Copyright
0360.3016/91 $3.00 + .oO 0 I99 I Pergamon Press plc
0 Brief Communication NON-HODGKIN’S LYMPHOMA CONFINED TO THE NASAL CAVITY: ITS RELATIONSHIP TO THE POLYMORPHIC RETICULOSIS AND RESULTS OF RADIATION THERAPY JUN
ITAMI,
M.D.,* TOSHIO
MAKIKO KANEKO,
ITAMI,
M.D.,’
M.D.,*
HITOSHI
ATSUO
AND NOBORU
MIKATA,
OGATA,
M.D.,+
M.D.,*
ARIMIZU,
JUN-ICHI
KIMIICHI
TAMARU,
UNO,
M.D.,+
M.D.*
M.D.*
Chiba University School of Medicine, Inohana I -8- 1, Chiba, 280 Japan. From 1975 through 1988, nine patients with locally confined nasal non-Hodgkin’s lymphoma (NHL) were treated with radiation therapy in the Department of Radiology, Chiba University Hospital. Immunohistochemical study disclosed that all NHL’s have T-lineage. Additionally, unique histological pictures of polymorphism, angiodestruction, and necrosis were seen in most of cases. These three findings are the histological features of polymorphic reticulosis (PMR), which is the main cause of lethal midline granuloma and has recently been shown to belong to T-cell malignancy. Therefore, it is concluded that the nasal T-cell NHL and PMR are really a single disease entity. The predominance of the T-cell lymphoma in the nasal cavity as well as its histological distinctness clearly indicate that the head and neck extranodal NHL cannot be discussed together. Although the disorder was considered to be locally limited at presentation, only 3 of the 9 patients with nasal NHL could be induced into long-term remission with involved field radiotherapy. The distant extranodal spread was the primary cause of failure. Multimodality treatment using intensive chemotherapy might improve the prognosis of nasal NHL. Non-Hodgkin’s
lymphoma,
Nasal cavity, Radiation therapy, Polymorphic reticulosis.
and necrosis (5, 6, 11, 17). Recent advances in immunohistopathology have obviously shown that PMR is an unusual type of lymphoma with T-cell lineage ( 12, 16). However, the pathological as well as clinical relationship of PMR and the conventional NHL remains largely unresolved. We, therefore, reviewed NHL patients with lesion confined to the intrinsic nasal cavity who were treated in the Department of Radiology, Chiba University Hospital to investigate its pathological and clinical features. We also compared the pathological findings and clinical behaviors of the NHL’s in this study to those of reported series on PMR’s (4-6, 17).
INTRODUCTION Because of the rare occurrence of non-Hodgkin’s lymphoma (NHL) in the nasal cavity, its pathological and clinical features are far from being clearly defined. Furthermore, the anatomical neighborhood ofthe nasal cavity and the paranasal sinuses often causes difficulty in determining the precise origin of locally advanced NHL, so that most series have reported NHL in the nasal cavity and the paranasal sinuses together (2,7,8, 15,20-22,25). However, there is controversy as to whether NHL’s in the nasal cavity and the paranasal sinuses show similar clinical behavior and can be discussed as a single entity (23). Polymorphic reticulosis (PMR), or midline malignant reticulosis, is one of the major causes of lethal midline granuloma in the nasal cavity. PMR was formerly classified as a non-lymphomatous lesion which was, however, considered to be closely related to lymphoma (5, 6, 17). PMR is pathologically characterized by the presence of polymorphic lymphoreticular infiltrate, angiodestruction,
* Dept. + Dept. * Dept. Reprint
of Radiology. of Pathology. of Otorhinolaryngology. requests to: Jun Itami, M.D., Department
diology, Chiba University Chiba, 280 Japan.
School of Medicine,
Inohana
METHODS
AND
MATERIALS
From 1975 through 1988, 12 patients with NHL in the nasal cavity were referred to the Department of Radiology, Chiba University Hospital, for radiation therapy. Three
Acknowledgements-The
technical Azuma. of RaI-8-1,
Accepted
797
assistance
authors gratefully acknowledge the of Toshifumi Umemiya and Kazuhiro
for publication
8 October
1990.
I. J. Radiation
798
Fig. 1. Computed tomography of the intrinsic nasal cavity. The tumor in the septum and protrudes into the although there is no invasion of the
Oncology
0 Biology 0 Physics
April 1991, Volume
20. Number
4
nasal NHL confined to the the left nasal cavity erodes contralateral nasal cavity. antrum.
Fig. 2. Polymorphism found in NHL ofthe nasal cavity. Tumor cells are of various size and with bizarre nuclei and there is marked infiltration of histiocytes. eosinophils, and plasma cells (Hematoxylin-Eosin, X 132).
of the I2 patients were excluded from the study because of paranasal extension and extrafacial nodal and/or extranodal involvement at initial presentation. The remaining nine patients showed disease confined to the nasal cavity without radiological evidence of paranasal extension (Fig. 1). The male to female ratio of the nine patients was 5:4 with a mean age of 55 years (range 31 to 76). In the 14-year period of this study. the staging procedures varied greatly. All nine patients underwent physical examination including special ENT mirror examinations, chest X rays, and special x-ray studies including polytomographies and complete blood counts with biochemistry. Lymphography was performed in only two patients; Ga scintigraphy was performed in six patients with negative results except in the nasal cavity. Bone marrow biopsy and/or aspiration did not show involvement in four patients. Abdominal involvement was also ruled out by CT in five patients. All nine patients were diagnosed as clinical Stage I according to Ann-Arbor classification (3). The hematoxylin-eosin stained sections were reviewed by an experienced hematopathologist (AM) and all cases were confirmed as NHL and classified according to the Working Formulation for clinical usage (WF) (24). To compare the pathological features of NHL and PMR. each material was further reviewed, taking into consideration the presence of polymorphism (Fig. 2). angiodestruction (Fig. 3) and necrosis (Fig. 4). The formalin-fixed paraffin-embedded tissue blocks were resectioned and re-stained by the avidin-biotin-peroxidase complex (ABC) method ( 10) using a series of monoclonal antibodies: UCHLl* and MT 1’ for T-cell markers, L26* and MB It for B-cell markers. Three patients were initially treated by local application of steroid and/or per oral steroid with no response and secondarily referred for radiation therapy. All nine patients
were treated with radiation therapy using megavoltage photons (6”Co or 10 MV X rays with appropriate bolus) or high-energy electrons (15 MeV or 18 MeV). of which three underwent combination chemotherapy simultaneously. The radiation portal encompassed only clinically involved area with a generous margin (involved field radiation therapy = IFRT). In six patients, single anterior portal to the nasal cavity was used and the remaining three were treated by lateral opposing fields with an additional anteroposterior portal. Prophylactic irradiation to the neck lymph nodes was not performed. The radiation dose ranged from 2 1 Gy to 60 Gy with a mean of 4 1.4 Gy. In all patients, a conventional fractionation scheme with a weekly dose of 5 X 2 Gy was used. The combination chemotherapy was not an intensive regimen and consisted of weekly vincristine iv (1 mg/week) and daily per oral cyclophosphamide (50 mg/day), 6-mercaptopurine (50 mg/day), and prednisone (VEMP) ( 14).
* DAK0
Japan,
Kyoto, Japan.
RESULTS The presenting symptoms of the nine patients with NHL originating in the nasal cavity are shown in Table 1. Nasal obstruction was seen in all patients, of whom seven complained of unilateral obstruction. Persistent fever up to 38°C was recognized in four patients, which was followed in frequency by the swelling of the ala nasi in three patients. The interval from the onset of symptoms to the first hospital visit ranged from 2 months to 3 years (mean 6 months). Three patients had a longstanding history of chronic nasal obstruction with purulent discharge. The initial involved sites in the nasal cavity are demonstrated in Table 2. The inferior turbinate was the most frequent primary site (seven patients), whereas the nasal septum was involved in four patients at initial presenta-
+ Bioscience
Products
AG, Emmenbriicke,
Switzerland.
199
NHL in the nasal cavity 0 J. ITAMIPI a/
Fig. 3. Angiodestruction found in NHL of the nasal cavity. (a) The arterial wall is infiltrated by the lymphoid tumor cells (Hematoxylin-Eosin. X50). (b) The Elastica-staining clearly demonstrates the destruction of lamina elastica of the nasal artery and intraluminal tumor thrombosis (Elastica-staining, X33).
tion. The local findings were crust formation with underlying cartilage exposure in seven patients and slight swelling of the turbinate and/or septum in two patients. Histopathological review revealed that all cases belonged to NHL and their classification by WF is shown in Table 2. One patient showed immunoblastic histology, whereas two patients had diffuse large cell type, five had diffuse mixed small and large cell. and the remaining patient had diffuse small cleaved cell. The immunohistopathological studies using monoclonal antibodies revealed that all the nine patients had NHL with T-cell surface antigens demonstrated by the positive staining with UCHL 1 and/or MT 1. Concerning polymorphism, angiodestruction, and necrosis. all three findings were seen in four patients with nasal NHL (Table 2). The remaining five patients had at least one of the three findings. In contrast to the monomorphic infiltrate seen in the typical primary nodal NHL, infiltrating cells of the polymorphic lymphoma ofthe nasal cavity were not of uniform size and they were accompa-
nied by an infiltration of neutrophils, plasma cells, epithelioid histiocytes, and eosinophils (Fig. 2). In five patients, angiodestruction was demonstrated in which the arterial wall was infiltrated and destroyed by lymphoid cells and in some cases the lymphoid cells formed even tumor emboli in the involved arteries (Fig. 3). Only two patients remain presently without recurrence with follow-up lengths of 1 and 2 years, respectively (Table 3). In another patient (patient No. 4) late recurrence in the nasal cavity occurred 8.5 years after the initial treatment and second remission was attained with reirradiation in extended field. This patient has no evidence of disease at 4.5 years follow-up after the recurrence. The remaining six patients succumbed to recurrence with fatal outcome. All fatal recurrences occurred within 6 months after the initial treatment. The recurrence in the nasal cavity was seen in five patients, which was accompanied by other generalized extranodal recurrences. Involvement in the lung and skin was also seen frequently, whereas lymph node recurrence in the neck, which would be within extended radiation field, was observed in only one patient. The chemotherapy regimen used in three patients could not prevent recurrence.
Table 1. The presenting symptoms of the nine patients with non-Hodgkin’s lymphoma (NHL) in the nasal cavity Symptoms
Fig. 4. Widespread necrosis (below) found in NHL of the nasal cavity. In the neighboring region angiodestruction involving several arteries is also seen (above left) (Hematoxylin-Eosin, X25).
Nasal obstruction Bilateral Unilateral Fever Swelling of ala nasi Purulent discharge Night sweating Epistaxis 1975-1988, Hospital.
Department
No.
(%)
9 2 I 4 3 2 1
(100) (22) (78) (44) (33) (22) (11)
1
(11)
of Radiology,
Chiba
University
800
I.
J.
Radiation
Oncology 0
Biology 0 Physics
Table 2. Primary
non-Hodgkin’s
April 199 I. Volume
lymphoma
20. Number
4
in the nasal cavity Histological
Patient no.
Sex
Age
F M M F F M
40 31 59 51 53 76
I
F
51
8 9
M M
72 62
Primary
site
WF
Rt. inf. turb. Lt. inf. turb. Rt. inf. turb. Lt. inf. turb. Nasal septum Nasal septum, t-t. middle turb., rt. inf. turb. Nasal septum, It. inf. turb. Lt. inf. turb. Nasal septum, hard palate
Cell lineage
Polymorphism
dm dm dm dsc dl dl
Angiodestruction
+ + _ + + +
+ + + _ +
Necrosis
+ + + + +
dm
T
+
_
+
imb dm
T T
+ +
+
+ +
M = Male; F = Female: turb. = Turbinate: WF = Working formulation: cleaved; dl = Diffuse large; imb = Immunoblastic. I975- 1988, Department of Radiology, Chiba University Hospital.
DISCUSSION
dm = Diffuse mixed small and large; dsc = Diffuse small
contrasts in other
The study using a batch of monoclonal antibodies to T and B-cell surface antigens revealed that all nasal NHL’s in this report are derived from T lymphocyte. The predominance of T-cell lymphoma in the nasal cavity has also been reported by other investigators (26). This finding
Table 3. Primary
non-Hodgkin’s
with the frequent occurrence of B-cell lymphoma head and neck extranodal regions. such as in the
Waldeyer’s ring ( 19, 26). Additionally, the histological states of our patients with nasal NHL revealed distinct features with resemblance to the PMR. PMR is histologically characterized by the presence of polymorphic lymphoreticular infiltrate, angiodestruction, and necrosis. Its clinical features correspond most often with the lethal
lymphoma
in the nasal cavity
Radiotherapy Patient no.
features
Portal
Dose
Chemotherapy
Site of recurrence
I 2
IFRT IFRT
56 Gy 50 Gy
No No
3 4 5
IFRT IFRT IFRT
50 Gy 42 Gy 30 Gy
No No VEMP + 5-FU
6
IFRT
40 Gy
No+
7
IFRT
60 Gy
VEMP
8
IFRT
60 Gy
VEMP+
9
IFRT
21 Gy
No+
No Nasal cavity, lung, spleen No Nasal cavity Nasal cavity, brain, lung Nasal cavity. neck lymph node, lung Larynx, skin, inguinal lymph node Nasal cavity, lung, skin Nasal cavity. skin
Follow-up length (mos.) 10 II 23 154 3
Outcome NED DOD NED NED* DOD
4
DOD
6
DOD
2
DOD
15
DOD
* After the first recurrence, re-irradiation with extended field was performed and the second remission was obtained. + Radiation therapy and/or chemotherapy was instituted after the failure of initial treatment with steroid. IFRT = Involved field radiation therapy; NED = No evidence of disease; DOD = Dead of disease. 1975-1988, Department of Radiology, Chiba University Hospital.
NHL in the nasal cavity 0 J.
midline granuloma, with unrelenting course resulting in the destruction of midfacial structures when untreated ( 1, 4-6,8, 11, 17, 18). It has only recently been demonstrated that the atypical cells of the PMR are indeed derived from monoclonal malignant proliferation of T-lymphocytes and that PMR is a type of peripheral T-cell lymphoma (9, 12, 16). All nine cases examined in this study showed histological resemblance to PMR. Our observations are totally in accordance with the view that the nasal T-cell NHL and PMR constitute pathologically a single disease entity as peripheral T-cell NHL. The old literature had made a distinction between PMR and NHL presumably because of the lack of the recognition of the unique histological pictures of the peripheral T-cell lymphomas ( 12). The distinct histological characters of the nasal NHL as well as its T-cell origin may make it difficult to discuss together the nasal NHL and the other head and neck extranodal NHL, which is predominantly derived from Bcell. In our study diffuse mixed small and large cell lymphoma was observed most frequently, whereas the predominance of diffuse large cell lymphoma as well as immunoblastic lymphoma has been emphasized ( 15,20,2 I, 26). The reason for the difference is not clear, but the inclusion of the paranasal NHL in other series might provide an explanation. We confined this study to clinical Stage I patients with nasal NHL who had no radiological involvement of the paranasal sinuses. It remains controversial whether NHL primary to the nasal cavity and the paranasal sinuses has the same pathological features as well as a similar prognosis in spite of the anatomical neighborhood of both structures. Takenaka et al. emphasize more favorable prognosis of the nasal NHL (median survival 33 months) in comparison with the paranasal NHL (median survival 11 months) (23). It seems presently preferable to discuss them separately. The initial rhinoscopic findings of NHL of our series were also shown to be same with those of PMR. The exposure of the nasal cartilages and bony destruction by necrosis is the most common presenting signs of PMR (5, 6, 8, 17). Most of our patients with NHL had crusting on the nasal turbinate with underlying cartilage exposure, and one patient showed even bony destruction of the hard palate at his final stage. In some series dealing with PMR, the interval between the initial appearance of the symptoms and the hospital
ITAMI
er al.
801
visit has been reported to be very long, often in the range of years (5, 6, 18). In contrast, our patients with nasal NHL showed a relatively rapid time course before seeking medical consultation (mean 6 months), although three patients had a history of nasal discharge of more than 5 year’s duration. Debate continues about the prognosis of PMR. Eichel rf al. demonstrated an excellent local control rate (7/9) with IFRT alone (6) and they stressed the more favorable prognosis of PMR compared with the “typical” monomorphic NHL of the nasal cavity. Other series also pointed out favorable prognosis of PMR (4, 5, 17). In contrast, less favorable prognosis of PMR has been reported from some institutions (8, 12. 18). Our study, as discussed later in detail, showed poor prognosis, in which only 3 out of 9 patients had long-term remission. The reason for different treatment results remains unknown. With respect to the prognosis of the nasal NHL in this study, all the patients with diffuse large or immunoblastic lymphoma succumbed to fatal recurrence. whereas 2 out of the 5 patients with diffuse mixed small and large cell lymphoma obtained disease control. However, the small number of the patients limits the statistical significance. The prognostic significance of the presence of polymorphism, angiodestruction, and necrosis remains unclear also because of the small number of patients. The unfavorable prognosis of our series indicates the need to change the primary management policy of the nasal NHL. Despite the clinically confined lesion in the nasal cavity. the nasal NHL tends to recur mainly in distant extranodal regions, such as in lung and skin, which unequivocally demonstrates that radiation therapy alone is inadequate to achieve long-term remission. This notion might be clinically quite important because some authors recommend IFRT for the treatment of PMR, which is really nasal T-cell NHL. In contrast, a considerable proportion of the patients with the localized Waldeyer’s ring NHL can be cured with radiation therapy alone ( 13, 2 1. 26). The difference of the clinical course of NHL in the nasal cavity and the Waldeyer’s ring might reflect the difference of cell lineages in both primary sites (26). Because mild regimen such as VEMP used in our patients did not prevent distant spread, the multimodality approach incorporating intensive chemotherapy and radiotherapy must be tried to improve the prognosis of patients with NHL in the nasal cavity.
REFERENCES 1. Batsakis, J. G. Tumors of the head and neck. Baltimore: Williams & Wilkins; 1979:492-500. 2. Birt, B. D. Reticulum cell sarcoma of the nose and paranasal sinuses. J. Laryngol. 84:6 15-630; 1970. 3. Carbone, P. P.; Kaplan, H. S.; Musshoff, K.; Smithers, D. W.; Tubiana, M. Report ofthe Committee on Hodgkin’s Disease Staging Classification. Cancer Res. 3 1: 1860- I86 1; 1971. 4. Crissman, J. D.; Weiss, M. A.; Gluckman, J. Midline gran-
uloma syndrome. A clinicopathologic study of 13 patients. Am. J. Surg. Pathol. 6:335-346: 1982. 5. DeRemee, R. A.; Weiland, L. H.; McDonald, T. J. Polymorphic reticulosis, lymphomatoid granulomatosis. Two diseases or one? Mayo Clin. Proc. 53:634-640; 1978. 6. Eichel, B. S.; Harrison Jr., E. G.; Devine, K. D.; Scanlon, P. W.; Brown, H. A. Primary lymphoma of the nose in&ding a relationship to lethal midline granuloma. Am. J. Surg. 112:597-605; 1966.
802
I. J. Radiation Oncology
0 Biology 0 Physics
7. Frierson, Jr., H. F.; Mills. S. E.; Innes. D. J. Non-Hodgkin’s lymphomas of the sinonasal region: Histologic subtypes and their clinicopathologic features. Am. J. Clin. Pathol. 8 1:72 l727; 1984. tumors of the nasal 8. Fu, Y. S.; Perzin, K. H. Nonepithelial cavity, paranasal sinuses and nasopharynx. A clinicopathologic study. X. Malignant lymphomas. Cancer 43:6 I l-62 I : 1979. 9. Gaulard, P.; Henni, T.: Marolleau, J. P.; Haioun, C.; Henni, Z.; Voisin, M. C.; Divine, M.; Goossens. M.; Farcet. J. P.: Reyes. F. Lethal midline granuloma (polymorphic reticulosis) and lymphomatoid granulomatosis. Evidence for a monoclonal T-cell lymphoproliferative disorder. Cancer 62: 705-710; 1988. IO. Hsu, S. M.: Raine, L.: Fanger, H. The use of avidin-biotinperoxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J. Histochem. Cytochem. 29:577-580: 1981. 1I. Hyams. H. J.: Batsakis. J. G.; Michaels. L. Tumors of the upper respiratory tract and ear. In: Atlas of tumor pathology, Fast. 25. Washington D. C.: US Armed Forces Institute of Pathology; 1988:2 16-220. 12. Ishii, Y.; Yamanaka, N.: Ogawa. K.: Yoshida, Y.; Takami, T.; Matsuura, A.: Isago, H.: Kataura, A.: Kikuchi, K. Nasal T-cell lymphoma as a type of so-called “lethal midline granuloma.” Cancer 50:2336-2344; 1982. 13. Jacobs. C.: Hoppe. R. T. Non-Hodgkin’s lymphomas of head and neck extranodal sites. Int. J. Radiat. Oncol. Biol. Phys. I1:357-364: 1985. 14. Kimura, K.; Sakai, Y.: Konda. C.; Kashiwada, N.; Kitahara, T.; Inagaki. J.: Mikuni, M.; Sakano, T. Chemotherapy of the malignant lymphoma. Saishin Igaku 24:8 16-824: 1972 (in Japanese). 15. Kondo, M.; Mikata, A.: Inuyama. Y.: Uematsu, M.: Shigematsu. N.; Nishiguchi. I.: Hashimoto, S. Treatment of non-Hodgkin lymphomas in the nasal cavities and paranasal sinuses. A failure analysis. Acta Radiol. Oncol. 25:91-97: 1986.
April 199 I. Volume
20. Number
4
16. Lippman, S. M.; Grogan, T. M.; Spier, C. M.; Koopmann Jr., C. F.: Gall, E. P.; Shimm, D. S.; Durie, B. G. M. Lethal midline granuloma with a novel T-cell phenotype as found in peripheral T-cell lymphoma. Cancer 59:936-939; 1987. 17. McDonald, T. J.; DeRemee. R. A.; Harrison, E. G.; Facer. G. W.; Devine, K. D. The protean clinical features of polymorphic reticulosis (lethal midline granuloma). Laryngoscope 86:936-945; 1976. 18. Michaels, L.; Gregory, M. M. Pathology of “non-healing (midline) granuloma.” J. Clin. Path. 30:317-327; 1977. 19. Mohri, N. B-cell lymphomas of extranodal origin. Jpn. J. Clin. Oncol. 13:591-606: 1983. 20. Robbins, K. T.: Fuller, L. M.; Vlasak, M.; Osborne, B.; Jing. B. S.: Velasquez, W. S.; Sullivan, J. A. Primary lymphomas of the nasal cavity and paranasal sinuses. Cancer 56:814-819; 1985. 21. Shibuya. H.: Kamiyama, R.; Watanabe, I.; Horiuchi, J.; Suzuki, S. Stage I and II Waldeyer’s ring and oral-sinonasal non-Hodgkin’s lymphoma. Cancer 59:940-944. 1987. 22. Silver. W. E.: Daly, J. F.; Friedman, M. Reticulum cell sarcoma of the nose and paranasal sinuses. Head Neck Surg. 87:532-535: 1968. 23. Takenaka, T.; Konda, C.; Sakano, T.; Kitahara, T.; Tobinai, K.: Shimoyama, M. The clinical study on non-Hodgkin’s lymphoma of nasal cavity and paranasal sinus. J. Jpn. Sot. Cancer Ther. 23:2779-2784: 1988. 24. 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 formulation for clinical usage. Cancer 49:21 12-2135; 1982. 25. Wilder, W. H.: Harner, S. G.; Banks, P. M. Lymphoma of the nose and paranasal sinuses. Arch. Otolaryngol. 109:3 IO312; 1983. 26. Yamanaka, N.; Harabuchi, Y.: Sambe, S.; Shido. F.; Matsuda, F.: Kataura. A.: Ishii, Y.; Kikuchi. K. Non-Hodgkin’s lymphoma of Waldeyer’s ring and nasal cavity: Clinical and immunologic aspects. Cancer 56:768-776; 1985.
0360.3016/91 $3.00 + .oO 0 I99 I Pergamon Press plc
0 Brief Communication NON-HODGKIN’S LYMPHOMA CONFINED TO THE NASAL CAVITY: ITS RELATIONSHIP TO THE POLYMORPHIC RETICULOSIS AND RESULTS OF RADIATION THERAPY JUN
ITAMI,
M.D.,* TOSHIO
MAKIKO KANEKO,
ITAMI,
M.D.,’
M.D.,*
HITOSHI
ATSUO
AND NOBORU
MIKATA,
OGATA,
M.D.,+
M.D.,*
ARIMIZU,
JUN-ICHI
KIMIICHI
TAMARU,
UNO,
M.D.,+
M.D.*
M.D.*
Chiba University School of Medicine, Inohana I -8- 1, Chiba, 280 Japan. From 1975 through 1988, nine patients with locally confined nasal non-Hodgkin’s lymphoma (NHL) were treated with radiation therapy in the Department of Radiology, Chiba University Hospital. Immunohistochemical study disclosed that all NHL’s have T-lineage. Additionally, unique histological pictures of polymorphism, angiodestruction, and necrosis were seen in most of cases. These three findings are the histological features of polymorphic reticulosis (PMR), which is the main cause of lethal midline granuloma and has recently been shown to belong to T-cell malignancy. Therefore, it is concluded that the nasal T-cell NHL and PMR are really a single disease entity. The predominance of the T-cell lymphoma in the nasal cavity as well as its histological distinctness clearly indicate that the head and neck extranodal NHL cannot be discussed together. Although the disorder was considered to be locally limited at presentation, only 3 of the 9 patients with nasal NHL could be induced into long-term remission with involved field radiotherapy. The distant extranodal spread was the primary cause of failure. Multimodality treatment using intensive chemotherapy might improve the prognosis of nasal NHL. Non-Hodgkin’s
lymphoma,
Nasal cavity, Radiation therapy, Polymorphic reticulosis.
and necrosis (5, 6, 11, 17). Recent advances in immunohistopathology have obviously shown that PMR is an unusual type of lymphoma with T-cell lineage ( 12, 16). However, the pathological as well as clinical relationship of PMR and the conventional NHL remains largely unresolved. We, therefore, reviewed NHL patients with lesion confined to the intrinsic nasal cavity who were treated in the Department of Radiology, Chiba University Hospital to investigate its pathological and clinical features. We also compared the pathological findings and clinical behaviors of the NHL’s in this study to those of reported series on PMR’s (4-6, 17).
INTRODUCTION Because of the rare occurrence of non-Hodgkin’s lymphoma (NHL) in the nasal cavity, its pathological and clinical features are far from being clearly defined. Furthermore, the anatomical neighborhood ofthe nasal cavity and the paranasal sinuses often causes difficulty in determining the precise origin of locally advanced NHL, so that most series have reported NHL in the nasal cavity and the paranasal sinuses together (2,7,8, 15,20-22,25). However, there is controversy as to whether NHL’s in the nasal cavity and the paranasal sinuses show similar clinical behavior and can be discussed as a single entity (23). Polymorphic reticulosis (PMR), or midline malignant reticulosis, is one of the major causes of lethal midline granuloma in the nasal cavity. PMR was formerly classified as a non-lymphomatous lesion which was, however, considered to be closely related to lymphoma (5, 6, 17). PMR is pathologically characterized by the presence of polymorphic lymphoreticular infiltrate, angiodestruction,
* Dept. + Dept. * Dept. Reprint
of Radiology. of Pathology. of Otorhinolaryngology. requests to: Jun Itami, M.D., Department
diology, Chiba University Chiba, 280 Japan.
School of Medicine,
Inohana
METHODS
AND
MATERIALS
From 1975 through 1988, 12 patients with NHL in the nasal cavity were referred to the Department of Radiology, Chiba University Hospital, for radiation therapy. Three
Acknowledgements-The
technical Azuma. of RaI-8-1,
Accepted
797
assistance
authors gratefully acknowledge the of Toshifumi Umemiya and Kazuhiro
for publication
8 October
1990.
I. J. Radiation
798
Fig. 1. Computed tomography of the intrinsic nasal cavity. The tumor in the septum and protrudes into the although there is no invasion of the
Oncology
0 Biology 0 Physics
April 1991, Volume
20. Number
4
nasal NHL confined to the the left nasal cavity erodes contralateral nasal cavity. antrum.
Fig. 2. Polymorphism found in NHL ofthe nasal cavity. Tumor cells are of various size and with bizarre nuclei and there is marked infiltration of histiocytes. eosinophils, and plasma cells (Hematoxylin-Eosin, X 132).
of the I2 patients were excluded from the study because of paranasal extension and extrafacial nodal and/or extranodal involvement at initial presentation. The remaining nine patients showed disease confined to the nasal cavity without radiological evidence of paranasal extension (Fig. 1). The male to female ratio of the nine patients was 5:4 with a mean age of 55 years (range 31 to 76). In the 14-year period of this study. the staging procedures varied greatly. All nine patients underwent physical examination including special ENT mirror examinations, chest X rays, and special x-ray studies including polytomographies and complete blood counts with biochemistry. Lymphography was performed in only two patients; Ga scintigraphy was performed in six patients with negative results except in the nasal cavity. Bone marrow biopsy and/or aspiration did not show involvement in four patients. Abdominal involvement was also ruled out by CT in five patients. All nine patients were diagnosed as clinical Stage I according to Ann-Arbor classification (3). The hematoxylin-eosin stained sections were reviewed by an experienced hematopathologist (AM) and all cases were confirmed as NHL and classified according to the Working Formulation for clinical usage (WF) (24). To compare the pathological features of NHL and PMR. each material was further reviewed, taking into consideration the presence of polymorphism (Fig. 2). angiodestruction (Fig. 3) and necrosis (Fig. 4). The formalin-fixed paraffin-embedded tissue blocks were resectioned and re-stained by the avidin-biotin-peroxidase complex (ABC) method ( 10) using a series of monoclonal antibodies: UCHLl* and MT 1’ for T-cell markers, L26* and MB It for B-cell markers. Three patients were initially treated by local application of steroid and/or per oral steroid with no response and secondarily referred for radiation therapy. All nine patients
were treated with radiation therapy using megavoltage photons (6”Co or 10 MV X rays with appropriate bolus) or high-energy electrons (15 MeV or 18 MeV). of which three underwent combination chemotherapy simultaneously. The radiation portal encompassed only clinically involved area with a generous margin (involved field radiation therapy = IFRT). In six patients, single anterior portal to the nasal cavity was used and the remaining three were treated by lateral opposing fields with an additional anteroposterior portal. Prophylactic irradiation to the neck lymph nodes was not performed. The radiation dose ranged from 2 1 Gy to 60 Gy with a mean of 4 1.4 Gy. In all patients, a conventional fractionation scheme with a weekly dose of 5 X 2 Gy was used. The combination chemotherapy was not an intensive regimen and consisted of weekly vincristine iv (1 mg/week) and daily per oral cyclophosphamide (50 mg/day), 6-mercaptopurine (50 mg/day), and prednisone (VEMP) ( 14).
* DAK0
Japan,
Kyoto, Japan.
RESULTS The presenting symptoms of the nine patients with NHL originating in the nasal cavity are shown in Table 1. Nasal obstruction was seen in all patients, of whom seven complained of unilateral obstruction. Persistent fever up to 38°C was recognized in four patients, which was followed in frequency by the swelling of the ala nasi in three patients. The interval from the onset of symptoms to the first hospital visit ranged from 2 months to 3 years (mean 6 months). Three patients had a longstanding history of chronic nasal obstruction with purulent discharge. The initial involved sites in the nasal cavity are demonstrated in Table 2. The inferior turbinate was the most frequent primary site (seven patients), whereas the nasal septum was involved in four patients at initial presenta-
+ Bioscience
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Switzerland.
199
NHL in the nasal cavity 0 J. ITAMIPI a/
Fig. 3. Angiodestruction found in NHL of the nasal cavity. (a) The arterial wall is infiltrated by the lymphoid tumor cells (Hematoxylin-Eosin. X50). (b) The Elastica-staining clearly demonstrates the destruction of lamina elastica of the nasal artery and intraluminal tumor thrombosis (Elastica-staining, X33).
tion. The local findings were crust formation with underlying cartilage exposure in seven patients and slight swelling of the turbinate and/or septum in two patients. Histopathological review revealed that all cases belonged to NHL and their classification by WF is shown in Table 2. One patient showed immunoblastic histology, whereas two patients had diffuse large cell type, five had diffuse mixed small and large cell. and the remaining patient had diffuse small cleaved cell. The immunohistopathological studies using monoclonal antibodies revealed that all the nine patients had NHL with T-cell surface antigens demonstrated by the positive staining with UCHL 1 and/or MT 1. Concerning polymorphism, angiodestruction, and necrosis. all three findings were seen in four patients with nasal NHL (Table 2). The remaining five patients had at least one of the three findings. In contrast to the monomorphic infiltrate seen in the typical primary nodal NHL, infiltrating cells of the polymorphic lymphoma ofthe nasal cavity were not of uniform size and they were accompa-
nied by an infiltration of neutrophils, plasma cells, epithelioid histiocytes, and eosinophils (Fig. 2). In five patients, angiodestruction was demonstrated in which the arterial wall was infiltrated and destroyed by lymphoid cells and in some cases the lymphoid cells formed even tumor emboli in the involved arteries (Fig. 3). Only two patients remain presently without recurrence with follow-up lengths of 1 and 2 years, respectively (Table 3). In another patient (patient No. 4) late recurrence in the nasal cavity occurred 8.5 years after the initial treatment and second remission was attained with reirradiation in extended field. This patient has no evidence of disease at 4.5 years follow-up after the recurrence. The remaining six patients succumbed to recurrence with fatal outcome. All fatal recurrences occurred within 6 months after the initial treatment. The recurrence in the nasal cavity was seen in five patients, which was accompanied by other generalized extranodal recurrences. Involvement in the lung and skin was also seen frequently, whereas lymph node recurrence in the neck, which would be within extended radiation field, was observed in only one patient. The chemotherapy regimen used in three patients could not prevent recurrence.
Table 1. The presenting symptoms of the nine patients with non-Hodgkin’s lymphoma (NHL) in the nasal cavity Symptoms
Fig. 4. Widespread necrosis (below) found in NHL of the nasal cavity. In the neighboring region angiodestruction involving several arteries is also seen (above left) (Hematoxylin-Eosin, X25).
Nasal obstruction Bilateral Unilateral Fever Swelling of ala nasi Purulent discharge Night sweating Epistaxis 1975-1988, Hospital.
Department
No.
(%)
9 2 I 4 3 2 1
(100) (22) (78) (44) (33) (22) (11)
1
(11)
of Radiology,
Chiba
University
800
I.
J.
Radiation
Oncology 0
Biology 0 Physics
Table 2. Primary
non-Hodgkin’s
April 199 I. Volume
lymphoma
20. Number
4
in the nasal cavity Histological
Patient no.
Sex
Age
F M M F F M
40 31 59 51 53 76
I
F
51
8 9
M M
72 62
Primary
site
WF
Rt. inf. turb. Lt. inf. turb. Rt. inf. turb. Lt. inf. turb. Nasal septum Nasal septum, t-t. middle turb., rt. inf. turb. Nasal septum, It. inf. turb. Lt. inf. turb. Nasal septum, hard palate
Cell lineage
Polymorphism
dm dm dm dsc dl dl
Angiodestruction
+ + _ + + +
+ + + _ +
Necrosis
+ + + + +
dm
T
+
_
+
imb dm
T T
+ +
+
+ +
M = Male; F = Female: turb. = Turbinate: WF = Working formulation: cleaved; dl = Diffuse large; imb = Immunoblastic. I975- 1988, Department of Radiology, Chiba University Hospital.
DISCUSSION
dm = Diffuse mixed small and large; dsc = Diffuse small
contrasts in other
The study using a batch of monoclonal antibodies to T and B-cell surface antigens revealed that all nasal NHL’s in this report are derived from T lymphocyte. The predominance of T-cell lymphoma in the nasal cavity has also been reported by other investigators (26). This finding
Table 3. Primary
non-Hodgkin’s
with the frequent occurrence of B-cell lymphoma head and neck extranodal regions. such as in the
Waldeyer’s ring ( 19, 26). Additionally, the histological states of our patients with nasal NHL revealed distinct features with resemblance to the PMR. PMR is histologically characterized by the presence of polymorphic lymphoreticular infiltrate, angiodestruction, and necrosis. Its clinical features correspond most often with the lethal
lymphoma
in the nasal cavity
Radiotherapy Patient no.
features
Portal
Dose
Chemotherapy
Site of recurrence
I 2
IFRT IFRT
56 Gy 50 Gy
No No
3 4 5
IFRT IFRT IFRT
50 Gy 42 Gy 30 Gy
No No VEMP + 5-FU
6
IFRT
40 Gy
No+
7
IFRT
60 Gy
VEMP
8
IFRT
60 Gy
VEMP+
9
IFRT
21 Gy
No+
No Nasal cavity, lung, spleen No Nasal cavity Nasal cavity, brain, lung Nasal cavity. neck lymph node, lung Larynx, skin, inguinal lymph node Nasal cavity, lung, skin Nasal cavity. skin
Follow-up length (mos.) 10 II 23 154 3
Outcome NED DOD NED NED* DOD
4
DOD
6
DOD
2
DOD
15
DOD
* After the first recurrence, re-irradiation with extended field was performed and the second remission was obtained. + Radiation therapy and/or chemotherapy was instituted after the failure of initial treatment with steroid. IFRT = Involved field radiation therapy; NED = No evidence of disease; DOD = Dead of disease. 1975-1988, Department of Radiology, Chiba University Hospital.
NHL in the nasal cavity 0 J.
midline granuloma, with unrelenting course resulting in the destruction of midfacial structures when untreated ( 1, 4-6,8, 11, 17, 18). It has only recently been demonstrated that the atypical cells of the PMR are indeed derived from monoclonal malignant proliferation of T-lymphocytes and that PMR is a type of peripheral T-cell lymphoma (9, 12, 16). All nine cases examined in this study showed histological resemblance to PMR. Our observations are totally in accordance with the view that the nasal T-cell NHL and PMR constitute pathologically a single disease entity as peripheral T-cell NHL. The old literature had made a distinction between PMR and NHL presumably because of the lack of the recognition of the unique histological pictures of the peripheral T-cell lymphomas ( 12). The distinct histological characters of the nasal NHL as well as its T-cell origin may make it difficult to discuss together the nasal NHL and the other head and neck extranodal NHL, which is predominantly derived from Bcell. In our study diffuse mixed small and large cell lymphoma was observed most frequently, whereas the predominance of diffuse large cell lymphoma as well as immunoblastic lymphoma has been emphasized ( 15,20,2 I, 26). The reason for the difference is not clear, but the inclusion of the paranasal NHL in other series might provide an explanation. We confined this study to clinical Stage I patients with nasal NHL who had no radiological involvement of the paranasal sinuses. It remains controversial whether NHL primary to the nasal cavity and the paranasal sinuses has the same pathological features as well as a similar prognosis in spite of the anatomical neighborhood of both structures. Takenaka et al. emphasize more favorable prognosis of the nasal NHL (median survival 33 months) in comparison with the paranasal NHL (median survival 11 months) (23). It seems presently preferable to discuss them separately. The initial rhinoscopic findings of NHL of our series were also shown to be same with those of PMR. The exposure of the nasal cartilages and bony destruction by necrosis is the most common presenting signs of PMR (5, 6, 8, 17). Most of our patients with NHL had crusting on the nasal turbinate with underlying cartilage exposure, and one patient showed even bony destruction of the hard palate at his final stage. In some series dealing with PMR, the interval between the initial appearance of the symptoms and the hospital
ITAMI
er al.
801
visit has been reported to be very long, often in the range of years (5, 6, 18). In contrast, our patients with nasal NHL showed a relatively rapid time course before seeking medical consultation (mean 6 months), although three patients had a history of nasal discharge of more than 5 year’s duration. Debate continues about the prognosis of PMR. Eichel rf al. demonstrated an excellent local control rate (7/9) with IFRT alone (6) and they stressed the more favorable prognosis of PMR compared with the “typical” monomorphic NHL of the nasal cavity. Other series also pointed out favorable prognosis of PMR (4, 5, 17). In contrast, less favorable prognosis of PMR has been reported from some institutions (8, 12. 18). Our study, as discussed later in detail, showed poor prognosis, in which only 3 out of 9 patients had long-term remission. The reason for different treatment results remains unknown. With respect to the prognosis of the nasal NHL in this study, all the patients with diffuse large or immunoblastic lymphoma succumbed to fatal recurrence. whereas 2 out of the 5 patients with diffuse mixed small and large cell lymphoma obtained disease control. However, the small number of the patients limits the statistical significance. The prognostic significance of the presence of polymorphism, angiodestruction, and necrosis remains unclear also because of the small number of patients. The unfavorable prognosis of our series indicates the need to change the primary management policy of the nasal NHL. Despite the clinically confined lesion in the nasal cavity. the nasal NHL tends to recur mainly in distant extranodal regions, such as in lung and skin, which unequivocally demonstrates that radiation therapy alone is inadequate to achieve long-term remission. This notion might be clinically quite important because some authors recommend IFRT for the treatment of PMR, which is really nasal T-cell NHL. In contrast, a considerable proportion of the patients with the localized Waldeyer’s ring NHL can be cured with radiation therapy alone ( 13, 2 1. 26). The difference of the clinical course of NHL in the nasal cavity and the Waldeyer’s ring might reflect the difference of cell lineages in both primary sites (26). Because mild regimen such as VEMP used in our patients did not prevent distant spread, the multimodality approach incorporating intensive chemotherapy and radiotherapy must be tried to improve the prognosis of patients with NHL in the nasal cavity.
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I. J. Radiation Oncology
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20. Number
4
16. Lippman, S. M.; Grogan, T. M.; Spier, C. M.; Koopmann Jr., C. F.: Gall, E. P.; Shimm, D. S.; Durie, B. G. M. Lethal midline granuloma with a novel T-cell phenotype as found in peripheral T-cell lymphoma. Cancer 59:936-939; 1987. 17. McDonald, T. J.; DeRemee. R. A.; Harrison, E. G.; Facer. G. W.; Devine, K. D. The protean clinical features of polymorphic reticulosis (lethal midline granuloma). Laryngoscope 86:936-945; 1976. 18. Michaels, L.; Gregory, M. M. Pathology of “non-healing (midline) granuloma.” J. Clin. Path. 30:317-327; 1977. 19. Mohri, N. B-cell lymphomas of extranodal origin. Jpn. J. Clin. Oncol. 13:591-606: 1983. 20. Robbins, K. T.: Fuller, L. M.; Vlasak, M.; Osborne, B.; Jing. B. S.: Velasquez, W. S.; Sullivan, J. A. Primary lymphomas of the nasal cavity and paranasal sinuses. Cancer 56:814-819; 1985. 21. Shibuya. H.: Kamiyama, R.; Watanabe, I.; Horiuchi, J.; Suzuki, S. Stage I and II Waldeyer’s ring and oral-sinonasal non-Hodgkin’s lymphoma. Cancer 59:940-944. 1987. 22. Silver. W. E.: Daly, J. F.; Friedman, M. Reticulum cell sarcoma of the nose and paranasal sinuses. Head Neck Surg. 87:532-535: 1968. 23. Takenaka, T.; Konda, C.; Sakano, T.; Kitahara, T.; Tobinai, K.: Shimoyama, M. The clinical study on non-Hodgkin’s lymphoma of nasal cavity and paranasal sinus. J. Jpn. Sot. Cancer Ther. 23:2779-2784: 1988. 24. 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 formulation for clinical usage. Cancer 49:21 12-2135; 1982. 25. Wilder, W. H.: Harner, S. G.; Banks, P. M. Lymphoma of the nose and paranasal sinuses. Arch. Otolaryngol. 109:3 IO312; 1983. 26. Yamanaka, N.; Harabuchi, Y.: Sambe, S.; Shido. F.; Matsuda, F.: Kataura. A.: Ishii, Y.; Kikuchi. K. Non-Hodgkin’s lymphoma of Waldeyer’s ring and nasal cavity: Clinical and immunologic aspects. Cancer 56:768-776; 1985.
