Most Hodgkin lymphoma (HL) patients present with disease in nodal regions. However, in a small subset, disease develops in unique anatomic sites such as the head and neck area. This study aims to identify the characteristics and outcomes of patients who develop HL involving extranodal and nodal head and neck sites.
The authors searched The University of Texas M. D. Anderson Cancer Center's database for HL patients treated between 1967 and 2007 and included those with HL at head and neck sites. They reviewed the records for site of involvement, pathology, treatment, and survival.
The authors identified 39 patients with extranodal and nodal HL of the head and neck. Five patients with lymphocyte predominant HL were excluded. Specifically, 10 of 34 patients had disease in the tonsils, 9 in the nasopharynx, 8 in the thyroid, 3 in the parotid, 2 in the adenoids, and 1 each in Waldeyer's ring and nasal antrum. Median age at diagnosis was 31.5 years, average age at diagnosis was 38 years, and 22 of 34 were male; 23 had stage I or II disease. Pathologically, 14 of 34 had the nodular sclerosis subtype, whereas 15 had mixed cellularity. Twenty-nine of 34 had nodal neck disease at presentation. Five of 34 received chemotherapy alone, 5 received radiation alone, and 24 received combination therapy. Twenty-one of 34 received 39.6 gray of external beam radiation. The most commonly used chemotherapy regimens were ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and MOPP (mechlorethamine, vincristine, procarbazine, and prednisone). At last follow-up, 85% were disease-free.
Approximately 8000 new Hodgkin lymphoma (HL) cases were expected to be diagnosed in 2009, and 133,819 patients to have HL in remission.1 A majority of HL lesions originate at nodal sites, and excellent control rates have been achieved with the use of combination chemotherapy and involved-field radiation therapy.
Among HL patients, however, is a subset in whom disease develops in more unique anatomic sites, including the head and neck area (eg, Waldeyer's ring). Waldeyer's ring is a term that has historically been used to define the lymphoid tissue involving the nasopharynx, base of the tongue, oropharynx, and faucial tonsils. These lymphoid basins are considered extranodal but not extralymphatic.
Most published studies on HL of the head and neck are either case reports or very small series. Therefore, it is difficult to gain a true grasp of this subset of HL's clinical characteristics, including preferred treatments and consequent outcomes of disease. Some published papers suggest that disease occurs in Waldeyer's ring in approximately 1% to 2% of all HL cases.2 The rarity of the disease in this location prompted us to question the optimal approach for treating such patients. Does the unique anatomic distribution of these lesions influence their clinical outcomes? This analysis attempts to gain some insight into the clinical characteristics and outcomes of patients diagnosed and treated for HL of the head and neck, including specifically evaluating the effect of radiation on local control at these extranodal and nodal sites.
METHODS AND MATERIALS
From 1967 to 2007, The University of Texas M. D. Anderson Cancer Center evaluated >3500 patients for HL. All of these patients were treated with some combination of chemotherapy and/or radiation therapy. Of the >3500 HL patients, 39 were found to have disease originating in 1 or more sites of the head and neck. Specifically, HL was found in either Waldeyer's ring (including the nasopharynx, base of tongue, faucial tonsils, oropharynx, and adenoids) or in other sites including the parotid, thyroid, or even nasal apparatus. Presence or absence of nodal disease extension to the neck had been identified by clinical examination and/or imaging. Pathology slides were reviewed and confirmed to be HL by The University of Texas M. D. Anderson Cancer Center Pathology Department on both initial diagnosis and re-evaluation for this retrospective review. Five patients were excluded from the study from the initial 39 because of the confirmation of lymphocyte predominant HL.
After obtaining institutional review board approval, we conducted a retrospective review of all HL charts from the designated year for basic clinical information, that is, sex, age at diagnosis, origin of disease (as determined clinically from physician evaluations and/or through imaging), extent of disease, pathologic subtypes, stage of disease, original treatment, evidence (if any) of recurrence, time to failure or last follow-up, types of radiation administered (total dose, fractionation, and technique), and types of chemotherapy given. Kaplan-Meier plots were then generated for actuarial disease-free survival rates and overall survival rates.3
Clinical and Pathologic Characteristics
We found 39 patients who had HL of primary head and neck sites, cumulatively approximately 17% of all HL cases. Five of these patients were excluded because of confirmation of their diagnosis of lymphocyte predominant HL. The specific sites of disease included: 10 of 34 in the tonsils, 9 in the nasopharynx, 8 in the thyroid, 3 in the parotid, 2 in what was called the adenoids, 1 in what was termed Waldeyer's ring, and 1 in the nasal antrum. The median age at diagnosis was 31.5 years (range, 6-88 years), and 65% of the patients (22 of 34) were male. Interestingly, 8 of 9 patients who developed HL of the nasopharynx were male, whereas 6 of the 8 patients having HL of the thyroid were female. The other disease sites had a balanced sex distribution. All sites of disease other than the thyroid were considered true lymphoid structures.
Fifteen (44%) of 34 patients were younger than 30 years of age, 15 (44%) patients were aged between 30 and 60 years, and 4 (12%) patients were aged over 60 years. In other words, almost 60% of patients were older than 30 years at the time of diagnosis. The average age of the females in the group at the time of diagnosis was 36 years, whereas the average age for males was 38 years. The average ages for those having the most frequent sites of disease presentation were 33 years (nasopharynx) and 27 years (tonsil).
Most (23 of 34) patients had stage I or II disease, with more than half (59% of all patients) presenting with stage II. Eleven of 34 patients had stage III or IV disease, with a majority being given such designations for having extranodal disease along with nodal disease on both sides of the diaphragm or for bone marrow involvement. There was no association between having stage III or IV disease and the anatomic site of presentation within the head and neck, age, or sex. The 3 stage I patients were male, but of various ages. There was clearly a diversity of sexes, anatomic sites, and ages within the stage II cohort. If the HL in the thyroid were the only site of disease involvement, these patients were given IE staging designations.
Pathologically, 41% of the patients (14 of 34) had the nodular sclerosis HL subtype, 44% (15 of 34) had the mixed cellularity subtype, and the remaining 5 members of our cohort had the classic lymphocyte-rich subtype. All 5 patients having the classic lymphocyte-rich subtype had involvement of the tonsils. Otherwise, there appeared to be no correlation between pathology and disease site. We also found no significant correlation between pathology and stage at initial presentation. Patients with the classic lymphocyte-rich subtype showed no particular age pattern. Only 3 of 14 patients having nodular sclerosis were older than 30 years at diagnosis, whereas 10 of 15 having mixed cellularity were older than 30 years at initial presentation.
A majority of patients in our cohort (29 of 34) had nodal neck disease at presentation; 13 patients had bilateral neck disease. Disease in the neck nodes included those of the cervical chain, jugular/jugulodigastric chain, mediastinal basin, posterior triangle area, spinal accessory chain, low tracheal lymph area, perivascular nodes, and subclavian basins.
Because patients in our cohort had presented with their disease as long ago as 1967, the shift in treatment strategies over time was represented in our data. The overriding theme maintained, however, was use of combined modality treatment when indicated. Patients in our study who were treated only with chemotherapy all had stage III/IV disease (5 of 34; 15%). Radiation alone was used for patients treated before 1980 (5 of 34; 15%). The remaining patients were treated with combination therapy (24 of 34; 70%). One aspect of the treatment paradigm that has not changed was the treatment of a majority of stage III and IV patients with chemotherapy alone. The 5 stage III/IV patients treated with chemotherapy alone received MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) plus bleomycin or CVPP (cyclophosphamide, vinblastine, prednisone, procarbazine)-ABDIC (doxorubicin, bleomycin, dacarbazine, 1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea, and prednisone). ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and MOPP were the most frequently used chemotherapy regimens, with patients receiving 2 to 6 cycles.
As of the mid 1980s, ABVD chemotherapy has been the standard of care. There did not appear to be a predilection to use a certain type of chemotherapy or number of treatments for any particular anatomic site of disease, sex, age, pathology, or extent of neck nodal disease. Of note, there was 1 definitive pediatric case in our cohort, a 6-year old boy with stage IA mixed cellularity HL of the nasopharynx. This patient was treated with radiotherapy alone because of concerns of abnormal bone development.
Primary or consolidation radiation therapy was given to 29 of 34 patients in our cohort. Only 5 patients with stage III or IV disease did not receive any radiation. A significant number of our subset, 21, received 39.6 gray (Gy) of external beam radiation as a total dose in 20 to 22 fractions. Two patients received doses of >40 Gy for bulky disease (46 Gy and 50 Gy, respectively), and the other 6 patients received a dose of 30.6 Gy in 17 fractions. In general, the 18 earliest cases chronologically were treated with mantle or modified mantle radiation fields to encompass disease and at-risk lymphatics. In the modern era, 11 patients were treated with involved-field radiation.
The disease-free survival and overall survival rates of the 34 patients were 71% and 78%, respectively, at 10 years (Figs. 1 and 2). Four of 34 patients had HL recurrences. Three of 4 had the mixed cellularity subtype, and 1 had nodular sclerosis. All 4 recurrences occurred in patients with stage III or IV disease and were treated with single-modality chemotherapy.
Specifically, a woman who was 67 years old at initial presentation with stage IVB HL of the thyroid of the mixed cellularity subtype had a recurrence in the abdomen 7 years after treatment with MOPP and bleomycin alone (Table 1). A 29-year-old (on initial presentation) woman with stage IVA mixed cellularity HL of the parotid treated with single-modality MOPP chemotherapy developed a pelvic recurrence 8 years after treatment as well as primary breast cancer 9 years after treatment. A woman who was 31 years old on initial presentation was treated with MOPP alone for stage IVA nodular sclerosing HL of the thyroid, later developed disseminated recurrences <1 year after completing treatment, and died from her disease soon thereafter. A 30-year-old (on initial presentation) man with stage IIIB mixed cellularity HL of the tonsil treated with the MOPP-ABVD combination developed a bone marrow recurrence within a year of completing therapy. Table 1 summarizes characteristics of the patients who developed recurrences.
MC indicates mixed cellularity; HL, Hodgkin lymphoma; NS, nodular sclerosis; MOPP, mechlorethamine, vincristine, procarbazine, and prednisone; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine.
Years refer to years post-treatment.
Stage IVB MC HL of thyroid
MOPP + bleomycin
Abdominal recurrence at 7 years
Stage IVA MC HL of the parotid
Pelvic recurrence at 8 years, primary breast cancer at 9 years
Stage IVA NS HL of the thyroid
Widely disseminated recurrences within 1 year
Stage IIIB MC HL of the tonsil
Bone marrow recurrence at 1 year
Four patients developed second malignancies (nonprostate or skin) without suffering HL recurrences. A man initially presenting at age 50 years with stage IIA nodular sclerosing HL of the tonsil treated with radiation alone was found to have lung cancer 8 years after the completion of therapy. A woman initially presenting at age 32 years with stage IIEA mixed cellularity HL of the tonsil and nasopharynx treated with combination mitoxantrone (Novantrone), vincristine (Oncovin), vinblastine (Velban), and prednisone (NOVP) chemotherapy (2 treatments) and mantle field radiation eventually developed breast cancer 14 years after treatment completion. A man presenting at age 59 years with stage IIIA mixed cellularity HL of the nasopharynx treated with NOVP and radiation developed diffuse large B-cell lymphoma 11 years after therapy. Finally, a man first presenting at age 6 years with stage IA mixed cellularity HL of the nasopharynx developed glioblastoma multiforme 6 years after therapy but is still alive 31 years after the completion of radiation for his lymphoma.
Follow-up data longer than 20 years was available in 6 patients. There were only 3 disease related deaths in our cohort. Because of the extended follow-up in our series only 26 patients continue to live, however, 85.3% of patients were without relapse at last follow-up. Some other nonlymphoma causes for patient death included postsplenectomy infection in 1 of the older patients in the cohort, lung cancer, natural causes (old age), and unknown causes in 2 patients who were disease-free.
Our study provides the largest published series to date involving outcomes of HL of nodal and extranodal sites of the head and neck. In our cohort, HL of the head and neck represented approximately 1% of all HL cases, a value that is consistent with the percentages found in smaller studies.4-20 HL of the head and neck is primarily a disease of men and of early to middle age. The major pathologies are mixed cellularity and nodular sclerosing. Patients having mixed cellularity appeared to have an older average age as well as a greater range of age distributions than those having nodular sclerosing HL, suggesting a possible difference in biology. An earlier paper in the American Journal of Clinical Pathology characterized 22 cases evaluated at The University of Texas M. D. Anderson Cancer Center for HL of Waldeyer's ring.21 This study was able to identify 11 patients treated at M. D. Anderson and another 11 whose samples were sent to M. D. Anderson for pathologic consultation but focused on the pathologic features of the HL patients rather than significant clinical outcomes data. Only the 11 patients treated at M. D. Anderson were part of our 34-patient cohort.
Chemotherapy and consolidative radiation therapy appear to offer excellent long-term local and systemic control in patients who present with HL of the head and neck, a result comparable to those reported in HL from more commonly occurring disease sites.22 At a median follow-up of nearly 10 years, 71% of our cohort was disease-free. We only found disease-related deaths in 3 of 34 patients. In fact, no stage I or II patient treated with combined modality therapy failed locally or distantly. Because there was relative uniformity in the total dose and field of radiation administered for treatment of HL, there was minimal gain in subset analyses. In particular, we were unable to find a significant correlation between radiation dose and technique, anatomic site, sex, or pathology with survival outcome. Every treatment was customized to fit the extent and sites of disease, as is the case with all radiation therapy courses. Despite the evaluation of patients treated over several decades, outcomes were quite similar from decade to decade while chemotherapy regimens were evolving and involved-field radiation became more commonplace. Our cohort was equally distributed throughout each decade of the study, offering us a chance to compare historical outcomes.
In the patients with recurrences (12%), the lack of a combined modality treatment because of the age of the patients and advanced stages (III or IV) may have contributed to poorer prognoses. Furthermore, with the advent of less toxic chemotherapies and involved-field and intensity-modulated radiation therapy, secondary malignancies should have decreased, which is reflected with the presence of only 4 second malignancies, 2 of which were in the radiation field. Recurrences may be a consequence of pathology, stage, and/or treatment; however, we had too few cases for significant statistical correlation. The degree to which continuous or noncontinuous nodal disease extension to the neck from the primary disease site in the head and neck did not alter outcomes could be the result of the involved-field radiation offered to most patients.
In conclusion, although relatively rare, HL of the extranodal and nodal sites of the head and neck represents a unique form of the disease. Our study provides the largest single-institution evaluation of the characteristics, treatments, and outcomes of this population. These lesions should be treated as standard HLs, not necessarily as other pathologies of the head and neck.