oral pathoses as diagnostic indicators in leukemia

Oral pathoses as diagnostic indicators in leukemia Richard Stafford, D.D.S., * Stephen Sonis, D.M.D., D.M.Sc., * Peter Lockhart, D.D.S., * and Andrew Sonis, D.M.D., ** Boston, Mass.

A retrospective chart review of 500 leukemia patients was carried out to analyze the role of oral pathoses in the presentation of leukemia and to determine those factors which affect the frequency of oral involvement during the initial clinical phases of the disease. The data indicate that oral pathoses were frequent signs or symptoms in patients with undiagnosed acute leukemia but were less prevalent in patients with undiagnosed chronic leukemia. Neither age nor sex appeared to bs a significant factor affecting oral involvement. Oral signs of thrombocytopenia were the most prevalent complaint of patients seeking diagnosis for their leukemia because of an oral problem, and they were also most frequently responsible for oral problems found at initial physical examination. Head and neck lymphadenopathy was also a frequent presenting sign or symptom. Dentists were responsible for initiating the diagnosis of leukemia in a significant number of patients with acute nonlymphoblastic leukemia.

T here are numerous reports documenting the rela- tionship of leukemia to a wide variety of oral pathoses.le4 The role of the oral cavity as a diagnostic indicator of leukemia was suggested in 1936 in a report by Love,5 who studied the pathologic changes in the mouths of eighty-two patients with leukemia. In a later investigation, Lynch and Ship6 evaluated the initial oral manifestations of leukemia and demonstrated the relative frequency of oral involvement early in the disease process. The present study was undertaken to define the role of the oral cavity as a primary diagnostic indicator in leukemia and to determine those factors which affect the frequency of oral involvement during the initial clinical phases of the disease.

MATERIALS AND METHODS

A retrospective chart review was performed for ap- proximately 500 patients who were diagnosed as having leukemia at the Peter Bent Brigham Hospital, the Sidney Farber Cancer Institute, and the Children’s Hospital Medical Center between 1974 and 1979. The following information was determined for each patient: age, sex, hemogram at diagnosis (which included absolute and differential white blood cell counts and platelet count),

This work was supported in part by the Brigham Surgical Group Foundation. *Division of Dentistry, Peter Bent Brigham Hospital and the Sidney Farber Cancer Institute, and the Harvard School of Dental Medicine. **Department of Dentistry, Children’s Hospital Medical Center, and Harvard School of Dental Medicine.

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classification of type of leukemia, reason for seeking treatment, symptoms, oral findings at initial physical examination, and profession of the person responsible for initiating the diagnosis of leukemia. Leukemias were classified by histologic criteria of bone marrow into acute myelogenous (AML), acute lymphoblastic (ALL), acute myelomonocytic (AMML), chronic myelocytic (CML), and chronic lymphocytic (CLL) forms. Sub- classifications of leukemia (T-cell leukemias) were included in major classification headings.

Oral findings were defined in one of three categories: (1) primary oral problems, those for which the patient sought professional consultation which led to the diagnosis of leukemia; (2) secondary oral problems, those which, combined with other symptoms, caused the patient to seek professional consultation which led to the diagnosis of leukemia; and (3) asymptomatic oral problems , those which were not described by the patient, but which were noted at the time of physical examination.

Patients with incomplete charts or with diagnoses of preleukemia and patients who had previously received treatment for leukemia were not included in the study. The final number of patients analyzed was 429 (Table I).

RESULTS Frequency of oral problmr (Fig. 1)

In agreement with other report~,~-~ oral manifestations were more common in patients with acute leukemia than in patients with chronic leukemia. The frequency of primary oral problems was relatively consistent among

0030-4220/80/080134+O6S00.60/0 @ 1980 The C. V. Mosby Co.

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patients with acute leukemia (mean, 16 percent). While the frequency of head and neck pathoses as a collaborative (secondary) symptom was relatively high in patients with ALL, it was much less significant as a secondary symptom in patients with either AML or AMML. Oral findings at initial physical examination, exclusive of primary or secondary symptoms, were noted in slightly more than one fourth of the patients with acute leukemia.

There were significantly fewer oral problems in patients with chronic leukemia. Fewer than 10 percent of the patients with CML or CLL demonstrated either primary or secondary oral symptoms, and positive asymptomatic oral findings on initial physical examination were only slightly more common.

Distribution of primary oral signs and symptoms (Fig. 2)

The most frequent primary oral problems in patients with AML were associated with bleeding and were manifested as gingival oozing, petechiae, hematomas, or ecchymoses . Sore throat, pharyngitis , nonspecific oral ulceration, and pain caused a significant number of patients to seek care. Bacterial infection of teeth, gin- giva, or oral mucosa affected four patients. Lym- phadenopathy and periodontal problems were mentioned only occasionally as reasons for seeking care. The distribution of primary oral signs and symptoms in patients with AMML resembled those of AML patients.

In contrast to patients with AML, more than half of the patients with ALL described head and neck lymphadenopathy as their chief complaint. Oropharyngeal involvement, bacterial infection, bleeding and oral pain accounted for other primary signs and symptoms in patients with ALL.

No patients who were diagnosed with CML sought treatment solely because of an oral problem. Only two patients with CLL complained of a head and neck symptom (lymphadenopathy) as their motive for seeking diagnosis.

Distribution of secondary oral symptoms (Fig. 3)

Secondary oral symptoms were defined as those symptoms mentioned in the statement of the chief complaint as co-factors with some other nonoral symptom which caused the patient to seek care. Secondary oral symptoms were more common in ALL than in other forms of acute leukemia. As with primary oral symptoms, few patients with chronic leukemia mentioned problems of the head and neck as a secondary reason for seeking diagnosis.

Oral bleeding was a common secondary oral problem among patients with acute leukemia. Lymphaden- opathy was especially frequent in patients with ALL.

Oral pathoses as diagnostic indicators in leukemia 135

r--

Fig. 1. Frequency of primary a, secondary t33 , and asymptomatic tH oral problems in study patients with acute lymphoblastic (ALL), acute myelogenous (A&K), acute myelomonocytic (AMML), chronic myelocytic (CML), and chronic lymphocytic (CLL) leukemia. Primary oral problems were those for which the patient sought professional consultation which led to the diagnosis of leukemia. Secondary oral problems were those which, combined with other symptoms, caused the patient to seek professional consultation which led to the diagnosis of leukemia. Asymptomatic oral problems were those which were not described by the patient but which were noted at the time of the prediagnostic physical examination.

Table I. Distribution of leukemias studied

No. oJ Percent Classification patients studied of total

Acute lymphoblastic (ALL) 180 42 Acute nonlymphoblastic

Acute myelogenous (AML) 149 35 Acute myelomonocytic (AMML) 25 6

Chronic myelocytic (CML) 45 10 Chronic lymphocytic (CLL) 30 7

Total 429 100

Periodontal problems (gingival enlargement, redness, pain), oropharyngeal symptoms, infection, ulcertation , and salivary gland involvement were also mentioned as secondary oral signs or symptoms.

Distribution of positive oral findings at initial physical examination (Fig. 4)

Findings at physical examination were defined as those described in the initial work-up by the admitting physician. Although dental consultations were often sought by the admitting physician, the dental consul- tant’s findings were included in this section only if the patient was examined prior to the initiation of therapy.

Whereas oral bleeding problems were the most commonly observed at initial physical examination in patients with AML, lymphadenopathy was the most

136 Staflord et al. Oral Surg. August, 1980

Fig. 2. Percent distribution of primary oral problems.

Fig. 3. Percent distribution of secondary oral problems.

consistent finding on physical examination in patients with ALL. Other positive findings in patients with acute leukemia included leukoplakia and cracked lips.

Few patients with chronic leukemia had oral symptoms at the initial physical examination. Bleeding and

Fig. 4. Percent distribution of asymptomatic oral findings re- corded at the time of prediagnostic physical examination.

lymphadenopathy were the most common findings in patients in both categories.

Analysis of systemic symptoms as related to oral findings (Fig. 5)

No significant differences were noted in the frequency or distribution of systemic symptoms between patients with oral problems and patients without oral problems in any of the types of leukemia studied.

Age distribution of patients studied (Table II)

The age distribution of patients was related to the type of leukemia. The majority of patients with ALL were children. No trend in age was observed in patients with AML. Patients with AMML tended to be slightly older than the AML group, as did patients with CML. Patients with CLL were the oldest of the patients examined. In no instance was there any correlation between the age of the patient and the relative frequency of primary or secondary oral problems or positive asymptomatic oral findings on physical examination.

Distribution of practitioners making the diagnosis of leukemia

Physicians were primarily responsible for diagnosing all types of leukemia, although a significant number of patients with acute nonlymphoblastic leukemia was diag-

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Fig. 5. Distribution of systemic symptoms in patients with EI and without q oral findings compared to the distribution of systemic symptoms in the over-all population studied with the specific classification of leukemia W.

nosed by dentists. In one fourth of the patients with AML and one third of the patients with AMML, dentists were responsible for prescribing the appropriate hematologic tests which led to a diagnosis of leukemia.

DISCUSSION

Our results indicate that oral pathoses tend to be frequent signs or symptoms in patients with undiagnosed leukemia. Of the patients studied, 65 percent had some form of oral pathosis which caused them to seek care (primary symptom), which contributed to their reason for seeking care (secondary symptom), or which was noted during the diagnostic physical examination. In agreement with other studies,6, ’ the frequency of oral pathoses tended to be higher in patients with acute leukemia than in patients with chronic leukemia.

Of major importance was the frequency with which an oral problem was the primary reason for a patient seeking care for his or her leukemia. Of patients with acute lymphoblastic leukemia (ALL), 17 percent sought medical attention for their oral symptoms. Likewise, 17 percent of the patients with AML and 12 percent of the patients with AMML first sought treatment, which led to the diagnosis of leukemia, for an oral problem. In patients with ALL, pathoses of the head and neck also played a significant collaborative

role in leading the patients to seek treatment for leukemia. This finding assumes therapeutic significance, since ALL is the most treatable of the acute leukemias.

In contrast, oral symptoms did not play a major role in initiating the diagnosis of patients with chronic leukemia.

As described by other investigators,“, ‘” the frequency of oral pathoses at the time of the physical examination depended on the type of leukemia. Twen- ty-six percent of the patients with acute leukemia who did not report an oral problem as a reason for seeking care had positive oral findings at the time of their initial physical examination. While the frequency was essen- tially the same for patients with ALL and AML, it was slightly higher for patients with AMML. Only 11 percent of the patients with CML and 20 percent of the patients with CLL had positive oral findings at the initial examination.

Although our patient sample corresponded well to the incidence of leukemia in the general population with respect to age and sex,“’ l2 with the exception of AMML, neither sex nor age appeared to be a significant factor in affecting oral involvement in patients with acute leukemia. Of interest was the finding that the frequency of oral problems in patients with AMML decreased with age. It should be noted, however, that

138 Stafford et al. Oral Surg. August, 1980

Table II. Sex and age distribution of patients studied

Type of leukemia and classiJication of

oral pathoses

Sex Age fyr)

M F O-20 21-40 41-60 61+

Acute lymphoblastic Primary Secondary Finding at examination No oral findings Total

Acute myelogenous Primary Secondary Finding at examination No oral findings Total

Acute myelomonocytic Primary Secondary Finding at examination No oral findings Total

Chronic myelocytic Primary Secondary Finding at examination No oral findings Total

Chronic lymphocytic Primary Secondary Finding at examination No oral findings Total

19 (54)* 16 (46) 43 (53) 38 (47) 27 (61) 17 (39)

(65) 13 7 (35) 102 (57) 78 (43)

32 (91) 77 (96) 40 (91) 16 (80)

165 (92)

3 (9) 3 (4) 2 (4)

4 12 (7)

0 0 2 (4)

L!-.- 2 (1)

0 0 0

.A-.- 0

14 (54) 12 (46) 12 (60) 8 (4’3 23 (56) 18 (44 26 (42) 36 (58) 75 (50) 14 (50)

6 (23) 5 (19) 11 (42) 4 (15) 7 (35) 4 (20) 4 (20) 5 (25) 7 (17) 11 (27) 9 (22) 14 (34) 9 (14) 16 (25) 12 (19) 25 (4)

29 (19) 36 (24) 36 (24) 48 (32)

2 w 1 (33) 2 (66) 1 (33) 5 (56) 4 (4) 6 (50) 4 (40)

1 (33) 1 (33) 0 1 (33) 0 5 (56) 0 0

1 (33) 1 (33) 3 (33) 5 (50)

0 1 (33) 1(11) 5 (50) 7 (28) 15 (60) 10 (40) 1 (4) 7 (28) 10 (40)

0 0 2 (40)

0 1 (50) 1 (20)

0 1 (50) 2 WV

6 9 (20)

l(lW 0 0

18 (49) 19 (42)

l(lW 0 1 (50) 1 (50) 5 (1W 0

23 (62) 14 (38) 30 (67) 15 (33)

5 (14) 8 (22) 7 (16) 10 (22)

1 (50) 2 (1W 5 (83)

13 (65)

1 (50) 0 l(l7)

7 9 (30)

0 1 (50) 1 (50) 0 1 (50) 1 (50) 0 2 (33) 4 W) 1 (5) 6 (30) 13 (65)

1 (3) 10 (33) 19 (63) 21 (70) 0

*Percentage shown in parentheses.

the relative lack of high patient numbers makes this observation a trend rather than a statistically significant fact.

A variety of oral symptoms were initially responsible for patients seeking treatment of leukemia (Fig. 2). Among these, lymphadenopathy , oral bleeding, oropharyngeal involvement, and bacterial infections were the most frequent chief complaint. Of interest was the finding that, for the acute nonlymphoblastic leukemias , a significant proportion of patients sought primary care from dentists rather than physicians and that dentists were responsible for initiating the steps necessary to make a diagnosis of leukemia. The number of patients diagnosed by dentists in the current series was significantly higher than that reported by Lynch and Ship,6 who pointed out that this information was not available in 88 percent of the patients they studied. In addition, the awareness among dentists of the oral signs of leukemia may have increased since their study was com- pleted in 1967.

Oral bleeding was the most consistent secondary

symptom leading to a diagnosis of all forms of leukemia. Although thrombocytopenia is the most obvious cause of this finding, qualitative differences in platelets may also be associated with clinical bleeding.13* l4 Generally, signs of oral bleeding were manifested as petechiae or gingival oozing.

Oral findings on initial physical examination were relatively common: signs of oral bleeding, usually palatal petechiae, were frequent. This finding is consistent with Love’s5 report in which fifty of eighty-two leukemia patients had oral pathoses associated with bleeding. In agreement with others,r5* I6 lymphadenopathy, usually of the cervical nodes, was reported by patients with all forms of acute leukemia and by patients with CLL. Oral bacterial infection was a rare finding. No correlation was noted between the frequency or distribution of systemic symptoms and oral problems.

Unfortunately, the incidence of leukemia is rising.r8 The disease now affects 9.1 Americans per 100,000.19 The risk of developing acute leukemia is estimated to

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be 1 in 2,500 for children under 10 years of age.20 Advances in treatment, especially in cases of ALL, have increased the importance of early diagnosis. Even in those forms of leukemia with grim prognoses, early recognition of the disease may be of importance in attaining some period of remission following treatment. The frequency with which the mouth is involved, as suggested by the data in the present study, points to its role in the early diagnosis of the disease and should heighten the awareness of those who deal with the oral cavity to their role in disease detection.

We thank Susan Prignano and Mark Kilgore for their assis- tance in the preparation of this manuscript.

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Curtis, A. B.: Childhood Leukemias: Initial Oral Manifesta- tions. J. Am. Dent. Assoc. 83: 159-164, 1971. Roath, S., Israel, M., and Wilkinson, I.: Tbe Acute Leukemias: A Study of 580 Patients, Q. J. Med. 33: 257-283, 1964. Beck, W.: Hematology, ed. 2, Cambridge, 1977, The MIT Press, pp. 413. Thorn, G., Adams, R., Braunwald, E., Isselbacher, K., and Petersdorf, R. (editors): Harrison’s Principles of Internal Medicine, ed. 8, New York, 1977, McGraw-Hill Book Com- pany, Inc., p. 1768. Patrone, F., Dallegri, F., Brema, F., and Sacchetti, C.: In Virro Function of Chronic Myelocytic Leukemia Granulocytes: Ef- fects of Irradiation and Storage, Tumori 65: 27-37, 1979. Rosher, F., Valmont, I., Kozinn, P., and Caroline, L.: Leuko- cyte Function in Patients With Leukemia, Cancer 4: 835-842, 1970. White, G.: Oral Manifestations of Leukemia in Children, ORAL

SURG. 29: 420-427, 1970. Michaud, M., Baehner, R. L., Bixler, D., and Kafrawy, A.: Oral Manifestations of Acute Leukemia in Children, J. Am. Dent. Assoc. 95: 11451150, 1977. Sinrod, H. S.: Leukemia as a Dental Problem, 1. Am. Dent. Assoc. 55: 809-818, 1957. Gartinkel, L., and Silverberg, E.: Cancer Statistics, American Cancer Society, Professional educational publication, 1978. Cady , B. (editor): Cancer, a Manual for Practitioners, ed. 5, Boston, 1978, American Cancer Society. Massachusetts Division.

Reprint requests to: Dr. Stephen T. Sonis Division of Dentistry Peter Bent Brigham Hospital 721 Huntington Ave. Boston, Mass. 02115

oral pathoses as diagnostic indicators in leukemia

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