or headache. The lymphoma may invade adjacent structures such as the orbit, base of the skull, CNS, pterygopalatine fossa, nasopharynx, and palate. Such patients may present with neurologic abnormalities, proptosis, diplopia, decreased visual acuity, and even blindness. * Patients occasionally have fever and night sweats. Among the paranasal sinuses, the maxillary sinus is the most common site of involvement, followed by the ethmoid sinus, sphenoid sinus, and frontal sinus. Frequently, multiple sinuses are involved concurrently. These lymphomas are often associated with destruction of adjacent bone. Patients with nasal cavity DLBCL are usually middle-aged to older men (male-to-female ratio of 3-4 : 1) without B symptoms.

* References .

Pathologic Features

In Western countries, the most common paranasal sinus lymphoma is DLBCL, followed by extranodal NK/T-cell lymphoma. Other types are infrequent or rare, but Burkitt's lymphoma, follicular lymphoma, MALT lymphoma, peripheral T-cell lymphoma, NOS, and adult T-cell leukemia/lymphoma presenting with sinus involvement have been described. The lymphomas in HIV-positive patients are almost all DLBCL and Burkitt's lymphoma. Those in children are most often Burkitt's lymphoma, followed by DLBCL. Immunophenotypic features are similar to those seen in other sites. The proportion of sinonasal B-cell lymphomas containing EBV varies among different series ; in one study, EBV was encountered only in DLBCLs in patients with underlying immunodeficiencies.

Staging, Treatment, and Outcome

The majority of cases are localized at presentation. In one series, 71% of lymphomas of all types were stage I, 8% stage II, 2% stage III, and 18% stage IV. Patients with stage IV disease may have involvement of CNS, lung, bone, kidney, or gastrointestinal tract. Most patients receive radiation and chemotherapy. Some authorities recommend prophylactic treatment of the CNS to achieve long-term disease-free survival. When the lymphomas relapse or progress, they frequently involve lymph nodes and may also involve a variety of extranodal sites, including the CNS, lung, bone, ovary, testis, bone marrow, liver, spleen, and skin. Results of follow-up vary widely, with 5-year survival ranging from 29% to 80% in different series of paranasal sinus lymphoma patients treated with combined-modality therapy. Patients with nasal cavity DLBCL usually have localized disease and are reported to have a 3-year overall survival rate of 44%, with a more favorable outcome for those with localized disease and a favorable IPI score. Failures are often extranodal.

Differential Diagnosis

DLBCL and extranodal NK/T-cell lymphoma may be difficult to distinguish on routine sections. Angioinvasion and angiocentric localization, prominent necrosis, epitheliotropism, and pseudoepitheliomatous hyperplasia favor NK/T-cell lymphoma. DLBCL more commonly arises in paranasal sinuses, whereas nasal localization and midfacial destructive disease favor the NK/T-cell lymphoma. Most DLBCLs are composed of a diffuse proliferation of large cells; therefore, any other cellular composition with a diffuse pattern, especially a mixture of small and large cells or medium-sized cells, should raise the question of NK/T-cell lymphoma. B-cell and NK/T-cell lymphomas can be distinguished easily with immunophenotyping. Absence of EBV tends to exclude extranodal NK/T-cell lymphoma.

Clinical Features

Lymphomas account for 2% to 5% of salivary gland malignancies. The lymphomas arise in the parotid gland in at least 70% of cases, in the submaxillary gland in 15% to 25% of cases, and in the sublingual and minor salivary glands in less than 10% of cases. Almost all patients are older than 50 years, with a slight female preponderance. Patients are seen with an enlarging mass that is usually painless but is occasionally accompanied by facial nerve paralysis or cervical lymphadenopathy. Underlying Sjögren's syndrome, lymphoepithelial sialadenitis, or rheumatoid arthritis is common.

Pathologic Features

Extranodal marginal-zone lymphoma of MALT type (see Chapter 19 ) and DLBCL account for nearly all lymphomas arising in the area of the salivary glands and occur in roughly equal numbers. MALT lymphoma is the most common type that arises in salivary gland parenchyma. The lymphomas in patients with Sjögren's syndrome are mostly MALT type. MALT lymphoma affects predominantly females, in accordance with the greater incidence of Sjögren's syndrome in women. MALT lymphoma often arises in a background of lymphoepithelial sialadenitis with lymphoepithelial lesions. In contrast to lymphoepithelial sialadenitis without lymphoma, the lymphoepithelial lesions in MALT lymphoma are surrounded by large halos and broad, intersecting strands and sheets of monocytoid B cells, distorting and obliterating the salivary gland parenchyma. Also present are scattered reactive follicles and plasma cells, sometimes in large aggregates. In salivary glands other than the parotid, lymphoepithelial lesions may be less conspicuous, but the histologic features are otherwise similar. Follicular lymphoma may also arise in the salivary gland region but usually involves lymph nodes in the vicinity rather than salivary gland parenchyma. The pathologic features are similar to those of other nodal follicular lymphomas (see Chapter 18 ). At least some cases of DLBCL most likely represent large-cell transformation of an underlying MALT lymphoma or follicular lymphoma. Rare cases of Burkitt's lymphoma ; peripheral T-cell lymphoma, NOS; anaplastic large-cell lymphoma; and extranodal NK/T-cell lymphoma, nasal type, have also been reported.

Staging, Treatment, and Outcome

The majority of patients with salivary gland lymphoma present with localized disease. Patients with MALT lymphoma can develop extrasalivary disease in lymph nodes or in other MALT sites. In a minority of cases, the lymphoma undergoes transformation to DLBCL, which may behave in an aggressive manner.

Differential Diagnosis

In the differential diagnosis of MALT lymphoma and lymphoepithelial sialadenitis, extensive monocytoid B-cell proliferation outside lymphoepithelial lesions and extensive glandular obliteration favor lymphoma. Monocytoid B cells confined to lymphoepithelial lesions and even discrete halos around such lesions can be seen in lymphoepithelial sialadenitis, but broad, intersecting bands of monocytoid B cells support a diagnosis of lymphoma. Demonstration of monotypic immunoglobulin in lymphoid cells or plasma cells supports lymphoma. Molecular genetic studies are usually not helpful because B-cell clones are found in more than 50% of cases of lymphoepithelial sialadenitis. HIV-associated cystic lymphoid hyperplasia involves lymph nodes, is often bilateral, and typically consists of multiple dilated ducts surrounded by floridly hyperplastic follicles with attenuated mantles. Lymphoepithelial lesions are not conspicuous, although large numbers of lymphoid cells may be found within the epithelium of dilated ducts. The differential diagnosis may also include chronic sclerosing sialadenitis (Küttner's tumor), which typically involves submandibular glands. Chronic sclerosing sialadenitis may have prominent follicular hyperplasia and a dense lymphoid infiltrate with numerous plasma cells and scattered eosinophils, but lymphoepithelial lesions are inconspicuous. There is typically sclerosis, beginning as bandlike, but increasing over time to obliterate parenchyma. IgG4-positive plasma cells are typically numerous; chronic sclerosing sialadenitis is considered a manifestation of IgG4-related disease.

Clinical Features

Approximately 2% of all extranodal lymphomas arise in the oral cavity (palate, gingiva, tongue, buccal mucosa, floor of the mouth or lips). Lymphoma arising in the bones of the jaw may invade adjacent soft tissues and present as an oral cavity lesion. Most patients are immunocompetent, middle-aged to older adults, with a median age in the sixth or seventh decade; there is a slight male preponderance. In recent years, there has been an increase in lymphomas of the oral cavity because of the tendency for patients with HIV infection to develop lymphoma in this site. Almost all HIV-infected patients are younger males, with an approximate median age of 40 years. Oral lymphomas have also been rarely reported in transplant recipients.

Patients are seen with soft tissue swelling, pain, mucosal ulceration or discoloration, paresthesias, anesthesia, and loosening of teeth. The sites most often affected, in both HIV-positive and HIV-negative patients, are the palate, maxilla, and gingiva, with the tongue, buccal mucosa, floor of the mouth, and lips affected less often. Physical examination reveals an exophytic, often polypoid mass in the majority of cases. In a minority of cases, the lymphoma is an infiltrative, ulcerated lesion with raised margins.

Pathologic Features

A wide variety of lymphomas arise in the oral cavity. Among non-immunosuppressed patients, approximately half are DLBCLs. The next most common type is follicular lymphoma ( Fig. 61-5 ), followed by MALT lymphoma; mantle cell lymphoma; peripheral T-cell lymphoma, NOS; extranodal NK/T-cell lymphoma; Burkitt's lymphoma; and others. MALT lymphomas may arise in minor salivary glands. Follicular lymphoma has a predilection to involve the palate. Mycosis fungoides occasionally involves the oral cavity; the majority of these cases are found in the setting of long-standing, advanced disease, but in exceptional cases the first manifestation of mycosis fungoides is in the oral cavity. It has been suggested that the uncommon aggressive epidermotropic CD8-positive cutaneous T-cell lymphoma is more likely to involve the oral cavity than the more common mycosis fungoides type.

Oral lymphomas in HIV-infected individuals are less heterogeneous than those found in the general population; they are almost all high-grade lymphomas. Most are DLBCLs, with occasional peripheral T-cell lymphoma, NOS, and a few cases of Burkitt's lymphoma and anaplastic large-cell lymphoma. Plasmablastic lymphoma is a distinctive subset of HIV-associated DLBCL that often occurs in the oral cavity; it is composed of cells with the appearance of immunoblasts or plasmablasts with vesicular nuclei, prominent nucleoli, abundant eccentrically placed cytoplasm with a paranuclear hof, high mitotic rate, frequent single-cell necrosis, and scattered tingible body macrophages (see Chapter 25 ). The immunophenotype is distinctive: neoplastic cells usually lack both leukocyte-common antigen (CD45) and CD20, although they are usually CD138 positive, IRF4/MUM-1 positive, and CD79a positive; often contain cytoplasmic immunoglobulin; and show clonal immunoglobulin heavy-chain gene rearrangement, confirming their B lineage.

The majority of HIV-associated oral lymphomas, both B-cell and T-cell types, including plasmablastic lymphoma, contain EBV. In contrast, only about 9% of oral lymphomas in non-immunosuppressed patients are EBER positive. EBV may play a role in the pathogenesis of the majority of HIV-associated lymphomas, but it is not a major factor in the pathogenesis of oral lymphoma in the general population.

Staging, Treatment, and Outcome

Staging reveals localized disease in approximately 70% of cases. The proportion with localized and disseminated disease is similar in HIV-positive and HIV-negative patients. Outcome depends on stage, type of lymphoma, and HIV status. Patients with localized, histologically low-grade lymphomas have an excellent outcome, whereas patients with high-grade lymphoma or disseminated disease have significantly lower survival rates. AIDS patients have a very poor prognosis; 75% of patients die within 18 months of the diagnosis of lymphoma, although other HIV-associated illnesses may contribute to their deaths.

Differential Diagnosis

The most important diagnostic pitfall is failing to consider lymphoma during the physical examination. Oral lymphomas can mimic dental conditions such as periodontal disease, acute necrotizing gingivitis, and dental infections. The appearance of some lesions suggests carcinoma. In HIV-positive patients, Kaposi's sarcoma, deep fungal infections, and HIV-associated periodontal disease also enter the differential diagnosis.

Clinical Features

Primary lymphomas of the thyroid gland are uncommon and have distinctive clinical and pathologic features. They account for 1% to 5% of all thyroid malignancies and 1% to 2.5% of all lymphomas. Patients have a wide age range, but most are older adults with a median age between 60 and 70 years. There is a striking female preponderance. Most patients have evidence of underlying chronic lymphocytic thyroiditis/Hashimoto's thyroiditis. Patients with Hashimoto's thyroiditis have an estimated 40- to 80-fold increased risk for thyroid lymphomas compared with individuals without this disorder. Patients complain of the presence of a mass, sometimes described as rapidly enlarging. They may also have dysphagia, cough, dyspnea, and hoarseness. The lesion may result in tracheal compression.

Pathologic Features

On gross examination the tumors range from 0.5 to 19 cm (mean, 7 cm) and form multinodular or diffuse, firm or soft masses with smooth, pale tan or white-gray surfaces on sectioning. DLBCL is the most common type, accounting for 50% to more than 90% of cases. MALT lymphoma is the next most common type, accounting for 10% to 28% of cases. A subset of DLBCL cases has a component of MALT lymphoma, consistent with transformation of the underlying low-grade lymphoma. All other types of lymphoma are quite uncommon; among those reported are Burkitt's lymphoma, follicular lymphoma, and rare peripheral T-cell lymphomas.

The histologic features of these lymphomas are similar to those seen in other sites, although thyroidal MALT lymphoma has some distinctive characteristics. Tumors often contain a characteristic type of lymphoepithelial lesion consisting of round aggregates of marginal-zone cells filling and expanding the lumens of thyroid follicles—so-called MALT-ball lymphoepithelial lesions. Follicular colonization tends to be prominent, in some cases resulting in a follicular architecture so striking that it mimics follicular lymphoma. Blast transformation of neoplastic cells within colonized follicles is more common in the thyroid gland than elsewhere. Changes of Hashimoto's thyroiditis are often seen adjacent to the lymphoma ( Fig. 61-6 ). The immunophenotypic features are similar to those seen in other sites. A subset of marginal-zone lymphomas of the thyroid gland has a translocation involving the genes for FOXP1 and IGH ([3;14][p14.1;q32]) that results in upregulation of FOXP1 and could play a role in the pathogenesis of marginal-zone lymphoma. Although follicular lymphoma in the thyroid gland is rare, it has distinctive features. One subset of thyroidal follicular lymphomas is characterized by grade 3 histology; lack of CD10 and BCL2 protein expression; lack of IGH -BCL2 translocation; and with disease confined to the thyroid gland. A second subset of follicular lymphomas involving the thyroid gland is characterized by grade 1 or 2 histology, expression of CD10 and BCL2, and presence of an IGH -BCL2 translocation, usually in the setting of disease outside the thyroid gland, all features commonly associated with follicular lymphoma arising in lymph nodes, and possibly representing secondary thyroidal involvement by follicular lymphoma arising in lymph nodes.

Staging, Treatment, and Outcome

The majority of patients have localized disease at presentation; 50% to 70% of patients have stage I disease, and most of the remainder have stage II disease, usually with cervical or perithyroidal lymph node involvement. A minority of patients have more widespread nodal and extranodal involvement. Extranodal sites that may be involved include the bone marrow, gastrointestinal tract, lung, liver, and bladder. MALT lymphomas are almost always localized (stage I or II). DLBCLs are also usually localized but are associated with stage III or IV disease more often than MALT lymphomas.

Treatment has not been uniform. Some patients with MALT lymphoma have been treated with surgery alone; others have received radiation or chemotherapy, or both. The 5-year disease-specific survival rate of thyroid lymphoma patients ranges from 46% to 79%. Patients with MALT lymphoma and patients with stage I disease, regardless of histologic type, have an excellent prognosis. The outcome is less favorable for those with higher-stage disease or DLBCL.

Differential Diagnosis

Both Hashimoto's thyroiditis and MALT lymphoma have reactive lymphoid follicles and lymphoepithelial lesions, but obliteration of thyroid parenchyma by a diffuse infiltrate of marginal-zone B cells, or the presence of lymphoid or plasma cells expressing monotypic immunoglobulin favor MALT lymphoma. Lymphoepithelial lesions are larger and much more numerous in MALT lymphoma. A number of cases of extramedullary plasmacytoma arising in the thyroid gland have been described; it is likely that at least some of these represent MALT lymphomas with marked plasmacytic differentiation. Reactive follicles; an extrafollicular component of B cells, particularly if they have the morphology of marginal-zone cells; and lymphoepithelial lesions make plasmacytoma unlikely. It may be difficult to distinguish undifferentiated carcinoma from DLBCL on routine sections, but a diagnosis can be established with immunohistochemical studies.