Acta Oncologica

ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: https://www.tandfonline.com/loi/ionc20

Treatment of Lethal Midline Granuloma Type

Nasal T-Cell Lymphoma

Kohichi Sakata, Masato Hareyama, Atushi Ohuchi, Mitsuo Sido, Hisayasu

Nagakura, Kazuo Morita, Yasuaki Harabuchi & Akikatsu Kataura

To cite this article: Kohichi Sakata, Masato Hareyama, Atushi Ohuchi, Mitsuo Sido, Hisayasu
Nagakura, Kazuo Morita, Yasuaki Harabuchi & Akikatsu Kataura (1997) Treatment of Lethal
Midline Granuloma Type Nasal T-Cell Lymphoma, Acta Oncologica, 36:3, 307-311, DOI:
10.3109/02841869709001268

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 ORIGINAL ARTICLE

Treatment of Lethal Midline Granuloma Type

Nasal T-cell Lymphoma
Koh-ichi Sakata, Masato Hareyama, Atushi Ohuchi, Mitsuo Sido, Hisayasu Nagakura,
Kazuo Morita, Yasuaki Harabuchi and Akikatsu Kataura

Department of Radiology (K. Sakata, M. Hareyama, A. Ohuchi, M. Sido, H. Nagakura, K. Morita),

Department of Otolaryngology (Y. Harabuchi, A. Kataura), Sapporo Medical University, School of Medicine,
Sapporo, Japan

Correspondence to: Dr Koh-ichi Sakata, Department of Radiology, Sapporo Medical University, School of
Medicine, SlW16, Chuo-Ku, Sapporo, 060, Japan, Fax: 011-81-11-613-9920, Tel: 011-81-11-611-2111
(ext. 3535).

Acta Oncologica Vol 36, No. 3. pp. 307-311, 1997

Nasal T-cell lymphoma of the LMG type (LMG-NTL) is characterized by progressive, unrelenting ulceration, and necrosis of the nasal
cavity and midline facial tissues. The clinical behavior of this tumor in 16 patients is compared with that of a nasal lymphoma of
non-LMG-NTL type (non-LMG-NTL) in 8 patients and a paranasal sinus lymphoma (PSL) in 6 patients. All patients had stage I or I1
disease. Fourteen of the 16 patients with LMG-NTL received chemotherapy before and/or after radiotherapy. Cause-specific 5-year
survival rates for patients with LMG-NTL, non-LMG-NTL, and PSL were 22%, 75%, and 67'%, respectively. Seven patients with
LMG-NTL, had complete response, although 3 recurred, whereas it was incomplete in 9 patients. The data indicates that it is desirable
to deliver 50 Gy or more to achieve in-field control of LMG-NTL.
Rewired 16 April 1996
Accepted 12 January 1997

Lethal midline granuloma (LMG) (1) is characterized by
progressive, unrelenting ulceration, and necrosis of the
nasal cavity and midline facial tissues. Histologically,
L M G is characterized by angiocentric, polymorphorous
lymphoreticular infiltrates, and termed polymorphic reticu-
losis (2). On the basis of phenotypic analysis. several
investigators have demonstrated that L M G is a peripheral
T-cell lymphoma, and the term nasal T-cell lymphoma of
the LMG type (LMG-NTL) has since been widely used.
Recently, expression of the natural killer (NK) cell marker
CD56 on tumor cells has been reported in some cases (3).
Although progress in understanding the biologic nature
of LMG-NTL and in its diagnosis has been achieved, there
is little information about the optimal treatment for this
disease. Several reports have described the treatment re-
sults (4-7). However, as with reports on all rare lesions,
these are limited by the small number of cases and varied
treatment methods involved. N o single report contains the
information necessary to devise a definitive treatment.
Therefore, the accumulated experiences of various institu-
tions may be useful in devising more effective treatments.
This paper reviews the results of our treatment of LMG-
NTL compared with nasal lymphoma of non-NTL-LMG
type (non-LMG-NTL) that makes tumor mass and with
paranasal sinuses lymphoma (PSL).
MATERIAL AND METHODS
A total of 30 patients, 16 patients (10 men, 6 women) with
LMG-NTL, 8 patients (4 men. 4 women) with non-LMG-
NTL and 6 patients (4 males, 2 females) with PSL were
treated with radiation therapy at the Department of Radi-
ology, Sapporo Medical University, between January 1975
and December 1994. Patient ages ranged from 27 to 71
years with a mean of 46 years in cases of LMG-NTL, from
35 to 73 years with a mean of 54 years in cases of
non-LMG-NTL, and from 51 to 73 years with a mean of
63 years in cases of PSL. Patients with LMG-NTL were
diagnosed clinically and histopathologically.
All surviving patients except one had a minimum follow-
up of 3 years and median follow-up period was 72 months
(range 14- 137 months). Pertinent clinical information and
follow-up data were obtained from hospital charts for all
cases. The clinical records of each patient were reviewed for
type and duration of symptoms, initial sites, and involve-
ment of distant sites discovered during the clinical course.

8 Scandinavian University Press 1997. ISSN 0284-186X Acta Oticologica

308 K.-I. Sakata et al.
The clinical stage as defined according to the Ann Arbor
system (8) was assessed by physical examination, gallium-
67 (67Ga),technetium 99 m egmTc)scintiscans, computer-
ized tomography, lymphangiograms, roentgenographic
and fiberscopic examination of the gastrointestinal tract,
and bone marrow aspiration.
Radiation therapy was performed with 6oCo.The radia-
tion portal encompassed only clinically involved areas with
a generous margin (involved field radiation therapy,
IFRT) in 24 patients and prophylactic irradiation in the
neck and supraclavicular lymph nodes in 6 patients. For
nasal lymphomas, 8 patients were treated with a single
anterior portal, 7 patients with an anteroposterior portal,
and 9 patients with parallel opposed lateral fields. For
PSL, a single anterior portal or a pair of wedge filtered
portals using anterior and lateral fields was the main
irradiation technique. Doses reported refer to the absorbed
dose at 5 cm depth from the surface, calculated at the
central axis. The fractional dose ranged from 1.5 to 3 Gy.
Irradiation was performed 5 times a week. Continuous
course therapy was given in 25 cases and split-course
therapy in 5. The median dose received was 40 Gy (range
9-74 Gy) and the median TDF (time-dose-fractionation)
delivered was 63.3 (range 13.7-103.5). The radiation doses
were heterogeneous since the radiation was interrupted in
2 patients due to deterioration of general condition and
the standard radiation dose was increased from 40 to 50
Gy as of 1990. In this series, patients were treated with
different fraction sizes, and some patients had treatment
breaks. In order to take these factors into account we used
TDF derivation (12).
One or two courses of VEPA chemotherapy (vincristine
(1 mg/m2 i.v. days 1, 8, 15, 22), cyclophosphamide (500
mg/body, i.v. days 1, 8, 15, 22), prednisolone (50 mg/m2
P.o., days 1-3, 8-10, 15-17, 22-24), and doxorubicin (20
mg/body i.v., days 2, 9, 16, 23)) (9) were delivered to the
patients with non-LMG-NTL after radiotherapy and to
the patients with PSL before radiotherapy. For patients
with LMG-NTL, there were changes in chemotherapy
regimen used, Between 1975 and 1981, one patient was
treated with CVP (cyclophosphamide (500 mg/m2 i.v., day
l), vincristine (1 mg/m2 i.v., day I), prednisolone (50 mg
P.o., days 1-3)), one with VEMP (vincristine (1 mg/m2
i.v., day I), cyclophosphamide (100 mg/m2 i.v., days 1, 2),
6-mercaptopurine (100 mg/m2 i.v., days 1, 2) prednisolone
(40 mg P.o., days 1-3)) after radiotherapy, and two with
radiotherapy alone. From 1982 to 1986, all three LMG-
NTL patients were treated with VEPA before radiother-
apy. As of 1987, 10 of 11 patients with LMG-NTL were
treated with two courses of MACOP-P (vincristine (1.2
mg/m2 i.v., days 8, 22), cyclophosphamide (350 mg/m2 i.v.,
days 1, 15), prednisolone (40 mg/m2 P.o., dose tapered to
10 mg/m2 every week, weeks 1-4), doxorubicin (50 mg/m2
i.v., days 1, 15), methotrexate (400 mg/m2 i.v., day 8),
pepleomycin (10 mg/m2 i.v., day 22)) or MEPP (mitox-
Acta Oncologica 36 (1997)
antrone (8 mg/m2 i.v., day l), etoposide (140 mg/m2 i.v.,
days 1, 3, 5 ) , cisplatin (20 mg/m2 i.v., days 1-5), pred-
nisolone (40 mg/m2 P.o., days 1-5)) (f8) before and after
radiotherapy. In MACOP-P regimen, pepleomycin was
used instead of bleomycin and only the first 4 weeks of
MACOP-B (17) regimen were administered.
The date of diagnosis was the date of biopsy confirma-
tion of disease, and survival was calculated from this date
to the time of death or last follow-up. Survival was
calculated by the Kaplan-Meier method (10). Differences
were analyzed by the generalized Wilcoxon test.
RESULTS
Histologic jindings
Biopsies from LMG-NTL patients showed diffuse
infiltrates of pleomorphic large lymphoid cells and atypical
small lymphoid cells with frequent mitotic figures, admixed
with a large number of inflammatory cells such as granulo-
cytes, macrophages, and plasma cells. Extensive ischemic
necrosis was the common characteristic of these lesions.
Angiocentric and/or angioinvasive infiltrates were also
prominent. The pathologic subtypes according to the
Working Formulation System of the National Cancer
Institute (1 1) are shown in Table 1 .
All 16 patients with LMG-NTL had tumors of T-cell
origin. Four non-LMG-NTL had tumors of B-cell origin
and four had T-cell derived tumors. All 6 patients with
PSL had a B-cell phenotype.
Symptoms
In cases of LMG-NTL, systemic symptoms such as pro-
longed fever and weight loss, and local symptoms such as
nasal obstruction and/or bloody rhinorrhea were common
at the time of diagnosis (Table 2). Systemic symptoms
were much more common in LMG-NTL than in the other
subtypes.
*' 1 2 3 4 5 6 7 8 9 1'0
Years
Fig. I . Disease-specific survival rates: 1-( LMG-NTL; (---)
non-LMG-NTL; (-) PSL.
Acta Oncologica 36 (1997) Nasal T-cell lymphoma 309

Table I non-LMG-NTL, the response to therapy was complete in

Stage and pathology of' patients with LMG-NTL, non-LMG-NTL. all 8 patients with only one recurrence after 40 months. In
or PSL 6 patients with PSL, the response to therapy was complete
in 4 patients.
*LMG-NTL non-LMG-NTL **PSL Fig. 2 shows the relationship between TDF values at 5
Stage cm from the skin and complete remission rates. It appears
I 10 7 5 as if LMG-NTL may require a TDF of 80 o r more for
I1 6 1 I remission. In contrast, all 7 patients with non-LMG-NTL
*Pathology obtained remission with T D F values ranging from 37 to
Diffuse, 7 0 6 65.
large cell
Diffuse, 9 3 0
mixed Salvage treatment
Diffuse, 0 3 0
small cleaved Three patients with LMG-NTL who had recurrences were
Large cell, 0 1 0 re-treated with combination chemotherapy and radiother-
immunoblastic apy. However, the responses were poor and all three
* According to the Working Formulation System of the National patients died of relapse or dissemination within 7 months
Cancer Institute (1 I). from recurrence.
One patient with non-LMG-NTL who had local recur-
Cause -speciJic survival rence was re-irradiated; this patient's disease has been
Cause-specific 5-year survival rates for patients with controlled for 32 months.
LMG-NTL, non-LMG-NTL, and PSL were 22%, 75%
and 67% respectively (Fig. 1). The survival rates for pa- Distant involvement
tients with LMG-NTL were significantly poorer than those
The most common distant sites involved in the 12 recur-
for patients with non-LMG-NTL or PSL (p<O.OI).
rent patients with LMG-NTL were lymph nodes (n = 1l),
Twelve LMG-NTL patients died of relapse and disseniina-
lungs (n = I I), liver and/or spleen (n = 9), skin (n = 8), and
tion to distant sites after a median of 6 months (range 1 to
gastrointestinal tract (n = 5). Only 2 patients had bone
31 months). The causes of death was distant involvement
marrow involvement.
without local recurrence in two patients with non-LMG-
Of both patients with non-LMG-NTL who died of the
NTL. In PSL, one patient died of uncontrolled local
disease, one had bone, skin, and nasopharyngeal involve-
disease and two died of distant involvement.
ment, while the other had paraaortic lymph node involve-
Sex appeared to relate to the prognosis of LMG-NTL,
ment.
although the difference between sexes was not significant.
Of 2 of 3 patients with PSL who died of the disease, one
Three of 5 women with LMG-NTL survived more than 30
had bone and pleural involvement, while the other had lung,
months, whereas, the longest survival time for the men was
stomach, spleen, and paraaortic lymph node involvement.
14 months.

Complications
Local control
Leukopenia was the most common complication in pa-
In 16 patients with LMG-NTL, 7 patients had a complete
tients who received chemotherapy but this was not life-
response. Three of these recurred locally. In patients with
threatening. N o important neurological, renal, hepatic, or
Table 2 pulmonary toxicity was seen. N o treatment-related death
occurred.
Presenting symptoms of patients with LMG-NTL, non-LMG-NTL,
or PSL
DISCUSSION
*LMG-NTL non-LMG-NTL **PSL
The unique clinical characteristics in LMG-NTL were
Fever 14/16 (88%) 2/8 (25%) 0/6 (O'%I) noted in this series. Patients with LMG-NTL were signifi-
Weight loss 14/16 (88%) I/8 (13%)) 0/6 (0%) cantly younger than the other patients. This tendency has
***Nasal 13/16 (81%) 8/8 (loo'%!) 1/6 (17%) been found in other series too (6, 7). Better survival of
symptoms
women compared with that of men were also noted.
Cheek 12/16 (75Yu) 0/8 (OYu) 5/6 (83%)
swelling Although Smalley et al. (6) have reported a similar finding,
Sore throat 5/16 (31%) 0/8 (0%) 0/6 (0%) the reason for the apparently better survival in women
* Nasal T-cell lymphoma of the lethal midline granuloma type. remains unknown.
** Paranasal sinus lymphoma. LMG-NTL had more stage I1 disease and the clinical
*** These include nasal obstruction and bloody rhinorrhea. behavior of LMG-NTL was aggressive, and experience
3 10 K. -I. Sakata et al. Acta Oncologica 36 (1997)

A) 3)
120 120

I00 I00

80 I 80

5 5
Ln

i.
vl
Z @ p 60
Ll. U
0
2 e
40 4c

20 m 2c
B

0 c
No Yes No Yes No Yes
Remission Remission Remission
Fig. 2. Relationship between TDF values at 5 cm from the skin and local remission rates for A) non-LMG-NTL,B) LMG-NTL and C)
PSL. Three patients with LMG-NTL and one patient with non-LMG-NTL developed subsequent recurrences.

suggests that a negative lymphoma work-up for this partic-
ular extranodal lymphoma is certainly no indication of the
disease not being disseminated. Thus, LMG-NTL has a
much poorer prognosis than non-LMG-NTL or PSL, al-
though LMG-NTL develops in anatomic structures similar
to those giving rise to these other disorders.
It appears that a TDF of at least 80 is necessary to
achieve in-field disease control of LMG-NTL (Fig. 2). This
corresponds to 50 Gy (2 Gy/fraction, 5 fractions/week
given daily in a continuous fashion) which contrasts with
the radiosensitivity of non-LMG-NTL and PSL. In this
regard, LMG-NTL should be considered to be a different
entity from non-LMG-NTL from the position of radio-
therapy. The cause of this difference in radiosensitivity
remains unknown. Differences in cell lineage cannot be the
reason because tumors in 4 patients with non-LMG-NTL
were of T-cell origin.
During the period covered here, the total dose of radia-
tion used for treatment of LMG-NTL has increased and
the chemotherapy regimen used has also been more intense.
The results shown in Table 3 demonstrate that increments
in the radiation dose appear to have had a greater impact
on induction of remission than chemotherapy.
It is important to make a definitive diagnosis of
LMG-NTL and select treatments suitable for LMG-
NTL. Nonspecific nasal complaints and cheek swelling
are often reported prior to the diagnosis of LMG-NTL,
and severe constitutional symptoms, such as prolonged
fever unresponsive to antibiotics and weight loss are
characteristic (Table 2). However, histologic confirmation
is indispensable. Angiodestruction and necrosis are char-
acteristic for LMG-NTL. Of importance is also to demon-
strate diffuse infiltration of cells with T-cell-surface mark-
ers. Genotypic analysis by Southern blotting typically
discloses a clonal rearrangement of the beta T-cell receptor
gene in many cases (19). It is important to distinguish
LMG-NTL from Wegener's granulomatosis which is char-
acterized by necrotizing granulomas and vasculitis, and
associated with glomerulonephritis. Antineutrophil cyto-
plasmic antibodies (C-ANCA) are present in patiens with
Wegener's granulomatosis, which is useful in diagnosis
(20).

Table 3
The relationship among TDF values, drug combinations and induction of remission

TDF values

80 > 80 I Total

Drug combinations
None 0% (0/3) 0% (0/3)
CHOP, COPP, VEMP *25% (1/4) *100% ( l / l ) 40Yu ( 2 / 5 )
MACOPP, MEPP 25%) (1/4) **100%1 (4/4) 63% ( 5 / 8 )
Totdl 18% (2/11) 100Y" ( 5 / 5 ) 44% (7/16)
* This patient had recurrence and died of disease.
** One of them had recurrence and died of disease.
Acia Oncofogica 36 ( 1997)
There are discrepancies in the rates of local control of
L M G - N T L achieved with radiotherapy between different
series. Sobrevilla-Calvo et al. (7) have reported a complete
response rate of 74Yn with a median dose of 45.8 G y (range
3.6-60 G y ) of primary local irradiation. Also other series
have reported that L M G - N T L is potentially controllable
with a median dose of 40 t o 46 G y (4, 6, 13). In contrast,
Itami et al. (5) have reported that only 3 of 9 patients with
L M G - N T L could be induced into long-term remission
with a median dose of 41.4 G y (range 21-60 Gy). O u r
study also shows poor local control. Although the differ-
ence of prognosis of LMG-NTL might depend on geo-
graphic o r racial differences, there might be other reasons.
Sobrevilla-Calvo et al. (7) and others (4, 6, 13) did not use
immunohistochemistry in biopsy materials whereas we and
Itami et al. ( 5 ) used it in all patients. W e think that
findings by the hematoxylin-eosin stained sections are not
enough in the definitive diagnosis of LMG-NTL.
Frequent dissemination into systemic disease has also
been reported in EBV-associated T-cell lymphoma (14,
15). Interestingly in o u r series, bone marrow infiltration
developed only in 2 cases and leukemic changes were never
seen. This clinical feature seems to b e distinct from that of
T-lymphotrophic retrovirus type 1 associated adult T-cell
lymphoma, in which bone marrow infitrates and leukemic
changes are common and may represent a unique homing
nature of the L M G - N T L cells (16).
I n conclusion, the cause-specific survival rate for L M G -
N T L is significantly poorer than those for non-LMG-NTL
o r PSL. LMG-NTL is much more aggressive and more
radioresistant, and tends to cause disseminate widely.
L M G - N T L should be considered to be a different entity
from non-LMG-NTL from the treatment’s point of view.
It is desirable to deliver 50 G y or more t o achieve in-field
disease control of LMG-NTL. A t present, we use the dose
of 60 G y and more intensive chemotherapy regimens, such
as MACOP-P o r MEPP, with two courses of these admin-
istered before and after radiotherapy to improve the prog-
nosis of patients with LMG-NTL.
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