Extranodal non-Hodgkin's lymphoma of the oral tissues an analysis of 20 cases

]. max.-fac. Surg. 13 (1985) j. max.-fac. Surg. 13 (1985) 85-92 © Georg Thieme Verlag Stuttgart - New York

Extranodal non-Hodgkin's Lymphoma of the Oral Tissues An Analysis of 20 Cases PieterJ. Slootweg, Albert R. M. Wittkampf, Philip M. Kluin, Peter C. M. de Wilde, Jan A. M. van Unnik Department of Oral Pathology (Head: P. J. Slootweg, M.D., D.M.D.) Department of Maxillo-Faciai Surgery (Head: Prof. P. Egyedi, M.D., D.M.D.) Institute of Pathology (Head: Prof. J.A.M. van Unnik, M.D.) State University of Utrecht, the Netherlands Submitted 18.4. 1984; Accepted 26.6. 84

Introduction Extranodal non-Hodgkin's lymphoma (ENHL) is one of the more common non-epithelial malignancies in the head and neck region (Duurkens et al., 1981). Occurrence in the oral cavity has been noticed for many years (Christiansen, 1938) and in addition to reports of single cases, some larger series or review articles on the subject have been published (Gerry and Williams, 1955; Steg et al., 1959; Cook, 1961). Some of these papers have been devoted to a particular lymphoma sub-type (Campbell et al., 1975; CIine and Stenger, 1977), others paid attention to a specific location (Tomich and Sharer, 1975; Blok et al., 1979). Originally termed lymphosarcoma or reticulum cell sarcoma, these intra-oral ENHL have not been further classified with regard to morphological and biological variation as was done for those arising in lymph nodes (Rappaport, 1966; Lennert and Stein, 1981; N-HLPC Project 1982). The present study was undertaken to determine whether these NHL-classifications as based on nodal NHL could also serve to subdivide intra-oral ENHL into prognostically different categories. Moreover, the relative frequency of the various ENHL subtypes occurring intra-orally was compared with those occurring in lymph nodes, thus enabling us to establish whether one or more of these histological patterns are most commonly seen in the oral cavity.

Materials and Methods Specimens from 20 patients with ENHL in the oral cavity were drawn from the files of the Department of Oral Pathology at the Uni;cersity of Utrecht. The material had been submitted for diagnosis between 1950 and 1983 and formed part of approximately 10 000 specimens that were received during the same period. Histological material was reviewed. I f available, paraffin blocks were re-cut (3--4 micron) and studied using the following stains: haematoxylin and eosin, periodic acid Schiff, Giemsa, reticulin and methylgreen-pyronin. Cases

85

Summary A series of 20 patients with extra-nodal non-Hodgkin's lymphoma (ENHL) of the oral cavity was analysed with the emphasis on histopathological variability and prognostic factors. The current diagnostic schemes as devised for nodal NHL proved also to be useful in diagnosing ENHL in the oral cavity. With respect to histopathology, intra-oral ENHL differs from nodal NHL in a lower incidence of nodular growth pattern and a relative predominance of the lymphoma sub-type with large vesicular indented nuclei. These are features, however, that are shared with ENHL in other body sites and thus are not unique to the oral location. Another salient histological feature was the presence of proliferating bizarre spindle cells with formation of whorling bundles of reticulin, thus creating a pseudosarcomatous growth pattern in some cases. The clinical stage proved to be the main discriminating factor between those who survived and those who died of their lyrnphoma. Of the patients who were in stage IE on admission, 70 % survived as opposed to only 20 % of those who were in stage II or IV. A better prognosis for cases with soft tissue involvement as opposed to intraosseous lymphoma is probably due to a consistently lower clinical stage in the former group. The prognostic value of the clinical stage emphasizes the importance of adequate clinical staging procedures.

Key-Words Oral lymphoma - Lymphoma of bone - Reticulum cell sarcoma - Tumour

were classified in conformity with each of the current diagnostic schemes (Table 1). Clinical data and radiographs were available within the files of the Clinic for Maxillofacial Surgery of the Utrecht University Hospital. These clinical data are summarized in Tables 2 and 3. Cases in bone and soft tissue have been tabulated separately to evaluate whether they show a differing clinical course. After 1974, clinical staging of patients (Cases 7-14, 19, 20) was performed according to the Ann-Arbor Conference directives (Carbone et al., 1971) with the exception of laparotomy; this is justified as it has been established that with ENHL in the head and neck region, the value of laparotomy is low and therefore not indicated (Duurkens et al., 1981). Patients seen before 1974 were staged retrospectively as accurately as was possible with the available historical data. As the search for distant sites of disease was carried out less frequently in earlier years, some of these patients may have been understaged. Some cases were incompletely documented. They will be discussed using the available data. The oral cavity was the site of primary clinical manifestation of ENHL in all cases. Patients in whom the lymphoma had been discovered in other parts of the body prior to the onset of symptoms of jaw involvement were not included in this study. Neither were cases with primary involvement of the salivary glands.

J. max.-fac. Surg. 13 (1985)

86 Table 1

Histological classification of reported patients

Case no.

A. Cases in bone 1. 2. 3. 4. 5. 6. 7. 8. 9.

Classified according to Rappaport (1966)

Classified according to Lennert (1981 )

diffuse histiocytic diffuse histiocytic and lymphocytic diffuse histiocytic and lymphocytic diffuse histiocytic diffuse histiocytic

centroblastic centrocytic/centroblastic

diffuse histiocytic diffuse histiocytic dlffuse histiocytic nodular lymphocytic poorly differentiated diffuse histiocytic diffuse histiocytic nodular mixed histiocytic and lymphocytic diffuse histiocytic diffuse histiocytic

10, 11. 12. 13. 14. B. Cases in soft tissue 15. 16. 17. 18. 19. 20.

Table 2. Case no.

PieterJ. Slootwegetal.

diffuse lymphocytic poorly differentiated nodular lymphocytic poorly differentiated diffuse histiocytic undifferentiated diffuse lymphocytic poorly differentiated diffuse histiocytic

Classified according to the Working Formulation (1982)

diffuse large cell diffuse mixed small and large ceil centroblastic diffuse mixed small and large cell centrocytic diffuse large cell centrocytic/centroblastic diffuse mixed small and large cell centroblastic diffuse large cell centrocytic/centroblastic diffuse large celt immunoblastic large cell, immunobtastic follicularcentrocytic/centro- follicular, predominantly blastic small cleaved cell diffuse centrocytic diffuse large cell diffuse centrocytic diffuse large cell follicularcentrocytic/centro- follicular mixed small blastic cleaved and large cell centrocytic/centrob/astic diffuse large cell centrocytic/centroblastic diffuse large cell

Histological grade of malignancy according to the Working Formulation (1982)

intermediate intermediate intermediate intermediate intermediate intermediate intermediate high low intermediate intermediate low intermediate intermediate

centrocytic

diffuse small cleaved cell

intermediate

follicular centrocytic/centroblastic centrocytic/centroblastic lymphoblastic centrocytic

follicular predominantly small cleaved cell diffuse large cell small non-cleaved diffuse small cleaved cell

low intermediate high intermediate

immunob/astic

large cell, immunoblastic

high

Clinical data of patients in whom the lymphoma originated intra-osseously

Sex

Age*

Time initial symptoms to diagnosis* * Pat's Doct's delay delay

Clinical stage

Intra-oral location

Initial therapy

Follow up

Survival***

Persistent/ Disserecurrent mination local disease

1. 2. 3.

F M F

68 42 72

0 0 1

4~/~ 47 1

lie liE IE

Maxilla Mandible Hard palate

Irradiation Irradiation Resection

+ + +

+ -

4. 5. 6. 7. 8. 9. 10.

M M F M M M F

61 9 80 49 69 55 51

? 0 3 0 0 3 4

? 2 0 0 60 2 9

lIE IE liE IVE IE IE IVE

Resection Irradiation Irradiation Irradiation Irradiation Irradiation Chemotherapy

+ + + + -I+

+ + + + + -

11. 12. 13.

F F F

58 72 36

0 1 0

2 0 9

IE IE tE

Maxilla Maxilla Maxilla Maxilla Maxilla Maxilla Hard and soft pal. Maxilla Maxilla Maxilla

Died after 5 mo's Died after 6 mo's Died after 10 mo's (unrelated cause) ? Survived >10 yrs. Died after 9 mo's Died after 11 mo's Died after 5 yrs. Died after 2 yrs. Survived >2 yrs.

-

Survived >2 yrs. Survived >2 yrs. Survived >11/2 yr.

14.

M

38

1

1

IE

Mandible

-

Died of intractable bleeding before therapy had started

* Age in years at time of diagnosis ** Time interval in months * * * Time interval dated from the initial therapy.

Irradiation Irradiation Resection, irradia-tion, chemother. None -

ExtranodaI non-Hodgkin's Lymphoma of the Oral Tissues

Fig. 1 Low power view shows tumour nodules composed of intertwining fascicles that extend into the periodontal ligament space. Alveolar bone is present on the left side and root dentine on the right side of the photomicrograph. HE, x 15.

Table 3. Case no.

J. max. ffac. Surg. 13 (1985)

87

Fig. 2 Photomicrograph shows the pseudo-sarcomatous growth pattern of whorled fibrous fascicles. HE, x 36.

Clinical data of patients in whom the soft tissues were primarily involved*

Sex

Age

Time initial symptoms to diagnosis Pat's Doct's delay delay

Clinical stage Intra-oral location

Follow-up

Survival

Persistent/ Dissemirecurrent nation local disease

15. 16. 17.

M F M

53 72 58

0 ? 0

0 ? 1

IE liE IE

Palate Floor of mouth Palate

18. 19.

F M

54 62

? 2

? 26

? IE

20.

M

79

18

0

IE

Floor of mouth Perimandibular soft tissues Perimandibular soft tissues

See footnotes to Table 2

Initial therapy

Resection Resection Irradiation, chemotherapy Resection Resection, Irradiation Chemotherapy

? -

? -

Survived >16 yrs. ?

? -

? -

? Survived >8 yrs.

+

Survived >14 yrs.

Died after 2 yrs. (unrelated cause)

88

J. max.-fac. Surg. 13 (1985)

Fig. 3 Photomicrograph shows lymphoma cells with vesicular nuclei that are diffusely scattered between the pieomorphic spindle cells. These latter ceils predominate in the histological picture. HE, x 150.

PieterJ. Slootwegetal.

Fig. 4 Photomicrograph shows peripheral part of the tumour where the fibrosis is rather pronounced. Lymphoma cells are not observed in this area. HE, x 150.

Results

Histological Findings Most cases could be classified within one of the wellestablished entities as defined in the several NHL-classifications (Rappaport, 1966; Lennert and Stein, 1981; N-HLPC Project, 1982). There were, however, 5 cases (2, 10, 11, 13, 14) with a peculiar histomorphology not seen in nodal NHL. They were characterized by a proliferation of pleomorphic spindle cells lying in a dense network of whorled reticulin fibres (Figs. 1-4). Intermingled lymphoma cells exhibiting vesicular, irregularly outlined and hypersegmented nuclei (Figs. 5, 6) were mainly observed in the central turnout areas and did not form a conspicuous histopathological feature in these cases. This fibrobtastic proliferation had led to an erroneous interpretation of sarcoma in 3 of these patients and to a diagnosis of reactive inflammatory lesion in the 2 other cases. Additional immunohistochemical and ultrastructural investigations (reported in detail elsewhere, Kluin et al. in press) disclosed that these cases actually represent lymphomas in spite of their predominant pseudo-sarcomatous histomorphology as they showed monoclonal immunoglobulin expression of the intermingling lymphoid cells. As a consequence they

were classified according to the nuclear morphology of the vesicular lymphoid cells (Figs. 5, 6): histiocytic (Rappaport, 1966), centroblastic-centrocytic (Lennert and Stein, 1981) or diffuse large cell (N-HLPC Project, 1982). Individual diagnoses of the various cases are summarized in Table 1. Conforming to Lennert and Stein (1981), the diffuse centroblastic-centrocytic sub-type is the most frequently occurring lymphoma. When considering the Working Formulation (N-HLPC Project, 1982) 3 cases are of low-grade malignancy, 14 of intermediate malignancy and 3 of high grade malignancy. Within this classification, the diffuse large cell lymphoma is the most frequent one, whereas within the classification of Rappaport (1966), diffuse histiocytic lymphoma is the most frequently occurring sub-type.

Clinical Findings Age and sex distribution: ENHL of the oral cavity usually develops in the 6th to 8th decade of life. About 75 % of our cases fell within this age group. Only 3 patients developed ENHL before the age of 40. The average age of the 20 patients at the time of admission was 57 years. Average

Extranodal non-Hodgkin's L ymphoma of the Oral Tissues

]. max.-fac. Surg. ~3 (1985)

89

Fig. 5 Centrally in the lesion, the lymphoma ceils are a more conspicuous feature than in the peripheral parts. Within a dense cluster of cells with vesicular, irregular outlined nuclei, several mitotic figures are observed. HE, x 240.

Fig. 6 At high-power view, the extensively Iobuiated appearance of the nuclei of the lymphoma cells is easily observed, HE, x 600,

age of cases with osseous locations was 54 years whilst soft tissue cases showed an average age of 63 years. No sex predominance was found, Location: The lymphoma was located intraosseously in 14 cases whereas the soft tissues were involved in 6 patients. The majority of cases involved the maxillary bone (10 out of 20, 50%). The hard palate and the mandible were involved in 2 patients each. Palate, floor of the mouth and perimandibular soft tissues each accounted for 2 cases in the soft tissue group. Signs and symptoms: In all but one patient, intra-oral swelling was the predominant symptom. Ulceration was noted in 3 patients and 4 patients suffered from numbness due to neural invasion by the neoplastic process. In one patient in whom nasal obstruction was the predominant symptom, chronic maxillary sinusitis had been the presumptive diagnosis for which he had been treated for 5 years elsewhere, without biopsy. In 5 other cases, initial symptoms mimicked an inflammatory process and these had been treated as such for various periods. Lymphadenopathy, observed in 7 patients, involved the submandibular and upper cervical lymph nodes.

The average time from onset of symptoms to diagnosis for the entire group was l0 months with the range being from 1 week to 5 years. The doctor's delay in diagnosis exceeded the patient's delay in seeking treatment in almost all cases.

Radiographic Findings Radiographs were available in all cases. Bone involvement was noted in 16 of these. In 2 cases the lymphoma had caused cortical erosion and these have been tabulated as soft tissue cases. In 3 cases the radiographs had initially suggested periapical inflammation (Fig. 7) and treatment had consisted of extraction and periapical surgery. In another case, radiographs had initially suggested mandibular osteomyelitis (Fig. 8).

Clinical Stage In 19 patients, the available data, obtained retrospectively or by staging procedures on admission, enabled us to establish their clinical stage. Twelve of these were in stage IE, the intra-oral disease being the single manifestation, whereas 5 patients were in stage IIE as evidenced by the involvement of intra-oral tissues and submandibular or cervical lymph

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J. max.-fac. Surg. 13 (1985)

Fig. 7 Radiograph shows moth-eaten destruction of the periodontal ligament space with diffuse involvement of the central jaw area. The second premolar tooth treated endodonticatly as the initial symptoms mimicked periapical disease.

Table 4

Fig. 8 Panoramic radiograph shows incomplete dentition with several root fragments in situ. Irregular destruction with accompanying sclerosis of the alveolar bone in the right mandibular molar area. Initial diagnosis was osteomyelitis.

ENHL of the oral cavity. Ctinical course

tncompieteremission, longer than 5 years In complete remission, for not yet 5 years Alive with active local disease Died oftumour

Table 5 survival

PieterJ. Slootwegetal.

Cases in bone

Cases in soft Whole group tissue

1/12(8%)

3/3 (100%)

4/15 (27%)

3/12 (24%)

-

3/15 (20%)

1/12(8%)

-

1/15(7%)

7/12 (58%)

-

7/15 (47%)

nodes. No patients were in stage III and 2 patients were in stage IV. In one of these cases, physical examination revealed additional lymphomatous involvement at distant body sites whereas in the other stage IV case, the disease was limited to multiple extranodal as well as nodal locations in and around the oro- and nasopharynx.

Treatment and Clinical Course

ENH L of the oral cavity. Influence of clinical stage on

Clinical stage

Cases in bone

Cases in soft Whole group tissue

IE liE IV Total number of survivors

4/7 0/3 1/2 5/12

3/3 (100%) 3/3 (100%)

(57%) (0%) (50%) (42%)

7/10 0/3 1/2 8/15

(70%) (0%) (50%) (53%)

Table 6 ENHL of the oral cavity. Relationship between clinical stage and histological grade of malignancy (Working Formulation 1982) Clinical stage

Low-grade NHL

Intermediate NHL

High-grade NHL

IE liE IV

2 1 -

8 4 2

2 -

Five patients underwent surgery, 9 radiation therapy and 2 chemotherapy as single mode of treatment. One patient received post-operative radiation therapy after incomplete surgical removal and another patient was treated with irradiation and chemotherapy. One patient received postoperative radiation therapy and chemotherapy after incomplete surgical removal of the local lesion. The outcome for the patients is summarized in Table 4. Three patients were lost to follow-up and 2 died of an unrelated cause (Case3, metastatic breast carcinoma; Case 20, carcinoma of colon). These 5 patients have not been tabulated here. Seven patients died after an interval of 1 month to 5 years after diagnosis. The reason for death was disseminated disease (5 patients) or intractable local disease (1 patient). One patient died of profuse bleeding from the tumour before appropriate treatment could be given. The relationship between clinical stage and survival is presented in Table 5. It is seen that the majority of survivors were in stage IE on admission. To rule out the possibility that this is due to an over-representation of low-grade malignant ENHL in the stage IE group, grades of malignancy have been separately tabulated (Table 6). It is noted that most IE cases are of intermediate, and not low-grade, malignancy. Moreover, the importance of clinical stage with respect to survival is stressed by the observation that within the group of intermediate malignancy, survival was 86 % as opposed to 20 % (one out of 5) for stage lie and IV

Extranodal non-Hodgkin's Lymphoma of the Oral Tissues Table 7 ENHL of the oral cavity. Influence of clinical stage on survival within the intermediate malignant group (Working Formulation 1982) Clinical stage

Survival

tE liE IV

6/7 (86 %) 0/3 ( 0 % ) 1/2 (50%)

Table 8 ENHL of the orN cavity. Relationship between histological grade of malignancy (Working Formulation 1982) and survival. Grade of malignancy Cases in bone Low grade Intermediate High grade Total numberof survivors

1/2 4/9 0/1 5/12

(50%) (44%) (0%) (42%)

Cases in soft tissue 3/3 (100%) 3/3 (100%)

Whole group 1/2 7/12 0/1 8/15

(50%) (58%) (0%) (53%)

cases (Table 7). From Tables 4, 5, and 8, it can be inferred that cases in which the lymphoma involves soft tissues exhibit a better prognosis than those in which the lymphoma was located intra-osseously. This finding can be explained by the influence of stage on survival. All soft tissue cases with follow-up data were in stage 1E at admission. Table 8 presents the relationship between histological grade of malignancy and survival but because of the small number of cases that are of low- or high grade malignancy, conclusions about the influence of histological grade on survival cannot be drawn. Irradiation and resection provided a permanent cure in all but two stage IE cases but were not succesful when the clinical stage was IIE or IV.

Statistical Analysis To study the relationship between clinical stage and survival some assumptions have been made. Patients have been divided into two groups: one consisting of IE cases and the other consisting of stage IIE and IV. Moreover all tumours were considered independent of location. To meet the small number of patients in this study, the exact test of Fisher was used in the analysis of the 2 x 2 contingency for Tables 5 and 7 (Sachs, 1978). Applying this test for Table 5 results in a one-tailed p of 0.1002. This pvalue is on the threshold of significance. Applying the same test for Table 7 results in a one-tailed p of 0.045. This pvalue is weakly significant. It seems that the clinical impression of negative correlation between stage and survival is underscored by the statistical analysis for the intermediate malignant group only. Discussion

Primary ENHL in the oral cavity appears to be rare. In our material it makes up 0.2 % of the total number of cases processed in our oral pathology service. This compares very well with the 0.1% mentioned by Tomich and Sharer (1975). According to Freeman et al. (1972), ENHL

]. max. ffac. Surg. 1.3 (1985)

~t

accounts for 2 4 % of all NHL's and 3 % of these were primarily located in the oral cavity. A comparison of the histopathological features of our series with those reported for nodal NHL revealed several points that warrant further discussion. The first distinctive observation was the pseudo-sarcomatous growth pattern that was exhibited by several cases. Abundant production of reticulin has been recognized previously as a feature of reticulum cell sarcoma of bone (Parker and Jackson, 1939; Cline and Stenger, 1977). Also, the typical morphology of the intermingling lymphoid cells with their irregularly outlined and hypersegmented nuclei has already been mentioned (Parker and Jackson, 1939; Dosoretz et al., 1982) and discussed extensively under the label "multilobated" by Pinkus et al. (1979). We have not been able to trace any previous reference to the accompanying bizarre spindle cells that had given rise to an initial erroneous diagnosis of sarcoma, with the consequence of inappropriate surgical treatment. The question whether these cells represent a reaction of the bone marrow to the neoplastic infiltration of lymphoma cells or that they represent a distinctive feature of a peculiar type of lymphoma is still unresolved. Two arguments favour the first possibility. Firstly, a pseudosarcomatous growth pattern was exhibited by the maxillary tumour in case 10 whereas it was absent in the involved cervical lymph node. Secondly, the whorled fascicles of fibrous tissue extended beyond the lymphomatous area in the surgical specimen of case 13. So it is probable that the fibrosis is a reaction of the bone marrow to the tumour. Secondly, there was a difference in the relative frequency of growth patterns. A nodular pattern was present in 15 % of our series as opposed to 40 % in the series reported by the N-HLPC Project (1982). A proportionately low incidence of nodular NHL has also been reported for oral ENHL by Eisenbud et al. (1983), for ENHL elsewhere in the body (Brown et al., 1975; Reimer et al., 1977; Kapadia et al. 1981; Duurkens et al., 1981), and in a series of ENHL throughout the body that was compiled in the Netherlands (Parren and van Unnik, in press). Therefore, this histological feature is not exclusive to the oral cavity but represents a common feature of all ENHL. When the relative frequencies of the NHL sub-types occurring in our series are compared with the N-HLPC series (1982), several differences are noted. Using Rappaport's classification (1966), diffuse histiocytic lymphoma accounted for 60 % of the cases in our series as opposed to only 30 % in the reference series (N-HLPC Project, 1982). A similar predominance of diffuse histiocytic lymphoma in lymphomas of the oral cavity has been noted by other authors (Steg et al., 1959; Hashimoto and Kuribara, 1982). It seems to be a consistent finding that this NHL sub-type is the one most often encountered in the oral cavity. In addition, the same high incidence of diffuse histiocytic lymphoma has been reported for ENHL in other parts of the head and neck region (Duurkens et al., 1981), in bone (Reimer et al., 1977), and in the nose and paranasal sinuses (Kapadia et al., 1981). Therefore the relative predominance of the diffuse histiocytic lymphoma sub-type is not confined only to the oral cavity but is a common feature of ENHL in general. When discussing the influence of clinical stage on prognosis, one must keep in mind the lack of uniformity in the staging procedures used during the period in which this series was compiled. Patients seen before 1974 may have

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J. max.-fac. Surg. 13 (1985)

Pieter J. Slootweg et al.: Extranodal non-Hodgkin's Lymphoma

been understaged for reasons as stated above. It is noted that only 2 stage IE patients (cases 8 and 9), both being staged in conformity with the Ann Arbor directives (Carbone et al., 1971), exhibited dissemination in their clinical courses while the other stage IE patients did not, this notwithstanding local therapy as the single mode of treatment. This might be considered to suggest that the patients staged retrospectively were indeed devoid of disseminated disease at the time of diagnosis, justifying their stage IE classification. Table 5 presents the prognostic significance of the clinical stage. It is seen that 7 out of the 10 patients in stage IE survived as opposed to only 1 out of the 5 patients in stage IIE or IV. This negative correlation between clinical stage and prognosis agrees very well with the results of Freeman et al. (1972) who established a poorer survival rate for regional ENHL in comparison with localized ENHL. It also supports the observation of Steg et al. (1959) who reported a poor prognosis of oral lymphoma with lymph node involvement but is at variance with the study of Kapadia et al. (1981) who did not find any effect of clinical stage on the duration of survival. When considering therapy, it is seen that varying modes of treatment have been used. Patients in stage IE were cured by irradiation or resection. However, irradiation is preferred to mutilating surgery. In addition, surgery was occasionally the result of an erroneous diagnosis of sarcoma due to the predominant pseudo-sarcomatous histomorphology as described above. The recognition of this histomorphological appearance of ENHL has prevented mutilating surgery in 2 recent patients (cases 11 and 12). Irradiation failed to provide cure in a more advanced clinical stage. This stresses the importance of adequate clinical staging for every patient with ENHL of the oral cavity for determining whether therapy must be directed towards a local lesion or disseminated disease. Acknowledgement Thanks are due to Dr. H. Vercruysse, Antwerp, for contributing case 11 and to Dr. A. van den Broek, Rotterdam, for contributing case 12.

References

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P. J. Slootweg, M.D., D.M.D. Dept. Oral Pathology Sorbonnelaan 16 NL-3584 CA Utrecht