Non-Hodgkin's Lymphoma of the Tonsil

A Clinicopathologic Study of 65 Cases

JOEL H. BARTON, MD.' BARBARA M. OSBORNE, MD,' JAMES J. BUTLER, MD,' RAUL T. MEOZ, MD,t
JOSEPH KONG, MD,t LILLIAN M. FULLER, MD,t AND JANE A. SULLIVAN, BSS

Sixty-five patients presenting to M. D. Anderson Hospital and Tumor Institute with Stages IE and IIE
primary tonsillar lymphoma between 1954 and 1981 were reviewed. All cases were non-Hodgkin's
lymphomas, with the majority being diffuse large cell lymphoma (85%). Initial therapy was radiotherapy
alone in 54 patients, radiotherapy combined with chemotherapy in 8 patients, and chemotherapy alone
in 3 patients. Stage was the most important prognostic factor, with 86% and 41% 5-year survivals for
Stages I E and IIE, respectively (P = 0.006). Lymphangiography was crucial in staging patients with
clinically positive cervical lymph nodes because 94% of clinically staged IIE patients developed recurrent
disease, in comparison with only 50% of lymphangiogram-staged IIE patients. The incidence of large
cell lymphoma was so high a s to preclude analysis of survival by histologic type. From this limited
series, radiotherapy alone would appear to be sufficient initial therapy for Stage I E patients, whereas
Stage IIE patients probably benefit from the addition of prophylactic chemotherapy. Relapses were most
common in nonirradiated lymph-node-bearing areas, with the majority presenting in the first 2 years
following initial therapy. The salvage of relapsing patients has been disappointing, with the best hope
residing in combination chemotherapy.
Cancer 53236-95, 1984.

N ON-HODGUN'S MALIGNANT LYMPHOMAS frequently

occur in extranodal sites, where they account for
10%to 50% of all lymphomas in reported series.'-3 Of
Materials and Methods
A search was made of the files of M. D. Anderson
Hospital and Tumor Institute (MDAH) for all cases of
the extranodal non-Hodgkin's lymphomas, the gastroin-
malignant lymphoma presenting in the faucial tonsil. The
testinal tract and Waldeyer's ring (nasopharynx, faucial
initial search recovered 84 cases presenting for evaluation
tonsils, base of tongue) usually predominate as primary
between 1949 and 198 I . For inclusion in the study it was
sites.I-' The faucial tonsil comprises approximately 37%
required that ( 1 ) clinical records and pathologic accessions
to 62%9,10 of Waldeyer's ring presentations, thus making
be available for review; (2) tonsillar lymphomatous in-
it the most frequent site of primary extranodal non-
volvement be proven by b i o p ~ y ~(3) , ' ~oropharyngeal
; dis-
Hodgkin's lymphoma of the head and neck
ease be confined to one or both tonsils (or if there was
In contrast, Hodgkin's disease of Waldeyer's ring is dis-
extension beyond the tonsil, the involvement was uni-
tinctly uncommon. 14-"
lateral with the tonsil as epicenter); (4) regional lymph
This report deals with the survival of 65 patients with
node involvement, if present, be confined to the cervical
primary tonsillar non-Hodgkin's lymphoma (Ann Arbor
and supraclavicular regions: (5) no treatment be received
Stages IE and IIE") evaluated and treated at M. D. An-
prior to referral to MDAH; (6) all treatment be at MDAH
derson Hospital and Tumor Institute between 1954 and
or under careful scrutiny of an MDAH physician; and
1981.
(7) there be follow-up extending to death or into 1981.
After application of the above criteria, 19 patients were
From the Departments of Pathology,* Radi0therapy.t and Internal excluded for the following reasons: slides and paraffin
Medicine,$ The University of Texas System Cancer Center. M. D. An- blocks not available for review (7 patients): Stage IIE with
derson Hospital and Tumor Institute, Houston, Texas.
Address for reprints: Barbara M. Osborne, MD. Department of Pa- lymph node involvement below the clavicles (6 patients);
thology, M. D. Anderson Hospital and Tumor Institute. Texas Medical tonsil not diagnostic by biopsy (4 patients); and no biopsy
Center, 6723 Bertner, Houston, TX 77030. of tonsil available (2 patients).
The authors thank Pamela Powell, Mary Carroll, and Susan Barton
for their valuable assistance in the preparation of this manuscript. Of the remaining eligible patients, hematoxylin and
Accepted for publication October 18. 1982. eosin (H & E) stained sections of tonsillar biopsies (or

86
No. I TONSILLAR
LYMPHOMAS
ua
c 16
K
.2
CI
Q
n
rc
FIG. I . Age distribution of tonsillar non-Hodgkin's
lymphoma Stages IE-IIE with method of staging of
the entire group of 65 patients. &
9
t€
excisions)were reviewed in all cases, in addition to cervical
lymph node biopsy specimens where available (seven of
the Stage I1 cases). In many instances methyl green py-
ronine stained sections were also reviewed. Histologic
classification was done independently by three of us
(J.H.B., B.M.O., and J.J.B.) using the working formulation
for clinical usage." When a discrepancy arose, the material
was again reviewed and a consensus reached. Radio-
therapy charts and radiographs were reviewed by two of
us (R.T.M. and L.M.F.) when questions arose concerning
the initial clinical staging.
Staging evaluation consisted of thorough history-taking,
physical examination with indirect laryngoscopy, chest
radiographs, hemograms, and leukocyte counts in all
cases. Lymphangiography was performed in 40 cases (62%
of the entire series, and 70% of patients admitted after
1961 ). Of the 25 patients who were not staged with lym-
phangiography, 18 were 70 years of age or older. Nine
patients had a staging laparatomy. Bone marrow biopsies
were performed on selected patients in the early years,
and on all patients after 1970. Nuclear scans of liver-
spleen and bone, gastrointestinal series and abdominal
computerized axial tomography (CAT) were performed
in the later years on selected patients. All patients were
staged according to the Ann Arbor system."
Initial treatment consisted of radiotherapy alone in 54
patients, radiotherapy combined with chemotherapy in
8 patients, and chemotherapy alone in 3 patients. Of the
eight patients who received combined therapy, seven pa-
tients were treated with radiation followed by chemo-
therapy as planned prophylactic treatment, and one
patient received chemotherapy followed b y radiation
therapy.
For all but three patients, radiation therapy was ad-
ministered to the primary site and neck through parallel
opposed fields, which included the nasopharynx in the
majority of patients. Prior to 1960, patients were treated
with orthovoltage. Thereafter, megavoltage, usually Cobalt
- Barton et af. 87
Lymphangiogram Staged
15
'0
5
1-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90 91-100
Age in Years
60, was used. In general, tumor doses to the primary site,
ranged from 4000 to 6000 rad, given over 4 to 7 weeks
at 1000 rad per week. Only six patients received less than
4000 rad tumor dose. Excluding these, the mean tumor
dose approximated 5200 rad. In addition, both supra-
clavicular regions were treated with anterior fields with
doses ranging between 4000 and 5000 rad in 4 to 5.5
weeks. Only two patients did not have the supraclavicular
fields treated.
The 1 1 patients treated with chemotherapy, either in
combination with radiotherapy or alone, received a com-
bination of cyclophosphamide, doxorubicin hydrochlo-
ride, vincristine sulfate, prednisone and bleomycin sulfate
(CHOP-Bleo), with modifications in individual patients.
Follow-up information was obtained from MDAH
charts and from communication with private physicians,
patients, patient families, and the Texas State Department
of Health, Bureau of Vital Statistics, Austin, Texas.
Calculation of survival curves was done by the Kaplan
and Meier method,*' and Gehan's modification of the
generalized Wilcoxon test was used to evaluate differences
in survival curves.21
Results
Clinical Characteristics
There were 40 men and 25 women, for a male to
female ratio of 1.6 to 1. The age range was 17 to 92 years
(mean, 59 years; median, 62 years). The peak incidence
was during the 6th, 7th, and 8th decades (Fig. I). There
were 57 whites and 8 blacks. A clinical estimate of the
tumor size was available in 22 cases (range, 2.5-10 cm;
average, 4.6 cm).
Palhology
Information on the gross pathology of many of the
tonsils was unavailable because a large number of the
88 CANCERJanuary I
TABLE1. Tonsillar Non-Hodgkin’s Lymphomas Distribution
by Cell Type and Stage
Cell Type
Stage DLC FLC FSCC DSCC DMCEH DSCCEH
IE 17 I I I I
IIE 38 2 1 I 7
DLC: diffuse large cell (histimytic) lymphoma; FLC. follicular large cell (his-
timytic) lymphoma: FSCC: follicular small cleaved cell lymphoma: DSCC: diffuse
small cleaved cell lymphoma: DMCEH: diffuse mixed cell lymphoma with epi-
thelioid histiocytes: DSCCEH: diffuse small cleaved cell lymphoma with epithelioid
histiocytes: SLW. small lymphocytic lymphoma. plasmacytoid.
original accessions were small incisional biopsies, rather
than excisions. However, the gross descriptions of the
larger tissue fragments consistently mentioned “homo-
geneous. fleshy. rubbery, gray-white to tan” characteristics,
similar to lymphomas in other sites.
Based on the working formulation of non-Hodgkin’s
lymphomas for clinical usage,” the tonsillar lymphomas
were subdivided histiologically by pattern and cell type
as listed i n Table 1 (which also includes the stage on
presentation). Fifty-eight (89%)of the cases fell into the
large cell lymphoma (LCL) group, with 55 of these dem-
onstrating a diffuse pattern; the other three cases had a
follicular pattern (Fig. 2 ) . The pattern in four cases was
vaguely suggestive of a follicular pattern, but this could
not be determined with certainty; these cases were in-
cluded within the diffuse group. The morphologic pattern
of the LCL group was typified by a monomorphic pro-
liferation of large lymphoid cells with variably prominent
nucleoli. In some of the cases, the cleaved or noncleaved
nature of the nuclei of the large cells could be distinguished
(Fig. 3). while in many of the remainder there was a
mixture of the two. In four of the diffuse cases, the large
FIG.2. Representative low-power view of one of the follicular large
cell (histiocytic) lymphomas (H & E, original magnification XlOO).
1984 VOl. 53
SLPC
FIG. 3. Diffuse large cell lymphoma with a predominance of large
cleaved cells (H & E, original magnification X400).
cells had distinct plasmacytoid features with eccentrically
placed nuclei, thick nuclear membranes, clumped chro-
matin, prominent nucleoli, and copious pyroninophilic
cytoplasm. These features were felt to be indicative of
large cell lymphoma, immunoblastic, and plasmacytoid”
(Fig. 4).
The remaining seven cases comprised a histologically
mixed group. There were three cases of small cleaved cell
lymphoma, two of which were follicular. The biopsy
specimen in the third case was small, without a demon-
strable follicular pattern and was therefore considered
diffuse. There was one case of small lymphocytic lym-
phoma with plasmacytoid features, and three cases of
diffuse lymphoma with benign epithelioid histiocytes. The
last three cases were of considerable interest: one was
composed predominantly of small cleaved lymphocytes;
the other two contained similar cells with a mixture of
large lymphoid elements (diffuse mixed cell lymphoma
with epithelioid histiocytes). The background of the latter
two cases was heterogeneous with a broad range of cell
sizes, vascular proliferation, occasional plasma cells and
eosinophils in addition to numerous macrophages (Fig.
5). Though cell surface markers were not done in these
cases, the morphology was quite suggestive of that de-
scribed for the group of lesions referred to as peripheral
T-cell lymphomas.23-’5
Locd Conirol
Of the entire group of 65 patients, local control of both
Waldeyer’s ring and the associated cervical lymph nodes
was achieved in 56 patients (86%).Of the nine patients
with local recurrences, five developed disease in cervical
lymph nodes, three in Waldeyer’s ring, and one in Wal-
No. 1 LYMPHOMAS
TONSILLAR - Barton ef al. 89

FIG. 4. Diffuse large cell lymphoma, immunoblastic, plasmacytoid FIG. 5. Diffuse mixed cell lymphoma with epithelioid histiocytes
(H & E. original magnification X400). showing characteristic heterogeneous background ( H & E. original mag-
nification X400).

deyer's ring and cervical lymph nodes. Eight of the patients
were Stage IIE, and one was Stage IE; eight were diffuse
LCL, and one was diffuse small cleaved cell lymphoma.
Seven of the local failures developed as initial recurrences,
whereas the other two followed initial relapses in non-
irradiated lymph-node-bearing areas.
Review of the treatment technique in the seven patients
with initial local failures, revealed that three had been
treated inadequately because of suboptimal tumor dose
( 2 patients) or inadequate margins ( 1 patient). Two ad-
ditional patients had residual disease at the primary site
after tumor doses of 5700 and 6800 rad, respectively.
Siirvivul
The effect of histologic examination alone on survival
could not be evaluated because there were so few patients
with histologic subtypes other than diffuse LCL in this
group of 65 tonsillar lymphomas.
significant (P = 0.053). When the 5-year survivals were
compared within each stage for patients who did and did
not undergo lymphangiography, the only significant dif-
ference was within the Stage IIE group, with the lym-
phangiogram-staged patients having a very significant
survival advantage (66% and 12% respectively, at 5 years;
P = 0.006). Within Stage IE, nonlymphangiogram-staged
patients did not have a significantly worse survival ( P
= 0.091).
1.o
.9
.8
.7
z 6

8.1
0'
The five year survival for the entire group was 54%
(Fig. 6 ) . with a 5-year disease-free survival of 42%. There
was a highly significant difference (P = 0.006) between a .4
the 5-year survival of the 2 I Stage IE patients (86%)and
the 44 Stage IIE patients (41%).
TOTAL FAIL SURVIVAL
When the 40 patients staged by lymphangiography were 65 30 ALL PATIENTS
compared with the 25 clinically staged patients, the sur- 5 0 ALL STAGE IE
vivals at 5 years were 77% and 24%, respectively (Fig. 7). 44 25 A ALL STAGE IIE
I NON-FAILURE
This difference was highly significant (P = 0.002). If only
the lymphangiogram-staged patients are considered, the
0 II---1 1
5-year survivals for Stages IE and IIE were 100% and 0 3 6 9 12 15
6676, respectively. This difference was not significant (P YEARS
= 0.103). However, the difference in the corresponding
FIG.6. Tonsillar non-Hodgkin's lymphomas. Stages IE and IIE. Sur-
survival rates of the nonlymphangiogram-staged patients vival of the entire group of 65 patients by stage. At 5 years. the Stage
(62% for Stage IE, and 12% for Stage IIE) was probably IE patients had an 86% survival i w \ u . s 41'% for Stage IIE ( P = 0.006).
90 CANCERJanuary 1 1984 VOl. 53

1.0 TB( are emphasized. Of these 55 patients, 22 patients did not

have lymphangiography, 25 patients had lymphangiog-
raphy, and 8 patients had both lymphangiography and
staging laparotomy. Initial therapy consisted of radiation
alone in 44 patients (including 6 patients who underwent
laparotomy), radiation combined with chemotherapy in
8 patients (including 2 patients who underwent laparot-
-
z .6 omy), and chemotherapy alone in 3 patients.
0
c Within the same group of 55, the survival of those
8 .5
n
-
TOTAL FAIL SURVIVAL patients treated with radiation alone was more closely
8 .4-
40
25
11
19
0 LYMPHANGIOGRAM
A CLINICAL
I NON-FAILURE
examined. There were 18 lymphangiogram-staged patients
(no laparotomy), and 20 clinically staged patients who
.3 - received only radiotherapy. At 5 years there was a sig-
nificantly better survival in the lymphangiogram-staged

.* t patients treated with radiation alone than in the similarly

0
’ l0 L-s: 3 6 YEARS 9 12
FIG.7. Tonsillar non-Hodgkin’s lymphoma. Stages IE and IIE survival
by method of staging. Survival at 5 years was 77% L W S I I S 24%for lymph-
angiogram-staged wr.su.v nonlymphangiogram-staged (clinical) patients
(P = 0.002).
The survival of patients age 40 and younger was sig-
nificantly better than for those older than age 40 ( P
= 0.031). At 5 years, the respective survivals were 86%
and 49%.In contrast, there was not a significant difference
( P = 0.849) in the 5-year disease-free survival rates of
the two age groups which were 53% and 4 I%, respectively.
However, all of the patients 40 years of age and younger
(12) were staged with lymphangiograms, while only 28
of the 53 patients older than age 40 (53%) were staged
with lymphangiography. When the 12 patients 40 years
of age and younger (all of whom had undergone staging
lymphangiography) were compared with the patients older
than age 40 who had been staged with lymphangiography,
there was no significant difference in the 5-year survivals
of 85% and 74%, respectively ( P = 0.170).
When the 28 patients older than age 40 who were
lymphangiogram-staged, were compared with the 25 pa-
tients older than age 40 who were clinically staged, the
5-year survivals were 75% and 25%, respectively. This
difference was highly significant ( P = 0.009).
Therapy
The results of therapy were difficult to analyze because
cell type, staging techniques, and therapeutic approaches
were heterogeneous among the 6 5 patients in the entire
group. T o provide the most homogeneous group for anal-
ysis of therapy, the results in patients with diffuse LCL
treated nonlymphangiogram-staged patients (70% versus
18%; P = 0.027). However, the difference in the 5-year
15
disease-free survival was not significant (49% ver.yiiS 19%:
P = 0.577).
Survival by stage was examined within the same two
groups. The resulting numbers of patients in each group
were small, thus making comparisons difficult. Survivals
at 5 years of lymphangiogram-staged IE patients (7) versus
IIE patients ( 1 I ) were 100% and 519’0, respectively ( P
= 0.066). whereas survivals of nonlymphangiogram-
staged IE patients ( 5 ) versus IIE patients ( I 5 ) were 75%
and 7%. respectively ( P = 0.123). Survivals at 5 years of
lymphangiogram-staged IE patients (7) verszis nonlym-
phangiogram-staged IE patients ( 5 ) were 100%and 75%.
respectively (P= 0.478): whereas the comparable survivals
of lymphangiogram-staged IIE patients ( 1 I ) vcrszis non-
lymphangiogram-staged IIE patients ( 15) were 5 1% and
770, respectively ( P = 0.159). All 15 of the nonlymphan-
giogram-staged IIE patients treated with radiation alone
died of their disease. Although these numbers are too
small to determine statistical significance, they d o suggest
that nonlymphangiogram-staged IIE patients treated with
radiotherapy alone have an appreciably poorer survival.
The remaining six diffuse LCL patients who received
radiotherapy alone were all staged with lymphangiography
and staging laparotomy. There were three Stage IE patients
and three Stage IIE patients. Two of these patients man-
ifested new disease, and both were Stage IIE. One patient
relapsed in the axillary lymph nodes at 4 months from
admission. and the other relapsed in the stomach at 9
months.
The effectiveness of chemotherapy in combination with
radiation or alone was also difficult to evaluate because
of the small number of patients treated in this fashion.
Of our total group of patients. there were I I who were
treated with chemotherapy, 8 in combination with ra-
diation, and 3 with drugs alone. All I 1 patients had diffuse
No. I TONSILLAR
LYMPHOMAS - Burton et al. 91

TABLE2. Patterns of First Manifestation of New Disease: Tonsillar Lymphomas, Lymphangiogram-Staged IE and IIE

Relapse sites

Nodalt Extranodal

Stage Patients Local: WR* Ax Med Abd Ing GI Pancreas Spleen Bone Skin Unknown

IE 14(11) I 1 I
IIE 26 (13) I 2 2 4 I 2 1 I I I 3
Total 40 (24) 2 2 2 5 1 2 I I 2 I 3

* Local relapse or persistant disease refers to Waldeyer’s ring (WR). (Abd), or inguinal (Ing) lymph nodes.
$ Nodal relapse refers to axillary (Ax), mediastinal (Med). abdominal ( ): number of patients with no subsequent disease.

LCL, and all received CHOP-Bleo with modifications in
individual patients. Of the eight patients who received
combination radiation and chemotherapy, (including two
who also underwent staging laparotomy), there were no
local failures, and only one patient relapsed in a distant
site. This patient was staged as IIE without lymphangi-
ography (or laparotomy), and relapsed in abdominal
lymph nodes 48 months after admission. Of the three
patients who received chemotherapy alone, all were Stage
IIE and one (lymphangiogram-staged, no laparotomy)
suffered a relapse in the axillary, inguinal, and pelvic
lymph nodes 3 months following admission. The other
two are free of disease.
Of the ten patients whose tonsillar lymphomas were
of cell types other than diffuse LCL (Table l ) , all were
treated with radiotherapy alone. Four were Stage IE (in-
cluding two lymphangiogram-staged), and six were Stage
11E (including four lymphangiogram-staged, and one both
lymphangiogram and laparotomy staged). Well-docu-
mented relapses occurred in four patients (two Stage IE
and two Stage IIE), and two patients (one Stage IE and
one Stage IIE) died of disease without specific information
as to the site or time of relapse. Of the six who developed
new disease, three had follicular lymphomas and three
diffuse. The cell types were too heterogeneous and the
number of patients too small in this group to suggest any
conclusions.
Patterns of’ First Muni$estution qf New Diseuse
The incidence of new disease was strongly correlated
with the initial stage. Of the 21 Stage IE patients, 6 ( 3
diffuse LCL) had progression or local recurrence (28.5%).
Of the 44 Stage IIE patients, 30 (25 diffuse L C L ) expe-
rienced local recurrence or progression of disease (68%)
(Tables 2 and 3). Within this group of 36 patients, there
were 26 patients in whom the first evidence of new disease
was well documented; 10 patients died of disease without
specific information concerning the initial site or time of
relapse. In 13 of these 26 patients, more than one anatomic
site was involved in the initial relapse. The most common
initial manifestation of new disease was in lymph nodes
outside the initial treatment fields, with abdominal lymph
nodes the most common lymph node area. Extranodal
relapse, outside the original irradiated fields, was the sec-
ond most common type of initial relapse; it occurred in
12 patients. Within this group, the gastrointestinal tract
(five patients) was the most frequent site, with the stomach
involved in four patients, and the duodenum in one.
Local recurrence or persistent local disease was the initial

TABLE3. Patterns of First Manifestation of New Disease: Tonsillar Lymphomas, Nonlymphangiogram-Staged IE and IIE

Relaose Sites

Local* Nodalt Extranodal

Stage Patients WR Cer Ax AM Ing Lung GI Liver Disseminated Unknown

IE 7 (4) 1 2
1IE 18 ( 0 2 4 3 5 3 1 3 I 5
Total 25 ( 5 ) 2 4 3 5 3 I 3 1 I 7

* Local relapse or persistant disease refers to Waldeyer’s ring (WR) (Ing) lymph nodes.
and/or cervical lymph nodes (Cer). (): number of patients with no subsequent disease.
t Nodal relapse refers to axillary (Ax), abdominal (AM), or inguinal
92 CANCERJanuary I
manifestation of new disease in seven patients; and in
one patient disseminated disease was the first evidence
of relapse.
When the incidence of relapse was examined with re-
gard to the method of staging, there was a striking contrast
among the Stage IIE patients. Of the clinically staged IIE
patients, 94%( 17) manifested relapsing disease. However,
only 50% ( 13) of the lymphangiogram-staged IIE patients
developed a relapse (Tables 2 and 3). The Stage IE patients
did not display such a difference.
Time int erval.fiom admission to progression of disease:
The approximate time period from admission to the first
manifestation of new disease was documented in 26 pa-
tients; in 10 other patients who died of disease, the initial
site and time of relapse were unknown. Of these 36 pa-
tients, the time of initial relapse or death was as follows:
18 patients (50%)within I year; 6 patients ( 17%) between
1 to 2 years; 2 patients (6%) between 2 to 3 years; 3
patients (8%)between 3 to 4 years; 3 patients (8%)between
4 to 5 years; and 4 patients ( 1 170) after 5 years. There
was no significant difference in time of relapse between
clinically and lymphangiogram-staged patients.
Therapy of initial relapse: Twenty of the 26 patients
(77%)with well-documented sites of initial relapse died
of disease. The therapy employed is known in 22 patients
(85%). The therapy of the remaining four patients ( 15%)
is unknown, but all four are dead of disease, an average
of 4.5 months after the first evidence of new disease. Of
these 22 patients, 6 of 1 I (55%; 1 Stage IE, 5 Stage HE)
Iymphangiogram-staged, and 10 of the I 1 (9 I %; all Stage
HE) who did not have lymphangiograms died of their
disease. Five patients (23%) received radiotherapy only,
two (9%) single-agent chemotherapy only, eight (36%)
combination chemotherapy, two (9%)combination che-
motherapy and radiotherapy, and five (23%)received no
therapy. Sixteen of these 22 patients (73%)died of their
disease within an average time of 10 months from the
first evidence of relapse. Three patients ( 14%)are currently
without evidence of disease, following an average interval
of 36 months since presenting with new disease. All three
patients had diffuse LCL and were lymphangiogram-
staged as IIE. All were treated with CHOP-Bleo (one with
the addition of cytosine arabinoside, and one with the
addition of radiotherapy). Three other patients (1470)are
currently alive with disease following an average time
period of 14 months since first manifesting new disease.
All three have diffuse LCL; two initially lymphangiogram-
staged (IE and IIE), and one nonlymphangiogram-staged
as IIE. Two received CHOP-Bleo as therapy (one with
cytosine arabinoside), and one patient received a com-
bination of doxorubicin hydrochloride, vincristine sulfate,
cytosine arabinoside, prednisone, and bleomycin sulfate
1984 VOl. 53
(HOAP-Bleo). Persistent disease is located in Waldeyer’s
ring, cervical lymph nodes, and abdominal lymph nodes
in one each of the three patients. Of seven patients who
received only radiotherapy or single-agent chemotherapy,
all were dead of disease following an average interval of
10 months from the time of initial relapse. All five re-
lapsing patients who received no therapy were dead of
disease an average of 4.6 months from the first evidence
of new disease.
Discussion
The difficulty in obtaining an adequate biopsy specimen
of the tonsil cannot be overemphasized. A large number
of the biopsy specimens in this series were small, thus
rendering them more susceptible to crush and drying
artifact if not handled with care. Because of this, it was
not uncommon for second and third biopsy specimens
to be required prior to a definitive histologic diagnosis.
As others have stressed,2hfrozen section examination has
utility in this situation only as a means of identifying
diagnostic tissue, not as a means of definitive diagnosis.
Important differential diagnostic considerations include
the more common squamous carcinoma,I2.l6 as well as
poorly differentiated carcinoma with lymphoid stroma
(lymphoepithelioma). This latter diagnosis can be par-
ticularly difficult to distinguish from large cell lym-
p h ~ m aespecially
,~~ if the epithelial clusters lack cohesion.
Lymphoepithelioma displays two histologic patterns
whether in Waldeyer’s ring28or in metastases to cervical
lymph nodes2’ The more common Regaud type (discrete
nests) is easier to distinguish from large cell lymphoma
because of the cohesive nature of its epithelial cells. The
less common Schmincke type (diffuse sheets) is much
more difficult to separate from large cell lymphoma be-
cause the individual tumor cells can be dispersed by mixed
inflammatory cells and fibrosis, masking its epithelial na-
ture.2y Helpful features in distinguishing lymphoepithe-
lioma from large cell lymphoma include the syncytial
arrangement, uniformity of the small nucleoli, and nuclear
molding of the former, as well as the thicker, nuclear
membranes, larger, variable-sized nucleoli, and cyto-
plasmic pyroninophilia of the latter.*‘)
In this study of primary tonsillar lymphomas, all of
the patients had non-Hodgkin’s lymphomas, with a pre-
ponderance of diffuse LCL (85%). There were only five
follicular lymphomas, three large cell and two small
cleaved cell. The high frequency of LCL and the rarity
of Hodgkin’s disease in this location have been reported
by other^.^^.'"^^^ The specific effect of histologic subtype
alone on survival could not be evaluated in this study
because there were so few patients with cell types other
No. I TONSILLAR
LYMPHOMAS
than LCL. In previous series, however, some investigators
have given prognostic importance to the histologic subtype
of primary non-Hodgkin's lymphomas in Waldeyer's
ring,8 whereas other^^.^'.^^ did not believe that histologic
subtyping has prognostic significance.
The increasing age of the patient at presentation with
lymphomas of Waldeyer's ring has been variously men-
tioned in the literature as having no significant a f f e ~ t ' , ' ~ . ' ~
on survival or as indicating a poor p r o g n ~ s i s . In
~ , ~this
~ significance of cervical lymph node involvement as a poor
analysis, no significant survival difference could be at-
tributed to age alone. On first examination, the patients
40 years of age and younger appeared to have a significant
survival advantage. However, the staging workup in all
these patients had included lymphangiograms. When this
group was compared with the patients older than age 40
who were also lymphangiogram-staged, no significant dif-
ference in survival could be detected. Of further interest
is the fact that the patients older than age 40 who had
undergone lymphangiography did significantly better than
their age-matched counterparts who were only clinically
staged.
The single most important prognostic factor in this
study was stage on presentation. The importance of stage
has been stressed repeatedly in the literature for non-
Hodgkin's lymphomas in general,35and for those in the
head and and Waldeyer's ring in particu-
lar.7-9.13.31.32.34.36 The survival at 5 years for Stage IE pa-
tients was significantly better than that for Stage IIE pa-
tients (86% and 4 l%, respectively). Lymphangiography
was important in increasing the accuracy of staging. This
was demonstrated by the highly significant difference in
the 5-year survivals of the entire group of patients staged
with and without lymphangiograms, 77% and 24%, re-
spectively (P= 0.002). For the Stage IIE patients alone,
the 5-year survivals for lymphangiogram-staged and clin-
ically staged patients were 66% and 12%, respectively (a
highly significant difference, P = 0.006). A similar survival
advantage could not be seen within the Stage IE group
(P = 0.091). This may mean that lymphangiography is
not as essential in patients with lymphoma clinically lim-
ited to the tonsillar fossa. Once contiguous spread to cer-
vical lymph nodes has taken place35(Stage IIE), our data
indicate that lymphangiography is important in identi-
fying those patients with abdominal disease not detectable
by clinical staging alone. When the lymphangiogram-
staged IE and IIE 5-year survivals were compared, they
were not significantly different (P= 0.103).
Comparison of survivals for our patients with those
previously reported for similar lesions is difficult, because
diagnostic criteria4and treatment techniques3' have varied
greatly over the time span involved. Comparable primary
lymphoma series from the head and neck and Waldeyer's
- Barton et al. 93
ring, published since 1948, have reported 5-year survivals
of 37.1% to 52%,'0.".13 as compared with 54% survival
at 5 years for our entire group of 65 tonsillar lymphomas.
In those studies in which 5-year survivals were determined
separately for Stages 1 and 11, the percentages ranged
from 47.3% to 79% for Stage I and from 16.7% to 48%
for Stage II.7.31-33 In our patients, 5-year survivals for
Stages IE and IIE were 86% and 41%, respectively. The
prognostic sign was repeatedly emphasized, '2~'6 and is
reflected in the poorer survival of our Stage IIE patients
if both clinically and lymphangiogram-staged patients are
included.
Definitive recommendations for therapy of primary
tonsillar malignant lymphoma are difficult to make from
a series of 65 patients, with only 55 patients having the
same cell type. However, of the I5 patients with Stage
IE diffuse LCL (all methods of staging, including lapa-
rotomy in 3 patients), treated with radiotherapy alone,
12 (75%)are without evidence of disease. Of the remaining
three, one (nonlymphangiogram-staged)died from disease
at 10 months, following admission without specific in-
formation as to site or time of recurrence, one (lym-
phangiogram-staged) died of disease at 62 months from
admission following a relapse in abdominal lymph nodes
at 57 months, and one patient (lymphangiogram-staged)
currently has persistent local disease. Although previous
studies have reported improved survival in Stages I and
11, large cell lymphoma with combination chemotherapy,
or combination chemotherapy and radiation the rap^,^','^
our study suggests that in the specific instance of Stage
IE tonsillar lymphoma, radiation therapy may be adequate
for sequentially-staged patients.
Twenty-nine Stage IIE diffuse LCL patients were treated
with radiotherapy alone. The 15 patients who were staged
without lymphangiography, developed new disease within
3 to 80 months following admission, and all were dead
of disease within 90 months of admission. Eight of I I
patients staged with lymphangiography had relapsing dis-
ease within 2 to 63 months from admission, and 6 died
of their disease within 63 months. Two of the remaining
Stage IIE patients staged with lymphangiography and lap-
arotomy manifested relapsing disease, one in the axillary
lymph nodes at 4 months following admission (dead of
disease at 24 months), and one in the stomach at 9 months
(currently without evidence of disease).
Eleven patients with tonsillar diffuse LCL received
chemotherapy (CHOP-Bleo with some individual mod-
ifications) either alone (three patients) or combined with
radiotherapy (eight patients). Of the three patients who
received chemotherapy alone, two are currently without
evidence of disease, whereas one lymphangiogram-staged
94 CANCERJanuary 1 1984
IIE patient developed new disease at 3 months and is
currently alive with disease. Of the eight Stage IIE patients
who received chemotherapy combined with radiotherapy,
including two that were laparotomy-staged, only one de-
veloped new disease. This occurred in a nonlymphan-
giogram-staged IIE patient currently alive with disease in
abdominal lymph nodes at 48 months following initial
evaluation.
Although the number of our patients with tonsillar
diffuse LCL in each therapeutic group are too small for
statistical analysis, combined treatment with radiation
and chemotherapy appears indicated for Stage IIE pa-
tients, while radiation alone might be adequate for Stage
IE patients. In previous series of patients with malignant
lymphomas of the t ~ n s i l , ' ~Waldeyer's
.'~ ring,',3',32 head
and n e ~ k , " . ' ~and
.~~localized extranodal sites,"" treated
from 1941 through 1976, radiation alone had been the
mainstay of treatment. More recent work dealing with
the therapy of localized diffuse LCL in all sites has sug-
gested that radiotherapy alone may be adequate for small
lesions, especially extranodal lymphoma of the head and
neck. However, for Stage I1 disease, particularly if bulky,
combination chemotherapy, followed by radiotherapy, is
recom mended.4"
Fifty percent ( 18) of the patients with relapsing disease
in this study presented within the first year following
admission, and 67% (24) within the first 2 years. The 24
patients within this group were equally divided between
those who had and those who had not undergone lym-
phangiography, but only two of them were Stage IE, one
each in the lymphangiogram and nonlymphangiogram-
staged groups. Comparable intervals to progression of
disease have been published previously for similar groups
of patient^.','.'".'^ Relapsing disease in this study was a
very poor prognostic sign as in previous studies. 1".27.32.3y
The majority of patients (77%) died from their disease.
Fifty percent of the initial relapse sites were within non-
irradiated lymph-node-bearing areas, with abdominal
lymph nodes the most common site. The gastrointestinal
tract was the location of 12% of the initial relapses ( 5
patients). In other series, the most common patterns of
new disease have been dissemination in 50'30,~~ nonir-
radiated lymph-node-bearing areas in 46% to 67%,9.3'and
extranodal sites in 58% to 78%1'0~14 of the relapses. New
disease in the gastrointestinal tract has been reported to
comprise 6.5% to 20% of initial relapse^^^'^^^'^" following
therapy of lymphoma arising in Waldeyer's ring. Local
failures (Waldeyer's ring and/or cervical lymph nodes)
occurred in nine patients (14%), presenting as the first
manifestation of new disease in seven patients. Previously
reported local failure rates following radiotherapy have
ranged from 0%34to 16%.'3,32.39
The results of therapy given to patients with relapsing
disease has been disappointing, though experience is lim-
Vol. 53
ited. Only 3 of 22 patients (14%) with recurrent disease
in whom the specific therapy given is known, are currently
without evidence of disease. All three of these patients
received CHOP-Bleo either alone or with the addition of
irradiation or cytosine arabinoside. Three other patients
who are currently alive with disease received similar che-
motherapy protocols. All patients whose initial relapse
was treated with irradiation or single-agent chemotherapy
alone are dead of disease.
REFERENCES
I . Freeman C. Berg JW. Cutler SJ. Occurrence and prognosis of
extranodal lymphomas. Cuncer 1972: 29:252-260.
2. Luetje CM. Erickson C. Current management of non-Hodgkin's
malignant lymphoma of the head and neck. Arch O~oluryngol1975;
101:l 1-14.
3. Rudders RA, Ross ME, DeLellis RA. Primary extranodal lym-
phoma: Response to treatment and factors influencing prognosis. Cunwr
1978: 42:406-416.
4. Jones SE, Fuks 2, Bull M el ul. Non-Hodgkin's lymphomas: IV.
Clinicopathologic correlation in 405 cases. Cunccv 1973; 3 I :806-823.
5. Ree HJ, Rege VB. Knisley RE el al. Malignant lymphoma of
Waldeyer's ring following gastrointestinal lymphoma. Cuncer 1980;
46: 1528-1 535.
6. Robinson T, Fischer JJ, Vera R. Reticulum cell sarcoma treated
by radiation. Radiology 197 I : 99:669-675.
7. Rosenberg SA. Diamond HD, Jaslowitz B. Craver LF. Lympho-
sarcoma: A review of I269 cases. Medicine I96 I : 40:3 1-84.
8. Tokunaga M, Sato E. Non-Hodgkins' lymphomas in a southern
prefecture in Japan: An analysis of 7 15 cases. Cuncer 1980: 46: I23 I -
1239.
9. Banfi A, Bonadonna G. Ricci SB el ul. Malignant lymphomas of
Waldeyer's ring: Natural history with survival after radiotherapy. Br
Med J 1972; 3:140-143.
10. Brugere J, Schlienger M, Gerard-Marchant R, Tubiana M, Pouil-
lart P. Cachin Y. Non-Hodgkin's malignant lymphomata of upper diges-
tive and respiratory tract: Natural history and results of radiotherapy.
Br J C'uncer 1975: 3I(Suppl I1):435-440.
I I . Catlin D. Lymphosarcoma of the head and neck. Am J Roenigenol
1948: 59:354-358.
12. Cortez EA, Mattox DE, Holt G R , Gates GA. Unilateral tonsillar
enlargement. Otolaryngol Head Neck Slug 1979: 87:707-7 16.
13. Terz JJ, F a n HW. Primary lymphosarcoma of tonsil. Surgery
1969: 65:772-776.
14. Banfi A, Bonadonna G, Carnevali G , Molinari R. Monfardini S.
Salvini E. Lymphoreticular sarcomas with primary involvement of Wal-
deyer's ring: Clinical evaluation of 225 cases. Cancer 1970: 26:341-351.
15. Fuller LM. Results of intensive regional radiation therapy in the
treatment of Hodgkin's disease and the malignant lymphomas of the
head and neck. Am J Romlgi,nol Radium Thrr h"rc.1 .Wed 1967: 99:340-
351.
16. McNelis FL, Pai VT. Malignant lymphoma ofthe head and neck.
Luryngo.rcope 1969: 79: 1076- 1087.
17. Todd GB. Michaels L. Hodgkin's disease involving Waldeyer's
lymphoid ring. Cuncer 1974: 34: 1769-1 778.
18. Carbone PP. Kaplan HS, Musshoff K, Smithers DW, Tubiana
M. Report of the committee on Hodgkin's disease staging classification.
Cuncer Res 197 1 : 3 I : 1860- I86 I .
19. The non-Hodgkin's lymphoma pathologic classification project:
National Cancer Institute sponsored study of classifications of non-
Hodgkin's lymphomas. Summary and description of a working for-
mulation for clinical usage. Cuncer 1982: 49:2 I 12-21 35.
20. Kaplan EL, Meier P. Nonparametric estimation from incomplete
observations. J A m Siul .Is.soc 1958; 53:457-482.
2 I . Gehan EA. A generalized Wilcoxon test for comparing arbitrary
singly censored samples. Biometriku 1965: 52203-223.
22. Maurer R. Taylor CR, Parker JW. Cramer A. Lukes RJ. lm-
No. I TONSILLAR
LYMPHOMAS *
munoblastic sarcoma: Morphologic criteria and the distinction of B and
T-cell types. Oncology 1982; 39:42-50.
23. Palutke M. Tabaczka P, Weise RW i’i a/. T-cell lymphomas of
large cell type. A variety of malignant lymphomas: “Histiocytic” and
mixed lymphocytic-”histiocytic.” Cunwr 1980: 46:87-101.
24. Stein H. TolksdorfG. Lennert K. T-cell lymphomas: A cell origin-
related classification on the basis of cytologic. immunologic. and enzyme
cytochemical criteria. Puihol Rex Pruct 1981; 171:197-215.
25. Waldron JA. Leech JH. Click AD, Flexner JM. Collins RD.
Malignant lymphoma of peripheral T-lymphocyte origin: Immunologic.
pathologic. and clinical features in six patients. Cuncw 1977;40:1604-
1617.
26. Bailey BJ. Brindley PC. Manifestations of malignant lymphomas
in the head and neck. Trans ,4171 Acud Ophrhulmol Otoluryngol 1970;
74:283-290.
27. Al-Saleem T, Hanvick R. Robbins R, Blady JV. Malignant lym-
phomas of the pharynx. Cuncer 1970: 26:1383-1387.
28. Yeh S. A histological classification of carcinomas of the naso-
pharynx with a critical review as to the existence of lymphoepitheliomas.
Cancer 1962: 15:895-920.
29. Griffler RF. Gillespie JJ. Ayala AG. Newland JR. Lymphoepi-
thelioma in cervical lymph nodes of children and young adults. Am J
Slug Puihol 1977: 1 :293-302.
30. Banfi A. Bonadonna G. Carnevali G . Oldini C, Salvini E. Pref-
erential sites of involvement and spread in malignant lymphomas. Eitr
J Cunccv 1968: 4:319-324.
31. Hoppe RT. Burke JS. Glatstein E. Kaplan HS. Non-Hodgkin’s
Barton et al. 95
lymphoma: Involvement of Waldeyer’s ring. Chnccr 1978; 42:1096-
1104.
32. Wang CC.Malignant lymphoma of Waldeyer’s ring. Radiology
1969;92:1335-1339.
33. Wong DS. Fuller LM, Butler JJ. Shullenberger CC. Extranodal
non-Hodgkin’s lymphomas of the head and neck. Am J Roenrgenol
Rudiitrn Ther Nucl Mrd 1975; 12347 1-481.
34. Shanmugham MS. Malignant lymphoma of the faucial tonsil. J
Lurjngol 0101 1978;92:357-359.
35. Fuks Z.Glatstein E, Kaplan HS. Patterns of presentation and
relapse in the non-Hodgkin’s lymphomata. Br J Cuncer 1975;3 I(Suppl
I I ):286-297.
36. Peckham MJ. Guay JP, Hamlin IME, Lukes RJ. Survival in
localized nodal and extranodal non-Hodgkin’s lymphomata. Br J Cuncer
1975: 3I(Suppl 11):413-424.
37. Miller TP, Jones SE. Chemotherapy of localized histiocytic lym-
phoma. Luncci 1979; 1:358-360.
38. Cabanilkas F. Bodey GP, Freireich EJ. Management with che-
motherapy only of Stage I and I1 malignant lymphoma of aggressive
histologic types. Cuncer 1980;46:2356-2359.
39. Van Der Werf-Messing B. Reticulum cell sarcoma and lympho-
sarcoma: A retrospective study of potential survival in locoregional dis-
ease. Eitr J Cancer 1968;4349-557.
40. Lester JN, Fuller LM, Conrad FG el ul. The roles of staging
laparotomy, chemotherapy, and radiotherapy in the management of
localized diffuse large cell lymphoma: A study of 75 patients. Cancer
1982;49:1746-1753.