Clinicopathologic effects of cancer chemotherapeutic agents on human buccal mucosa James Guggenheimer, D.D.S., + Robert N. I’erbin, D.X.D., Billy N. dppel, D.D.9.,#*” crrld *Jack Schmutz, D.D.S.“““” Pittsburgh, Pn. SCHOOI,
OF
DENTAL
MEDICISE,
USIVERSITY
T
OF
Ph.D.,“”
I’ITTS:HURGH
he administration of c~hr~mothcrapeuti~ agents for t,he treatment of’ malignant spstcmiv disorders is frcyucntly associated with a variety of toxic side effkts, including the tlevc~lopmcnt of stomatitis and oral ulecrations.‘~ 2 ‘IThex adverse I’(‘aetions owur with many drugs currently ustd,:’ ant1 in onv study in which fluorinated pyrimidines (e.g., 5-fluorourac4l) \vcw c~mplo~wl oral lesions tlcvelopctl in 75 per cent of the patients.’
*Professor, Jkp&tment of Oral Mdicinc~. i “Profr~ssor and Head, Department of Pathology. ’ *“Associate Professor, Department of Pathology. ‘**Assistant Profwsor, 1)epartment of Pathology.
58
It has been established that one of the mechanisms by which these antinco1)lastic agents affect rapidly proliferating cells in both normal and nroplastic tissues is via an interference with I)NA synthesis.” Thr epithelium of the oral mucos:a has been shown to have a high rate of I>XA synthesis and a turnover time of approsimatcly 5 day~.~ Therefore, an inhibition of DNA production may also tlisrupt, the normal replication and replacement of the mucosal epithclial cells and cventuatc in atrophy followed by ulceration of the oral mucous membranes.’ This phenomenon has been produced experimentally in animal models with both methotrexate ant1 5-fluorouracil,h. !’ but it has not been demonstrated in human subjects. The purpose of the present study \vas to assess the histopathologic alterations in human buccal mucosa, the anatomic site where ulcers have most frequentI\ been notetl during or following cancer chemotherapy.l”-lz The information thus obtained might provide some insight into the pathogenesis of the observed clinical oral lesions. MATERIALS
AND
METHODS
A portion of buccal mucosa was obtained at autopsy from 216 patients. The csperimental group included all patients who had received more than one dose of a cancer chemotherapeutic agent between 1 and 3 weeks prior to death. The control group consisted of two populations of patients-( 1) those with malignant disease who had ?mt received treatment during their final hospitalization and (2) patients who died of causes not related to cancer. All specimens were stored in formalin and then sectioned and stained with hematoxylin and eosin. Each section was interpreted independently by three oral pathologists who were not aware of the nature of the patient’s clinical diagnosis. The histologic findings were then correlated with the therapeutic regimen employed and any oral symptoms that appeared during the t,erminal 4 lveeks of hospitalization as documented in the medical record. RESULTS
There were no significant histopathologic changes in 186 (86 per cent) of the specimens. The remaining thirty (14 per cent) specimens showed atrophy of the oral epithelium. This morphologic alteration was found in the buccal mucosa obtained from thirteen (52 per cent,) of those patients who had been treated with various antineoplastic drugs (Table I) as well as in seventeen (9 per cent) members of the control population. Fig. 1 shows representative examples of the atrophic cpithelium. A comparison of the findings between the esperimcntal and control groups by the chi-square test revealed a significantly 1 greater incidence of atrophy among those patients receiving chemotherapy (p < O.OOI). Review of the medical records also disclosed that four patients developed symptoms of stomatitis during their course of treatment. Furthermore, three of these patients had histologic evidence of mucosal atrophy (Table I). The seventeen cases of atrophic oral mucosa among the 191 control patients were randomly distributed, with no readily identifiable common etiologic factor.
Case No. Age
Sex
19 62
M
Adenocarcinoma,
21 45 29 X3 3X 35
M M M
Renal-cell carcinoma Acute myelogenous leukemia Bronchogenic carcinoma, lung
Primary
neoplasm
pancreas
44
49
F
45
41
F
46 47 86
12 56 53
Ll M
Acute myelogenous leukemia Duct-cell carcinoma, breast Carcinoma, endometrium Squamous-cell carcinoma, lung Hodgkin’s disease
91
64
F
Carcinoma, breast
IIX 121 172 I24 134
64 55 4X 6X x0
M M F L
Acute myelogenous leukemia Lymphosarcoma Carcinoma, breast Carcinoma, breast Acute myelogenous leukemia
152 50
M
Acute myelogenous leukemia
161 19 177 48 180 55
M F F
Acute myelogenous leukemia Chronic lymphocytic leukemia Acute myelogenous leukemia
186
59
F
I90
3:
F
Adenocarcinoma, rectum Acute myelogenous leukemia
lY3
5h
I-
Carcinoma, breast
1%
2‘
M
201
05
M
4cute myelogenous leukemia Lymphocytic lymphoma
207
07
M
Multiple myeloma
Chemotherapeutic
drugs
5-fluorouracil, cyclophosphamide. cyclohexyl nitrosourea Mithramycin 6-mercaptopurine Methotrexate, cyclophosphamide. cyclohexyl nitrosourea. hydroxyurea 6-mercaptopurine Methotrexate Thiotepa, 5-fluorouracll Thiotepa, 5-fluorouracil Nitrogen mustard, vincristme. procarbazine Cyclophosphamide, methotrexate. 5-fluorouracil, vincristine Cytarabine, thioguanine Cyclophosphamide Mithramycin. adriamjcln Mithramycin, 5-fluorouracll Vincristine, cyclophosphamide, cytarabine Vincristine, cytarabine. daunomycin Cytarabine, daunomycin Vincristine, bleomycin Vincristine, cytarabine. daunomycin 5-fluorouracil Vincristine. cqclophosphamlde, daunomycin ( yclophosphamide. S-tluorouracil. adriamycin. methotrexate Cytarahine Nitrogen mustard. wncrlstine, procarbazine I-phenylalanine mustard. hischloroethyl nitrosourea
Sfomatitis
Atrophy +
t +
1
i
Fig. 1. A, A section of buccal rnucosa that was obtained from a patient rewiring cancer c~hemotberxpy (Case 122). Note the atrophic epitheliuru. B, Atrophic epithelium covering the ln~c;~l ~nucosa of a patient who did of causm not relatrd to canwr. (Hemtoxylin :ln(l cosin stain. Magnification, x400.)
tra&13-1J Clcerations of the oral mucosa are another commonly encountered adverse reaction to these cytotoxic agents.“, i Thcsc particular lesions may bc the result of a drug-induced inhibition of cell division in the proliferative compartment of epithelial tissues which continuously replicate. Sinw cell migration and extrusion from an epithelial surface have been shown to be independent of new cell formatiOn,lC-lX atrophy followed by ulceration of the oral mucosa could therefore also occur. Methotrexatc has been shown to produce oral ulcerations betwell t5 and 7 days following initiation of therapy. I1 The interval required for the evolution of these ulcers corresponds to the estimatetl turnover time of human mucosa.” The results o-f the present stutlv show that atrophy of the oral mucosa did, indeed, owur and was significantly associated with cancer chemotherapy. With one csccption (Case 202, Table I), each patient with mucosal atrophy had been OK11
REFERENCES
IO. I I. 1”. 1R. 13.
13. I Ii. IT. IS. 19. “0. 21. .).> _I. Lrfrxk,
E:. A., Pitlla, ,J., Xoscnllrim, R., and Gottlieb, .I. A.: .\ Clitlic~oJ)xtholo~ic I\ualysis of A(lri:tmyvin Cardiotosicity, Caner 32: X02-3 I4 19;::. ‘3. Post, ,J., and Hcfban, J. : Cull Xw(~\val Pnttcr:ls, N. Engf. .I. hlctl. 279: 24%2% 196s. “4. Solomon, H. A. : Stomatitis hlcdicamc>ntosx ,\c~c,orllpa”yillg Actinomycin J) 'l'llc~rxpy 'in .\tlx-rurwtl Cancer, OKAI, RtlR(:. 15: 5.+4-547, 1962. 22. I3urket, I,. TV. : Oral Mcdic+nr~, cstl. 6, I’liiladelpllia, 1971 , J. 1%.Lif)pinc>ott Cornpny, fj. 16X. ‘fi. l':rgv, A. f
OF
DENTAL
MEDICISE,
USIVERSITY
T
OF
Ph.D.,“”
I’ITTS:HURGH
he administration of c~hr~mothcrapeuti~ agents for t,he treatment of’ malignant spstcmiv disorders is frcyucntly associated with a variety of toxic side effkts, including the tlevc~lopmcnt of stomatitis and oral ulecrations.‘~ 2 ‘IThex adverse I’(‘aetions owur with many drugs currently ustd,:’ ant1 in onv study in which fluorinated pyrimidines (e.g., 5-fluorourac4l) \vcw c~mplo~wl oral lesions tlcvelopctl in 75 per cent of the patients.’
*Professor, Jkp&tment of Oral Mdicinc~. i “Profr~ssor and Head, Department of Pathology. ’ *“Associate Professor, Department of Pathology. ‘**Assistant Profwsor, 1)epartment of Pathology.
58
It has been established that one of the mechanisms by which these antinco1)lastic agents affect rapidly proliferating cells in both normal and nroplastic tissues is via an interference with I)NA synthesis.” Thr epithelium of the oral mucos:a has been shown to have a high rate of I>XA synthesis and a turnover time of approsimatcly 5 day~.~ Therefore, an inhibition of DNA production may also tlisrupt, the normal replication and replacement of the mucosal epithclial cells and cventuatc in atrophy followed by ulceration of the oral mucous membranes.’ This phenomenon has been produced experimentally in animal models with both methotrexate ant1 5-fluorouracil,h. !’ but it has not been demonstrated in human subjects. The purpose of the present study \vas to assess the histopathologic alterations in human buccal mucosa, the anatomic site where ulcers have most frequentI\ been notetl during or following cancer chemotherapy.l”-lz The information thus obtained might provide some insight into the pathogenesis of the observed clinical oral lesions. MATERIALS
AND
METHODS
A portion of buccal mucosa was obtained at autopsy from 216 patients. The csperimental group included all patients who had received more than one dose of a cancer chemotherapeutic agent between 1 and 3 weeks prior to death. The control group consisted of two populations of patients-( 1) those with malignant disease who had ?mt received treatment during their final hospitalization and (2) patients who died of causes not related to cancer. All specimens were stored in formalin and then sectioned and stained with hematoxylin and eosin. Each section was interpreted independently by three oral pathologists who were not aware of the nature of the patient’s clinical diagnosis. The histologic findings were then correlated with the therapeutic regimen employed and any oral symptoms that appeared during the t,erminal 4 lveeks of hospitalization as documented in the medical record. RESULTS
There were no significant histopathologic changes in 186 (86 per cent) of the specimens. The remaining thirty (14 per cent) specimens showed atrophy of the oral epithelium. This morphologic alteration was found in the buccal mucosa obtained from thirteen (52 per cent,) of those patients who had been treated with various antineoplastic drugs (Table I) as well as in seventeen (9 per cent) members of the control population. Fig. 1 shows representative examples of the atrophic cpithelium. A comparison of the findings between the esperimcntal and control groups by the chi-square test revealed a significantly 1 greater incidence of atrophy among those patients receiving chemotherapy (p < O.OOI). Review of the medical records also disclosed that four patients developed symptoms of stomatitis during their course of treatment. Furthermore, three of these patients had histologic evidence of mucosal atrophy (Table I). The seventeen cases of atrophic oral mucosa among the 191 control patients were randomly distributed, with no readily identifiable common etiologic factor.
Case No. Age
Sex
19 62
M
Adenocarcinoma,
21 45 29 X3 3X 35
M M M
Renal-cell carcinoma Acute myelogenous leukemia Bronchogenic carcinoma, lung
Primary
neoplasm
pancreas
44
49
F
45
41
F
46 47 86
12 56 53
Ll M
Acute myelogenous leukemia Duct-cell carcinoma, breast Carcinoma, endometrium Squamous-cell carcinoma, lung Hodgkin’s disease
91
64
F
Carcinoma, breast
IIX 121 172 I24 134
64 55 4X 6X x0
M M F L
Acute myelogenous leukemia Lymphosarcoma Carcinoma, breast Carcinoma, breast Acute myelogenous leukemia
152 50
M
Acute myelogenous leukemia
161 19 177 48 180 55
M F F
Acute myelogenous leukemia Chronic lymphocytic leukemia Acute myelogenous leukemia
186
59
F
I90
3:
F
Adenocarcinoma, rectum Acute myelogenous leukemia
lY3
5h
I-
Carcinoma, breast
1%
2‘
M
201
05
M
4cute myelogenous leukemia Lymphocytic lymphoma
207
07
M
Multiple myeloma
Chemotherapeutic
drugs
5-fluorouracil, cyclophosphamide. cyclohexyl nitrosourea Mithramycin 6-mercaptopurine Methotrexate, cyclophosphamide. cyclohexyl nitrosourea. hydroxyurea 6-mercaptopurine Methotrexate Thiotepa, 5-fluorouracll Thiotepa, 5-fluorouracil Nitrogen mustard, vincristme. procarbazine Cyclophosphamide, methotrexate. 5-fluorouracil, vincristine Cytarabine, thioguanine Cyclophosphamide Mithramycin. adriamjcln Mithramycin, 5-fluorouracll Vincristine, cyclophosphamide, cytarabine Vincristine, cytarabine. daunomycin Cytarabine, daunomycin Vincristine, bleomycin Vincristine, cytarabine. daunomycin 5-fluorouracil Vincristine. cqclophosphamlde, daunomycin ( yclophosphamide. S-tluorouracil. adriamycin. methotrexate Cytarahine Nitrogen mustard. wncrlstine, procarbazine I-phenylalanine mustard. hischloroethyl nitrosourea
Sfomatitis
Atrophy +
t +
1
i
Fig. 1. A, A section of buccal rnucosa that was obtained from a patient rewiring cancer c~hemotberxpy (Case 122). Note the atrophic epitheliuru. B, Atrophic epithelium covering the ln~c;~l ~nucosa of a patient who did of causm not relatrd to canwr. (Hemtoxylin :ln(l cosin stain. Magnification, x400.)
tra&13-1J Clcerations of the oral mucosa are another commonly encountered adverse reaction to these cytotoxic agents.“, i Thcsc particular lesions may bc the result of a drug-induced inhibition of cell division in the proliferative compartment of epithelial tissues which continuously replicate. Sinw cell migration and extrusion from an epithelial surface have been shown to be independent of new cell formatiOn,lC-lX atrophy followed by ulceration of the oral mucosa could therefore also occur. Methotrexatc has been shown to produce oral ulcerations betwell t5 and 7 days following initiation of therapy. I1 The interval required for the evolution of these ulcers corresponds to the estimatetl turnover time of human mucosa.” The results o-f the present stutlv show that atrophy of the oral mucosa did, indeed, owur and was significantly associated with cancer chemotherapy. With one csccption (Case 202, Table I), each patient with mucosal atrophy had been OK11
REFERENCES
IO. I I. 1”. 1R. 13.
13. I Ii. IT. IS. 19. “0. 21. .).> _I. Lrfrxk,
E:. A., Pitlla, ,J., Xoscnllrim, R., and Gottlieb, .I. A.: .\ Clitlic~oJ)xtholo~ic I\ualysis of A(lri:tmyvin Cardiotosicity, Caner 32: X02-3 I4 19;::. ‘3. Post, ,J., and Hcfban, J. : Cull Xw(~\val Pnttcr:ls, N. Engf. .I. hlctl. 279: 24%2% 196s. “4. Solomon, H. A. : Stomatitis hlcdicamc>ntosx ,\c~c,orllpa”yillg Actinomycin J) 'l'llc~rxpy 'in .\tlx-rurwtl Cancer, OKAI, RtlR(:. 15: 5.+4-547, 1962. 22. I3urket, I,. TV. : Oral Mcdic+nr~, cstl. 6, I’liiladelpllia, 1971 , J. 1%.Lif)pinc>ott Cornpny, fj. 16X. ‘fi. l':rgv, A. f
