TITLE: LYMPHOMAS OF THE HEAD AND NECK
SOURCE: Dept. of Otolaryngology, UTMB, Grand Rounds
DATE: September 13, 1995
RESIDENT PHYSICIAN: Gregory Young, MD
FACULTY: Byron J. Bailey, MD
SERIES EDITOR: Francis B. Quinn, Jr., M.D.

|Return to Grand Rounds Index|

"This material was prepared by resident physicians in partial fulfillment of educational requirements established for the Postgraduate Training Program of the UTMB Department of Otolaryngology/Head and Neck Surgery and was not intended for clinical use in its present form. It was prepared for the purpose of stimulating group discussion in a conference setting. No warranties, either express or implied, are made with respect to its accuracy, completeness, or timeliness. The material does not necessarily reflect the current or past opinions of members of the UTMB faculty and should not be used for purposes of diagnosis or treatment without consulting appropriate literature sources and informed professional opinion."

Introduction:

Lymphomas are the most common nonepithelial head and neck malignancies.1 They often present as enlarged lymph nodes in the neck. Extranodal site involvement is also common in the head and neck, as 10% of lymphomas occur in areas such as Waldeyer's ring(tonsil ,nasopharynx, base of tongue), paranasal sinuses, nasal cavity, larynx, oral cavity, salivary glands(parotid), thyroid, and orbit(2). The location and extent of lymphoma in the head and neck affects the staging of the disease, as well as treatment selection and predicted response to therapy. Lymphomas are usually divided into two main subgroups, Hodgkin's disease, and non-Hodgkin's lymphoma. Hodgkin's disease is thought to originate from B-cells, while non-Hogdkin's lymphomas come from B-cells and T-cells.3

Incidence, Etiology and Epidemiology:

Hodgkin's Disease:
Hodgkin's disease accounts for about 1% of new cancers in the United States each year.3 It has a bimodal age incidence, with a rise in the second decade, a peak in the third decade, followed by a decline until age 45. The incidence then increases with age after 50. Hodgkin's disease is more prevalent in smaller and more weathly families(4). The etiology of Hodgkin's disease is unclear. However, it may be a rare manifestation of a common infectious disease. Current thinking is that viruses such as Ebstein-Barr Virus, infect lymphocytes, and somehow promote their transformation into malignant cells(3).
Non-Hodgkin's Lymphoma:
Non-Hodgkin's lymphoma accounts for 4% of all malignancies in the United States, or about 37,000 new cases per year(3)) Non- Hodgkin's lymphoma is not a single disease, but rather a group of related malignancies. The incidence of non-Hogkin's lymphoma has increased by 57% in the past 15 years. The annual incidence rate per 100,000 persons in the United States was 5.9 in 1950, 9.3 in 1975, and 13.6 in 1988(3). This increase is not attributable to AIDS, as patients are both male and female, and primarily elderly. Several factors have been suggested as possible etiologies for non-Hogkin's lymphoma; and indeed, this heterogeneous group of diseases likely has more than one etiology. Putative causative factors include exposure to drugs, infectious agents, or ionizing radiation; or immunosuppressive or immunoproliferative states(4). Chromosomal abnormalities and immunoglobulin gene rearrangement are frequently seen, and their study may portend the origin of these diseases. The incidence of non-Hodgkin's lymphoma increases from childhood to late adulthood in the United States. The incidence of individual sub-groups of non-Hodgkin's lymphoma varies with geographic region. For example, Burkitt's lymphoma is common in Africa, but rare in the United States.

Clinical Presentation:

Hodgkin's Disease:
Hodgkin's disease typically presents as painless lymphadenopathy, most commonly in the lower cervical or supraclavicular region. Involved lymph nodes are usually in localized region, or in contiguous groups. The nodes are nontender, mobile and rubbery. Mediastinal or hilar nodes are frequently involved at presentation. Abdominal involvement is unusual unless the patient has systemic symptoms(weight loss, fever, night sweats), or histologic examination shows the lymphocyte depleted subtype. Primary extranodal Hodgkin's disease is rare.
Non-Hodgkin's Lymphoma:
Patients with non-Hodgkin's lymphoma often have cervical lymphadenopathy, and it is the presenting complaint in 15% of patients(2). Unlike Hodgkin's disease, non-Hodgkin's lymphoma often presents with both nodal and extranodal disease. The most common extranodal site is Waldeyer's ring (usually tonsil)(2). Primary extranodal lymphoma also occurs in the bone, brain, stomach, intestine, and kidney. Few patients present with localized disease, and contiguous lymph node spreading is uncommon(3). Mediastinal involvement is rare, and abdomenal involvement is more common. Twelve percent of patients have systemic symptoms(Fever > 38.0, night sweats, weight loss > 10% body weight in 6 months)(2). In higher grade lymphomas, systemic symptoms may be the presenting complaint.

Non-Hodgkin's lymphoma in the head and neck is usually submucosal, instead of ulcerative like squamous cell carcinoma. However, the presenting symptoms of the two malignancies are quite similar. One half of head and neck lymphomas occur in Waldeyer's ring(tonsil > nasopharyx > base of tongue). Tonsillar lymphoma presents as tonsillar swelling and a sore throat. Nasopharygeal lymphoma presents with a neck mass, nasal obstruction, decreased hearing, and serous otitis media(2). Presenting sites, signs and symptoms, and relative frequency of head and neck lymphomas are listed in the table below.

Site of Lymphoma Signs/Symptoms % H&N Lymphoma
Tonsil Swollen tonsil, Sore throat 40
Nasopharynx Neck mass, Nasal obstruction, Serous otitis, Hearing loss 18
Sinus/Nasal Cavity Sinusitis symptoms, then Diplopia and Exophthalmos 13
Oral Cavity Oral swelling, Pain, Ulcers 10
Salivary Glands Mass, Rarely CNVII paresis 09
Base of Tongue Foreign body sensation, sore throat 08
Larynx Hoarseness, Dyspnea, Dysphagia 02

(Adapted from Jacobs C. Lymphoma of the Head and Neck. In: Bailey BJ, ed. Head and Neck Surgery, Otolaryngology. Philadelphia:JB Lippincott, 1993:1222.)

Not listed in the table above are primary thyroid lymphoma and lymphoma of the orbit. Primary thyroid gland lymphoma accounts for 5-10% of all thyroid cancer(2). Its etiology is unclear, although occassionally is seen in patients with autoimmune thyroiditis or in those with a history of nodular goiter. Seventy-five percent of patients present with hoarseness, dysphagia, or a rapidly enlarging anterior neck mass.2 Orbital lymphoma presents with orbital swelling and exophthalmos. Later changes may include blurry vision, ptosis, epiphora, and eye pain. Visual fields usually remain intact, and fundoscopic examination is benign(2).

Diagnosis:

Diagnosis is similar for non-Hodgkin's lymphoma and Hodgkin's disease. An excisional biopsy of an enlarged lymph node is obtained. Frozen sections inform the surgeon as to the adequacy of the sample, but are not useful in determining the type of lymphoma.1 The pathologist is alerted, so that the biospy material can be quickly processed fresh, rather than fixed in formaldehyde. Fresh tissue allows immunohistochemical stains to be used. These stains can distinguish anaplastic neoplasms from lymphoma, and can differentiate between subtypes of lymphomas. For example, antikeratin antibodies detect carcinomas, anti-S100 antibodies bind to melanomas, and panleukocyte antibodies stain lymphoma. Similar types of stains can also differentiate benign lymphoid infiltrates from lymphoma. Electron microscopy may be required to distinguish poorly differentiated squamous cell carcinoma from lymphoma. Excisional biopsy is preferable to fine needle aspiration(FNA) because needle aspiration may miss the diseased region of a partially involved node(1). In addition, FNA does not preserve tissue architecture, so histologic subtypes(follicular, diffuse) cannot be distinguished.

Classification:

Hodgkin's Disease:
The Rye classification of Hodgkins Disease was developed at the International Symposium in Rye, NY in 1965(4). It divides Hodgkin's disease into 4 subtypes. The divisions lack objective, clearcut cytologic and histologic guidelines. However, it is widely used because of its simplicity, and its clinical and prognostic value. With the exception of nodular sclerosis, Hodgkin's disease may evolve from one subtype to another(4). The table below lists the 4 subtypes of Hodgkin's disease, their main histogical features, and their relative clinical prognosis.

Rye Classification Histologic Features Prognosis
Lymphocyte predominant +++ Lymphocytes +Reed-Sternberg(RS) Best
Nodular sclerosis Nodules of lympho-reticular cells ++ Lacunar RS Good
Mixed cellularity Mixture of lymphs, Eosinophils, Plasma cells + Reed-Sternberg Fair
Lymphocyte depleted + Lymphocytes +++ Reed-Sternberg Poor

(Adapted from Jacobs JR and Negendank WG. Lymphomas of the Head and Neck. In: Paparella, et al, eds. Otolaryngology, Third Edition. Philadelphia, W.B. Saunders Company, 1991:2592.)

At the cellular level, most cells associated with Hodgkin's disease are not malignant. Instead, there is a heterogenous population of lymphocytes, histiocytes, plasma cells, eosinophils, monocytes, and Reed-Sternberg (RS) cells(5). Histologic diagnosis of Hodgkin's disease depends on the presence of RS cells surrounded by a characteristic heterogenous background of inflammatory cells(5). The RS cell is a giant cell with abundant cytoplasm and a large multilobulated nucleus. Most RS cells are thought to originate from B-cells, although there is evidence that some have T-cell lineage(3).

Non-Hodgkin's Lymphomas:
More than five systems have been used in recent years to classify non-Hodgkin's lymphomas, which led to difficulty communicating results among investigators. The National Cancer Institude combined the strong points of previous classification schemes to develop a system called A Working Formulation of Non- Hodgkin's Lymphomas for Clinical Usage, or simply "The Working Formulation"(1). This system divides non-Hodgkin's lymphoma into 3 major subgroups(low, intermediate, and high grade) based on their usual clinical course and outcome. Large retrospective studies have shown that The Working Formulation classification system can be substituted for any of previous classification systems without losing prognostic value(1). It is based on the general clinical course of the disease, the presence or absence or a follicular histologic pattern, and the Lukes-Collins cytologic categories of lymphocytes(1) The table below contains the clinical grade, the cell of origin(T-cell or B-cell) and the relative frequency in the head and neck for each of the 10 subtypes of non-Hodgkins lymphoma.

Working Formulation Subtype Grade Origin H&N%
Small lymphocytic Low B 12
Follicular small cleaved Low B
Follicular mixed small/large cell Low B
Follicular large cell Intermed. B 01
Diffuse small cleaved cell Intermed. B 11
Diffuse mixed small/large cell Intermed B 17
Diffuse large cell Intermed. B 42
Large cell immunoblastic High B or T 10
Diffuse small noncleaved(Burkitt's) High B 04

(Adapted from Jacobs C. Lymphoma of the Head and Neck. In: Bailey BJ, ed. Head and Neck Surgery, Otolaryngology. Philadelphia:JB Lippincott, 1993:1222.)

The grade of the various subtypes are based on the general clinical course of the disease. The low, intermediate, and high grade tumors had mean survival times of 7.5 years, 2.5 years, and 1 year, respectively(prior to modern combination chemotherapy)(1). Most non-Hodgkin's lymphomas are derived from B-cells. The various subtypes are derived from B-cells or T-cells at different stages of maturation(1).

The classification of non-Hodgkin's lymphomas utilizes the Lukes and Collins cytologic categories of lymphocytes(5). Small lymphocytic cells are well differentiated, and are often found around the margins of follicles. These are the same malignant cells as in chronic lymphocytic leukemia (CLL). Follicular cells are the malignant cells of most lymphomas. However, they are relatively rare in the head and neck region. Some follicular cells are small and cleaved, while others are large and resemble histiocytes. Immunoblastic lymphomas are derived from cells within the paracortical regions of lymph node.

Staging:

Hodgkin's Disease:
The exact stage of the disease is more important for Hodgkin's disease than for non-Hodgkin's lymphoma. The main reason is that substantial numbers of patients present in each of the 4 stages, and each stage is managed with a distinct treatment regimen. Each stage also carries a distinct prognosis. The Ann Arbor Staging System for Hodgkin's Lymphomas takes into account 1)the extent of nodal involvement , 2) the presence or lack or splenic or other extralymphatic tissue involvement(E), and 3) the presence or lack of systemic "B" symptoms (4).

Ann Arbor Staging System for Hodgkin's Disease:

Stage Characteristic
I Single node region(I) or single localized extralymphatic organ/site(IE)
II single node in region(II) and/or localized extralymphatic organ/site(IIE) on same side of diaphragm
III Node regions on both sides of diaphragm, may include localized extralymphatic organ/site(IIIE)
IV Diffuse/disseminated extralymphatic organ(s)/site(s) involvement
Symptoms:

(Adapted from Jacobs C. Lymphoma of the Head and Neck. In: Bailey BJ, ed. Head and Neck Surgery, Otolaryngology. Philadelphia:JB Lippincott, 1993:1223.)

Staging of Hodgkin's disease is appropriate only in those cases where a change in stage would change initial therapy. For example, complete staging would not be appropriate in a patient with biopsy proven bone marrow involvement. Treatment in this case would be combination chemotherapy, regardless of findings during laparotomy. Careful staging would, however, be indicated for isolated cervical lymphadenopathy. In this case, radiation therapy would be the treatment of choice if staging revealed truly localized disease. The following is required for complete staging of Hodgkins disease (4).

The staging laparotomy includes the following:

Non-Hodgkin's Lymphoma:
Complete staging with laparotomy is less commonly performed for non-Hodgkin's lymphoma. Prognosis and management of stage III and IV disease are similar, and relatively few patients with non- Hodgkin's lymphoma are stage I or II upon clinical evaluation. However, it is important to define those patients with earlier stage disease, so they can be treated with XRT as well as combination chemotherapy. In addition, staging helps to establish a baseline for evaluation of response to therapy (1).

Lymphoma presenting in the head and neck tends to be associated with an earlier stage. In a series of 544 patients with head and neck lymphoma, 40% presented with stage I(IE) disease, 29% had stage II(IIE) disease, and 12% and 19% had stage III, and IV disease, respectively(2).

The staging workup for non-Hodgkin's lymphoma is similar to that for Hodgkin's disease, with the following modifications (1).

Treatment:

Hodgkin's Disease:
Radiation therapy is potentially curative for Stage Ia, IIa, and some IIIa disease. Its use for "B" patients is contraversial. In stage I and IIa disease, mantle field radiation is used (6). This includes all suboccipital, cervical, supraclavicular, mediastinal, and hilar nodes, and usually is extended to the celiac axis and splenic hilum. The radiation dosage is 40-45 Gray(Gy) to involved areas and 30-35 Gy to surrounding areas. Head and neck lymphoma is often treated with Waldeyer field irradiation, which includes the nasopharynx, oropharynx, oral cavity, base of tongue, preauricular and occipital areas (2). Stage IIb disease is treated with more extensive radiation, such as extended field irradiation or total nodal irradiation(TNI) (1). Patients with stage IIIa disease limited to the spleen or para-aortic nodes may also be treated with TNI. Complications of radiation therapy include radiation pneumonitis, chronic pericarditis, hypothyroidism, myelosuppression, and infertility (if gonads are not shielded)(1). Complications of head and neck irradiation include mucositis, dysphagia, alopecia, xerostomia, and hypothyroidism (2).

Combination systemic chemotherapy is the treatment of choice for stage IIIb, IVa, and IVb Hodgkin's disease(1). This treatment is also indicated for some patients with stage IIb and IIIa disease. Several combinations of chemotherapeutic agents have been developed, but none have been proven more effective than MOPP(nitrogen mustard, vincristine(oncovin), prednisone, and procarbazine) (1). MOPP is usually given in four week cycles for eight to nine weeks. Toxicities include nausea, vomiting, pancytopenia, neuropathy, infertility, and mood disorders.

The following are relapse-free survival rates at 5-10 years for stages I-IV Hodgkin's Disease using the treatments described above:

XRT- radiation therapy: limited- disease limited to spleen or para-aortic nodes Note: lymphocyte depleted histologic group requires TNI or MOPP.

(Adapted from text in Jacobs JR and Negendank WG. Lymphomas of the Head and Neck. In: Paparella, et al, eds. Otolaryngology, Third Edition. Philadelphia, W.B. Saunders Company, 1991:2596.)

New treatment strategies include the development of different chemotherapeutic drug combinations. The combination ABVD(adriamycin, bleomycin, vinblastine, and dacarbazine) has been used successfully alone for relapses, and alone and in combination with MOPP for initial therapy(1). Further studies are needed to determine if these new drug combinations are more effective than MOPP. Studies of the etiology of Hodgkin's disease may eventually lead to preventive therapies.

Non-Hodgkin's Lymphoma:
The management of non-Hodgkin's lymphoma is different for the three grades of disease. Low grade disease is often treated symptomatically, while patients with intermediate and high grade lymphomas are treated with aggressive, potentially curative combination chemotherapy. Overall, survival is better for lower stage disease, and lower grade disease.

In addition to stage and histologic grade, outcome is also dependent upon site of presentation. In head and neck lymphoma, 5 year survival rates for 156 patients at Stanford University were 61% for salivary gland disease, 57% for oral cavity disease, 49% for tonsil primaries, 47% for base of tongue, 36% for nasopharygeal disease, and 12% for paranasal sinus primaries(2).

Low Grade Disease:
Low grade non-Hodgkin's lymphomas are characteristically indolent but incurable. Stage I and II disease has a median survival of 7.5-10 years, which is usually not affected by the nature or timing of therapy(1). Localized symptomatic disease treated with radiation therapy(30-40 Gy) has a near 100% complete response rate. Patients have long symptom free periods, so no initial systemic therapy is usually recommended. Single agent chemotherapy(cyclophoshamide, chlorambucil) is usually initiated when the disease rapidly progresses or when systemic symptoms develop(1). If rapid progression persists while on single agent therapy, combination chemotherapy(CVP- cyclophosphamide, vincristine, prednisone) is begun, which leads to clinical remission in most patients. There is a relapse rate of 10-15% per year, with fewer than 30% of patients disease free at 10 years. If a low grade malignancy evolves into a higher grade, a more aggressive chemotherapy regimen is initiated.1
Intermediate Grade Disease:
In the past, Stage I intermediate grade non-Hodgkin's lymphomas were treated with 45-50 Gy of radiation(1). Five year survival was 40%. Now, primary XRT plus combination chemotherapy are used for Stage I and II disease (2). Overall 5-year survival with this regimen is about 95% and 80%, and disease free 5-year survival is 90% and 75%, respectively(2). CHOP(cyclophosphamide, doxorubicin, vincristine, prednisone) is commonly used. Stage III and IV are treated with combination chemotherapy. Overall 5- year survival is about 50%, and disease-free survival is about 45%.2 Curative therapy is offered, regardless of presence or absence of systemic symptoms. However, prognosis is worse and the relapse rate is higher for those with "B" symptoms, as well as those with bone marrow or liver involvement, or bulky(>10cm) abdomenal disease.1 Elderly patients and those with sinus, bone marrow, or testicular involvement are at higher risk for central nervous system(CNS) disease. These patients are treated prophylactically with CNS treatment.1 Cranial XRT(25Gy) and several courses of intrathecal methotrexate or cytosine arabinoside, or both are given.
High Grade Disease:
High grade non-Hodgkin's lymphoma is treated with aggressive combination chemotherapy. These patients are at high risk for CNS involvement, so CNS prophylaxis is given as part of the initial therapy. In some series, 60% of patients were cured with aggressive treatment(2). For patients that fail initial therapy, bone marrow transplantation is becoming a viable option(2). The patient's marrow is harvested, cryopreserved, then transplanted back into the patient after high dose chemotherapy and total body irradiation.

Tumor lysis syndrome is a potentially fatal complication of treating high-grade bulky lymphomas(2). In these patients, massive tumor lysis results in acute renal failure, hyperkalemia, hyperphosphatemia, and hypocalcemia. Lethal cardiac arrhythmias within hours of initiating chemotherapy have been reported.

Conclusions:

The most common presenting feature of lymphoma is cervical lymphadenopathy. Otolaryngologists are often the first physicians to see patients with lymphoma, and a detailed head and neck examination is essential for correct staging of the disease.

Hodgkin's disease is a lymphoma of B-cell origin with four prognostically significant subtypes. There is typically contiguous nodal involvement, and disease is rarely below the diaphragm. Accurate staging of Hodgkin's disease is needed to begin appropriate treatment. The cure rates are 80-90% for stage I and II with radiation therapy, and about 50% for stage III and IV with combined chemotherapy.

Non-Hodgkin's lymphoma is actually a varied group of lymphocytic malignancies. Low and intermediate grade non- Hodgkin's lymphomas are derived from B cells. Low grade disease present with slowly progressing lymphadenopathy, and 10-20% have systemic symptoms. They have an inherent median survival of 7.5 years, which varies little with type or timing of treatment. Intermediate grade lymphomas are treated with combination chemotherapy, with stage I and II disease also receiving XRT. Five year survival varies from 95% for stage I disease to 50% for stage III and IV disease. High grade lymphomas present with a rapidly progressing lymphadenopathy, and frequent extranodal disease (Waldeyer's ring, GI, meninges, skin, and lung). They usually have an aggressive course with early death. Inherent median survival is 1 year. However, if complete remission is obtained, a significant fraction of these patients are cured.

BIBLIOGRAPHY

1) Jacobs JR and Negendank WG. Lymphomas of the head and neck. In: Paparella, et al, eds. Otolaryngology, Third Edition. Philadelphia, W.B. Saunders Company, 1991.

2) Jacobs C. Lymphoma of the head and neck. In: Bailey BJ, ed. Head and Neck Surgery, Otolaryngology. Philadelphia:JB Lippincott, 1993.

3) Grogan TM. Hodgkin's disease. In: Jaffe ES, ed. Surgical Pathology of the Lymph Nodes and Related Organs, 2nd ed. Philadelphia: WB Saunders, 1995.

4) Marion J. Diagnosis and treatment of lymphomas. In: Thawley SE, Panje WR, eds. Comprehensive Management of Head and Neck Tumors. Philadelphia: WB Saunders, 1987.

5) Henry K, Farrer-Brown G. Lymph nodes. In: Henry K, Farrer-Brown G, eds. Color Atlas of Thymus and Lymph Node Histopathology with Ultrastructure. Chicago: Year Book Medical Publishers, Inc., 1982.

6) Eyre HJ, Farver ML. Hodgkin's disease and non-Hodgkin's lymphomas. In: Holleb AI, Fink DJ, and Murphy GP, eds. American Cancer Society Textbook of Clinical Oncology. Atlanta, GA: The American Cancer Society, Inc., 1991.

Stage I Treatment Disease-Free Survival
I XRT 90%
IIa XRT 80%
IIb XRT-TNI or MOPP 80%
IIIa-limited XRT-TNI or MOPP 60%
III/IV MOPP 50%
Working Formulation Subtype Corresponding Gall and Mallory Classification
Small lymphocytic Lymphosarcoma, lymphocytic
Follicular small cleaved Follicular lymphoma
Follicular mixed small/large cell Follicular lymphoma.
Follicular large cell Follicular lymphoma
Diffuse small cleaved cell Lymphosarcoma, lymphocytic
Diffuse mixed small/large cell Reticulum cell sarcoma
Diffuse large cell Reticulum cell sarcoma
Large cell immunoblastic Reticulum cell sarcoma
Lymphoblastic Lymphosarcoma, lymphoblastic
Diffuse small noncleaved(Burkitt's) Lymphosarcoma, lymphoblastic