Non-Hodgkin’s Lymphoma

AIDS, most of the increase has occurred in the elderly. Secondly, workers in occupations such as farming, processing of forestry products, paper processing, and others that involve long-term exposure to bioactive solvents and reagents have an increased risk of developing NHL, which is 1.5–4.0 times normal. Thirdly, the increase in lymphomas is exactly parallel to that seen in melanoma, the only other cancer with a rising incidence unrelated to smoking. It is possible that exposure to solar radiation plays a role in both increases.

There is a 50-fold increase in incidence of NHL between infancy and old age, and the average lifetime risk of developing NHL in North America is 1=50. The median age of patients with NHL is at least 60–65 years, and approximately one-third of patients are over 70 years at the time of diagnosis.

ETIOLOGY AND RISK FACTORS

The cause of NHL is unknown. Individuals with the following risk factors have an increased likelihood of developing NHL:

1.congenital immunodeficiency,

2.acquired immunodeficiency syndrome (AIDS),

3.organ transplant-related immune suppression, and

4.chronic immunoregulatory or autoimmune diseases such as rheumatoid arthritis, Hashimoto’s thyroiditis, or celiac sprue and more recently, autoimmune thyroid disease [editor’s comment].

The theme common to these conditions is dysregulation of the immune system. Although some authorities think this leads to the increased risk of lymphoma by causing diminished immune surveillance, it is more likely that these conditions are associated with overactivity (hyperstimulation) of a damaged system leading to genetically stable loss of growth control, perhaps through loss of usual apoptosis (programmed cell death).

Certain viruses are associated with NHL.

1.Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). It

appears to increase the risk of developing lymphoma primarily by profoundly depleting the pool of T-cells, which in turn leads to an immunodeficiency state that is permissive for the development of lymphomas, especially those associated with Epstein–Barr virus. Patients with AIDS have a markedly increased risk of developing lymphoma and the risk seems to be closely related to the degree of T-cell depletion. These lymphomas are often seen at unusual extranodal sites, such as the central nervous system (CNS) where 5% of the lymphomas seen in AIDS patients occur compared to only 1% of the lymphomas in the normal population.

2.Human lymphotrophic virus type I (HTLV-I) (1) is a retrovirus endemic to parts of Southern Japan and the Caribbean basin and sporadic elsewhere. It is transmitted in intact lymphocytes, therefore, by breast feeding, sexual contact, and blood product transfusion. Approximately, 1% of individuals infected in infancy, but none of those infected in adult life develop a T-cell lymphoma typically associated with leukemic peripheral blood involvement, skin and CNS infiltration, and hypercalcemia. Treatment is only transiently effective (2).

3.Epstein-Barr virus (EBV), the herpes virus that causes infectious mononucleosis, is present intracellularly in virtually all cases of Burkitt’s lymphoma and many of the NHLs seen in association with AIDS or transplant related immunosuppression. Epstein–Barr virus also can immortalize lymphocytes in vitro. Thus, it is strongly suspected to contribute causally to the development of some types of NHL but its precise role is unknown.

4.Hepatitis C virus has been found much more frequently than expected in patients with lymphoplasmacytic lymphomas (formerly called small lymphocytic lymphoma with plasmacytoid differentiation or Waldenstro¨m’s macroglobulinemia) in approximately 30% of

cases (3). The viral DNA is present in the malignant cells implying but not proving a possible etiologic role.

5.Human Herpes Virus 8, HHV-8 (Kaposi’s Sarcoma Herpes Virus, KSHV) is closely associated with AIDS-related and sporadic Kaposi’s sarcoma and may have a role in their etiology. It is also closely associated with body cavity associated or primary effusion lymphoma, a large cell B-cell lymphoma presenting primarily with pleural or peritoneal malignant effusion (4). HHV-8 has been recovered from virtually all studied cases and it is probably a crucial etiologic agent for this rare lymphoma whether it is seen sporadically or with AIDS.

Certain specific cytogenetic abnormalities and dysregulated expression of associated oncogenes are associated with specific lymphomas. Typically a known or putative tumor promoter gene is moved to a new location where it is upregulated or a tumor suppressor gene is mutated or suppressed. Any translocation involving the immunoglobulin H chain gene on 14q32 can occasionally alternatively involve the k light chain gene at 2p12 or the l light chain gene at 22p11. Hence, instead of a t(8;14)(q24;q32), one might encounter a t(2;8)(p12;q24), which has an equivalent effect. Table 1 contains a partial list of the most common lymphoma-associated oncogenes.

DIAGNOSIS, CLASSIFICATION, AND STAGING

Table 2 identifies the diagnosis, classification, and staging of non-Hodgkin’s lymphomas.

TREATMENT

The treatment plan for NHLs is listed in Table 3. This overall approach can be expected to produce results that reflect both the effectiveness of the treatment and the underlying natural history of the lymphoma (Table 4).

Table 2 Diagnosis, Classification, and Staging of non-Hodgkin’s Lymphomas

aFormerly plasmacytoid small lymphocytic with or without IgM paraprotein (Waldenstro¨m’s macroglobulinemia).

bSmall cleaved, mixed or large cell subtypes.

cMixed large and small cell, immunoblastic, primary mediastinal, T-cell rich B-cell, intravascular or B-cell anaplastic subtypes.

dAngioimmunoblastic lymphadenopathy with dysproteinemia.

eHuman herpes virus type 8.

SPECIAL COMMENTS ON LYMPHOMA

ASSOCIATED WITH THE EYE

Malignant lymphoma involves the structures of the eye and orbit in two quite distinct patterns (5–8). The most common presentation is in the periorbital soft tissues, particularly the conjunctival mucosal surfaces and around the lacrimal gland. Previously, the majority of these localized soft-tissue

Table 3 Treatment Regimens for non-Hodgkin’s Lymphomas

a The chemotherapy for aggressive type lymphoma should include doxorubicin, cyclophosphamide, vincristine, and prednisone in full standard doses. Acceptable regimens include CHOP, ACOP-12, and similar combinations.

lymphomas presenting in periorbital soft tissue were classified as small lymphocytic lymphomas or pseudolymphoma. With the ability to identify clonal B-cell disease on the basis of immunoglobulin gene rearrangement studies, it has become clear that these are definite clonal neoplasms of B-cells. Most fit best into the new category designated ‘‘MALT’’ for mucosa associated lymphoid tumor. Radiation is highly effective in eradicating this type of lymphoma and is potentially curative in the majority who present with localized disease (5–7). The dose of irradiation need not be high and should be kept in the range of 2500–3000 cGy to reduce the risk of cataract formation, xerophthalmia, and retinal damage. Shielding of the lens is also mandatory if cataract

Table 4 Prognosis of Treatment Regimens for non-Hodgkin’s Lymphomas

formation is to be avoided. Chemotherapy with agents suitable for low grade lymphoma is also capable of inducing prolonged remission and is the best choice if disease is widespread at diagnosis, recurs after irradiation, or if the morbidity of the irradiation might be excessive. Interestingly, bilateral eye involvement with MALT is not uncommon and may be synchronous or metachronous and can occur without other evidence of systemic disease, a pattern of spread implying 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 lymphoma of other indolent types than MALT or occasionally with variants of large cell lymphoma. 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. When this is done, results identical to those obtained for other sites of presentation can be secured. When the periorbital disease also involves the paranasal

sinuses, special precautions to avoid spread to the central nervous system must be employed.

The rarest presentation of lymphoma involving the eye is also the most unusual. Intraocular lymphoma (6) constitutes less than 1% of lymphomas and can be quite difficult to diagnose. Although almost all are B-cell large cell lymphomas, they often pursue a more indolent course and are frequently mislabeled as chronic uveitis or unexplained vitritis for months or even years before diagnosis, a mistake abetted by this lymphoma’s marked responsiveness to corticosteroids which may have been given empirically. The diagnosis is best established by vitrectomy performed when the patient has been off corticosteroids for at least several weeks. Although an experienced ophthalmologist can often recognize this distinct entity by appearance alone, the seriousness of the diagnosis still necessitates vitrectomy for certain diagnosis. Other important peculiarities of the natural history of intraocular lymphoma are its tendency to be bilateral, seen in at least 50% of cases, and its frequent association with brain or leptomeningeal involvement, also seen in at least 50% of cases. Slit lamp examination of the other eye, computerized tomographic scanning or magnetic resonance imaging of the brain and cytologic examination of the cerebrospinal fluid must be included in the staging evaluation. Current treatment results for intraocular lymphoma are unsatisfactory. Irradiation is the mainstay 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 penetrate the eye and brain poorly, limiting additional treatment. Presently 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 (8). Recently, it has been shown that very high dose methotrexate (> 8000 ma=m2) does penetrate the interior structures of the eye reaching therapeutic levels; subconjunctival antimetabolites have also been used [editor’s comment]. If preliminary observations of useful responses are

confirmed, this will constitute an alternative systemic treatment. Unfortunately, eventual progression in the eye or CNS usually leads to blindness or death indicating a clear need for more effective approaches.

REFERENCES

1.Hollsberg P, Hafler DA. Seminars in medicine of the Beth Israel Hospital, Boston. Pathogenesis of diseases induced by human lymphotrophic virus type I infection. N Engl J Med 1993; 328(16):1173–1182.

2.Gill PS, Harrington W Jr, Kaplan MH, et al. Treatment of adult T-cell leukemia-lymphoma with a combination of interferon alpha and zidovudine. N Engl J Med 1995; 332(26): 1744–1748.

3.Silvestri F, Pipan C, Barillari G, et al. Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders. Blood 1996; 87(10):4296–4301.

4.Nador RG, Cesarman E, Chadburn A, et al. Primary effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi’s sarcoma-associated herpes virus. Blood 1996; 88(2):645–656.

5.Esik O, Ikeda H, Mukai K, Kaneko A. A retrospective analysis of different modalities for treatment of primary orbital non-Hodgkin’s lymphomas. Radiother Oncol 1996; 38(l): 13–18.

6.Whitcup SM, de Smet MD, Rubin BI, et al. Intraocular lymphoma. Clinical and histopathologic diagnosis. Ophthalmology 1993; 100(9):1399–1406.

7.Smitt MC, Donaldson SS. Radiotherapy is successful treatment for orbital lymphoma. Int J Radiat Oncol Biol Phys 1993; 26(l):59–66.

8.Plowman PN, Montefiore DS, Lightman S. Multiagent chemotherapy in the salvage cure of ocular lymphoma relapsing after radiotherapy. Clin Oncol (R Coll Radiol) 1993; 5(5): 315–316.

malignant tumors (6). Based on this work, the first American Armed Forces Institute of Pathology (AFIP) classification, published in 1954, listed five benign and nine malignant diagnoses (7). Since that time, both the WHO and AFIP have published updated classification schemes, including the most recent WHO classification of 1991, which lists 14 adenomas and 17 carcinomas (8), and the most recent AFIP classification of 1996, which lists 13 benign and 23 malignant tumors (9).

A re-evaluation of lacrimal tumor classification is needed to reflect the recent advances in salivary tumor classifications. At the University of British Columbia, we reviewed a series of lacrimal gland epithelial tumors contributed from four orbital disease centers: the University of Naples, University of Amsterdam, and Kaiser Permanente Medical Center of Southern California combined with our own series. Our goal is to apply the most recent salivary classification schemes to lacrimal tumors, and to correlate clinical outcomes with histologic tumor type.

The combined series includes a total of 118 cases, with diagnoses as listed in Table 2. The most frequent diagnosis is pleomorphic adenoma, with 57 cases (48%) of the total series. Adenoid cystic carcinomas are next most numerous, with 38 cases (32%). There are nine cases of carcinoma ex pleomorphic adenoma, and 11 cases of various other rare diagnoses, including adenocarcinoma, mucoepidermoid carcinoma, ductal carcinoma, myoepithelial carcinoma, squamous cell carcinoma, myoepithelioma, and oncocytoma. Three tumors were found to be unclassifiable. Two of these were considered to have malignant features histopathologically, while the third was indeterminate.

We have confirmed that benign tumors by histologic criteria typically run a benign course clinically. All pleomorphic adenomas were treated with local excision only, without adjuvant therapy or more radical surgery. No patient with pleomorphic adenoma has died with disease, and no patient whose tumor was first diagnosed at one of our centers has had recurrence after surgical excision (median follow-up 3.0 years, range 0–25 years). This includes five cases of pleomorphic adenoma with various degrees of cellular atypia

(median follow-up 4.1 years, range 2.4–8.8 years). Of three patients who initially presented with recurrent disease after initial diagnosis and treatment elsewhere, one had further recurrence after treatment at our centers; none has died with disease (follow-up 0.4, 3.0, and 3.1 years after initial treatment at our centers). There was no recurrence over 5 years in the single case of oncocytoma. Follow-up data were not available for a single, very recent case of myoepithelioma.

In contrast, malignant tumors by histologic criteria are associated with a much worse prognosis. Carcinomas were treated with combinations of local excision, exenteration, orbitectomy, and local irradiation. No statistically significant correlation was seen between type of treatment and clinical outcome. Of 43 patients with primary malignant tumors (adenocarcinoma, adenoid cystic, mucoepidermoid, lacrimal duct, myoepithelial, or unclassifiable carcinoma but excluding malignant mixed tumors) with over 1 year of follow-up, 18 died with disease within a median of 2 years of diagnosis (range <1–25 years). Another eight patients are living with recurrence or metastasis. The remaining 17 patients remain disease free with a median of 10.6 years follow-up (range 1.2–17.8 years). Ductal carcinoma of the lacrimal gland was the one diagnostic category with a suggestion of better prognosis, with two patients disease-free after 3 and 4 years of follow-up, although the small number of cases makes any conclusion tenuous.

There were nine cases of malignant mixed tumor in our series, all of which were cases of carcinoma arising in pleomorphic adenoma, or ‘‘carcinoma ex pleomorphic adenoma.’’ (The diagnostic category ‘‘malignant mixed tumor’’ also includes carcinosarcoma and metastasizing pleomorphic adenoma, neither of which was seen in our series.) We were able to distinguish two subtypes of carcinoma ex pleomorphic adenoma based on histopathologic findings. One subtype had the carcinoma completely circumscribed within the pleomorphic adenoma or its pseudocapsule. We found three cases of this subtype, all with no recurrence within the follow-up period (range 0.4–3.0 years) with no adjuvant therapy or additional surgery beyond initial excision. The other subtype,

comprising six cases, had extension of the carcinoma beyond the margins of the pleomorphic adenoma. Patients with this subtype did poorly: of five patients with follow-up, two patients died with disease within 3 years of diagnosis and one patient developed recurrence 1 year and again 2 years after initial treatment.

Malignant transformation of pleomorphic adenoma appears to manifest a continuum of changes from minor atypia to clearly invasive carcinoma with little residual evidence of the original pleomorphic adenoma. Typical pleomorphic adenoma, pleomorphic adenoma with atypia, and circumscribed carcinoma ex pleomorphic adenoma (not extending beyond the margins of the pleomorphic adenoma) all appear to behave in a benign manner clinically. In contrast, for noncircumscribed carcinoma ex pleomorphic adenoma (where the carcinoma extends beyond the margins of the pleomorphic adenoma), the prognosis is much worse, similar to that of primary carcinomas. We recommend clearly distinguishing between the two diagnostic entities, ‘‘circumscribed carcinoma ex pleomorphic adenoma’’ and ‘‘noncircumscribed carcinoma ex pleomorphic adenoma.’’ Decisions regarding therapy should be made recognizing the prognostic differences among the various types of lacrimal gland tumors. Clinically, benign tumors can be treated with simple excision alone, sparing the added morbidity and mutilation of more aggressive surgery or adjuvant therapy. Clinically, malignant tumors may require additional treatment, such as exenteration, orbitectomy, and high-dose radiotherapy, and may well be fatal even with these measures.

Our proposed classification scheme for lacrimal gland tumors is listed in Table 3 and emphasizes the increasing range of potential epithelial tumor diagnoses arising from this site. It comprises the diagnoses included in our series, as well as a few diagnoses not seen in our series but described in the lacrimal or salivary tumor literature. The ambiguous term ‘‘malignant mixed tumor’’ has been deleted, and its three constituents, carcinoma ex pleomorphic adenoma, carcinosarcoma, and metastasizing pleomorphic adenoma are listed separately. The category ‘‘carcinoma

Table 3 Proposed Classification of Epithelial Lacrimal Gland

Tumors

Benign epithelial neoplasms

Pleomorphic adenoma

Without atypia

With atypia

Myoepithelioma

Oncocytoma

Malignant epithelial neoplasms

Adenoid cystic carcinoma

Carcinoma ex pleomorphic adenoma

Circumscribed

Noncircumscribed

Mucoepidermoid carcinoma

Adenocarcinoma

Lacrimal duct carcinoma

Myoepithelial carcinoma

Squamous cell carcinoma

Carcinosarcomaa

Acinic cell carcinomaa

Sebaceous adenocarcinomaa

Basal cell adenocarcinomaa

Epithelial-myoepithelial carcinomaa

Polymorphous low-grade adenocarcinomaa

Metastasizing pleomorphic adenomaa

aNot seen in our series, but reported in the literature.

ex pleomorphic adenoma’’ is subdivided into circumscribed and noncircumscribed carcinomas to reflect their different clinical prognoses.

REFERENCES

1.Warthin A. Endothelioma of the lacrimal gland. Arch Ophthalmol 1901; 30:601–620.

2.Sanders TE. Mixed tumor of the lacrimal gland. Arch Ophthalmol 1939; 21:239–260.

3.Godtfredsen E. Pathology of mucous and salivary gland tumors in the lacrimal gland and the relation to extra orbital mucous and salivary gland tumors. Br J Ophthalmol 1948; 32:171–179.

4.Duke-Elder S, MacFaul PA. The ocular adnexa. Part II. Lacrimal, orbital and para-orbital diseases. In: Duke-Elder S, ed. System of Ophthalmology. London: Henry Kimpton, 1974: 596–1163.

5.Zimmerman L, Sobin L. Histological typing of tumors of the eye and its adnexa. International Histological Classification of Tumors. Geneva: World Health Organization,1980:24.

6.Foote FW Jr, Frazell EL. Tumors of the major salivary glands. Cancer 1953; 6:1065–1133.

7.Foote F, Frazell E. Tumors of the major salivary glands. Atlas of Tumor Pathology. Series 1, Fascicle 11. Washington, DC: Armed Forces Institute of Pathology, 1954.

8.Seifert G, Sobin L. Histological classification of salivary gland tumours. International Histological Classification of Tumors. Berlin: Springer-Verlag, 1991.

9.Ellis GL, Auclair PL. Tumors of the salivary gland. Atlas of Tumor Pathology. 3rd Series, Fascicle 17. Washington, DC: Armed Forces Institute of Pathology, 1996.