oral pathology Editor:
CHARLES American
A. WALDRON, Academy
D.D.S.,
M.S.D.
of Oral Pathology
School of Dentistry, Emory 1462 Clifton Road, N.E. Atlanta, Georgia 30322
University
Lymphoproliferative disease of the hard palate: A clinicopathologic entity A study
of twenty-one
cases
Chrrrles E. Tomich, D.D.S., M.s’.D.,* TVillia,,l 6. Shafer, D.D.X., N.S.,#* I?ldiawnpolix, Ilzd. INDI,\NA
UNIVERSITY
SCHOOL
a?ld
OF DENTISTRY
Twenty-one cases of a lymphoproliferative disorder believed to represent a clinicopathologic entity were studied. These lesions, which appeared on the hard palate, occurred in elderly men and women with an average age of 70 years. The lesions presented as soft, fluctuant swellings which were occasionally bilateral, ulcerated, or discolored. Microscopically, the lesions were classified as lymphocytic lymphomas; eight were diffuse and well differentiated, seven were nodular and well differentiated, and six were diffuse and poorly differentiated. All lesions were characterized by a tendency of the lymphocytes to show nuclear fragility. Accessory salivary gland in volvement wvas common, this being characterized by acinar obliteration to varying degrees and by periductal hyalinization of collagen. lkterminate follow-up of fourteen patients disclosed that eight died of disseminated lymphomn, three are alive with disease, and three arc free of disease after treatment with radiation and/or chemotherapy. I~ympl~oproliferativr lesions in this location are believed to be malignant or potentially malignant processes.
T
he pathologist, because of the very nature of human disease, is repeatedly confronted by perplexing diagnostic problems. A given pathologist may develop remarkable expertise in one particular area but feel very uncomfortable in another. The broad spectrum of pathologic processes invol\-ing lymphoid tissues This investigation was supported in part by Public CA8006 from the National Cancer Institute. “Associate Professor, Department of Oral Pathology. **Distinguished Professor and Chairman, Department
754
Health
of Oral
Service
Training
Pathology.
Grant
5TlZ-
Volume Number
39 5
Lymphoproliferuthe
disease of hard palate
755
frequently presents one of the greatest of all diagnostic challenges. The parameters of disease of these lymphoid tissues extend from the obviously benign inflammatory or reactive lesions to the obviously malignant ones, The major diagnostic problems arise in the zone between the two opposite poles and, indeed, many of these are the lesions which remain equivocal microscopic enigmas. Lymphoid aggregates are present in a variety of locations in the oral cavitythe lateral border of the tongue, the ventral surface of the tongue and floor of mouth, the buccal mimosa, the fauces, and the soft palate. Quite obviously, these lymphoid tissues are subject to most, if not all, of the various reactive and neoplastic processes occurring in the extraoral lymphoid tissues. While at least some of these processes are not commonly encountered in the oral lymphoid tissues, they are not SO uncommon as to be considered rare. Such lymphoproliferative lesions encountered in the oral cavity pose the same diagnostic problems as those elsewhere, with benign proliferations being confused with malignant ones and vice versa. It has been our observation over the years that the hard palate is a relatively common site for lymphocytic proliferations and we have long considered the possibility of the occurrence of both a benign form, perhaps analogous to cutaneous lymphoid hyperplasia,4 and a malignant form, lymphosarcoma. The purpose of this study was to explore a group of lymphoproliferativc lesions of the hard palate, coded in our files under a variety of diagnoses, whose clinical description have all been dramatically similar and, by follow-up investigation, attempt to determine whether both a benign and a malignant form do exist. MATERIALS
AND
METHODS
Caseswith lymphoproliferative lesions of the hard palate were selected from the files of the tissue diagnostic service of Indiana University School of Dentistry, Department of Oral Pathology. These files consisted of 45,700 consecutive biopsy/surgical specimens accessionedbetween Oct. 1, 1950, and June 30, 1974. In the selection of casesfor study, all material coded in the Tumor Registry as leukemia, lymphosarcoma, and reticulum-cell sarcoma was reviewed. In addition, all material designated as some other intraoral benign lymphoid lesion was similarly reviewed. This included cases diagnosed as lymphoid hyperplasia, hyperplastic lingual tonsil, lymphadenitis, and benign cystic lymphoid aggregate. Significantly, there were no cases diagnosed as benign lymphoepithelial lesion (Mikulicz’s disease) of accessory salivary gland tissue in these files. Lymphoproliferative lesions from all intraoral sites other than the hard palate also were reviewed in order to obtain comparative data concerning frequency of occurrence of benign and malignant lymphoid diseasesin these locations as contrasted to the hard palate. AS suggested by Caro and Helwig,4 patients were considered to have a benign lesion if, with no definitive treatment, they were alive and free of disseminated disease (for example, leukemia or lymphoma) 5 years after biopsy. They were considered to have malignant diseaseif they died of leukemia or lymphoma or if a diagnosis of leukemia or lymphoma had been confirmed by bone marrow or lymph node biopsy, respectively. Microscopic slides and paraffin blocks were available in all cases. Histologic
Oral May,
756
To~mdz md
Table
I. Location of benign oral lymphoid hyperplasia
Shafer
Ruccal mucosa Tongue Floor of mouth Tonsillxr pillar Mucobuccal fold Mandihle, soft tissue Maxilla, soft tissue Soft palate Retromolar area Lower Iip Junction, hard and soft Palate ’ Unstated
Surg. 1975
31 11 10 7 7
palates
evaluation was made of sections stained with hematoxylin stains were not utilized.
% 3 2 2 1 1 1
and eosin. Special
RESULTS Clinical data
A total of eighty-three casescoded as benign Iymphoid hyperplasia, including benign cystic lymphoid aggregate, of the oral cavity were found in the files. The locations of these lesions arc shown in Table I. In addition, the files contained thirty-nine casesof hyperplastic lingual tonsil and nine casescoded as lymphadenitis. Of these latter nine cases,six occurred on the buccal mucosa and one each on the tongue, floor of the mouth, and tonsil. Significantly, of these 131 cases, there was not a single instance of a benign lymphoid lesion specifically designated as occurring primarily on the hard palate, However, there were three casesinvolving the soft palate, one occurring at the junction of the hard and soft palates, and one involving “palate.” There were eighteen casesof reticulum-cell sarcoma of the oral cavity; seven of these were either primary in the maxilla or involved the soft tissue of the maxilla but not the palate, while ten were either primary in the mandible or involved the soft tissue of the mandible. There were two caseswhich involved the palate, but they were unquestionably primary reticulum-cell sarcoma of bone and were excluded from the study. One case did occur on the hard palate. On reviewing this section, we concurred that it represented a poorly differentiated lymphocytic lymphoma with a. histiocytic component rather than a reticulum-cell sarcoma. Therefore, it was included in the present study. No case of reticulumcell sarcoma occurred in any other intraoral site, including even common sites of lymphoid aggregates, such as the tongue, tonsillar pillars, buccal mucosa, etc. There were thirty-four casesdiagnosed as lymphosarcoma of the oral cavity. The locations of these lesions were as follows : maxilla, five cases; mandible, six cases; buccal mucosa, two cases; tonsil, one case; and hard palate, twenty cases. These twenty casesand the one additional case mentioned above, representing all of the accessionedlymphoproliferative lesions occurring on the hard palate, form the basis of this study. The twenty-one palatal lesions occurred with equal frequency between the
Volume Number
Lyl,rphoZ,roliferatiz~e
39 5
disease
of
hrrrd pulrrte
757
SCSCS. There were eleven men and ten women and, with the exception of one lesion in a Negro man, all patients involved were Ca.ucasians. All of the palatal lymphoproliferative lesions had a remarkable predilection for occurrence in the elderly. The average age of the patients at the time of biopsy was 70 years, with a range of 50 to 81 years. Eighteen patients (86 per pent) were in the seventh and eighth decades of life, with only two in the sixth tlccn~lc and one in the ninth dccadc. The lesions most frequently involved one side of the hard palate, although four patients were described as having involvcmcnt of the entire palate. Both unilateral and bilateral involvement of tissue overlying the grcatcr palatine foramen also occurred. In six cases, thcrc was cstcnsion of the tumor onto the soft palate. The clinical description of the palatal lesion was remarkably consistent. \Vit,h the exception of two cases which were described as “firm swellings,” all cases were described as soft swellings in the palate. Descriptive terms included “spongy,” “cystic,” and “fluctuant.” As might be expected with lesions of such consistency, clinicians considered the possibility that the lesions contained fluid. In four instances the areas were incised ; however, this procedure yielded no tlrainagc. In most instances, the overlying mucosa was of normal color or was not described as being otherwise. The overlying mucosa was ulcerated in five instances. In three casts, the mucosa was said to be rcddencd, whereas in two additional caascs t,hc color deviated from normal, one bring described as “bluish” and the other as “grayish.” Eight, patients were known to bc denture wcarcrs, and in five of these cases the palatal swelling actually int,erfercd with the fit of the denture. In only a single instance (lit1 a clinician suspect lymphoproliferative discasc. The clinical impressions were usually rclatcd to suspcctcd salivary gland pathosis. A sa1ivar.v gland neoplasm was the provisional clinical diagnosis in eight cases, and cpitlermoic1 carcinoma was susIxctetl in two of the lesions which presented with ulceration. Four additional lesions were thought to he “abscesses.” Iirgional I~mph;rdcno~~atll~ was said to be absent in two cases. In all other cases, thc~rc WIS no mcntioll of l)alpablc nodes in the submitted histories. In one cast liematologi~ values wcrc submitted, and these were within normal limits. Microscopic
findings
In the microscopic evaluation of the palatal lesions, particular attention was given to epith~~lial cahangcs, the character of the cellular infiltrate, and the apl)carancc of the accessory salivary glands. In addition, stromal reactions or changes and cvitlcncc~ of mus~lc, fat, ant1 bone involvement wcrc recorded. Epithelitrl chtrn~e,s. There was a considrrablc mngc in changes occurring in the ovcrlyillg cpithclium. This varied from an cpithclium of normal thickness, usually whcrt~ the underlying tumor cdls were still some distance from the surface, to an atrophic cpithclium with blunting or loss of rcte ridges, where the tumor cells \vcrc’ impinging on the eovcring epithclium, to occasional ulceration (Fig. 1). In one instance, a “saw-tooth” pattern was apparent, but in no instance was thcro ally significant rcact,ivc ~)seudoepitheliomatous hypcrplasia. The
758
Tomich
and
Shafer
Oral May,
Surg. 19’75
Fig. 1. A diffuse, poorly differentiated lymphocytic lymphoma which has produced ulceration of the overlying mucosa. The cells are shown in greater detail in the inset. (Hematoxylin and eosin stain. Magnification, xl00 ; inset, x450.) Fig. 8. A nodular, well-differentiated lymphocytic lymphoma. Persistent accessory salivary gland ducts are present. (Hematoxylin and eosin stain. Magnification, x100.)
surface was usually covered with a layer of parakeratin of normal thickness, although occasionally this was orthokeratin. In no cases were there cytologic alterations in the epithelium. In general, any changes in the surface cpithelium appeared related to the proximity of the underlying tumor cells. Character of the cellular z’nfiltrclte. The cellular infiltrate consisted of lymphocytes in various stages of differentiation. Although histiocytic cells were occasionally present, they were not considered to be taking part in the neoplastic process. In one case, the histiocytic cells displayed active phagocytic properties. There was a marked tendency for the lymphocytic infiltrate to diffusely involve the palatal tissues. Only two cases displayed a “patchy” distribution. Three
Lymphoproliferative
Fig. 3. A diffuse, well-differentiated the tumor cells infiltrating the Magnification, x40.) Fig. 4. Detailed photomicrograph terized by elongated, streaked nuclei.
Note stain.
lymphocytic subepithelial showing the (Hematoxylin
disease
of hard
759
palate
lymphoma. Persistent ducts connective tissue. (Hematoxylin tendency toward cellular fragility and eosin stain. Magnification,
are present. and
eosin
characx450.)
cases exhibited “patchy” areas with an otherwise diffuse infiltrate. Since the majority of the specimens studied were from incisional biopsies, it may well be that a “patchy” distribution would be encountered more often peripheral to the main tumor mass. The lesions were categorized as nodular or difuse lymphocytic lymphomas with degree of differentiation classified as well differentiuted or poorly differentiated. With this classification, seven lesions were classified as “nodular, well differentiated” (Fig. 2) ; tight were classified as “diffuse, well differentiated” (Fig. 3) ; and six were classified as “diffuse, poorly differentiated” (Fig. 1). None were classified as “nodular, poorly differentiated.” Three of the nodular lym-
Oral May,
Surg. 1975
Fig. 5. A diffuse, well-differentiated lymphocytic lymphoma which has infiltrated palatal accessory salivary glands. The acinar structures are shown in greater detail in the inset. (Hematoxylin and rosin stain. Magnification, x100; inset,, x450.) Fig. 6. A higher-power photomicrograph of the diffuse, well-differentiated lymphocytic lymphoma shown in Fig. 3. Note persistent ducts and evidence of nuclear streaking. Periductal hyalinization is shown in greater detail in the inset. (Hematoxylin and eosin stain. Magnification, x100; inset, x450.)
phomas showed fairly well-defined germinal centers, whereas the remaining four merely exhibited a tendency to form follicular or nodular structures, this being a well-recognized phenomenon in lymphoreticular diseases.Three of the poorly differentiated lesions demonstrated a high degree of anaplasia characterized by extremely pleomorphic cells (Fig. 1, inset). Mitotic figures were present in large numbers in the poorly differentiated lesions, whereas they mere absent or sparse in the well-differentiated lesions. One finding which was consistently present in every case was a tendency for the lymphocytes to show evidence of cellular (or nuclear) fragility to a greater or lesser degree (Fig. 4).
Lymphoproliferative
disease of hard palate
Fig. 7. 8: A diffuse, poorly differentiated lymphocytic lymphoma zone. B, A diffuse, poorly differentiated lymphoeytic lymphoma with plastic process encroaches upon the overlying epithelium. (Hematoxylin nification, x100.)
761
with a well-defined grenz no grenz zone. The neoand eosin stain. Mag-
A’alivary glalad changes. The palatal tissues normally contain large numbers of accessory mucous gland acini, and these showed considerable alteration when there was impingement by tumor cells. As the tumor cells encroached on the collections of glands, the acini became obliterated through apparent cell rupture and disintegration. However, it was not uncommon to observe individual, intact, healthy acini within a solid sea of tumor cells (Fig. 5). The ducts were far more resistant to tumor cell onslaught and commonly persisted after all acini had been destroyed (Fig. 6). Alterations occurred in these ducts, characterized often by a mild squamous metaplasia. Significantly, there was no evidence of “epimyoepithelial cell” proliferation, as is characteristically seenin the benign lymphoepithelial lesion. It is of interest that intraductal mucin was frequently present in these isolated ducts, comparable to that commonly found in the tumor ducts of
762
Tomich
Oral May,
and Shafe?
Fig. 8. A diffuse, The tumor cells have cation, x40.)
well-differentiated infiltrated palatal
lymphocytic lymphoma with a “patchy” adipose tissue. (Hematoxylin and eosin
Surg. 1975
distribution. stain. Magnifi-
Fig. 9. A diffuse, well-differentiated lymphocytic lymphoma which has involved radicular bone of a maxillary molar. Periodontal ligament separates alveolar bone (Hematoxylin and eosin stain. Magnification, x40.)
the interand tooth.
such lesions as the pleomorphic adenoma. In contrast, intraductal mucin is a relatively infrequent finding in ducts affected by inflammatory changes, even a severe chronic sclerosing sialadenitis. One pertinent finding was so consistently present and so striking that it appears to be a component of this disease-periductal hyalinization. This appeared as a broad band of densely hyalinized collagen around many of the ducts involved by tumor (Fig. 6, inset). It appeared as though the continued proliferation of the neoplastic cells compressed the collagen more and more against the duct wall. Stromal changes. There were no consistent noteworthy stromal changes. A grenz zone sometimes separated the epithelium and the deeper tumor mass, but it
Volume Number
Ly?)lphoproliferatiz~
39 5
Table II. Patients Patient S. A. z: T. L. L. H. L.
FG. 8. c. D. L. R.
dead of lymphoproliferative
’ Histologic type N,WD D,WD D,PD D,PD D,WD N,WD D,PD D,WD
Type therapy Unknown Unknown Radiation Unknown Unknown Radiation Unknown Radiation
of
diseme of hnrd palate
disease Status
1
Time
763
of
death
Unknown 1 yr. 6 mo. 5 yr. 3 mo. 8 mo. 3 yr. 3 mo. 5 mo. 1 yr. 4 mo.
Present
of palatal /
Absent
lesion / Unknown
X X X X X X X X
D = Diffuse. N = Nodular. WD = Well-differentiated. PD = Poorly differentiated.
was absent as frequently as it was present (Fig. 7, A and B). In some instances, the tumor mass was rather sharply circumscribed but. did not appear to compress the adjacent collagen bundles significantly. Instead, there was generally some infiltration of tumor cells between collagen bundles for a varying distance beyond the main tumor mass. In a number of cases, there also was marked infiltration of the normal adipose tissue of the palate by tumor cells, leaving scattered and isolated fat cells within the deeper portions of the tumor mass (Fig. 8). Bone involvement was demonstrated histologically in three cases. This was dramatically evident in one case in which a molar tooth was removed at the time of the palatal biopsy (Fig. 9). One case showed extensive involvement of skeletal muscle of the soft palate. FOLLOW-UP
INFORMATION
Follow-up information was available in twenty of the twenty-one cases studied. Eight patients died of lymphoproliferative disease. The data on these patients are summarized in Table II. Two of the patients in this group received radiation therapy to the palatal lesion with subsequent regression; however, both succumbed to disseminated malignant lymphoma. The status of the palatal lesion was undetermined in one patient. The cause of death in this patient, as determined from the Indiana Division of Vital Records, was listed as “lymphosarcoma.” Six patients died of causes other than a lymphoproliferative disease. The data on these patients are summarized in Table III. In five of the six cases, it was not possible to determine the status of the palatal lesion, since this information was not mentioned on the death certificate; nor was it possible to gather this information from the practitioner who submitted the specimen. Interestingly, the palatal lesion in one patient (L. C., a 71-year-old woman) was said to have regressed without therapy. Unfortunately, the patient died of carcinoma of the colon with hepatic metastasis, and the status of the palatal lesion at the time of death was undetermined. Six patients are alive, three with disease and three apparently free of disease. The data on these patients are summarized in Table IV. Two of the patients in
Oral May,
764
Tomich and Shafer
Table
III. Patients dead due to other causes
hf. w. \V:. R.
D,WD DJ’D
iv:.
D,PD
Radiation Surgery and radiation Unknown
D,TVD N,WD
Unknown None
P.
A. M. I,. c.
infarct Pneumonia Myocardial infarct Renal failure Unknown Carcinoma of colon
1 yr. 2 yr.
3 mo.
2 yr.
5 mo.
0 yr. 1 yr.
10 mo.
Surg. 1975
x
D = Diffuse. N = Nodular. TVD = Well-differentiated. PD = Poorly differentiated.
this group have received no therapy. In one patient (R. C., nom an 82-year-old man), there is evidence of a large, inoperable palatal mass. In the other patient (C. S., now a 74-year-old woman), the palatal lesion has remained approximately the same size since it was originally biopsied. A third patient (L. M., now a 70-year-old woman) received no treatment after biopsy, which was essentially a subtotal excision. She is alive with a small massstill present in the palate. Three patients in this group are alive and apparently free of disease. One patient (E. w., now a 70-year-old woman) had evidence of a lymphoproliferative disorder when bone marrow studies were performed. She received radiation to the palatal lesion and was placed on chemotherapy. The palatal lesion regressed, and she is apparently in a state of remission. Another patient (H. S., nom a 66-year-old man) had histologic evidence of bony involvement (Fig. 9) in addition to his palatal lesion. He is alive and well after receiving radiation therapy to the area. A more recent case was treated by radiation and chemotherapy with regression of the palatal lesion. The patient (T. E., now a 69-year-old man) is alive and well 1 year after therapy. DISCUSSION
AND
CONCLUSIONS
The actual frequency of malignant lymphoma occurring primarily in and confined to the head and neck is difficult to assess.As Schnitzer and Weaver” have pointed out, lymphangiography and laparotomy mere not performed in most of the large series of head and neck lymphomas, and therefore these patients were not adequately studied for occult disease elsewhere in the body. However, Rosenberg and his colleagues1i have reported that more than 45 per cent of the malignant lymphomas initially manifest in the head and neck region, whereas Catlin” reported a lower frequency of approximately 20 per cent. Involvement of the head and neck region by malignant lymphoma is primarily nodal (usually the cervical nodes), with extranodal involvement being much less common. In the extensive Memorial Hospital series of 1,269 casesof malignant lymphoma, nearly 9 per cent of the cases appeared initially in the extranodal head and neck tissucs.17In a study of 153 casesof head and neck lymphomas,
Volume 39 Number
5
IV. Patients alive, either with discasc or free of discasc
Table
status of
Tiistologic Patient
type
c. s. L. M. E. WV.
11,wn N,WD N,WTl D,WD
H. S. T. E.
II,WD D,PD
R.
c.
Type
of
th,crnpy
None None Surgery Hadiation and chemotherapy Radiation Radiation and chemotherapy
Folh-~cp
intered
5 y1 yrtars 4 yr. 3 mo. 1 yr. 3 mo. 7 yr. 5 yr. 1 yr.
Present
pfdnta1
lwion
,4hrmt
x s s s x s
D = Diffuse. N = Nodular. WD = Well-differentiated.
McNelis and Pail* found that one third of the lesions wcrc in extranodal sites. Of these, one half involved Waldeyer’s ring. Similar data have been reported by Sugarbaker and Craver,l” who studied 196 casesof lymphosarcoma. Malignant lymphoma in the oral cavity is relatively uncommon. These lesions have constituted only 0.1 per cent of the total number of cases accessioned in our surgical pa.thology service. The palatal lesions reported herein accounted for 40 per cent of our lymphoma experience. In other studies, palatal lpmphomas in themselves have actually accounted for only a small segment of head and neck lymphomas, and the majority of these have been in the soft palate, this being considered an anatomic portion of Waldeyer’s ring. Banfi and his- colleagucs2 reported soft palate involvement in six of 225 cases (2.7 per cent) of lymphoma of Waldeyer’s ring. No lesions merr prcsent in the hard palate. There were two palatal lesions each in the series reported by Catlin” and by McNelis and l’ai,14 one of which was specifically found in the hard palate. It appears almost paradoxical that such a relatively large series of casesof lymphocytic lymphoma as that being reported here should occur at a site where there is no appreciable extranodal lymphoid tissue and yet there were no cases in intraoral sites of considerable quantities of extranodal lpmphoid tissue (lingual tonsil, floor of mouth, and soft palate) and only three cases involving faucial tonsil and buccal mucosa. However, in a study of 618 casesof malignant lymphoma, Gall and Mallory” observed, with respect to lymphosarcoma : “It is of interest that over half of these lesions appeared in non-lymphoid tissue, most frequently in bones and in the gastrointestinal tract, but occasionally in areas in which eyen isolated lymph follicles are not found under normal circumstances (i.e., the subcutaneous fat, the bladder and the cervix of the uterus) .” There have been numerous studies of the palatal tissues, both hard and soft, but even one of the earliest by Pendletonl” recognized that lymphoid tissue does not generally occur in the hard palate. KnappI’ has adequately demonstrated the common clinical appearcnce of lymphoid aggregates in the soft pal&e, however. It is equally surprising that there were no casesof benign lymphoid hyperplasia observed primarily in the hard palate; in fact, only five cases (3.8 per cent) were observed in the palatal tissues at all (Table I). This is in sharp contrast to Adkins” observation that benign lymphoid hyperplasia of the oral mucosa
Oral May,
Surg. 1975
is seen most commonly in the palate and tongue. In fact, he illustrated a bilateral lesion sit,uated in the posterior portion of the hard palate and described it as very soft, slowly growing, and deeply colored-a description amazingly similar to the malignant palatal lesions in our series. The palatal lymphomas appear to occur exclusively in elderly adults. The age range was 50 to 81 years, and eighteen patients (86 per cent) were in the seventh and eighth decades of life. This is in agreement with TdukeP’ observation that well-differentiated Iyml)hocytic lymphomas, the histologic type constituting two thirds of the palatal lesions, usually occur in patients over the age of 55 and arc rarely seen prior to the age of 45 years. Schnitzer and Weaver’” reported a nearly identical age predilection, and Catlin” likewise noted a tendency for elderly persons to manifest this form of lymphoma. The lesion usually occurs on one side of the hard palate, usually posteriorly near the greater palatine foramen. Although only four of twenty-one patients had bilateral palatal involvement, this finding is probably of clinical significance, since few other lesions, either benign or malignant, are manifest in such a manner. Thus, a soft, spongy, bilateral posterior palatal swelling in an elderly person should be considered highly suspect of malignant lymphoproliferative disease until proven otherwise. Schnitzer and Weave? state that the majority of extranodal head and neck lymphomas are histologically classified as diffuse lymphocytic lymphomas or reticulum-cell sarcomas. This has been our experience also. In fact, these two types constituted 88 per cent of our total lymphoma experience. A striking observation in all of the lesions was the tendency for the tumor cells to display a marked nuclear fragility characterized by elongated, streaked nuclei. While this phenomenon is not observed exclusively in malignant lymphoreticular disorders, it is observed so commonly in these lesions that we have come to regard it as a rather “reliable artifact.” It is surprising that this phenomenon has not been emphasized in the literature, and it may well be that most observers interpret it as artifact and therefore discount it. No special term has been previously suggested for this nuclear appearance, and we have been using the term sguigglies to describe this unusual, albeit reliable artifact. This infiltration of the hard palate by lymphocytes with eventual obliteration of accessory salivary gland acini, as has been pointed out, is characteristic of lymphosarcoma in this location. The infiltrates were either diffuse or nodular, not unlike the infiltrate described by Freedman8 in his study of ten malignant lymphomas considered to be primary in the major salivary glands. However, the infiltrate is also reminiscent of another more benign condition-the benign lymphoepithelial lesion, including Mikulicz’s disease, as well as Sjiigren’s syndrome. Characteristically, in these latter diseases, there is massive involvement of the major salivary glands by a lymphocytic infiltrate. However, it is now recognized that such involvement may also occur in the accessory glands of the palate and of the lip.3p B Although it would be most unlikely for the palate to be involved by the benign lymphoepithelial lesion without concomitant involvement of the major salivary glands, care must be taken in distinguishing histopathologically such a benign infiltrate from the malignant infiltrate de-
Lynzphoproliferatice
disease of hard palate
767
scribed in this series. Furthermore, there are now reports of the occurrence of a malignant form of the benign lymphoepithelial lesion in which the epithelial component undergoes malignant transformation with local or distant metastases.lO,I1 Finally, it has been recognized that, on occasion, malignant lymphoma will develop in association with or be preceded by the benign lymphoepithelial lesion or SjSgren’s syndr0me.l” In the present series, to the best of our knowledge, there was no indication of any other associated disease process affecting the major salivary glands, and these cases are all interpreted as representing primary extranodal lymphoma. In general, the acinar structures were not resistant to the neoplastic infiltrate; however, the ductal structures were quite resistant and invariably showed a marked periductal hyalinization (Figs. 5 and 6). This periductal response was observed by Freedman8 in the majority of the major salivary gland lymphomas, and, interestingly, Tarpley and his associateP observed similar findings in the labial glands of patients with Sjijgren’s syndrome. Thus, periductal hyalinization appears to result when salivary glandular tissues are invaded by a lymphoproliferative lesion such as a malignant or an autoimmune disorder. Determinate follow-up observations on fourteen patients with lymphoproliferative disease of the palate disclosed that eight patients died of disseminated disease. The remaining six patients are alive but have presented documented evidence of malignant lymphoma. Three of the patients are free of disease, but they have been treated with radiation and/or chemotherapy. Unfortunately, one patient was lost to follow-up and another six died of other causes. In this latter group, we were unable to determine precisely what role, if any, the palatal disease had played in five patients ; the disease was still present in one patient (W. R.), but it was not the primary cause of death. There does not appear to be a direct correlation between the histologic type and the eventual outcome of the process. However, the poorly differentiated lesions tended to result in the earlier death of the patient. In general, the palatal lesions are best treated by radiation. If disseminated disease is found to be present, chemotherapy is likewise indicated. This regimen has resulted in an apparent cure or state of remission in three patients. In two other patients, the palatal lesions regressed with radiation therapy, but the patients eventually died of disseminated lymphoproliferative disease. On the basis of our present state of knowledge, we believe that these lymphoproliferative lesions of the hard palate are malignant or potentially malignant. Therefore, radiation therapy is recommended, with or without chemotherapy depending upon the presence or absence of disseminated disease, respectively, for those patients presenting with such disease. REFERENCES
1. Adkins, K. F.: Lymphoid Hyperplasia in the Oral Mimosa, Aust. Dent. J. 18: 38-40, 1973. 2. Banfi, A., Bonadonna, G., Carnevali,, G., Molinari, R., Monfardini, S., and Salvini, E.: Lymphoreticular Sarcomas With Primary Involvement of Waldeyer’s Ring, Cancer 26: 341.351, 1970. 3. Bertram! IJ., and Hjiirting-Hansen, E.: Punch-Biopsy of Minor Salivary Glands in the Diagnosis of SjBgren’s Syndrome, Stand. J. Dent. Res. 73: 295-300, 1970.
768
Tomich
4. (‘are,
\V. A.,
a)ld
Oral May,
Shafer
ant1 Helwig,
E. B.:
Cutaneous
Lymphoitl
Hyperplasia,
(:ancer
24:
Surg. 1975
487-502,
1969
Am. .T. Roentgenol. Radium Ther. 5. Catlin, I).: L?mphosarcoma of the Heat1 and Xeck, Sucl. Xed. 59: 354-358, 1948. 6. Chisholm, D. BI., and Mason, D. I
CHARLES American
A. WALDRON, Academy
D.D.S.,
M.S.D.
of Oral Pathology
School of Dentistry, Emory 1462 Clifton Road, N.E. Atlanta, Georgia 30322
University
Lymphoproliferative disease of the hard palate: A clinicopathologic entity A study
of twenty-one
cases
Chrrrles E. Tomich, D.D.S., M.s’.D.,* TVillia,,l 6. Shafer, D.D.X., N.S.,#* I?ldiawnpolix, Ilzd. INDI,\NA
UNIVERSITY
SCHOOL
a?ld
OF DENTISTRY
Twenty-one cases of a lymphoproliferative disorder believed to represent a clinicopathologic entity were studied. These lesions, which appeared on the hard palate, occurred in elderly men and women with an average age of 70 years. The lesions presented as soft, fluctuant swellings which were occasionally bilateral, ulcerated, or discolored. Microscopically, the lesions were classified as lymphocytic lymphomas; eight were diffuse and well differentiated, seven were nodular and well differentiated, and six were diffuse and poorly differentiated. All lesions were characterized by a tendency of the lymphocytes to show nuclear fragility. Accessory salivary gland in volvement wvas common, this being characterized by acinar obliteration to varying degrees and by periductal hyalinization of collagen. lkterminate follow-up of fourteen patients disclosed that eight died of disseminated lymphomn, three are alive with disease, and three arc free of disease after treatment with radiation and/or chemotherapy. I~ympl~oproliferativr lesions in this location are believed to be malignant or potentially malignant processes.
T
he pathologist, because of the very nature of human disease, is repeatedly confronted by perplexing diagnostic problems. A given pathologist may develop remarkable expertise in one particular area but feel very uncomfortable in another. The broad spectrum of pathologic processes invol\-ing lymphoid tissues This investigation was supported in part by Public CA8006 from the National Cancer Institute. “Associate Professor, Department of Oral Pathology. **Distinguished Professor and Chairman, Department
754
Health
of Oral
Service
Training
Pathology.
Grant
5TlZ-
Volume Number
39 5
Lymphoproliferuthe
disease of hard palate
755
frequently presents one of the greatest of all diagnostic challenges. The parameters of disease of these lymphoid tissues extend from the obviously benign inflammatory or reactive lesions to the obviously malignant ones, The major diagnostic problems arise in the zone between the two opposite poles and, indeed, many of these are the lesions which remain equivocal microscopic enigmas. Lymphoid aggregates are present in a variety of locations in the oral cavitythe lateral border of the tongue, the ventral surface of the tongue and floor of mouth, the buccal mimosa, the fauces, and the soft palate. Quite obviously, these lymphoid tissues are subject to most, if not all, of the various reactive and neoplastic processes occurring in the extraoral lymphoid tissues. While at least some of these processes are not commonly encountered in the oral lymphoid tissues, they are not SO uncommon as to be considered rare. Such lymphoproliferative lesions encountered in the oral cavity pose the same diagnostic problems as those elsewhere, with benign proliferations being confused with malignant ones and vice versa. It has been our observation over the years that the hard palate is a relatively common site for lymphocytic proliferations and we have long considered the possibility of the occurrence of both a benign form, perhaps analogous to cutaneous lymphoid hyperplasia,4 and a malignant form, lymphosarcoma. The purpose of this study was to explore a group of lymphoproliferativc lesions of the hard palate, coded in our files under a variety of diagnoses, whose clinical description have all been dramatically similar and, by follow-up investigation, attempt to determine whether both a benign and a malignant form do exist. MATERIALS
AND
METHODS
Caseswith lymphoproliferative lesions of the hard palate were selected from the files of the tissue diagnostic service of Indiana University School of Dentistry, Department of Oral Pathology. These files consisted of 45,700 consecutive biopsy/surgical specimens accessionedbetween Oct. 1, 1950, and June 30, 1974. In the selection of casesfor study, all material coded in the Tumor Registry as leukemia, lymphosarcoma, and reticulum-cell sarcoma was reviewed. In addition, all material designated as some other intraoral benign lymphoid lesion was similarly reviewed. This included cases diagnosed as lymphoid hyperplasia, hyperplastic lingual tonsil, lymphadenitis, and benign cystic lymphoid aggregate. Significantly, there were no cases diagnosed as benign lymphoepithelial lesion (Mikulicz’s disease) of accessory salivary gland tissue in these files. Lymphoproliferative lesions from all intraoral sites other than the hard palate also were reviewed in order to obtain comparative data concerning frequency of occurrence of benign and malignant lymphoid diseasesin these locations as contrasted to the hard palate. AS suggested by Caro and Helwig,4 patients were considered to have a benign lesion if, with no definitive treatment, they were alive and free of disseminated disease (for example, leukemia or lymphoma) 5 years after biopsy. They were considered to have malignant diseaseif they died of leukemia or lymphoma or if a diagnosis of leukemia or lymphoma had been confirmed by bone marrow or lymph node biopsy, respectively. Microscopic slides and paraffin blocks were available in all cases. Histologic
Oral May,
756
To~mdz md
Table
I. Location of benign oral lymphoid hyperplasia
Shafer
Ruccal mucosa Tongue Floor of mouth Tonsillxr pillar Mucobuccal fold Mandihle, soft tissue Maxilla, soft tissue Soft palate Retromolar area Lower Iip Junction, hard and soft Palate ’ Unstated
Surg. 1975
31 11 10 7 7
palates
evaluation was made of sections stained with hematoxylin stains were not utilized.
% 3 2 2 1 1 1
and eosin. Special
RESULTS Clinical data
A total of eighty-three casescoded as benign Iymphoid hyperplasia, including benign cystic lymphoid aggregate, of the oral cavity were found in the files. The locations of these lesions arc shown in Table I. In addition, the files contained thirty-nine casesof hyperplastic lingual tonsil and nine casescoded as lymphadenitis. Of these latter nine cases,six occurred on the buccal mucosa and one each on the tongue, floor of the mouth, and tonsil. Significantly, of these 131 cases, there was not a single instance of a benign lymphoid lesion specifically designated as occurring primarily on the hard palate, However, there were three casesinvolving the soft palate, one occurring at the junction of the hard and soft palates, and one involving “palate.” There were eighteen casesof reticulum-cell sarcoma of the oral cavity; seven of these were either primary in the maxilla or involved the soft tissue of the maxilla but not the palate, while ten were either primary in the mandible or involved the soft tissue of the mandible. There were two caseswhich involved the palate, but they were unquestionably primary reticulum-cell sarcoma of bone and were excluded from the study. One case did occur on the hard palate. On reviewing this section, we concurred that it represented a poorly differentiated lymphocytic lymphoma with a. histiocytic component rather than a reticulum-cell sarcoma. Therefore, it was included in the present study. No case of reticulumcell sarcoma occurred in any other intraoral site, including even common sites of lymphoid aggregates, such as the tongue, tonsillar pillars, buccal mucosa, etc. There were thirty-four casesdiagnosed as lymphosarcoma of the oral cavity. The locations of these lesions were as follows : maxilla, five cases; mandible, six cases; buccal mucosa, two cases; tonsil, one case; and hard palate, twenty cases. These twenty casesand the one additional case mentioned above, representing all of the accessionedlymphoproliferative lesions occurring on the hard palate, form the basis of this study. The twenty-one palatal lesions occurred with equal frequency between the
Volume Number
Lyl,rphoZ,roliferatiz~e
39 5
disease
of
hrrrd pulrrte
757
SCSCS. There were eleven men and ten women and, with the exception of one lesion in a Negro man, all patients involved were Ca.ucasians. All of the palatal lymphoproliferative lesions had a remarkable predilection for occurrence in the elderly. The average age of the patients at the time of biopsy was 70 years, with a range of 50 to 81 years. Eighteen patients (86 per pent) were in the seventh and eighth decades of life, with only two in the sixth tlccn~lc and one in the ninth dccadc. The lesions most frequently involved one side of the hard palate, although four patients were described as having involvcmcnt of the entire palate. Both unilateral and bilateral involvement of tissue overlying the grcatcr palatine foramen also occurred. In six cases, thcrc was cstcnsion of the tumor onto the soft palate. The clinical description of the palatal lesion was remarkably consistent. \Vit,h the exception of two cases which were described as “firm swellings,” all cases were described as soft swellings in the palate. Descriptive terms included “spongy,” “cystic,” and “fluctuant.” As might be expected with lesions of such consistency, clinicians considered the possibility that the lesions contained fluid. In four instances the areas were incised ; however, this procedure yielded no tlrainagc. In most instances, the overlying mucosa was of normal color or was not described as being otherwise. The overlying mucosa was ulcerated in five instances. In three casts, the mucosa was said to be rcddencd, whereas in two additional caascs t,hc color deviated from normal, one bring described as “bluish” and the other as “grayish.” Eight, patients were known to bc denture wcarcrs, and in five of these cases the palatal swelling actually int,erfercd with the fit of the denture. In only a single instance (lit1 a clinician suspect lymphoproliferative discasc. The clinical impressions were usually rclatcd to suspcctcd salivary gland pathosis. A sa1ivar.v gland neoplasm was the provisional clinical diagnosis in eight cases, and cpitlermoic1 carcinoma was susIxctetl in two of the lesions which presented with ulceration. Four additional lesions were thought to he “abscesses.” Iirgional I~mph;rdcno~~atll~ was said to be absent in two cases. In all other cases, thc~rc WIS no mcntioll of l)alpablc nodes in the submitted histories. In one cast liematologi~ values wcrc submitted, and these were within normal limits. Microscopic
findings
In the microscopic evaluation of the palatal lesions, particular attention was given to epith~~lial cahangcs, the character of the cellular infiltrate, and the apl)carancc of the accessory salivary glands. In addition, stromal reactions or changes and cvitlcncc~ of mus~lc, fat, ant1 bone involvement wcrc recorded. Epithelitrl chtrn~e,s. There was a considrrablc mngc in changes occurring in the ovcrlyillg cpithclium. This varied from an cpithclium of normal thickness, usually whcrt~ the underlying tumor cdls were still some distance from the surface, to an atrophic cpithclium with blunting or loss of rcte ridges, where the tumor cells \vcrc’ impinging on the eovcring epithclium, to occasional ulceration (Fig. 1). In one instance, a “saw-tooth” pattern was apparent, but in no instance was thcro ally significant rcact,ivc ~)seudoepitheliomatous hypcrplasia. The
758
Tomich
and
Shafer
Oral May,
Surg. 19’75
Fig. 1. A diffuse, poorly differentiated lymphocytic lymphoma which has produced ulceration of the overlying mucosa. The cells are shown in greater detail in the inset. (Hematoxylin and eosin stain. Magnification, xl00 ; inset, x450.) Fig. 8. A nodular, well-differentiated lymphocytic lymphoma. Persistent accessory salivary gland ducts are present. (Hematoxylin and eosin stain. Magnification, x100.)
surface was usually covered with a layer of parakeratin of normal thickness, although occasionally this was orthokeratin. In no cases were there cytologic alterations in the epithelium. In general, any changes in the surface cpithelium appeared related to the proximity of the underlying tumor cells. Character of the cellular z’nfiltrclte. The cellular infiltrate consisted of lymphocytes in various stages of differentiation. Although histiocytic cells were occasionally present, they were not considered to be taking part in the neoplastic process. In one case, the histiocytic cells displayed active phagocytic properties. There was a marked tendency for the lymphocytic infiltrate to diffusely involve the palatal tissues. Only two cases displayed a “patchy” distribution. Three
Lymphoproliferative
Fig. 3. A diffuse, well-differentiated the tumor cells infiltrating the Magnification, x40.) Fig. 4. Detailed photomicrograph terized by elongated, streaked nuclei.
Note stain.
lymphocytic subepithelial showing the (Hematoxylin
disease
of hard
759
palate
lymphoma. Persistent ducts connective tissue. (Hematoxylin tendency toward cellular fragility and eosin stain. Magnification,
are present. and
eosin
characx450.)
cases exhibited “patchy” areas with an otherwise diffuse infiltrate. Since the majority of the specimens studied were from incisional biopsies, it may well be that a “patchy” distribution would be encountered more often peripheral to the main tumor mass. The lesions were categorized as nodular or difuse lymphocytic lymphomas with degree of differentiation classified as well differentiuted or poorly differentiated. With this classification, seven lesions were classified as “nodular, well differentiated” (Fig. 2) ; tight were classified as “diffuse, well differentiated” (Fig. 3) ; and six were classified as “diffuse, poorly differentiated” (Fig. 1). None were classified as “nodular, poorly differentiated.” Three of the nodular lym-
Oral May,
Surg. 1975
Fig. 5. A diffuse, well-differentiated lymphocytic lymphoma which has infiltrated palatal accessory salivary glands. The acinar structures are shown in greater detail in the inset. (Hematoxylin and rosin stain. Magnification, x100; inset,, x450.) Fig. 6. A higher-power photomicrograph of the diffuse, well-differentiated lymphocytic lymphoma shown in Fig. 3. Note persistent ducts and evidence of nuclear streaking. Periductal hyalinization is shown in greater detail in the inset. (Hematoxylin and eosin stain. Magnification, x100; inset, x450.)
phomas showed fairly well-defined germinal centers, whereas the remaining four merely exhibited a tendency to form follicular or nodular structures, this being a well-recognized phenomenon in lymphoreticular diseases.Three of the poorly differentiated lesions demonstrated a high degree of anaplasia characterized by extremely pleomorphic cells (Fig. 1, inset). Mitotic figures were present in large numbers in the poorly differentiated lesions, whereas they mere absent or sparse in the well-differentiated lesions. One finding which was consistently present in every case was a tendency for the lymphocytes to show evidence of cellular (or nuclear) fragility to a greater or lesser degree (Fig. 4).
Lymphoproliferative
disease of hard palate
Fig. 7. 8: A diffuse, poorly differentiated lymphocytic lymphoma zone. B, A diffuse, poorly differentiated lymphoeytic lymphoma with plastic process encroaches upon the overlying epithelium. (Hematoxylin nification, x100.)
761
with a well-defined grenz no grenz zone. The neoand eosin stain. Mag-
A’alivary glalad changes. The palatal tissues normally contain large numbers of accessory mucous gland acini, and these showed considerable alteration when there was impingement by tumor cells. As the tumor cells encroached on the collections of glands, the acini became obliterated through apparent cell rupture and disintegration. However, it was not uncommon to observe individual, intact, healthy acini within a solid sea of tumor cells (Fig. 5). The ducts were far more resistant to tumor cell onslaught and commonly persisted after all acini had been destroyed (Fig. 6). Alterations occurred in these ducts, characterized often by a mild squamous metaplasia. Significantly, there was no evidence of “epimyoepithelial cell” proliferation, as is characteristically seenin the benign lymphoepithelial lesion. It is of interest that intraductal mucin was frequently present in these isolated ducts, comparable to that commonly found in the tumor ducts of
762
Tomich
Oral May,
and Shafe?
Fig. 8. A diffuse, The tumor cells have cation, x40.)
well-differentiated infiltrated palatal
lymphocytic lymphoma with a “patchy” adipose tissue. (Hematoxylin and eosin
Surg. 1975
distribution. stain. Magnifi-
Fig. 9. A diffuse, well-differentiated lymphocytic lymphoma which has involved radicular bone of a maxillary molar. Periodontal ligament separates alveolar bone (Hematoxylin and eosin stain. Magnification, x40.)
the interand tooth.
such lesions as the pleomorphic adenoma. In contrast, intraductal mucin is a relatively infrequent finding in ducts affected by inflammatory changes, even a severe chronic sclerosing sialadenitis. One pertinent finding was so consistently present and so striking that it appears to be a component of this disease-periductal hyalinization. This appeared as a broad band of densely hyalinized collagen around many of the ducts involved by tumor (Fig. 6, inset). It appeared as though the continued proliferation of the neoplastic cells compressed the collagen more and more against the duct wall. Stromal changes. There were no consistent noteworthy stromal changes. A grenz zone sometimes separated the epithelium and the deeper tumor mass, but it
Volume Number
Ly?)lphoproliferatiz~
39 5
Table II. Patients Patient S. A. z: T. L. L. H. L.
FG. 8. c. D. L. R.
dead of lymphoproliferative
’ Histologic type N,WD D,WD D,PD D,PD D,WD N,WD D,PD D,WD
Type therapy Unknown Unknown Radiation Unknown Unknown Radiation Unknown Radiation
of
diseme of hnrd palate
disease Status
1
Time
763
of
death
Unknown 1 yr. 6 mo. 5 yr. 3 mo. 8 mo. 3 yr. 3 mo. 5 mo. 1 yr. 4 mo.
Present
of palatal /
Absent
lesion / Unknown
X X X X X X X X
D = Diffuse. N = Nodular. WD = Well-differentiated. PD = Poorly differentiated.
was absent as frequently as it was present (Fig. 7, A and B). In some instances, the tumor mass was rather sharply circumscribed but. did not appear to compress the adjacent collagen bundles significantly. Instead, there was generally some infiltration of tumor cells between collagen bundles for a varying distance beyond the main tumor mass. In a number of cases, there also was marked infiltration of the normal adipose tissue of the palate by tumor cells, leaving scattered and isolated fat cells within the deeper portions of the tumor mass (Fig. 8). Bone involvement was demonstrated histologically in three cases. This was dramatically evident in one case in which a molar tooth was removed at the time of the palatal biopsy (Fig. 9). One case showed extensive involvement of skeletal muscle of the soft palate. FOLLOW-UP
INFORMATION
Follow-up information was available in twenty of the twenty-one cases studied. Eight patients died of lymphoproliferative disease. The data on these patients are summarized in Table II. Two of the patients in this group received radiation therapy to the palatal lesion with subsequent regression; however, both succumbed to disseminated malignant lymphoma. The status of the palatal lesion was undetermined in one patient. The cause of death in this patient, as determined from the Indiana Division of Vital Records, was listed as “lymphosarcoma.” Six patients died of causes other than a lymphoproliferative disease. The data on these patients are summarized in Table III. In five of the six cases, it was not possible to determine the status of the palatal lesion, since this information was not mentioned on the death certificate; nor was it possible to gather this information from the practitioner who submitted the specimen. Interestingly, the palatal lesion in one patient (L. C., a 71-year-old woman) was said to have regressed without therapy. Unfortunately, the patient died of carcinoma of the colon with hepatic metastasis, and the status of the palatal lesion at the time of death was undetermined. Six patients are alive, three with disease and three apparently free of disease. The data on these patients are summarized in Table IV. Two of the patients in
Oral May,
764
Tomich and Shafer
Table
III. Patients dead due to other causes
hf. w. \V:. R.
D,WD DJ’D
iv:.
D,PD
Radiation Surgery and radiation Unknown
D,TVD N,WD
Unknown None
P.
A. M. I,. c.
infarct Pneumonia Myocardial infarct Renal failure Unknown Carcinoma of colon
1 yr. 2 yr.
3 mo.
2 yr.
5 mo.
0 yr. 1 yr.
10 mo.
Surg. 1975
x
D = Diffuse. N = Nodular. TVD = Well-differentiated. PD = Poorly differentiated.
this group have received no therapy. In one patient (R. C., nom an 82-year-old man), there is evidence of a large, inoperable palatal mass. In the other patient (C. S., now a 74-year-old woman), the palatal lesion has remained approximately the same size since it was originally biopsied. A third patient (L. M., now a 70-year-old woman) received no treatment after biopsy, which was essentially a subtotal excision. She is alive with a small massstill present in the palate. Three patients in this group are alive and apparently free of disease. One patient (E. w., now a 70-year-old woman) had evidence of a lymphoproliferative disorder when bone marrow studies were performed. She received radiation to the palatal lesion and was placed on chemotherapy. The palatal lesion regressed, and she is apparently in a state of remission. Another patient (H. S., nom a 66-year-old man) had histologic evidence of bony involvement (Fig. 9) in addition to his palatal lesion. He is alive and well after receiving radiation therapy to the area. A more recent case was treated by radiation and chemotherapy with regression of the palatal lesion. The patient (T. E., now a 69-year-old man) is alive and well 1 year after therapy. DISCUSSION
AND
CONCLUSIONS
The actual frequency of malignant lymphoma occurring primarily in and confined to the head and neck is difficult to assess.As Schnitzer and Weaver” have pointed out, lymphangiography and laparotomy mere not performed in most of the large series of head and neck lymphomas, and therefore these patients were not adequately studied for occult disease elsewhere in the body. However, Rosenberg and his colleagues1i have reported that more than 45 per cent of the malignant lymphomas initially manifest in the head and neck region, whereas Catlin” reported a lower frequency of approximately 20 per cent. Involvement of the head and neck region by malignant lymphoma is primarily nodal (usually the cervical nodes), with extranodal involvement being much less common. In the extensive Memorial Hospital series of 1,269 casesof malignant lymphoma, nearly 9 per cent of the cases appeared initially in the extranodal head and neck tissucs.17In a study of 153 casesof head and neck lymphomas,
Volume 39 Number
5
IV. Patients alive, either with discasc or free of discasc
Table
status of
Tiistologic Patient
type
c. s. L. M. E. WV.
11,wn N,WD N,WTl D,WD
H. S. T. E.
II,WD D,PD
R.
c.
Type
of
th,crnpy
None None Surgery Hadiation and chemotherapy Radiation Radiation and chemotherapy
Folh-~cp
intered
5 y1 yrtars 4 yr. 3 mo. 1 yr. 3 mo. 7 yr. 5 yr. 1 yr.
Present
pfdnta1
lwion
,4hrmt
x s s s x s
D = Diffuse. N = Nodular. WD = Well-differentiated.
McNelis and Pail* found that one third of the lesions wcrc in extranodal sites. Of these, one half involved Waldeyer’s ring. Similar data have been reported by Sugarbaker and Craver,l” who studied 196 casesof lymphosarcoma. Malignant lymphoma in the oral cavity is relatively uncommon. These lesions have constituted only 0.1 per cent of the total number of cases accessioned in our surgical pa.thology service. The palatal lesions reported herein accounted for 40 per cent of our lymphoma experience. In other studies, palatal lpmphomas in themselves have actually accounted for only a small segment of head and neck lymphomas, and the majority of these have been in the soft palate, this being considered an anatomic portion of Waldeyer’s ring. Banfi and his- colleagucs2 reported soft palate involvement in six of 225 cases (2.7 per cent) of lymphoma of Waldeyer’s ring. No lesions merr prcsent in the hard palate. There were two palatal lesions each in the series reported by Catlin” and by McNelis and l’ai,14 one of which was specifically found in the hard palate. It appears almost paradoxical that such a relatively large series of casesof lymphocytic lymphoma as that being reported here should occur at a site where there is no appreciable extranodal lymphoid tissue and yet there were no cases in intraoral sites of considerable quantities of extranodal lpmphoid tissue (lingual tonsil, floor of mouth, and soft palate) and only three cases involving faucial tonsil and buccal mucosa. However, in a study of 618 casesof malignant lymphoma, Gall and Mallory” observed, with respect to lymphosarcoma : “It is of interest that over half of these lesions appeared in non-lymphoid tissue, most frequently in bones and in the gastrointestinal tract, but occasionally in areas in which eyen isolated lymph follicles are not found under normal circumstances (i.e., the subcutaneous fat, the bladder and the cervix of the uterus) .” There have been numerous studies of the palatal tissues, both hard and soft, but even one of the earliest by Pendletonl” recognized that lymphoid tissue does not generally occur in the hard palate. KnappI’ has adequately demonstrated the common clinical appearcnce of lymphoid aggregates in the soft pal&e, however. It is equally surprising that there were no casesof benign lymphoid hyperplasia observed primarily in the hard palate; in fact, only five cases (3.8 per cent) were observed in the palatal tissues at all (Table I). This is in sharp contrast to Adkins” observation that benign lymphoid hyperplasia of the oral mucosa
Oral May,
Surg. 1975
is seen most commonly in the palate and tongue. In fact, he illustrated a bilateral lesion sit,uated in the posterior portion of the hard palate and described it as very soft, slowly growing, and deeply colored-a description amazingly similar to the malignant palatal lesions in our series. The palatal lymphomas appear to occur exclusively in elderly adults. The age range was 50 to 81 years, and eighteen patients (86 per cent) were in the seventh and eighth decades of life. This is in agreement with TdukeP’ observation that well-differentiated Iyml)hocytic lymphomas, the histologic type constituting two thirds of the palatal lesions, usually occur in patients over the age of 55 and arc rarely seen prior to the age of 45 years. Schnitzer and Weaver’” reported a nearly identical age predilection, and Catlin” likewise noted a tendency for elderly persons to manifest this form of lymphoma. The lesion usually occurs on one side of the hard palate, usually posteriorly near the greater palatine foramen. Although only four of twenty-one patients had bilateral palatal involvement, this finding is probably of clinical significance, since few other lesions, either benign or malignant, are manifest in such a manner. Thus, a soft, spongy, bilateral posterior palatal swelling in an elderly person should be considered highly suspect of malignant lymphoproliferative disease until proven otherwise. Schnitzer and Weave? state that the majority of extranodal head and neck lymphomas are histologically classified as diffuse lymphocytic lymphomas or reticulum-cell sarcomas. This has been our experience also. In fact, these two types constituted 88 per cent of our total lymphoma experience. A striking observation in all of the lesions was the tendency for the tumor cells to display a marked nuclear fragility characterized by elongated, streaked nuclei. While this phenomenon is not observed exclusively in malignant lymphoreticular disorders, it is observed so commonly in these lesions that we have come to regard it as a rather “reliable artifact.” It is surprising that this phenomenon has not been emphasized in the literature, and it may well be that most observers interpret it as artifact and therefore discount it. No special term has been previously suggested for this nuclear appearance, and we have been using the term sguigglies to describe this unusual, albeit reliable artifact. This infiltration of the hard palate by lymphocytes with eventual obliteration of accessory salivary gland acini, as has been pointed out, is characteristic of lymphosarcoma in this location. The infiltrates were either diffuse or nodular, not unlike the infiltrate described by Freedman8 in his study of ten malignant lymphomas considered to be primary in the major salivary glands. However, the infiltrate is also reminiscent of another more benign condition-the benign lymphoepithelial lesion, including Mikulicz’s disease, as well as Sjiigren’s syndrome. Characteristically, in these latter diseases, there is massive involvement of the major salivary glands by a lymphocytic infiltrate. However, it is now recognized that such involvement may also occur in the accessory glands of the palate and of the lip.3p B Although it would be most unlikely for the palate to be involved by the benign lymphoepithelial lesion without concomitant involvement of the major salivary glands, care must be taken in distinguishing histopathologically such a benign infiltrate from the malignant infiltrate de-
Lynzphoproliferatice
disease of hard palate
767
scribed in this series. Furthermore, there are now reports of the occurrence of a malignant form of the benign lymphoepithelial lesion in which the epithelial component undergoes malignant transformation with local or distant metastases.lO,I1 Finally, it has been recognized that, on occasion, malignant lymphoma will develop in association with or be preceded by the benign lymphoepithelial lesion or SjSgren’s syndr0me.l” In the present series, to the best of our knowledge, there was no indication of any other associated disease process affecting the major salivary glands, and these cases are all interpreted as representing primary extranodal lymphoma. In general, the acinar structures were not resistant to the neoplastic infiltrate; however, the ductal structures were quite resistant and invariably showed a marked periductal hyalinization (Figs. 5 and 6). This periductal response was observed by Freedman8 in the majority of the major salivary gland lymphomas, and, interestingly, Tarpley and his associateP observed similar findings in the labial glands of patients with Sjijgren’s syndrome. Thus, periductal hyalinization appears to result when salivary glandular tissues are invaded by a lymphoproliferative lesion such as a malignant or an autoimmune disorder. Determinate follow-up observations on fourteen patients with lymphoproliferative disease of the palate disclosed that eight patients died of disseminated disease. The remaining six patients are alive but have presented documented evidence of malignant lymphoma. Three of the patients are free of disease, but they have been treated with radiation and/or chemotherapy. Unfortunately, one patient was lost to follow-up and another six died of other causes. In this latter group, we were unable to determine precisely what role, if any, the palatal disease had played in five patients ; the disease was still present in one patient (W. R.), but it was not the primary cause of death. There does not appear to be a direct correlation between the histologic type and the eventual outcome of the process. However, the poorly differentiated lesions tended to result in the earlier death of the patient. In general, the palatal lesions are best treated by radiation. If disseminated disease is found to be present, chemotherapy is likewise indicated. This regimen has resulted in an apparent cure or state of remission in three patients. In two other patients, the palatal lesions regressed with radiation therapy, but the patients eventually died of disseminated lymphoproliferative disease. On the basis of our present state of knowledge, we believe that these lymphoproliferative lesions of the hard palate are malignant or potentially malignant. Therefore, radiation therapy is recommended, with or without chemotherapy depending upon the presence or absence of disseminated disease, respectively, for those patients presenting with such disease. REFERENCES
1. Adkins, K. F.: Lymphoid Hyperplasia in the Oral Mimosa, Aust. Dent. J. 18: 38-40, 1973. 2. Banfi, A., Bonadonna, G., Carnevali,, G., Molinari, R., Monfardini, S., and Salvini, E.: Lymphoreticular Sarcomas With Primary Involvement of Waldeyer’s Ring, Cancer 26: 341.351, 1970. 3. Bertram! IJ., and Hjiirting-Hansen, E.: Punch-Biopsy of Minor Salivary Glands in the Diagnosis of SjBgren’s Syndrome, Stand. J. Dent. Res. 73: 295-300, 1970.
768
Tomich
4. (‘are,
\V. A.,
a)ld
Oral May,
Shafer
ant1 Helwig,
E. B.:
Cutaneous
Lymphoitl
Hyperplasia,
(:ancer
24:
Surg. 1975
487-502,
1969
Am. .T. Roentgenol. Radium Ther. 5. Catlin, I).: L?mphosarcoma of the Heat1 and Xeck, Sucl. Xed. 59: 354-358, 1948. 6. Chisholm, D. BI., and Mason, D. I
