Department of Dental Science, Royal College of Surgeons of England
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1 PLASMACYTOSIS OF THE GINGIVA DAVID POSWILLO, D.D.S.(N.Z.), F.D.S.R.C.S.Eng. Department of Dental Science, Royal College of Surgeons of England INTRODUCTION PLASMA cells, in conjunction with lymphocytes and histiocytes, occur in large numbers in inflammatory conditions of the gingiva (Fig. I). Smaller numbers of plasma cells are also found in the normal gingiva of both young and mature humans and non-human primates. Large aggregations of plasma cells to which the name 'plasmacytosis' has been given may be found in the tissues of the tonsil, spleen and bone marrow of patients in the acute stages of both rheumatic fever and streptococcal pharyngitis and other infectious diseases. Yet in none of these infectious disorders producing plasmacytosis in special organs is there evidence of a corresponding plasmacytosis of the gingiva (Anderson, I96 I). The suggestion has been made by Good and Campbell (I95o) that plasmacytosis of the bone marrow is evidence of an antibody response. The concomitant increase in blood globulin levels in these diseases supports this contention for there is considerable evidence that the serum proteins which produce hyperglobulinaemia are produced in the mature plasma cell (Erich, I956). The classical experiments of Bjorneboe et al. (I947), in which multiple injections of antigenic material from a number of types of pneumococcus were given to rabbits, showed great collections of plasma cells concentrated in the spleen, liver, medullary cords of lymph nodes and even the fatty tissues of the renal pelvis. There was a corresponding marked increase in the blood globulin in these experiments, attributed wholly to antibodies; thus in immunological reactions both plasmacytosis and raised blood globulins are closely linked. In fact, Bing and colleagues (I945) by microspectrographic and michrochemical techniques adduced evidence of protein formation in developing plasma cells in these reactions. Plasma cell aggregations and raised blood globulin levels are also found in association in the diseases of solitary myeloma, multiple myeloma and, occasionally, extramedullary plasmacytoma. Multiple myeloma, a malignant tumour of bone marrow, may be preceded by the solitary myeloma lesion which is believed to be, in many instances, an early manifestation of myelomatosis, rather than an independent lesion. Sometimes the multiple form of the disease may take many years to develop. Microscopically, the bone lesions of both these diseases reveal solid tumour tissue composed exclusively of normal and abnormal plasma cells. There is almost invariably a raised serum gamma globulin level, and the Bence Jones (myeloma) protein is frequently present in the urine. Sternal and iliac marrow punctures show typical myelomatous changes, both in cellularity and composition. The extramedullary plasmacytoma is also composed exclusively of typical and atypical plasma cells with few if any inflammatory cells in association. In contrast to the bony lesions, however, laboratory tests for myeloma proteinuria are usually negative, though electrophoresis of the serum proteins may show a sharp peak in the gamma globulin. These soft tissue lesions are usually found in I94
2 PLASMACYTOSIS OF THE GINGIVA 195 the upper respiratory tract and oral cavity, especially in the muco-periosteum of the nasal cavity and the maxilla, and the mucosa of the soft palate. It is not possible, because of inadequate data in the literature relating to treated cases, to decide whether this lesion is a true neoplasm: it is probably far less fatal than multiple myeloma, but there is ample evidence to show that the lesion is potentially and actually malignant (Stout & Kenny, I949; Dollin & Dewar, I956; Cataldo & Meyer, 1966). Plasma cell aggregations are also found in the nasal and oral mucosa, especially the gingiva, in lesions described as 'plasma cell granulomas'. These represent FIG. I Inflamed human gingiva showing infiltration by lymphocytes~ histiocytes and plasma cells. 13o. purely inflammatory phenomena, and can be distinguished readily by the vascularity of the lesion and the admixture of normal plasma cells with lymphocytes, neutrophils and other inflammatory cells. These lesions are benign, and are treated by simple excision. As previously mentioned, the true plasmacytoma consists of a solid core of both typical and atypical plasma cells. These cells vary in size, present multinucleated forms, and display varying numbers of mitoses. Russell bodies are absent. The masses of plasma cells are tightly packed into compartments in the connective tissue, segmentation being achieved by fibrous septa. The lesions are locally infiltrative, and in a considerable proportion of cases metastasize to the local lymph nodes and occasionally to bone and other sites. Histological examination has, in the past, provided no guide to the malignancy of a particular lesion; the degree of differentiation of the plasma cells is of no assistance in this respect, for even in the highly malignant lesions of multiple myeloma the plasma cells exhibit a high degree of differentiation. Ewing and Foote (I952),
3 196 BRITISH JOURNAL OF ORAL SURGERY in their review of 27 cases of plasma cell turnouts, concluded that a solitary extramedullary lesion involving adjacent bone possessed a very poor prognosis. The occurrence of a diffuse hyperplastic plasma cell lesion of the gingiva in a middle-aged patient which conformed to the criteria for plasmacytoma set out above would therefore be regarded as a sinister disorder. A case history of such a lesion is presented, and two additional cases involving similar clinical and histological characteristics are reported as evidence of an unusual and previously unreported gingival plasma cell lesion. CASE REPORTS Case i. Mrs. H. O., aged 37, of Central European descent, married with one normal child aged 4, was referred on 5. I 1.58 for examination and treatment of a gingival FIG. 2 Clinical photograph of gingival lesion described in Case I. disorder. For approximately one year she had been troubled by redness and swelling of the upper and lower gingival crests which had increased despite tooth brushing and 'herbal mouthwashes'. The natural dentition was intact, with very few filled teeth, no carious lesions detectable, and no obvious intra-bony peridontal pockets. The hyperplastic gingivitis (Fig. 2) extended from first molar to first molar in both arches, and in places--especially from upper canine to canine---seemed to be well differentiated from the granular surface of the alveolar mucosa by a distinct colour gradient. The past medical history revealed nothing significant to the present problem. Both the patient and her son had been in a European camp for displaced persons for almost two years, but there was no evidence of malnutrition or starvation. There was no record of prolonged administration of drugs, and regular chest radiographs had revealed no abnormalities. The recent dental history provided no additional information. Routine prophylaxis had been carried out annually, and no restorations placed in the past two years. There was clinical evidence of moderate sub-gingival calculus at the base of the false gingival pockets on most teeth. No other lesions could be found after clinical and radiographic examinations of the mouth, nose and oropharynx, and there were no
4 PLASMACYTOSIS OF THE GINGIVA 197 palpable lymph nodes other than one calcified node in the left upper cervical group which was said to have been present for the past 2o years. The gingival lesion was biopsied in the area of maximum swelling in the vicinity of /23. Histologic sections showed the tissue to be covered by squamous epithelium which was largely normal. There were some small areas of acanthosis, and one of ulceration. In the supporting tissues, separated by a narrow zone of fibrous tissue from the epithelium were masses of densely packed plasma cells, divided into irregular groups by fibrous tissue. The plasma cells showed ragged cytoplasm, and typical nuclei. The only other inflammatory cells present were few in number and almost entirely related FIG. 3 Photomicrograph showing massed plasma cells and fibrous septal segmentation in gingival tissues from Case I. H. and E. r3o. to the area of ulceration (Fig. 3). The appearance was typical of extramedullary plasmacytoma. On the basis of the histological examination of the patient, additional laboratory and radiological tests were carried out. No Bence Jones protein was detected in the urine which was normal in other respects also. Iliac marrow puncture showed no significant abnormality either in cellularity or composition. Electrophoresis of the serum proteins yielded the following results, as reported in Fig. 4. There was no evidence to support the presence of a myeloma protein. The albumin fraction was moderately decreased, and the 71, ~z and fl globulin fractions were a little above the upper limits of normal. Blood examination revealed the following information. The R.B.C. count, the Hb, the P.C.V. and the mean cell Hb Concentration were all within normal limits. The white blood corpuscles totalled IO,OOO per cu. ram. and consisted of polymorphs 57 per cent., lymphocytes 41 per cent., eosinophils I per cent. and basophils I per cent. There was no significant abnormality in any of the laboratory tests, and radiological screening of the skeleton revealed no abnormalities. The patient was advised that this was a potentially malignant lesion that required adequate excision, and was advised to accept a full dental clearance, alveolectomy and
5 198 BRITISH JOURNAL OF ORAL SURGERY wide excision of the affected gingival tissues. Despite several attempts to assure the patient of the necessity for radical surgery she was convinced that negative laboratory and radiological tests precluded the possibility of a serious lesion, and steadfastly refused to permit extraction of any teeth. Finally, permission was obtained to perform a radical gingivectomy with electro-coagulation, and preservation of all teeth. This treatment was performed two weeks after the original biopsy. Histological examination of the resected gingival tissues from all four quadrants of the mouth revealed appearances identical with the original biopsy sections. The wounds healed satisfactorily beneath a standard periodontal pack, and the patient was Mrs. H. O. ELECTROPHRESIS OF SERUM PROTEINS, i6.ii.58 Percentage of Total Grams per cent. Determined Av. Normal Determined Av. Normal Albumin. 42.o 59.o 3 4 Globulins Alpha z Alpha 2 Beta Gamma Others 7"8 12 "2 2I " "7 8.1 z "6 0.6 o. 9 I. 7 I "3 0"6 0'9 I'I I00"0 IO0"O 8.o 7"3 Total protein- Albumin: Globulin Ratio--o'75 : I.o (I "5 : I.o) Fro. 4 Serum protein estimations in Case I. instructed in total mouth hygiene with tooth-brushes and interdental wooden points. Regular recall examinations were conducted, and showed adequate oral hygiene but a tendency to mild recurrence of the hyperplastic appearance of the gingiva. One year after the surgical procedure a section of gingival tissue was removed from 43 / region and biopsied. Appearances were exactly as before, though the amount of supporting fibrous tissue in the base of the biopsy tissue was reduced. Laboratory and radiological tests were repeated with no abnormalities detected. The patient was re-examined at six-monthly intervals for the next two years, and then at yearly intervals to the present date. There has been a small increase in the gingival hyperplasia, but this is obviously only slowly progressive and is well controlled by methodical home care. The introduction of an electric toothbrush into the oral hygiene programme produced an improvement in the overall appearance of the gingiva. Laboratory and radiological examinations have remained negative for myeloma to date. Case 2. Mrs. M. N., aged 39, presented with generalised gingival hypertrophy especially in the upper and lower anterior regions. This hypertrophy was'free-standing', nodular, and very red in colour. She gave a history of having had gingivectomy performed three years previously for a similar condition; she had been referred on this presentation because of this recurrence. The blood tests as reported in Case I were
6 PLASMACYTOSIS OF THE GINGIVA Fro. 5 Photomicrograph of gingiva from Case 2, Showing features identical with those of Case r. H. and E. IOO. FIG. 6 Photomicrograph of plasma cells in gingiva enlarged from Figure 5H. a n d E. 4oo. I99
7 200 BRITISH JOURNAL OF ORAL SURGERY carried out without abnormality being detected, and no signs of pathology in the bone marrow or lymph nodes were elicited. Histopathological examination of the biopsy specimens of the affected gingival tissues revealed appearances identical with those in Case I (Figs. 5 and 6). This case is reported by courtesy of Mr. D. Adams, B.Sc., M.D.S., Department of Oral Medicine, Welsh National School of Medicine. Case 3. Miss L. N., aged 21, a white female with Downs' syndrome, was referred to the Oral Surgery Clinic in January 1967, with a I "5 by I cm. hyperplastic red lesion in the maxillary labial vestibule, and generalised hypertrophic erythematous gingivae. The lesion was excised and the base electrocoagulated, and healing was uneventful. The lesion recurred in October, and because of the histologic appearance further medical FIG. 7 Photomicrograph of gingiva from Case 3, showing marked resemblance to Cases I and x. H. and E. i3o. tests were carried out. The histological features of the excised lesions, and further biopsy excisions from the right molar and left cuspid areas, all showed marked resemblance to the tissues described in Case I, and Case 2 (Fig. 7)- General physical examination revealed mongoloid characteristics, but no other special findings. Laboratory tests included a C.B.C. which revealed a haemoglobin of iz.e g./ioo c.c., W.B.C. of 55o% with a differential count of 52 per cent. neutrophils, 32 per cent. lymphocytes, 3 per cent. eosinophils, I per cent. basophils, and I per cent. monocyte and I per cent. neutrophil bands. The peripheral blood smear was normal, and the Bence Jones protein test was negative. There was no abnormality detected in bone marrow smears, and no myeloma or tumour cells were seen. Serum protein electrophoresis was normal except for an elevated gamma globulin at 2"41 g./ioo ml. (This elevation of the gamma globulin is a common finding in cases of Downs' Syndrome.) A radiographic survey of the skeleton showed no abnormalities. Treatment consisting of intensive oral hygiene measures, using toothbrush and water pic aids, produced rapid and marked improvement in the gingival lesions.
8 PLASMACYTOSIS OF THE GINGIVA 201 This case is reported by courtesy of Dr. F. Henny, D.D.S., F.D.S.R.C.S., Division of Dentistry and Oral Surgery, Henry Ford Hospital, Detroit, Michigan. DISCUSSION Extramedullary plasmacytomas may vary considerably in size : they may be spherical, lobulated, pedunculated or polypoid, but they are usually all well limited. Their clinical behaviour falls into a well-defined category such as : i. A limited solitary tumour. 2. A locally destructive infiltrating tumour. 3. A tumour which metastasizes to the lymph nodes or other sites. 4. An isolated soft tissue lesion with multiple myelomatous bone lesions. All these tumours are prone to recur after inadequate excision or insufficient radiotherapy. The diffuse gingival plasma cell lesions reported in these three cases differ from the usual cases of extramedullary plasmacytoma of the oral mucosa in that these lesions are most definitely not well limited. In all other respects though, certainly histologically, they resemble the lesions of solitary extramedullary tumours. There is, however, no evidence of adjacent tissue destruction, and no evidence of metastases. In Case i, the lesion recurred after excision and electrocoagulation but the recurrence was controlled for ten years by rigorous attention to those factors known to limit hyperplastic gingivitis. In this respect the lesion resembles the plasma cell granuloma. Histologically, however, there is no evidence to suggest that the diffuse lesion is a plasma cell granulomatous lesion, for the specific features of proliferating blood vessels, and the presence of macrophages and lymphocytes are absent except in rare areas of ulceration. Although the plasma cells found in multiple myelomatosis have the same characteristics as those in extramedullary plasmacytoma, the cells in the solitary soft tissue lesions do not produce manifestations of myelomatous disturbance in the plasma proteins. For this reason, extramedullary plasmacytoma may be regarded as a distinct entity, but one that is potentially a precursor of disseminated myelomatosis. It is difficult, on the basis of clinical distribution and behaviour, to classify the reported gingival plasma cell lesions as extramedullary plasmacytoma despite the similarity in histological appearance. Most authorities conclude that the clinical behaviour, rather than the histological appearance, should form the final basis for evaluation of non-inflammatory plasma cell lesions. The response of the gingiva in Case I to periodontal massage corresponds with the results achieved in the management of leukaemic gingivitis. In both instances, the swelling and hypertrophy of gingival tissues are produced by engorgement with abnormal cells, and in both instances control is gained by gum massage. It is suggested that the diffuse plasma cell lesion of the gingiva described in the cases cited is also a distinct entity, differing from both plasma cell granuloma of the gingiva and extramedullary plasmacytoma of the gingiva. The clinical behaviour of one case followed for IO years suggests that this lesion may occupy an intermediate position between the very benign granulomatous lesion at one end of the scale, and the potentially sinister plasmacytoma at the other. Plasmacytosis of the gingiva is a descriptive term which appears to fit this specific lesion.
9 202 BRITISH JOURNAL OF ORAL SURGERY There is no evidence to suggest that this gingival lesion is a manifestation of the response of the gingiva to antigens, or to concurrent systemic disease, for there is little or no deviation from normal in the serum protein levels in this disorder. Experience in one long-term case has shown that treatment of this lesion may perhaps be more conservative than that generally employed for confirmed extramedullary plasmacytoma, especially in cases where there is considerable opposition to the loss of the natural dentition. If conservative treatment is employed, it is mandatory that local and general re-examination be conducted at regular intervals for long periods until more is learned of the long-term behaviour of this lesion in a considerable number of cases. ACKNOWLEDGEMENTS I am indebted to Mr D. Adams and Dr. 17. Henny for permission to cite details of cases under their care, to Professor B. Cohen for advice and assistance, and Mr. E. B. Brain for photographic assistance. REFERENCES ANDERSON, D. L. (I96I). Bienn. Rep. Div. dent. Res., Univ. Toronto, 27th May. BING, J., FAGRAEUS, A. & THEORELL, B. (1945). Acta physiol, scand, xo, 282. ]]JORNEBOE, M., GORMSEN, H. & LUNDQUIST, F. (I945). ]. Immunol. 55, 121. CATALDO, E. & MEYER, I. (1966). Oral Surg. 22, 628. DOLLIN, S. & DEWAR, J. P. (1956). Am. J. Path. 32, 83. ERICH, W. E. (1956). Handbuch der allgemein Pathologie (ed. Buchner, F., Letterer, E. and Roulet, F.), Vol. 7, Pt. I. Berlin: Springer. EWING, M. R. & FOOTE, F. W. (1952). Cancer, 5, 499. STOUT, A. P. & KENNY, F. R. (1949). Cancer, 2, 261.
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