Problems in Lymphoma Management: Special Sites of Presentation

During the past 4 decades, the curative potential of multiagent chemotherapy and selective irrad- iation of malignant lymphomas has become well established. Several subtypes of lymphoma can now be regularly cured and others palliated for long periods. A series of classification schemes have been developed, with each newer one bringing a better appreciation of the variability of these diseases and a better understanding of the basic biology, cellular and genetic characteristics, and natural history of each subtype.

As we have become able to identify the separate lymphomas and treat them with disease-specific programs, certain sites of lymphoma have been found to have special modes of presentation, patterns of metastatic spread, responses to treatment, and unique natural histories. Clinicians must understand these special natural histories if they are to deliver optimal care.

This review focuses on the problems posed by lymphoma presenting in five different anatomic sites: the eye, central nervous system (CNS), paranasal sinuses, testes, and stomach. The discussion concentrates on those aspects of presentation and natural history unique to each site.

Lymphoma of the Eye

Malignant lymphoma involves the structures of the eye in two quite distinct patterns.[1-4]

Periorbital Soft-Tissue Lymphoma

The most common presentation is in the periorbital soft tissues, particularly the conjunctival mucosal surfaces and area surrounding the lacrimal gland. Previously, the majority of these localized soft-tissue lymphomas presenting in periorbital soft tissue were classified as small lymphocytic lymphomas or pseudolymphoma—a term that indicates both the pathologist’s uneasiness with the diagnosis and the indolent, easily modified natural course of this entity. With the help of modern diagnostic tools, especially the ability to identify clonal B-cell disease on the basis of immunoglobulin gene rearrangement studies, it has become clear that these lymphomas are definite clonal neoplasms of B-cells. Most fit best into the new category designated mucosa-associated lymphoid tissue (MALT) lymphoma, an entity in the new Revised American-European Lymphoma (REAL) classification scheme.[5]

Radiation is highly effective in eradicating this type of lymphoma and is potentially curative in the majority of patients who present with localized disease.[1,3] The dose of irradiation should be kept in the range of 2,500 to 3,000 cGy to reduce the risk of cataract formation, xerophthalmia, and retinal damage. The lens must also be shielded if cataract formation is to be avoided.

Chemotherapy with agents suitable for low-grade lymphoma can induce prolonged remission and is the best choice if disease is widespread at diagnosis, recurs after irradiation, or if the morbidity of irradiation may be excessive. Interestingly, bilateral eye involvement with MALT is not uncommon. It may be synchronous or metachronous and can occur without other evidence of systemic disease. The pattern of spread implies a special interaction between these malignant B-cells and the mucosal microenvironment of the eye.

The periorbital soft tissues and bones may be involved with low-grade lymphomas other than MALT lymphoma or occasionally with variants of large cell lymphomas. In such cases, there is nothing unique about the natural history. Treatment should be based on the overall clinical picture and should take into consideration the histologic subtype, stage, age and frailty of the patient, and expected toxicity of the chosen regimen. Done this way, treatment has results identical to those obtained in other sites of presentation. When periorbital disease also involves the paranasal sinuses, special precautions must be taken to avoid spread to the CNS.

Intraocular Lymphoma

Intraocular lymphoma,[2] the rarest presentation of lymphoma of the eye and the most unusual, constitutes less than 1% of all lymphomas and can be quite difficult to diagnose. Although almost all are B-cell large cell lymphomas, they often take a more indolent course than is usual for that disease. They are frequently mislabeled chronic uveitis or unexplained vitreitis for months or even years before an accurate diagnosis is made—a mistake abetted by the lymphoma’s marked responsiveness to corticosteroids, which may have been given empirically.

The diagnosis is best established by a vitrectomy performed after the patient has been off corticosteroids for several weeks. However, an experienced ophthalmologist can often recognize this distinct entity by appearance alone, although the seriousness of the disease necessitates vitrectomy to confirm the diagnosis. Other important peculiarities of the natural history of intraocular lymphoma are its tendency to be bilateral (in up to 50% of cases) and its frequent association with brain or leptomeningeal involvement (in at least 50% of cases). Slit-lamp examination of the other eye, computed tomographic (CT) scanning or magnetic resonance imaging (MRI) of the brain, and cytologic examination of the cerebrospinal fluid (CSF) must be included in the staging evaluation.

Current treatment results for intra-ocular lymphoma are unsatisfactory. Irradiation is the mainstay of treatment and should be extended to include the other eye or brain if necessary. Despite irradiation, however, most patients relapse within the eye or brain. Unfortunately, chemotherapeutic agents other than corticosteroids and antimetabolites do not penetrate those organs well, thereby limiting additional treatment.

 At present, most patients can be offered excellent palliation for months to years with irradiation and corticosteroids, but recurrence is usual. Investigational approaches include the use of high-dose antimetabolites, such as intravenous methotrexate(Drug information on methotrexate) and cytarabine(Drug information on cytarabine) (ara-C).[4] Unfortunately, eventual progression in the eye or CNS usually leads to blindness or death, indicating a clear need for more effective approaches.

CNS Lymphoma

Malignant lymphoma may involve the CNS in one of three different patterns: metastatic spread to the brain or leptomeninges or primary parenchymal disease within the brain.

Metastatic Spread to the Brain or Leptomeninges

Relatively little specific experience is described in the medical literature regarding these two types of metastatic involvement, but our experience in British Columbia indicates some usefulness in separating them. Metastatic spread of lymphoma resulting in a solid lesion within the brain is a rare complication of large cell systemic lymphoma or other aggressive histologic subtypes. When it occurs as an isolated site of relapse or as a coincident metastasis of disease that can still be fully eradicated with systemic treatment, the use of brain irradiation can be curative.

Unfortunately, the more usual mode of metastatic spread to the CNS—involvement of the leptomeninges—can only rarely, if ever, be eliminated, even when aggressive intrathecal chemotherapy is combined with irradiation and systemic chemotherapy. Most patients with leptomeningeal progression of their systemic lymphoma are best treated with palliative intent using a judicious balance of high-dose corticosteroids and local irradiation for nerve root or spinal cord compression. A minority of patients with good performance status and control over their systemic disease may be helped by intrathecal chemotherapy, which is best delivered into a lateral ventricle via an Ommaya reservoir using standard doses of an antimetabolite such as methotrexate or cytarabine. Alternatively, such patients may benefit from systemic chemotherapy using high IV doses of the same agents.

Primary CNS Lymphoma

Primary CNS lymphoma is usually isolated to the brain and presents as a mass lesion with either focal neurologic symptoms or global cerebral dysfunction (with or without headache).[6-15] It occurs sporadically, causing about 1% to 2% of new lymphomas in the immunocompetent population and about 5% of lymphomas in patients with acquired immunodeficiency syndrome (AIDS).[14]

Most cases in the immunocompetent population are of large cell or immunoblastic subtypes and are seldom associated with Epstein-Barr virus (EBV). Those seen in patients who have AIDS or who are receiving immunosuppressants to preserve a transplanted organ are evenly split between large cell and small non-cleaved cell non-Burkitt types. They are frequently associated with EBV. Survival of patients with brain lymphoma in the setting of severe immunocompromise is seldom longer than a few months and is unlikely to change until we have more effective means of treating HIV infection or maintaining transplanted organs without profound systemic immunosuppression.

Primary CNS lymphoma, often multifocal, typically arises in a periventricular location. Brain edema is common, but symptomatic herniation or hydrocephalus is rare. Often, mild dementia, nonspecific personality changes, or persistent headache may be the only symptoms. Diagnosis rests on direct biopsy, usually best obtained under stereotactic guidance.

Patients with primary CNS lymphoma very seldom have any evidence of systemic lymphoma outside the CNS but are at risk for leptomeningeal or intraocular involvement. Cerebrospinal fluid should be examined cytologically and all patients should have careful slit-lamp examination by an ophthalmologist experienced in recognizing intraocular lymphoma.

The results of treatment of primary CNS lymphoma remain disappointing. The mainstays of treatment are high-dose corticosteroids and whole-brain irradiation. Pharmacologic doses of dexamethasone(Drug information on dexamethasone) or its equivalent should be given from the time of diagnosis until irradiation has been completed. Histamine-2 blockers, such as ranitidine(Drug information on ranitidine), an antifungal agent such as ketoconazole(Drug information on ketoconazole), and anti-Pneumocystis carinii antibiotics, such as cotrimoxazole, should be given to protect the patient until the corticosteroids are stopped.

Because of its tendency to be multifocal, primary CNS lymphoma should be treated with whole-brain irradiation. Given the frequent involvement of the eyes, it is usually prudent to include the posterior one-third of the globes in the treatment field. Although the dose and fractionation of radiation are not firmly settled, patients should receive at least 3,500 cGy in 15 to 20 fractions. Some prefer a higher dose or the addition of a focal boost to the tumor bed, but it is unclear whether the net balance between disease control and treatment toxicity is favorably affected by these higher doses. Inability to eradicate the local disease and relapse within the CNS, combined with a high rate of long-term central neurologic toxicity, compromise both the length and quality of survival. Currently, 20% to 30% of unselected patients will achieve a 2- to 3-year survival.

The disappointing results achieved with corticosteroids and irradiation have led to many attempts to improve outcome by adding systemic chemotherapy. Anecdotal results and experience in small series of selected patients appeared promising, especially when high-dose methotrexate or cytarabine were included.[9-13,15] However, these results must be interpreted with caution, because these series were small. Patients included were selected, and none of the trials had concurrent controls. Age, performance status, other important prognostic factors, and the bias to publish positive results could easily account for any apparent improvement. Indeed, the largest reported attempt to improve outcome using systemic chemotherapy did not do so.[7]

At present, adding chemotherapy to standard corticosteroid and irradiation regimens must be considered potentially valuable but experimental. The role of such additional treatment can only be established by properly controlled, multicenter, randomized trials.