non-hodgkin's lymphomas of head and neck extranodal sites

Inl. J. Radmion Oncology Biol. Phys., Vol. I I, pp. 357-364 Printed in the U.S.A. All rights reserved.

0360-3016/85 $03.00 + .OO Copyright 0 1985 Pergamon Press Ltd.

??Clinical Radiation Therapy

NON-HODGKIN’S LYMPHOMAS OF HEAD AND NECK EXTRANODAL SITES

CHARLOTTE JACOBS, M.D. AND RICHARD T. HOPPE, M.D.

Departments of Medicine and Radiology, Stanford University School of Medicine, Stanford, CA

The initial staging, therapy and course of 156 patients with non-Hodgkin’s lymphomas of head and neck extranodal sites were analyzed to determine whether they have a natural history which differs from primary nodal disease. The sites involved were: Waldeyer’s ring-103 patients (tonsil-60, nasopharynx-25, base of tongue-18), and extralymphatic sites-53 patients (salivary gland-20, paranasal sinus-20, oral cavity-lo, and larynx-3). Seventy-six percent had unfavorable histologies and 24% had favorable histologies. Fifty-three percent had pathologic Stages I-II and 47% had Stages III-IV. The 5-year survival was influenced by primary sites: salivary gland-610, oral cavity-57%, tonsil49%, base of tongue-47%, nasopharynx-36% and paranasal sinus-12%. The 5-year survival was also influenced by histology: unfavorable histologies-39%, favorable histologies-6996. The Ann Arbor staging system was more useful than TNM for determining outcome. For patients with Stage I-II unfavorable histologies treated with radiation alone, the 5-year survival was: involved field-24%, extended field-42%, total lymphoid irradiation-52%. The majority of patients who failed did so in extranodal sites. Forty-one patients with advanced disease received a variety of chemotherapy regimens as the sole treatment. There was a high percentage of CNS recurrence with paranasal sinus lymphoma, and CNS prophylaxis may be necessary. For head and neck extranodal lymphomas, limited radiation is inadequate, and combined modality programs should be considered.

Non-Hodgkin’s lymphoma, Head and neck, Tonsil, Paranasal sinus, Nasopharynx, Salivary gland.

INTRODUCTION

Non-Hodgkin’s lymphomas arising in extranodal sites often have a natural history which differs from primary nodal disease.*T9 Several series of patients with lymphomas involving Waldeyer’s ring (nasopharynx, base of tongue, tonsil, oropharyngeal wall) and/or other extranodal head and neck sites have been reported. 1.4.7*‘3*‘4,23*26*28 In an earlier report by our group, Waldeyer’s ring involvement occurred in only 7% of patients with non-Hodgkin’s lymphoma. I2 Because a relatively small subgroup of patients has been treated over many years, prospective studies are not feasible. However, retrospective analysis is often helpful in determining natural history, results of staging procedures and treatment outcome. This may aid in the evaluation and management of future patients.

The goal of this retrospective review was to evaluate our experience with head and neck lymphomas of Waldeyer’s ring and extra-lymphatic sites to investigate the following:

(1) What are the presenting symptoms, common sites and histologies of head and neck lymphomas?

(2) What staging procedures should be completed? (3) Which staging system is most useful? (4) Following treatment, what are the survival rates

and patterns of relapse? (5) Are there specific treatment recommendations

based on the natural history of disease arising at different sites?

METHODS AND MATERIALS

Between 1963 and 1982, 156 patients with non- Hodgkin’s lymphoma of head and neck extranodal sites were treated at Stanford University in the Divisions of Radiation Therapy and/or Oncology. All patients had biopsies of the primary head and neck site. The pathology slides were reviewed at Stanford University and classified according to the Rappaport classification.24 The staging evaluation included a thorough history and physical examination, including indirect laryngoscopy, complete blood count, liver function tests and chest X ray in all patients. Other X rays included a lymphangiogram in 111 patients (7 1%) and an upper gastrointestinal series in 40 patients (26%). One hundred and thirty-three

Supported by the Public Health Service Grants CA-05838 and CA-34233 from the National Cancer Institute and an American Cancer Society Junior Faculty Scholarship.

Reprint requests to: Charlotte Jacobs, M.D., COO5 Stanford University Medical Center, Stanford, CA 94305.

351

Acknowledgements-We would like to thank Anna Varghese for data analysis and Rose Harris for preparation of the manuscript.

Accepted for publication 5 September 1984.

358 Radiation Oncology 0 Biology 0 Physics February 1985, Volume I I, Number 2

patients (85%) had a percutaneous needle bone marrow biopsy, and 34 patients (22%) had a staging laparotomy and splenectomy. Lumbar puncture for chemistries, cell count, and cytology was performed in 2 1 patients (13%). All patients were staged according to the Ann Arbor staging system.6 To evaluate local extent of disease or bulk of tumor, patients were retrospectively staged according to the TNM system as described by the American Joint Committee on Cancer.3 Forty-one patients could not be staged by the TNM system because of inadequate initial description of local extent of disease.

Treatment involved radiation alone in 92 patients. Thirty-five had Stage I disease, 34 Stage II, 17 Stage III, and 6 Stage IV. The treatment was further defined as involved field (radiation only to sites of known disease) in 35 patients, extended field (radiation to involved sites plus the next lymph node group) in 27 patients, and total lymphoid irradiation in 30 patients.

All patients were treated with a 4.8 or 6 MeV linear accelerator. The total dose for involved sites ranged from 4400 to 5000 rad and for uninvolved sites from 4000 to 4400 rad. Patients were treated four to five times a week with a maximum weekly dose rate of 1000 rad. The Waldeyer’s field consisted of opposed lateral fields, which included all of the nasopharynx and oro- pharynx, adjacent base of skull, preauricular, subman- dibular, and upper cervical lymph nodes, and if indicated, the occipital, post-auricular, or submental nodes. The posterior margins encompassed the posterior cervical nodes. The lower margin was selected such that the matchline with the mantle field did not run through an area of clinical disease.12 A modified supra-mediastinal mantle or “mini-mantle” which shielded the medias- tinum and was matched to the lower border of the Waldeyer field was used in some patients.” Total lymphoid irradiation was as previously described.12 Che- motherapy was used alone in 41 patients, of whom 28 had Stage IV disease, 8 Stage III and 5 Stage II. Chemotherapy was used in combination with radiation therapy in 20 patients, of whom 2 had Stage I disease, 5 Stage II, 2 Stage III, and 11 Stage IV. Three patients had no initial therapy.

Freedom from relapse and survival were calculated from date of initiation of therapy using the technique of Kaplan and Meier.15 Differences between curves were assessed by the Wilcoxon test of Gehan. ” The median follow-up was 27 months.

RESULTS

Patient characteristics The group included 99 males and 57 females with a

ratio of 1.5 to 1. Eighteen percent of patients were Hispanic. The mean age was 53 years with a range of 16 to 8 1 years. Patients under the age of 16 years were excluded from analysis. Eighty-two percent of patients initially presented with local symptoms from involvement

of a particular head and neck site; 15% presented with complaints of head and neck adenopathy, and 4% presented with systemic complaints. One hundred and three patients (66%) had involvement of Waldeyer’s ring; that is, tonsil, nasopharynx or base of tongue. Fifty-three patients (34%) had involvement of extralymphatic sites; this is, salivary gland, paranasal sinuses, oral cavity and larynx. The tonsil was the most common site of involvement (Table 1).

One hundred and nineteen patients (76%) had unfavorable histologies, which include diffuse histiocytic, diffuse lymphocytic poorly-differentiated, diffuse mixed, lymphoblastic, diffuse undifferentiated and diffused unclassified lymphomas (Table 2). Thirty-seven patients (24%) had favorable histologies including nodular lymphocytic poorly differentiated, diffuse lymphocytic well- differentiated, and nodular mixed lymphomas. Diffise histiocytic and nodular lymphocytic poorly differentiated lymphomas were the most common histologies.

Seventy-two patients with clinical Stage I or II disease underwent a lymphangiogram (Table 3). Eight percent of patients with Waldeyer’s involvement, 20% of patients with extra-lymphatic involvement, or 11% of the entire group of patients with clinical Stage I or II disease were upgraded to clinical Stage III by the lymphangiogram. Of the 87 patients with clinical Stage I or II disease who underwent bone marrow biopsy, 13 ( 15%) were upgraded to Stage IV by the procedure. This was most common (56%) in patients with extra-lymphatic presentation and favorable histology. Of the 29 patients with Stage III disease who underwent bone marrow biopsy, 34% were upgraded to Stage IV by this procedure. This was more common in the unfavorable group of histologies. Thirty- four patients underwent staging laparotomy. Thirteen of these patients were upgraded, 18 had no change in stage, and 3 patients were downgraded. Following these staging procedures the patients were staged as follows (Table 4): I-24%, II-29%, III-17%, IV-30%. Eighty- eight percent of patients had no systemic symptoms, while 12% had “B” symptoms. Staging according to the TNM system was as follows: Tl-26%, T2-22%, T3- 13%, T4- 13%. Twenty-six percent were unable to be staged because of inadequate description of local extent of disease.

Table 1. Head and neck lymphomas-sites of presentation

Site No. patients Total %

Waldeyer’s Ring Tonsil Nasopharynx Base of tongue

Extralymphatic Paranasal sinus Salivary gland Oral cavity Larynx

60 38 25 16 18 12

20 13 20 13 10 6

3 2

Head and neck lymphomas 0 C. JACOBS AND R. T. HOPPE 359

Table 2. Histologies of head and neck lymphomas

Histology* No. patients Total %

Unfavorable 119 76 Diffuse histiocytic 78 Diffuse lymphocytic

poorly differentiated 15 Diffuse mixed 13 Lymphoblastic 7 Diffuse undifferentiated 5 Unclassified 1

Favorable Nodular lymphocytic 37 24

poorly differentiated 22 Diffuse lymphocytic

well differentiated 9 Nodular mixed 6

* Rappaport classification. ”

Treatment results Freedom from relapse and survival were influenced

by primary site of disease. The 5-year freedom from relapse for patients with paranasal sinus presentation was 24%, nasopharynx-21%, base of tongue-36%, tonsil-42%, oral cavity-42%, and salivary gland- 66%. Freedom from relapse for paranasal sinus and nasopharynx lymphomas was significantly worse than salivary gland (p < .03). Among Waldeyer sites, the freedom from relapse for nasopharynx lymphomas was significantly worse than for tonsil (p = .03). The 5-year survival for patients with paranasal sinus presentations was 12%, nasopharynx-36%, base of tongue-47%, tonsil-49%, oral cavity-57%, and salivary gland- 6 1% (Figure 1). Survival for paranasal sinus lymphoma was significantly worse than tonsil (p = .007), salivary gland (p = .059) or oral cavity (p = .03). The survival for nasopharynx was significantly worse than tonsil (p = .07).

Survival was also influenced by histology (Figure 2). The 5-year survival for favorable histologies was 69% and for unfavorable histologies was 39% (p = .005). However, freedom from relapse was similar in the two groups, 50% for favorable histologies and 34% for un-

favorable histologies (p = .45). Among patients with unfavorable histologies, disease-free survival was influenced by Ann Arbor stage (Figure 3). The disease-free survival at 5 years was 48% for Stage I and 35% for Stage II (p = .036). There was no significant difference in survival at 5 years: 53% for Stage I and 45% for Stage II (p = .3). In contrast, using the TNM staging system, there was no difference among stages in either survival or freedom from relapse for patients with unfavorable histologies. The 5-year survivals were: Tl-43%, T2-41%, T3-34%, and T4-34%.

Treatment involved radiation alone in nearly all patients with Stage I and II disease. Of the 51 patients with unfavorable histologies and Stage I or II disease, 45% received involved field, 35% were treated with extended field, and 20% received total lymphoid irradiation. The 5-year freedom from relapse based on treatment was as follows: involved field-24%, extended field- 42%, total lymphoid irradiation-52% (p = .28-.75). Five-year survival data were as follows (Figure 4): involved field-39%, extended field-50%, total lymphoid irradiation-60% (p = .36-.95).

Of all patients with Stage I and II disease, (favorable and unfavorable histologies) who relapsed following radiation, the sites of relapse included local or in-field relapses in 8% of cases, marginal relapse in 3%, nodal relapses outside the radiation field in 27%, and extranodal in 60% (Table 5). Of the 22 extranodal relapses, the sites included skin in 5 patients, gastrointestinal tract in 4, liver, bone marrow, and testis in 3 each, central nervous system in 2 and bone and lung in one each. All patients who presented with extra-lymphatic sites of disease (paranasal sinus, salivary gland, oral cavity, larynx) who relapsed, did so in extranodal sites. Overall, 60% of patients treated with radiation alone had extranodal sites of relapse. The percent of extranodal relapses was not influenced by treatment field.

Influence of initial site on natural history and outcome Some of the specific head and neck sites differed in

presentation and outcome. Twenty patients had paranasal sinus lymphomas. Seventeen of these patients

Table 3. Results of staging procedures for head and neck lymphomas

Group

Lymphangiogram (Stage I/II) Bone marrow (Stages I/II)

Unfavorable histology Favorable histology All histologies

Bone marrow (Stage III) Unfavorable histology Favorable histology All histologies

* No. positive/no. who had procedure.

Waldeyer’s

No. (%)

4/52* (8)

6/53 (11) l/9 (11) 7/62 (11)

5/8 (63) 219 (22) 7/17 (41)

Extralymphatic

No. (%)

4120 (20)

l/16 (6) 5/9 (56) 6125 (24)

317 (43) O/5 (0) 3/12 (25)

Total

No. (%)

8/72 (11)

7169 (10) 6/18 (33)

13/87 (15)

8/15 (53) 2/14 (14)

lo/29 (34)

360 Radiation Oncology 0 Biology 0 Physics February 1985, Volume 11, Number 2

Table 4. Pathologic stage of head and neck lymphomas

Ann Arbor system

TNM (AJC)

Stage No. patients Total %

I or IE 37 24 II or IIE 45 29

III or IlIE 27 17 IV 47 30 A 137 88 B 19 12 T, 41 26 7-z 34 22 T3 21 13 T4 20 13 Unknown 20 26

presented with local symptoms such as sinusitis, nasal obstruction and swelling, 2 with neck mass and one with night sweats. Twenty-five percent of the patients were Hispanic. All patients had unfavorable histologies. According to the Ann Arbor Staging system, 70% had early stage disease; Stages IE and IIE; whereas according to the TNM system, 75% had T3 or T4 disease. Thus most patients had bulky, but localized disease. Nine of 14 patients treated with radiation alone failed, and all had extranodal sites of failure. Of the 20 patients with pamnasal sinus lymphoma, 6 had central nervous system disease, one at presentation, 3 as the only site of failure and 2 with other sites of failure. Two of these patients

failed in the CNS despite prior prophylactic treatment of the central nervous system with intrathecal metho- trexate.

Twenty patients had salivary gland lymphomas. The male to female ratio was 1: 1, a higher proportion of females than in other sites. Nineteen patients presented with a neck mass and one with ear pain. Fourteen patients with salivary gland lymphomas presented with involvement of the parotid gland, and 6 in the submax- illary gland. Eleven patients had favorable histologies, all nodular lymphocytic poorly differentiated and 9 had unfavorable histologies, mostly diffise mixed lymphoma. Seventy-five percent of patients had advanced disease, Stage IIIE and IV at presentation, and yet their survival was excellent compared to the group as a whole.

Ten patients had oral cavity presentations, and 70% were unfavorable histologies. Nine presented with local pain or mass. In contrast to paranasal sinus sites, disease was not locally extensive (80% were T 1 or T2) and yet 60% had Stage III or IV disease by Ann Arbor staging.

Of the 25 patients with nasopharynx lymphomas, 18 presented with local symptoms of nasal obstruction or decreased hearing; 6 presented with neck mass, and one presented with night sweats. Eighty-eight percent had unfavorable histologies and 50% had Stage I or II disease. Five patients had baseline lumbar punctures which were all negative, and there were no relapses in the CNS in this group.

p (Gehanj naranasal sinus vs tonsil = ,007 paranasal sinus vs salivary qland = .059 paranasal sinus vs oral cavity = .‘)30

nasopharynx vs tonsil = .073

Sallvary wand (L(J)

rli Cabitv (10)

9as? of Tonnue (18)

Tonsil (bU)

Paranasal Sinus L-.-

Xasopharynx (2':) I1

2 4 6 T;K 10 12 14 16 18

(YRS) Fig. 1. Survival of head and neck lymphomas by site.

PRO

BA

BIL

ITY

(%

> PR

OB

AB

ILIT

Y

(%>


1 I

p (Gehan) TLI vs IF = .28

TLI vs EF = .38

EF vs IF = .75

Total lymphoid irradiation (lo) 6

Extended field (18) 4,

Involved field (23)

2 4 6 8 10 12 14 16 18

TIME (YRS) Fig. 4. Survival of Stage I/II unfavorable histologies by treatment.

Eighteen patients presented with base of tongue lymphomas, which occurred predominantly in males with a ratio of 5: 1. Fifty percent were unfavorable histologies, and 50% had Stage I or II disease. Twelve patients presented with local symptoms of dysphagia or sore throat, and 6 presented with a neck mass.

Sixty patients presented with tonsil lymphomas. Forty- eight presented with local symptoms of sore throat or a mass in the throat, 8 with a neck mass and 4 with systemic symptoms. Eighty-five percent of patients with tonsil presentation had unfavorable histologies, primarily diffuse histiocytic lymphoma. Fifty-seven percent had Stage I and II disease, and 58% had Tl and T2 lesions.

Twelve patients had bilateral tonsil involvement. Seven of those had Stage IV disease based on other sites, and 5 had Stage I or II disease (with the tonsils considered as a single site). The 5-year survival for the group with bilateral tonsil involvement was 5 1%.

Of the 103 patients with lymphomas of Waldeyer’s ring, 22 had multiple sites at presentation. Thirty-two percent of patients with nasopharynx presentation had multiple sites, 18% of patients with tonsil presentation and 17% of patients with base of tongue presentation. The 5-year survival for this group was 53%. Of the patients with Waldeyer’s ring involvement, 36% had an upper gastrointestinal series and usually a small bowel

Table 5. Sites of relapse for Stages I/II following radiation therapy

No. relansina Sites of relapse

patients - Local Margin Nodal Extranodal

Total group Presentation

Waldeyer’s Extralymphatic

Treatment field Involved field Extended field Total lymphoid

37* 3 (8%H 1 (3%) 10 (27%) 22 (60%)

30 3 I 10 16 6 6

19 1 1 6 11 12 1 4 7 5 1 4

* First site of relapse unknown for one patient. t Percent of relapsing patients.

Head and neck lymphomas 0 C. JACOBS AND R. T. HOPPE 363

follow-through as part of the initial staging, and 4 of these were positive for disease. Seven more patients relapsed in the gastrointestinal tract for an overall involvement of 11% in patients with Waldeyer’s ring presentation. The incidence of gastrointestinal involvement did not vary with site of involvement within the Waldeyer’s ring.

DISCUSSION

The evaluation, management and prognosis of non- Hodgkin’s lymphomas often varies with site for extranodal disease.8*9 From our review of lymphomas of the head and neck region at our institution we are able to make some management recommendations. .

The majority of patients with extranodal lymphomas of the head and neck presented with symptoms of a local mass or pain. Less commonly they presented with neck nodes or systemic symptoms. Most of the presenting complaints were indistinguishable from those of a patient presenting with squamous cancer of the head and neck. In fact, several patients had an original diagnosis of squamous cell cancer, and only with the subsequent course of the disease did it become apparent that lymphoma was the appropriate diagnosis.

As others,4,7,‘8,28 we found that Waldeyer’s ring, par- ticularly the tonsil, was the most common site of involvement. The majority had unfavorable histologies, usually diffuse histiocytic lymphoma. The age distribu- tion was similar to that of all non-Hodgkin’s lymphomas, but there were an increased number of Hispanics among patients with paranasal sinus presentation.

Staging should include a thorough head and neck examination with indirect laryngoscopy and nasopha- ryngoscopy. A third of patients with nasopharynx presentation and 18% of patients with tonsil and base of tongue presentations had multiple other sites of involvement in Waldeyer’s ring. Although there was no difference in prognosis between single and multiple sites, knowledge of all sites of involvement is crucial in treatment planning and assessment of response.

The bone marrow biopsy was important in upstaging 15% of patients with Stages I and II disease and one- third of those with Stage III disease. The lymphangiogram was positive in 20% of patients with Stages I and II with extra-nodal presentations and 11% of all Stage I and II patients. It was of particular help in following response to treatment for patients with more advanced disease. The abominal CT scan was not used in the staging of enough patients to comment on its value. The head CT was extremely valuable in assessing extent of paranasal sinus and nasopharynx disease.

As originally suggested by Banfi et aL2 we found involvement of the gastrointestinal tract in 11% of patients with Waldeyer’s ring presentation. We did not find this association for patients presenting with disease

in the paranasal sinuses, salivary glands or larynx. Thus we would recommend an upper gastrointestinal series with small bowel follow-through for patients with disease in Waldeyer’s ring.

Lumbar puncture was not a routine part of staging, but it should be included for patients with paranasal sinus disease. Six of our 20 patients with disease in this site developed CNS disease despite the fact that most had Stage I or II disease. The lumbar puncture need not be part of the initial staging for other head and neck sites, unless some other factor puts them at risk for CNS disease such as unfavorable histologies with bone marrow or testicular involvement. ~3’~ Lumbar puncture is part of the staging for all patients with lymphoblastic lymphoma or undifferentiated lymphoma because of their high propensity for CNS involvement.5,12,27

The Ann Arbor system has often been criticized as not being useful in determining outcome for non- Hodgkin’s lymphomas. It has been suggested that for patients with early stages of head and neck lymphomas that the TNM system, which uses size and local extent of disease, may be more predictive. Mill et al. found a relationship between distal relapse rate and tumor size.18 Platenga et al. found a relationship between prognosis and number of regions involved.‘* In our study, disease- free survival was influenced by Ann Arbor staging for the unfavorable histologies. There were too few patients with favorable histology and early stage disease for analysis. In contrast, neither survival nor disease-free survival was influenced by “T” status.

In recommending future treatment based on past experience it is important to consider primary site of involvement, histology, stage, and sites of failure. Lym- phoma of the paranasal sinuses was associated with a very poor prognosis. Most of the patients had early stage, but very bulky local disease. They were all unfavorable histologies. Despite good local control with radiotherapy, the majority had extranodal relapses, and survival was very poor- 12% at 5 years. Sofferman and Cummings25 reported on 19 patients with paranasal sinus lymphomas treated between 1946 and 1970 with a Caldwell-Luc procedure and 4500 to 6500 rad to involved field only. Only 5 patients survived 3 years. Fu and Perzin” reported on 21 patients with lymphoma of the nasal cavity, paranasal sinuses and nasopharynx. All patients had diffuse lymphomas and the majority were histiocytic lymphoma. All patients had localized disease and were treated with radiation therapy, and only 13% survived. Tumor was controlled locally with radiotherapy, and the majority of patients developed disseminated disease. It may be that adding combination chemotherapy early in the treatment of paranasal sinus lymphomas in addition to radiation will improve the disease-free survival. It would appear that patients should have early CNS prophylaxis.

In contrast, patients with salivary gland lymphomas had a relatively good prognosis with a 5-year survival of


6 1%. Most of the patients had disseminated disease, Stage IIIE or IV at presentation. Most of the lymphomas originated in the parotid gland. It has been suggested that there are lymphoid aggregates within the parotid gland, which are not present in minor salivary glands.” The ear, nose and throat surgeon should be aware of the potential for a lymphoma to present as a parotid mass, since a parotidectomy is not the proper treatment.

There is no question that patients with Stage III-IV unfavorable histology lymphoma should be treated with chemotherapy. A major question is whether Stage I or

II disease of the unfavorable histologies should be handled with radiation alone. For Stage I and II, although TLI and EF were superior to IF, the incidence of new disease in extranodal sites was high. The reported excellent outcome for patients with early stage disease treated with chemotherapylg suggests that chemotherapy should be used in the management of all these patients. How- ever, since radiation alone is often capable of controlling local disease in these patients, it is rational to employ it in conjunction with chemotherapy in attempts to improve outcome of head and neck lymphomas.

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non-hodgkin's lymphomas of head and neck extranodal sites

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