Clin. Otolaryngol. 1992, 17, 563-566
REVIEW
The diagnosis and treatment of nasal lymphoma, an important cause of upper respiratory tract destruction SURESH SENAN CRC Clinical Research Fellow. Department of Radiation Oncology, Cancer Research Campaign Beatson Laboratories, University of Glasgow, Garscube Estate, Bearsden. Glasgow G61 IBD, Scotland Accepted for publication 10 June 1992
The progressive ulceration and destruction of the nose and paranasal sinuses presents a striking clinical picture and the diseases responsible for this uncommon presentation are many (Table 1). However, it is a variant of peripheral (postthymic) T-cell lymphoma which has long been a source of diagnostic confusion. The prominent accumulation of nonmalignant cells in this type of lymphoma led to the use of the term 'granulomatous', i.e. non-neoplastic, to describe it.' A careful histological review in 1977 showed that evidence for a lymphoma could be found in all such cases when adequate histology was available.2 This was confirmed when imrnun~histochemistry~~~ and beta-T-cell receptor gene rearrangement studies were p e r f ~ r m e d . ~ . ~ However, variants of the term 'midline granuloma' are still to be found in the literature'.' and may perpetuate the view that a poorly defined cause of upper respiratory tract destruction still exists. The failure to investigate all such cases until a specific diagnosis is made can lead to inappropriate patient management.'.'' The aim of this review is to describe the characteristics of these peripheral T-cell lymphomas (PTCL), in particular those features which have contributed to the difficulty in diagnosis, and to outline a rational scheme for investigating the patient.
cytokines in large quantities'' and the presence of significant numbers of non-neoplastic cells has been shown to be restricted to those peripheral T-cell lymphomas which contain neoplastic T-cells with the features of activated cells." The malignant T-cells are often difficult to recognize. This is in part due to the neoplastic cell clone having a heterogenous cytological appearance as a result of malignant cells being a t different stages of differentiation and activation.12.'9 In one series, the scanty malignant cells formed homogenous groups in only half the cases of nasal lymphoma.2 The limited amount of biopsy material available from the nose adds to the diagnostic difficulty. Many of the lymphomas involving the uppcr respiratory tract belong to a variant called angiocentric lymphoma.20 These tend to occur in extralymphatic sites and the malignant lymphoid cells show a tendency to surround, invade and destroy vessel walls. Necrosis, involving both tumour cells and normal tissues, occurs as a result. Whilst a correlation between angiocentricity and necrosis has been shown in some report^,^,'^,^^ it has not been found by others.22Again, the small and often superficial biopsies may be responsible for this lack of correlation. Table 1. Causes of upper respiratory tract destruction
Nasal lymphoma
Wegener's granulomatosis
T-cell lymphoma predominates in the nasal cavity and this Infections Bacterial: Rhinoscleroma contrasts with the predominantly B-cell lymphomas which Tuberculosis occur in other extranodal head and neck regions." It occurs Leprosy more frequently in Oriental than in Western p o p ~ l a t i o n s l ~ . ' ~ Brucellosis and the T-cell predominance holds true in both Actinomycosis populations. 5. 14. I s Syphilis Parasitic: Leishmaniasis The delayed recognition that this 'granuloma' was in fact a lymphoma was mainly due to the large number of benign Neoplasms cells (plasma cells, histiocytes, small lymphocytes, foam cells) Peripheral T-cell lymphoma B-cell lymphoma in the lesion. These are at least partly secondary to the Carcinoma recognized phenomenon of cytokine secretion by malignant Sarcoma T-cells.I6 Only activated T-cells arc capable of secreting
Fungal: Blastomycosis Rhinosporidiosis Phycomycosis Coccioidomycosis Candidiasis Histoplasmosis
563
564
SSenan
Table 2. Investigating the patient with nasal destruction History, examination, urinalysis, serum electrolytes and chest
radiograph Serology for syphilis, fungal infections and the antineutrophil cytoplasmic antibody CT or MRI scan of the head and neck
Examination under anaesthetic to obtain tissue for cultures and histology lmmunocytochemistry using T- and B-cell markers on frozen and paraffin fixed tissue. Southern blot analysis or polymerase chain reaction to detect clonal beta or gamma T-cell receptor gene rearrangement Repeat biopsy and cultures if no diagnosis established
Investigations The diagnostic evaluation of patients with this presentation requires adherence to a systematic and comprehensive scheme (such as that in Table 2) in order to exclude the many non-malignant causes. The patient’s country of origin, travel history and pre-existing medical condition (diabetes mellitus, immunosuppression) all influence the differential diagnosis. Prior consultation with a pathologist and microbiologist are advised in order to hasten diagnosis and minimize the need for repeated biopsies. Adequate microbiological investigations to exclude unusual fungal and bacterial infections can then be performed at the initial examination as histology alone cannot exclude infective causes of this presentation.”.” A compelling case has been made for tissue biopsy to be directed by frozen section e ~ a m i n a t i o nThis . ~ ~ will hasten the diagnosis by allowing for the adequacy of tissue for diagnosis to be assessed and immediate rebiopsy performed if necrotic, severely crushed or insufficient tissue is obtained. Immunocytochemistry is best performed on fresh frozen tissue and samples for bacterial and fungal cultures can be obtained at the same time. Although frozen section permits the use of a broad range of diagnostic antibodies for lymphoid malignancies, it does not allow for the optimum correlation of morphology with phenotype because of the poor correlation of histological and cytological detail in cryostat sections. The combination of the monoclonal antibodies UHCLI (CD45RO) and poly-CD3 on paraffinembedded tissues allowed for the neoplastic cells to be identified in 98% of T-cell lymphomas, whilst allowing for the morphology of the stained cells to be ~ v a l u a t e d . ~ ~ In B-cell lymphomas, clonality can be shown by immunocytochemical techniques which show light-chain restriction, even in paraffin sections.26By contrast, the diagnosis of T C L depends on the application of multiple criteria, none of which is absolutely reliable. As no pathognomic phenotypic marker of T-cell malignancy is currently available, the aber-
rant expression of phenotypic markers is taken as a fairly reliable indicator of T-cell m a l i g n a n ~ y However, .~~ low grade lymphomas can still have a n immunophenotype identical to normal T - c ~ l l s . ~Tissue * should, therefore, be set aside for T-cell receptor gene rearrangement studies should the initial investigations prove inconclusive. In contrast to B-cell lymphoma, where genotypic evidence of monoclonality was present in nearly all cases, only 53% of phenotypic T-cell lymphoma in one series had TCR-beta gene rearrangement detected by Southern blotting.29 This finding has also been reported by others” and, therefore, cannot be used as the sole criterion in excluding the diagnosis. The polymerase chain reaction has high sensitivity (it can detect predetermined D N A sequences from a single cell) and is an ideal tool to detect the gene rearrangements in the often scanty malignant lymphoid cells in these tumours in both fresh and paraffin-embedded tissue. The nasal T-cell lymphoma belongs to the group of lymphomas associated with the Epstein-Barr virus (EBV). EBV DNA has been detected in all Oriental patients with nasal T-cell lymphoma^'.^' although in-situ hybridization performed on archival material from Western patients detected EBV viral DNA in only 63% cases.’’ T lymphocytes infected with EBV D N A can support sustained viral replication3’ and this suggests a role for EBV in the rnalignant process.
Differential diagnosis It is important to exclude the limited form of Wegener’s granulomatosis, where lesions of the upper respiratory tract have occurred for up to 18 years before the correct diagnosis was made.’4,’5 The mixed acute and chronic inflammatory reaction in Wegener’s may overshadow both the necrosis and vasculitis in the small biopsies from the nose. The histological distinction between angiocentric lymphoma and Wegener’s has been considered straightforward by some as multinucleated giant cells and true granulomas are not features of angiocentric lymphomas, whilst neutrophils are prevalent and lymphoid cells relatively sparse in Wegener’s.” However, half of the nasal biopsies from patients ultimately shown to have Wegener’s show only non-specific inflammatory change^.^' All new cases should have the assay for the antineutrophil cytoplasmic antibody (ANCA), a specific and sensitive test for Wegener’s and other vasculitic proce~ses.~’However. the sensitivity of ANCA depends on disease activity and a negative test cannot rule out the diagnosis. Lymphomatoid granulomatosis is a peripheral T-cell lymphoma which is often cited in the differential diagnosis of nasal destruction. The vast majority of these patients have pulmonary. cutaneous and neurological lesions which allow for this disease pattern to be recognized.’*
Diagnosis and treatment of nasal lymphoma 565
Treatment In patients with localized disease, treatment using external beam radiotherapy often shows disappointing results, with 40-66% of patients developing r e c ~ r r e n c e . ' ~ . ~There ' , ~ ~ is n o evidence for a radiation dose-response relationship from these series and aggressive multiagent chemotherapy regimes d o not appear to be more effective in preventing relapse^.^' Local recurrence tends to occur within months of treatment c ~ m p l e t i o n ' ~and ~ ' ~histological progression t o a more monomorphous lymphoma occurs in u p to 20% of these case^.^^.^' O n the other hand, the use of cyclophosphamide and prednisolone has resulted in complete remissions in some patients relapsing after r a d i ~ t h e r a p y .This ' ~ is not surprising as complete remissions have been reported in low grade angiocentric lymphomas treated using the same regime." Systemic lymphoma develops in 10-25% of patients initially presenting with localized nasal lesions2341and a response t o aggressive chemotherapy a t this stage is u n c ~ m m o n The .~ variable outcome t o a varying range o f treatments supports the concept that angiocentric lymphoma represents a single clinicopathologic entity with varying degrees of clinical aggressiveness. " A haemophagocytic syndrome characterized by fever, hepatosplenomegaly a n d pancytopaenia can develop in nasal (and other angiocentric) lymphomas.s This is believed t o be a result of the secretion of phagocytosis-inducing factors by angiocentric lymphomas.16 It is important t o recognize this association and instituting systemic chemotherapy in this setting has lead t o long-term survivors.
Conclusions The diagnosis of nasal peripheral T-cell lymphoma is occasionally a difficult one t o make. The histological findings in small biopsies may be non-specific a n d infections may be excluded only by meticulous investigation. Failure to adhere t o a systematic scheme of investigation and a willingness t o accept that ill-defined granulomatous conditions still exist can have disastrous consequences for the patient."
References 1 STEWART J.P. (1933) Progressive lethal granulomatous ulceration of the nose. J . Laryngol. 48, 657-701 2 MICHAELSL. & GREGORY M.M. (1977) Pathology of 'nonhealing (midline) granuloma'. J . Clin.Path. 30, 3 17-327 3 CHANJ.K.C., NG C.S., LAU W.H. & Lo S.T.H. (1987) Most nasal/nasopharyngeal lymphomas are peripheral T-cell neoplasms. Am. J . Surg. Path. 11, 418-429 4 CHOTT A., RAPPERSBERGER K., SCHLOSAREKW. & RADASZKIEWICZ T. (1988) Peripheral T-cell lymphoma presenting primarily as lethal midline granuloma. Hum.Path. 19, 1093-1 101 5 FERRYJ.A., SKLARJ., ZUKERBERG L.R. & HARRIS N.L. (1991) Nasal lymphoma. A clinicopathologic study with
immunophenotypic and genotypic analysis. Am. J . Surg. Path. 15, 268-279 6 GAULARD P., HENNIT., MARULLEAU J.P., HAIOUN C., HENNI Z., VOISINM. et al. (1988) Lethal midline granuloma (polymorphic reticulosis) and lymphomatoid granulomatosis; evidence for a monoclonal T-cell lymphoproliferative disorder. Cancer 62, 705-7 I0 7 HARABUCHI Y., YAMANAKA N., KATAURA A., IMAIS., KINOSHITA T., MIZUNOF. & OSATOT. (1990). Epstein-Barr virus in nasal T-cell lymphomas in patients with the lethal midline granuloma. Lancet 335, 128-130 J.. RAPHAEL M., LAMASG . , MOSSALAYI D., DUBOIS A., 8 CABANE CHOMETTE G . et al., (1991) Origin of malignant centrofacial granulomas: Surface markers and gene rearrangement of malignant cells. Laryngoscope 101, 998-1001 9 MICHAELS L. (1983) Midline granulomas. Am. J . Surg. Path. 7, 207 10 SEIDERM.J., CLEARY K.R. & FULLERL.M. (1991) Plasma cell granuloma of the nasal cavity. Cancer 68, 2490 1 1 YAMANAKA N., KATAURA A., SAMBE S., MINASE T. & ISHII Y. (1985) Midfacial T cell lymphoma: characterisation by monoclonal antibodies. Ann. Otol. Rhinol. Laryngol. 94, 207-21 1 12 SUCHIT., LENNERTK., Tu L.Y., KIKUCHIM., SATO E., STANSFELD A.G. & FELLERA.C. (1987) Histopathology and immunohistochemistry of peripheral T cell lymphomas: a proposal for their classification. J . Clin.Path. 40, 995-1015 13 AOZASAK., OHSAWAM., TAJIMAK., SASAKI R., MAEDAH., I. (1989) Nationwide study of MATSUNAGA T. & FRIEDMANN lethal midline granuloma in Japan: frequencies of Wegener's granulomatosis, polymorphic reticulosis, malignant lymphoma and other related conditions. Int. J . Cancer 44, 63-66 14 SENAN S., SYMONDS R.P. & BROWNI.L. (1992) Nasal peripheral T-cell lymphoma: a 20-year review of cases treated in Scotland. Clin.Oncol. 4, 96-100 5 CAMPOE., CARDESA A,, ALOS L., PALACIN A,, COBARRO J., E. (1991) Non-Hodgkin's TRASERRAJ. & MONTSERRAT lymphomas of nasal cavity and paranasal sinuses. An immunohistochemical study. Am. J . Clin. Path. 96, 184-190 6 SIMRELL C.R., MARGOLICK J.B., CRABTREE G.R., COSSMAN J., FAUCI A.S. & JAFFE E.S. (1985) Lymphokine induced phagocytosis in angiocentric immunoproliferative lesions (AIL) and malignant lymphoma arising in AIL. Blood 65, 1469 M. 17 STEINH., DIENEMANN D., DALLENBACH F. & KRUSCHWITZ (1991) Peripheral T-cell lymphomas. Ann. Oncol. 2, 163-169 18 STEIN H., GERDES J. & DIENEMANND. (1988) Differenierungslinien physiologischer und maligner Zellen des lymphatischen Systems. Verh. Dtsch. Ges. Path. 7 2 , 57-85 19 LIPFORDE.H., MARGOLICK J.B., LONGOD.L., FAUCIA.S. & JAFFEE.S. ( 1988) Angiocentric Immunoproliferative lesions: a clinicopathologic spectrum of post-thymic T-cell proliferations. Blood 72, 1 6 7 61681 20 JAFFEE.S. (1984) Pathologic and clinical spectrum of postthymic T-cell malignancies. Cancer Invest. 2, 413-426 21 RATECHH., BURKEJ., BLAYNEYD., SHEIBANI K & RAPPAPORT H. (1989) A clinicopathologic study of malignant lymphomas of the nose, paranasal sinuses, and hard palate, including cases of lethal midline granuloma. Cancer 64, 2525-253 1 22 Ho F.C.S., CHOYD., LOKES.L., KUNGI.T.M., Fu K.H., LIANG R. el 01. (1990) Polymorphic reticulosis and conventional lymphomas of the nose and upper aerodigestive tract: a clinicopathologic study of 70 cases and immunophenotypic studies of 16 cases. Hum.Path. 21, 1041-1050 23 WALDMAN S.R., LEVINEH.W. & SEBECKB.A. (1981) Nasal tuberculosis: a forgotten entity. Laryngoscope 91, 11-16
566
SSenan
24 OCONNORJ.C. & ROBINSONR.A. (1987) Midline destructive lesions. Acra Otolaryngol. Stockholm 439 (Suppl.), 1-1 6 25 CABECADOS J.M. & ISAACSONP.G. (1991) Phenotyping of T-cell lymphomas in paraffin sections-which antibodies? Hisroparhology 19, 419-424 26 ISAACSON P.G. (1991) Recent advances in the biology of lymphomas. Eur. J. Cancer 27, 795-802 27 PICKERL.J., WEISSL.M., MEDEIROS L.J., WOODG.S. & WARNKE R.A. (1987) lmmunophenotypic criteria for the diagnosis of nonHodgkin’s lymphoma. A m . J. Parhol. 128, 181-184 28 POPPEWA S., BHANA.K., RElSHERZ E.L., MCCLLSKEYR.T. & S.F. (1981) Distribution of T-cell subsets in human SCHLOSSMAN lymph nodes. J . E.xp. Med. 153, 30-41 29 CHEN Y.T., GODWIN T.A. & MOURADIANJ.A. (1991) lmmunohistochemistry and gene rearrangement studies in the diagnosis of malignant lymphomas: a comparison of 152 cases. Hunt. Parh. 22, 1249 1257 30 WEISSL.M., PICKERL.J., GROGAN T.M., WARNKE R.A. & SKLAR J. (1988) Absence of clonal beta and gamma T-cell receptor gene rearrangements in a subset of peripheral T-cell lymphomas. Am. J. Path. 130, 436-442 3 1 Ho F.C.S.. SRIVASTAVA G . , LOKES.L., F u K.H., LEUNGB.P.Y., LIANGR.H.S. & CHOYD. (1990) Presence of Epstein-Rarr virus DNA in nasal lymphomas of B and T cell type. Haematol. Oncol. 8, 271-281 32 WEISSL.M., GAFFEY M.J., CHEX Y.Y. & FRIERSON H I . (1992) Frequency of Epstein-Barr viral DNA in “Western” sinonasal and Waldeyer’s ring non-Hodgkin’s lymphomas. A m . J. Surg. Path. 16, 156-162 33 STEVENSON M., VOLSKYB., HEDENSKOG M. & VOLSKY D.J. (1986)
34 35
36
37
38
39
40
41
Immortalisation of human T lymphocytes after transfection of Epstein-Barr virus DNA. Science 233, 980-984 FIENBERG R. (1980) The protracted superficial phenomenon in pathergic (Wegener’s) granulomatosis. Hum. Path. 12, 4 5 8 4 6 7 E., ASHERSONR.A. & HUGHESG.R.V. D’CRUZD.P., BAGULEY (1989) Ear, nose and throat symptoms in subacute Wegener’s granulomatosis. Br. Med. J. 299, 419-422 DELBUONOE.A. & FLINT A. (1991) The diagnostic usefulness of nasal biopsy in Wegener’s granulomatosis. Hum. Path. 22, 107-1 10 VENNINGM.C., ARWENS. & BIRDA.E. (1987) Antibodies to neutrophil cytoplasmic antigen in systemic vasculitis. Lance/ i, 1389-1393 KATZENSTEINA.A., CARRINGTON C. & LIEBOW A. (1978) Lymphomatoid granulomatosis: a clinicopathologic study of I52 cases. Cuncer 43, 360-373 I T A MJ., ~ ITAMIM., MIKATAA,, TAMARU J., KANEKO T., O O A T A H. et ul. (1990) Non-Hodgkin’s lymphoma confined to the nasal cavity: its relationship to the polymorphic reticulosis and results of radiation therapy. Int. J. Radial. Oncol. Biol. P h ~ s .20, 797-802 LIANGR., TODDD., CHANT.K., CHIUE.. CHOYD., L o w S.L. er a / . (1990) Nasal lymphoma. A retrospective analysis of 60 cases. Cancer 66, 2205-2209 SMALLEY S., CUPPSR., ANDERSON J.. ILSTRUPD., MCDONALD T.J., WEILANDL.H. & DEREMEER.D. (1988) Polymorphic reticulosis limited to the upper aerodigestive tract- natural history and radiotherapeutic considerations. h i t . J. Rudiur. Oncol. Biol. Phys. 15, 599-605 ~
REVIEW
The diagnosis and treatment of nasal lymphoma, an important cause of upper respiratory tract destruction SURESH SENAN CRC Clinical Research Fellow. Department of Radiation Oncology, Cancer Research Campaign Beatson Laboratories, University of Glasgow, Garscube Estate, Bearsden. Glasgow G61 IBD, Scotland Accepted for publication 10 June 1992
The progressive ulceration and destruction of the nose and paranasal sinuses presents a striking clinical picture and the diseases responsible for this uncommon presentation are many (Table 1). However, it is a variant of peripheral (postthymic) T-cell lymphoma which has long been a source of diagnostic confusion. The prominent accumulation of nonmalignant cells in this type of lymphoma led to the use of the term 'granulomatous', i.e. non-neoplastic, to describe it.' A careful histological review in 1977 showed that evidence for a lymphoma could be found in all such cases when adequate histology was available.2 This was confirmed when imrnun~histochemistry~~~ and beta-T-cell receptor gene rearrangement studies were p e r f ~ r m e d . ~ . ~ However, variants of the term 'midline granuloma' are still to be found in the literature'.' and may perpetuate the view that a poorly defined cause of upper respiratory tract destruction still exists. The failure to investigate all such cases until a specific diagnosis is made can lead to inappropriate patient management.'.'' The aim of this review is to describe the characteristics of these peripheral T-cell lymphomas (PTCL), in particular those features which have contributed to the difficulty in diagnosis, and to outline a rational scheme for investigating the patient.
cytokines in large quantities'' and the presence of significant numbers of non-neoplastic cells has been shown to be restricted to those peripheral T-cell lymphomas which contain neoplastic T-cells with the features of activated cells." The malignant T-cells are often difficult to recognize. This is in part due to the neoplastic cell clone having a heterogenous cytological appearance as a result of malignant cells being a t different stages of differentiation and activation.12.'9 In one series, the scanty malignant cells formed homogenous groups in only half the cases of nasal lymphoma.2 The limited amount of biopsy material available from the nose adds to the diagnostic difficulty. Many of the lymphomas involving the uppcr respiratory tract belong to a variant called angiocentric lymphoma.20 These tend to occur in extralymphatic sites and the malignant lymphoid cells show a tendency to surround, invade and destroy vessel walls. Necrosis, involving both tumour cells and normal tissues, occurs as a result. Whilst a correlation between angiocentricity and necrosis has been shown in some report^,^,'^,^^ it has not been found by others.22Again, the small and often superficial biopsies may be responsible for this lack of correlation. Table 1. Causes of upper respiratory tract destruction
Nasal lymphoma
Wegener's granulomatosis
T-cell lymphoma predominates in the nasal cavity and this Infections Bacterial: Rhinoscleroma contrasts with the predominantly B-cell lymphomas which Tuberculosis occur in other extranodal head and neck regions." It occurs Leprosy more frequently in Oriental than in Western p o p ~ l a t i o n s l ~ . ' ~ Brucellosis and the T-cell predominance holds true in both Actinomycosis populations. 5. 14. I s Syphilis Parasitic: Leishmaniasis The delayed recognition that this 'granuloma' was in fact a lymphoma was mainly due to the large number of benign Neoplasms cells (plasma cells, histiocytes, small lymphocytes, foam cells) Peripheral T-cell lymphoma B-cell lymphoma in the lesion. These are at least partly secondary to the Carcinoma recognized phenomenon of cytokine secretion by malignant Sarcoma T-cells.I6 Only activated T-cells arc capable of secreting
Fungal: Blastomycosis Rhinosporidiosis Phycomycosis Coccioidomycosis Candidiasis Histoplasmosis
563
564
SSenan
Table 2. Investigating the patient with nasal destruction History, examination, urinalysis, serum electrolytes and chest
radiograph Serology for syphilis, fungal infections and the antineutrophil cytoplasmic antibody CT or MRI scan of the head and neck
Examination under anaesthetic to obtain tissue for cultures and histology lmmunocytochemistry using T- and B-cell markers on frozen and paraffin fixed tissue. Southern blot analysis or polymerase chain reaction to detect clonal beta or gamma T-cell receptor gene rearrangement Repeat biopsy and cultures if no diagnosis established
Investigations The diagnostic evaluation of patients with this presentation requires adherence to a systematic and comprehensive scheme (such as that in Table 2) in order to exclude the many non-malignant causes. The patient’s country of origin, travel history and pre-existing medical condition (diabetes mellitus, immunosuppression) all influence the differential diagnosis. Prior consultation with a pathologist and microbiologist are advised in order to hasten diagnosis and minimize the need for repeated biopsies. Adequate microbiological investigations to exclude unusual fungal and bacterial infections can then be performed at the initial examination as histology alone cannot exclude infective causes of this presentation.”.” A compelling case has been made for tissue biopsy to be directed by frozen section e ~ a m i n a t i o nThis . ~ ~ will hasten the diagnosis by allowing for the adequacy of tissue for diagnosis to be assessed and immediate rebiopsy performed if necrotic, severely crushed or insufficient tissue is obtained. Immunocytochemistry is best performed on fresh frozen tissue and samples for bacterial and fungal cultures can be obtained at the same time. Although frozen section permits the use of a broad range of diagnostic antibodies for lymphoid malignancies, it does not allow for the optimum correlation of morphology with phenotype because of the poor correlation of histological and cytological detail in cryostat sections. The combination of the monoclonal antibodies UHCLI (CD45RO) and poly-CD3 on paraffinembedded tissues allowed for the neoplastic cells to be identified in 98% of T-cell lymphomas, whilst allowing for the morphology of the stained cells to be ~ v a l u a t e d . ~ ~ In B-cell lymphomas, clonality can be shown by immunocytochemical techniques which show light-chain restriction, even in paraffin sections.26By contrast, the diagnosis of T C L depends on the application of multiple criteria, none of which is absolutely reliable. As no pathognomic phenotypic marker of T-cell malignancy is currently available, the aber-
rant expression of phenotypic markers is taken as a fairly reliable indicator of T-cell m a l i g n a n ~ y However, .~~ low grade lymphomas can still have a n immunophenotype identical to normal T - c ~ l l s . ~Tissue * should, therefore, be set aside for T-cell receptor gene rearrangement studies should the initial investigations prove inconclusive. In contrast to B-cell lymphoma, where genotypic evidence of monoclonality was present in nearly all cases, only 53% of phenotypic T-cell lymphoma in one series had TCR-beta gene rearrangement detected by Southern blotting.29 This finding has also been reported by others” and, therefore, cannot be used as the sole criterion in excluding the diagnosis. The polymerase chain reaction has high sensitivity (it can detect predetermined D N A sequences from a single cell) and is an ideal tool to detect the gene rearrangements in the often scanty malignant lymphoid cells in these tumours in both fresh and paraffin-embedded tissue. The nasal T-cell lymphoma belongs to the group of lymphomas associated with the Epstein-Barr virus (EBV). EBV DNA has been detected in all Oriental patients with nasal T-cell lymphoma^'.^' although in-situ hybridization performed on archival material from Western patients detected EBV viral DNA in only 63% cases.’’ T lymphocytes infected with EBV D N A can support sustained viral replication3’ and this suggests a role for EBV in the rnalignant process.
Differential diagnosis It is important to exclude the limited form of Wegener’s granulomatosis, where lesions of the upper respiratory tract have occurred for up to 18 years before the correct diagnosis was made.’4,’5 The mixed acute and chronic inflammatory reaction in Wegener’s may overshadow both the necrosis and vasculitis in the small biopsies from the nose. The histological distinction between angiocentric lymphoma and Wegener’s has been considered straightforward by some as multinucleated giant cells and true granulomas are not features of angiocentric lymphomas, whilst neutrophils are prevalent and lymphoid cells relatively sparse in Wegener’s.” However, half of the nasal biopsies from patients ultimately shown to have Wegener’s show only non-specific inflammatory change^.^' All new cases should have the assay for the antineutrophil cytoplasmic antibody (ANCA), a specific and sensitive test for Wegener’s and other vasculitic proce~ses.~’However. the sensitivity of ANCA depends on disease activity and a negative test cannot rule out the diagnosis. Lymphomatoid granulomatosis is a peripheral T-cell lymphoma which is often cited in the differential diagnosis of nasal destruction. The vast majority of these patients have pulmonary. cutaneous and neurological lesions which allow for this disease pattern to be recognized.’*
Diagnosis and treatment of nasal lymphoma 565
Treatment In patients with localized disease, treatment using external beam radiotherapy often shows disappointing results, with 40-66% of patients developing r e c ~ r r e n c e . ' ~ . ~There ' , ~ ~ is n o evidence for a radiation dose-response relationship from these series and aggressive multiagent chemotherapy regimes d o not appear to be more effective in preventing relapse^.^' Local recurrence tends to occur within months of treatment c ~ m p l e t i o n ' ~and ~ ' ~histological progression t o a more monomorphous lymphoma occurs in u p to 20% of these case^.^^.^' O n the other hand, the use of cyclophosphamide and prednisolone has resulted in complete remissions in some patients relapsing after r a d i ~ t h e r a p y .This ' ~ is not surprising as complete remissions have been reported in low grade angiocentric lymphomas treated using the same regime." Systemic lymphoma develops in 10-25% of patients initially presenting with localized nasal lesions2341and a response t o aggressive chemotherapy a t this stage is u n c ~ m m o n The .~ variable outcome t o a varying range o f treatments supports the concept that angiocentric lymphoma represents a single clinicopathologic entity with varying degrees of clinical aggressiveness. " A haemophagocytic syndrome characterized by fever, hepatosplenomegaly a n d pancytopaenia can develop in nasal (and other angiocentric) lymphomas.s This is believed t o be a result of the secretion of phagocytosis-inducing factors by angiocentric lymphomas.16 It is important t o recognize this association and instituting systemic chemotherapy in this setting has lead t o long-term survivors.
Conclusions The diagnosis of nasal peripheral T-cell lymphoma is occasionally a difficult one t o make. The histological findings in small biopsies may be non-specific a n d infections may be excluded only by meticulous investigation. Failure to adhere t o a systematic scheme of investigation and a willingness t o accept that ill-defined granulomatous conditions still exist can have disastrous consequences for the patient."
References 1 STEWART J.P. (1933) Progressive lethal granulomatous ulceration of the nose. J . Laryngol. 48, 657-701 2 MICHAELSL. & GREGORY M.M. (1977) Pathology of 'nonhealing (midline) granuloma'. J . Clin.Path. 30, 3 17-327 3 CHANJ.K.C., NG C.S., LAU W.H. & Lo S.T.H. (1987) Most nasal/nasopharyngeal lymphomas are peripheral T-cell neoplasms. Am. J . Surg. Path. 11, 418-429 4 CHOTT A., RAPPERSBERGER K., SCHLOSAREKW. & RADASZKIEWICZ T. (1988) Peripheral T-cell lymphoma presenting primarily as lethal midline granuloma. Hum.Path. 19, 1093-1 101 5 FERRYJ.A., SKLARJ., ZUKERBERG L.R. & HARRIS N.L. (1991) Nasal lymphoma. A clinicopathologic study with
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