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Improvement of oral lesions associated with malignant acanthosis nigricans after treatment of lung cancer
Improvement of oral lesions associated with malignant acanthosis nigricans after treatment of lung cancer Kazuhiko Nomachi, DDS,* Masatomo Mori, MD, DMSc,** and Noboru Matsuda. DDS, DMSc,* Maebashi, Japan SCHOOL
OF MEDICINE,
GUNMA
UNIVERSITY
A rare case of malignant acanthosis nigricans associated with lung cancer is presented. The case involved a 70-year-old man who had oral changes and various immunologic dysfunctions, including an increase in antinuclear antibodies. Oral lesions were characterized by papillary hyperplasia, formation of grooves, pigmentation of the upper lip and cheeks, and a loss of taste sensation. After the patient’s lung cancer was treated with anticancer drugs, the histopathologic examination showed a marked improvement in oral lesions and significant normalization of immunologic abnormalities. The present case provides unique evidence that oral lesions associated with acanthosis nigricans have a significant correlation with lung cancer and high titers of antinuclear antibodies. (ORAL SURC ORAL MED ORAL PATHOL 1989;68:74-9)
A
canthosis nigricans (AN) is an uncommon dermatologic condition with characteristic manifestations including hyperpigmentation, epidermal hypertrophy with histologic features of acanthosis, hyperkeratosis, and dermal papillomatosis. Two forms are well recognized: (1) the malignant or adult type, which arises in persons past middle age and is associated with internal malignancy, and (2) the benign or juvenile type, which may be present at birth or in childhood, and is associated with developmental endocrine or metabolic abnormalities.‘,2 Initially, extensive studies of the malignant type of AN were done by Pollitzer3 who emphasized the significant relationship of the skin lesions to abdominal malignancy. The characteristic lesions of AN observed in the skin also affect the oral mucous membranes. The incidence of oral involvement in patients with AN was estimated by Fladung and Heite4 to be 53%. Masson and Montgomery5 calculated the incidence to be approximately 50%. However, since most patients with AN and a malignant tumor have received anticancer treatment at the departments of internal medicine, dermatology, or *Department of Oral Surgery, School of Medicine, Gunma University. **First Department of Internal Medicine, School of Medicine, Gunma University 74
surgery, limited information is available with respect to oral lesions in these patients. In fact, Mostofi and coworkers6reported that they did not encounter any descriptions of oral lesions associatedwith AN in the English-language dental literature of the 1970s. We investigated oral mucosal lesions in a rare case of the malignant type of AN in a patient with lung cancer and abnormal immunologic findings. An apparent reduction in the size of the lung tumor was observed with a concomitant improvement both in the immunologic disturbances and the oral mucosal lesions after treatment with anticancer drugs. To our knowledge, this is the first case showing detailed histopathologic findings of improvement in the oral mucosal lesions in a patient with AN after treatment of the underlying malignant tumor. CASE REPORT
A 70-year-old man had a dry cough that began in January 1984, and he noticed a darkening of his face in March 1984. In December 1984, he consulted a physician, and an abnormal shadow was detected by means of radiographic examination of the chest. Becauseof this, he was hospitalized at the First Department of Internal Medicine, Gunma University Hospital, on January 8, 1985, and received an examination at the Dep-rtment of Oral Surgery on the day of admission. Physical examination revealed dry skin and a diffuse dark brown pigmentation of the face and the trunk. In
Volume68 Number 1
Improvement of oral lesions of malignant acanthosis nigricans
75
1985).
Fig. 2. Lesions of prolabium. A, At the first examination (Jan. 8, 1985). Note epithelial thickening with verrucosis and pigmentation. B, At the disappearance of lung tumor (Nov. 10, 1985).
addition, rice- to pea-sized nodules were scattered over the skin of the trunk (Fig. 1). His lips had a rough texture. A number of papillary hyperplastic growths, some of which were rice-sized, others 1 to 2 mm in diameter, were seenon the mucosal surface of the lips. The upper lip showed reddish brown plaques (Fig. 2, A). The buccal mucous membrane displayed furrows due to flat papillary hyperplasia with associatedbrown and gray-white pigmentation (Fig. 3, A). The dorsum of the tongue was rough and partially gray-white in color. The tongue papillae were 1 to 2 mm in size, giving a deeply fissured appearance. The patient’s sensation of taste was lost almost completely. The mucosa over the palate and the gingiva was intact. A radiograph of the chest revealed a shadow of a massin the right upper lung field, which was diagnosed as adenocarcinoma on cytologic examination (Fig. 4, A). General laboratory tests, including hematologic tests and urinalysis, showed no abnormalities. In addition, no abnormality was observed as a result of hormonal examination, including a 75 gm oral glucose tolerance test (the blood glucose level [mg/dl]: O-time, 99; 30 minutes, 155; 60 minutes, 141; 120 minutes, 129; the blood immunoreactive insulin level [pU/ml]: O-time, 1.6; 30 minutes, 56.5; 60 minutes, 38.0; 120 minutes, 19.6) the blood cu-melanostimulating hormone (
immunologic tests revealed a remarkable elevation in antinuclear antibody by a 2560-fold titer, anti-ribonuclear antibody by a 16-fold titer, and anti-Smith antibody by an 8-fold titer. Moreover, an elevation was seen in immune complex titer (15.5 pg/ml). Among tumor markers, carcinoembryonic antigen (CEA) was increased remarkably to 510 rig/ml, and immunosuppressive acidic protein (IAP, 710 rg/ml) and tissue polypeptide antigen (TPA, 210 pU/l) were also shown to be elevated. Histopathologicaliy, the lips and buccal mucous membranes exhibited slight keratosis and papillomatosis. Melanophages were observed in the subepithelial papillae, but not in the basal layer (Fig. 5, A). The skin showed hyperkeratosis and papillomatosis of the epithelium and an increase in melanin in the basal layer (Fig. 6). February 1985, the patient received three courses of chemotherapy at the Department of Internal Medicine, each course consisting of 140 mg of cisplatinum diammine dichloride, 40 mg of doxorubicin, and 10 mg of mitomycinC. In addition, the lung tumor was irradiated with Linac 70 gray. With reduction in the size of the pulmonary tumor, the CEA decreasedremarkably and the antinuclear antibody titer dropped progressively (Fig. 7). Similarly, the anti-Sm antibody, which had an 8-fold titer, was lowered to a 2-fold titer, and titers of all other autoantibodies were reduced. A chest radiograph in November 1985 showed that the
Fig.
1. Physiognomy at first
examination (Jan. 8,
76
Nomachi, Mori, and Matsuda
ORAL SURG ORAL
MED ORAL PATH~L July 1989
Fig. 3. Lesion of buccal mucous membrane. A, At the first examination. Consisting of papillary hyperplasia, formation of furrows, and pigmentation. B, At the disappearance of lung tumor.
mucosa did not show dark brown pigmentation, but was smooth as a result of disappearance of furrows (Fig. 3, B). The hypertrophied papillae on the dorsum of the tongue were reduced with improvement of the sensation of taste. Histopathologic examination of the buccal mucous membrane on Nov. 14, 1985, showed that the epithelium became free of papillary hypertrophy; melanophages could not be detected in the lamina propria and there was no evidence of AN (Fig. 5, B). On Feb. 27, 1986, the patient died suddenly as the result of metastasis to the liver, but he had no symptoms of AN. DISCUSSION The patient in the present study had AN and a malignant tumor simultaneously. With respect to the
relationship between AN and malignant tumors, Curth’ found that both developed simultaneously in 61.3% of cases,the tumor precededthe AN in 21.1% and the AN preceded the tumor in 17.6%. When AN was found in the skin and the oral mucosa without obvious manifestations of malignancy, the malignant tumor in many cases appeared
Fig. 4. Chest radiogr2 tphic findings. A, At the first examination (Jan. 8, 1985). The tumor is shown by the arrow. The size is approximately 7 X 5.5 X 6 cm. B, The tumor had disappeared as of Nov. 10, 1985. tumor had apparently disappeared (Fig. 4, B). This was accompanied by a remarkable decrease in pigmentation and nodules observed on the face and the trunk. Moreover, the roughness of the lips had disappeared and the pigmentation had faded (Fig. 2, B). At this time, the buccal
within
1 year.’ There-
fore, oral lesions that occur with AN have important implications in detection of early occurrence of malignancy. Some casesof AN have been observed to be associated with hormonal dysfunction, such as insulin resistance.*-loThe normal responsivenessof blood glucose and insulin to an oral glucose tolerance test was shown in the present patient. Therefore, the present casecould be categorized as a malignant type of AN without insulin resistance. The preferential oral sites of AN are the lips, the tongue, and the buccal mucous membranes. These structures feature papillary hyperplasia, with furrow formation changing to grayish white color. It has been reported that a dark brown pigmentation is seen less frequently in the mucous membranes than that observed on the skin.6~“~‘2The patient presented herein showed the typical dark brown pigmentation on the lips and the buccal mucous membranes, in addition to the main features previously described, followed by disturbance of taste sensation.
Volume68
Improvement of oral lesions of malignant
acanthosis nigricans
Number 1
Fig. 5. Histopathologic features of buccal mucous membrane (Hematoxylin and eosin stain). A, At the first examination. Papillary hyperplasia is seen at low magnification (Original magnification, x33), and melanophage in the subepithelial papillae is depicted at high magnification (Original magnification, ~88). B, Findings on Nov. 14, 1985, at the disappearance of the lung tumor (Original magnification, X88).
Fig. 6. Histopathologic features of skin. Papillomatosis and an increase in melanin are present in the basal layer. (Hematoxylin and eosin stain. Original magnification, X140.)
77
78
Nomachi, Mori, and Matsuda CLINICAL
ORAL SURG ORAL MED ORAL PATHOL July 1989 cyspiatin Lbxcmbicin l4itoncin C
COURSE
CEA
ANF
200100 0 Dec.
I
JGUl
I
F&
I
Lr
I
Apr. 4 fold titer 2 fold titer 244 S.I. 179 S.I. 105 S.I. 35 y.6 1%
Anti-R& antibody 13 fold titer Anti-% antibody 3 fold titer RLA-El 140 S.!. 122 S.I. CO&R7 109 S.I. PHI-R7 NKE activity 22 % I&-FcR ce I I 6%
Fig. 7. Changes in blood level of CEA and titers of ANF after treatment with anticancer drugs. CEA, carcinoembryonic antigen; ANF, anti-nuclear antibody factor; RNP, ribonucleoprotein; Sm, Smith; PHA, phytohemagglutinin; ConA, concanavalin A; PWM, pokeweed mitogen; ADCC, antibody-dependent cell-mediated cytotoxity; FcR, Fc-receptor.
There have been a few studies showing that the skin lesions occurring with AN decreasedin size and disappeared after treatment of cancer such as surgical resection of the malignant tumor, radiation therapy, and chemotherapy.‘3,I4 The data indicate the close relationship between AN and malignant tumors. However, detailed histopathologic examination of the skin and the oral mucous lesions occurring with AN has gained little attention. In particular, there are few articles describing the time-dependent changes in oral mucosal lesions after treatment of malignant tumors. In the present case, it is clear, from the histopathologic examination, that the papillary hyperplasia and melanophages within the lamina propria of the buccal mucosa decreased in size and later disappeared after treatment. In addition, pigmentation in the oral lesions lessened, and the sensation of taste was recovered during treatment of lung cancer with anticancer drugs. It was interesting to note that the gray-white pigmentation possibly due to hyperkeratosis did not change. The mechanisms by which lung cancer in patients with AN produces a significant increase in the titer of antinuclear antibodies remained to be determined. Recent studies have focused on the association of AN with connection tissue diseases.8s I5Alternatively, Sturner and coworkersI indicated that autoantibodies should be determined in patients with AN. In the present case, despite elevated titers of antinuclear antibodies, the possibility of connective tissue disease
was eliminated by findings dependent on both clinical and histopathologic criteria. Moreover, the elevated titer of antinuclear antibodies decreased with reduction in the tumor size after medical treatment. These findings imply the strong correlation between the antinuclear antibody and the lung cancer. It is known that immunosuppressive substancesincluding CEA, TPA, IAP, and the immune complex, as observed in the present case, are produced by malignant tumors.“.18 Therefore, these immunosuppressive substances may have led to a remarkable alteration in immune response systems in the present patient, eventually resulting in formation of antinu-
clear antibodies that are not observed in the normal condition. This concept appears likely to reflect the results of Hodson and Turner-Warwick,19 who reported that the antinuclear antibody was detected, but with weak titers, in 31% of the patients with bronchial carcinoma. REFERENCES 1. Beeson PB, McDermott W. Textbook of medicine. 14th ed. Philadelphia: WB Saunders Co, 1975: 1856-7. 2. Bang G. Acanthosis nigricans maligna. ORAL SURG ORAL MED ORAL PATHOL 1970;29:370-5.
3. Pollitzer S. Acanthosis nigricans: a symptom of a disorder of the abdomen. JAMA 1909;53: 1369-73. 4. Fladung G, Heite HJ. Haufigkeitsanalytische Untersuchungen zur Frage der symptomatologischen Abgrenzung verschiedener Formen der Acanthosis nigricans. Arch Klin Exp Dermatol 1957;205:282-3 11. 5. Masson JC, Montgomery H. Relationship of acanthosis nigricans to abdominal malignancy: report of cases, in which
Volume 68 Number 1
Improvement of oral lesions of malignant
the primary growth was in the pelvis. Am J Obstet Gynecol 1936;32:716-26. 6. Mostofi RZ, Hayden NP, Soltani K. Oral malignant acanthosis nigricans. ORAL SURG ORAL MED ORAL PATHOL 1983; 561372-4. I. Curth HO. Dermatoses and malignant internal tumors. Arch Dermatol Syphilol 1955;71:95-107. 8. Kahn RC. Flier JS. Bar RS. et al. The svndromes of insulin resistance’ and acanthosis nigricans. N Engl J Med 1976; 294~73945. 9. Kahn CR. Insulin resistance, insulin sensitivity, and insulin unresponsiveness:a necessary distinction. Metabolism 1978; 27:1893-902. 10. Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JW. Acanthosis nigricans in obesewomen with hyperandrogenism. Characterization of an insulin-resistance state distinct from the type A and B syndromes. Diabetes 1985;34:101-7. 11. Gorin RJ, Pindborg JJ, Cohen Jr MM. Syndromes of the head and neck. 2nd ed. New York: McGraw-Hill Co, 1976: 1-8. 12. Jakhi SA, Parekh BK. Acanthosis nigricans: a case report. J Oral Med 1982;37:18-20. 13. MSller H, Erikson S, Waldenstrom JP. Complete reversibility of paraneoplastic acanthosis nigricans after operation. Acta Med Stand 1978;203:245-6.
acanthosis nigricans
79
14. Brown J, Winkelman RK. Acanthosis nigricans: a study of 90 cases. Medicine 1968;47:33-51. 15. Waisman M. Dermatomyositis, calcinosis cutis, acanthosis nigricans, and exogenous hypercortisonism. Arch Dermatol 1970;102:572-4. 16. Sturner RA, Denning S, Marchase P. Acanthosis nigricans and autoimmunoreactivity. JAMA 1981;246:763-5. 17. Urushizaki I. Immunosuppression associated with cancer. Clin Immunol 1971;11:491-501. (in Japanese with English abstract). 18. Shibata Y, Tamura K, Ishida N. In vivo analysis of the suppressoreffect of immunosuppressive acidic protein, a type of q-acid glycoprotein, in connection with its high level in tumor-bearing mice. Cancer Res 1983;43:2889-96. 19. Hodson ME, Turner-Warwick M. Autoantibodies in patients with bronchial carcinoma. Thorax 1975;30:367-70. Reprint requests to:
Dr. Noboru Matsuda Department of Oral Surgery, School of Medicine Gunma University 3-39-15, Showa-machi, Maebashi, Japan 371
OF MEDICINE,
GUNMA
UNIVERSITY
A rare case of malignant acanthosis nigricans associated with lung cancer is presented. The case involved a 70-year-old man who had oral changes and various immunologic dysfunctions, including an increase in antinuclear antibodies. Oral lesions were characterized by papillary hyperplasia, formation of grooves, pigmentation of the upper lip and cheeks, and a loss of taste sensation. After the patient’s lung cancer was treated with anticancer drugs, the histopathologic examination showed a marked improvement in oral lesions and significant normalization of immunologic abnormalities. The present case provides unique evidence that oral lesions associated with acanthosis nigricans have a significant correlation with lung cancer and high titers of antinuclear antibodies. (ORAL SURC ORAL MED ORAL PATHOL 1989;68:74-9)
A
canthosis nigricans (AN) is an uncommon dermatologic condition with characteristic manifestations including hyperpigmentation, epidermal hypertrophy with histologic features of acanthosis, hyperkeratosis, and dermal papillomatosis. Two forms are well recognized: (1) the malignant or adult type, which arises in persons past middle age and is associated with internal malignancy, and (2) the benign or juvenile type, which may be present at birth or in childhood, and is associated with developmental endocrine or metabolic abnormalities.‘,2 Initially, extensive studies of the malignant type of AN were done by Pollitzer3 who emphasized the significant relationship of the skin lesions to abdominal malignancy. The characteristic lesions of AN observed in the skin also affect the oral mucous membranes. The incidence of oral involvement in patients with AN was estimated by Fladung and Heite4 to be 53%. Masson and Montgomery5 calculated the incidence to be approximately 50%. However, since most patients with AN and a malignant tumor have received anticancer treatment at the departments of internal medicine, dermatology, or *Department of Oral Surgery, School of Medicine, Gunma University. **First Department of Internal Medicine, School of Medicine, Gunma University 74
surgery, limited information is available with respect to oral lesions in these patients. In fact, Mostofi and coworkers6reported that they did not encounter any descriptions of oral lesions associatedwith AN in the English-language dental literature of the 1970s. We investigated oral mucosal lesions in a rare case of the malignant type of AN in a patient with lung cancer and abnormal immunologic findings. An apparent reduction in the size of the lung tumor was observed with a concomitant improvement both in the immunologic disturbances and the oral mucosal lesions after treatment with anticancer drugs. To our knowledge, this is the first case showing detailed histopathologic findings of improvement in the oral mucosal lesions in a patient with AN after treatment of the underlying malignant tumor. CASE REPORT
A 70-year-old man had a dry cough that began in January 1984, and he noticed a darkening of his face in March 1984. In December 1984, he consulted a physician, and an abnormal shadow was detected by means of radiographic examination of the chest. Becauseof this, he was hospitalized at the First Department of Internal Medicine, Gunma University Hospital, on January 8, 1985, and received an examination at the Dep-rtment of Oral Surgery on the day of admission. Physical examination revealed dry skin and a diffuse dark brown pigmentation of the face and the trunk. In
Volume68 Number 1
Improvement of oral lesions of malignant acanthosis nigricans
75
1985).
Fig. 2. Lesions of prolabium. A, At the first examination (Jan. 8, 1985). Note epithelial thickening with verrucosis and pigmentation. B, At the disappearance of lung tumor (Nov. 10, 1985).
addition, rice- to pea-sized nodules were scattered over the skin of the trunk (Fig. 1). His lips had a rough texture. A number of papillary hyperplastic growths, some of which were rice-sized, others 1 to 2 mm in diameter, were seenon the mucosal surface of the lips. The upper lip showed reddish brown plaques (Fig. 2, A). The buccal mucous membrane displayed furrows due to flat papillary hyperplasia with associatedbrown and gray-white pigmentation (Fig. 3, A). The dorsum of the tongue was rough and partially gray-white in color. The tongue papillae were 1 to 2 mm in size, giving a deeply fissured appearance. The patient’s sensation of taste was lost almost completely. The mucosa over the palate and the gingiva was intact. A radiograph of the chest revealed a shadow of a massin the right upper lung field, which was diagnosed as adenocarcinoma on cytologic examination (Fig. 4, A). General laboratory tests, including hematologic tests and urinalysis, showed no abnormalities. In addition, no abnormality was observed as a result of hormonal examination, including a 75 gm oral glucose tolerance test (the blood glucose level [mg/dl]: O-time, 99; 30 minutes, 155; 60 minutes, 141; 120 minutes, 129; the blood immunoreactive insulin level [pU/ml]: O-time, 1.6; 30 minutes, 56.5; 60 minutes, 38.0; 120 minutes, 19.6) the blood cu-melanostimulating hormone (
immunologic tests revealed a remarkable elevation in antinuclear antibody by a 2560-fold titer, anti-ribonuclear antibody by a 16-fold titer, and anti-Smith antibody by an 8-fold titer. Moreover, an elevation was seen in immune complex titer (15.5 pg/ml). Among tumor markers, carcinoembryonic antigen (CEA) was increased remarkably to 510 rig/ml, and immunosuppressive acidic protein (IAP, 710 rg/ml) and tissue polypeptide antigen (TPA, 210 pU/l) were also shown to be elevated. Histopathologicaliy, the lips and buccal mucous membranes exhibited slight keratosis and papillomatosis. Melanophages were observed in the subepithelial papillae, but not in the basal layer (Fig. 5, A). The skin showed hyperkeratosis and papillomatosis of the epithelium and an increase in melanin in the basal layer (Fig. 6). February 1985, the patient received three courses of chemotherapy at the Department of Internal Medicine, each course consisting of 140 mg of cisplatinum diammine dichloride, 40 mg of doxorubicin, and 10 mg of mitomycinC. In addition, the lung tumor was irradiated with Linac 70 gray. With reduction in the size of the pulmonary tumor, the CEA decreasedremarkably and the antinuclear antibody titer dropped progressively (Fig. 7). Similarly, the anti-Sm antibody, which had an 8-fold titer, was lowered to a 2-fold titer, and titers of all other autoantibodies were reduced. A chest radiograph in November 1985 showed that the
Fig.
1. Physiognomy at first
examination (Jan. 8,
76
Nomachi, Mori, and Matsuda
ORAL SURG ORAL
MED ORAL PATH~L July 1989
Fig. 3. Lesion of buccal mucous membrane. A, At the first examination. Consisting of papillary hyperplasia, formation of furrows, and pigmentation. B, At the disappearance of lung tumor.
mucosa did not show dark brown pigmentation, but was smooth as a result of disappearance of furrows (Fig. 3, B). The hypertrophied papillae on the dorsum of the tongue were reduced with improvement of the sensation of taste. Histopathologic examination of the buccal mucous membrane on Nov. 14, 1985, showed that the epithelium became free of papillary hypertrophy; melanophages could not be detected in the lamina propria and there was no evidence of AN (Fig. 5, B). On Feb. 27, 1986, the patient died suddenly as the result of metastasis to the liver, but he had no symptoms of AN. DISCUSSION The patient in the present study had AN and a malignant tumor simultaneously. With respect to the
relationship between AN and malignant tumors, Curth’ found that both developed simultaneously in 61.3% of cases,the tumor precededthe AN in 21.1% and the AN preceded the tumor in 17.6%. When AN was found in the skin and the oral mucosa without obvious manifestations of malignancy, the malignant tumor in many cases appeared
Fig. 4. Chest radiogr2 tphic findings. A, At the first examination (Jan. 8, 1985). The tumor is shown by the arrow. The size is approximately 7 X 5.5 X 6 cm. B, The tumor had disappeared as of Nov. 10, 1985. tumor had apparently disappeared (Fig. 4, B). This was accompanied by a remarkable decrease in pigmentation and nodules observed on the face and the trunk. Moreover, the roughness of the lips had disappeared and the pigmentation had faded (Fig. 2, B). At this time, the buccal
within
1 year.’ There-
fore, oral lesions that occur with AN have important implications in detection of early occurrence of malignancy. Some casesof AN have been observed to be associated with hormonal dysfunction, such as insulin resistance.*-loThe normal responsivenessof blood glucose and insulin to an oral glucose tolerance test was shown in the present patient. Therefore, the present casecould be categorized as a malignant type of AN without insulin resistance. The preferential oral sites of AN are the lips, the tongue, and the buccal mucous membranes. These structures feature papillary hyperplasia, with furrow formation changing to grayish white color. It has been reported that a dark brown pigmentation is seen less frequently in the mucous membranes than that observed on the skin.6~“~‘2The patient presented herein showed the typical dark brown pigmentation on the lips and the buccal mucous membranes, in addition to the main features previously described, followed by disturbance of taste sensation.
Volume68
Improvement of oral lesions of malignant
acanthosis nigricans
Number 1
Fig. 5. Histopathologic features of buccal mucous membrane (Hematoxylin and eosin stain). A, At the first examination. Papillary hyperplasia is seen at low magnification (Original magnification, x33), and melanophage in the subepithelial papillae is depicted at high magnification (Original magnification, ~88). B, Findings on Nov. 14, 1985, at the disappearance of the lung tumor (Original magnification, X88).
Fig. 6. Histopathologic features of skin. Papillomatosis and an increase in melanin are present in the basal layer. (Hematoxylin and eosin stain. Original magnification, X140.)
77
78
Nomachi, Mori, and Matsuda CLINICAL
ORAL SURG ORAL MED ORAL PATHOL July 1989 cyspiatin Lbxcmbicin l4itoncin C
COURSE
CEA
ANF
200100 0 Dec.
I
JGUl
I
F&
I
Lr
I
Apr. 4 fold titer 2 fold titer 244 S.I. 179 S.I. 105 S.I. 35 y.6 1%
Anti-R& antibody 13 fold titer Anti-% antibody 3 fold titer RLA-El 140 S.!. 122 S.I. CO&R7 109 S.I. PHI-R7 NKE activity 22 % I&-FcR ce I I 6%
Fig. 7. Changes in blood level of CEA and titers of ANF after treatment with anticancer drugs. CEA, carcinoembryonic antigen; ANF, anti-nuclear antibody factor; RNP, ribonucleoprotein; Sm, Smith; PHA, phytohemagglutinin; ConA, concanavalin A; PWM, pokeweed mitogen; ADCC, antibody-dependent cell-mediated cytotoxity; FcR, Fc-receptor.
There have been a few studies showing that the skin lesions occurring with AN decreasedin size and disappeared after treatment of cancer such as surgical resection of the malignant tumor, radiation therapy, and chemotherapy.‘3,I4 The data indicate the close relationship between AN and malignant tumors. However, detailed histopathologic examination of the skin and the oral mucous lesions occurring with AN has gained little attention. In particular, there are few articles describing the time-dependent changes in oral mucosal lesions after treatment of malignant tumors. In the present case, it is clear, from the histopathologic examination, that the papillary hyperplasia and melanophages within the lamina propria of the buccal mucosa decreased in size and later disappeared after treatment. In addition, pigmentation in the oral lesions lessened, and the sensation of taste was recovered during treatment of lung cancer with anticancer drugs. It was interesting to note that the gray-white pigmentation possibly due to hyperkeratosis did not change. The mechanisms by which lung cancer in patients with AN produces a significant increase in the titer of antinuclear antibodies remained to be determined. Recent studies have focused on the association of AN with connection tissue diseases.8s I5Alternatively, Sturner and coworkersI indicated that autoantibodies should be determined in patients with AN. In the present case, despite elevated titers of antinuclear antibodies, the possibility of connective tissue disease
was eliminated by findings dependent on both clinical and histopathologic criteria. Moreover, the elevated titer of antinuclear antibodies decreased with reduction in the tumor size after medical treatment. These findings imply the strong correlation between the antinuclear antibody and the lung cancer. It is known that immunosuppressive substancesincluding CEA, TPA, IAP, and the immune complex, as observed in the present case, are produced by malignant tumors.“.18 Therefore, these immunosuppressive substances may have led to a remarkable alteration in immune response systems in the present patient, eventually resulting in formation of antinu-
clear antibodies that are not observed in the normal condition. This concept appears likely to reflect the results of Hodson and Turner-Warwick,19 who reported that the antinuclear antibody was detected, but with weak titers, in 31% of the patients with bronchial carcinoma. REFERENCES 1. Beeson PB, McDermott W. Textbook of medicine. 14th ed. Philadelphia: WB Saunders Co, 1975: 1856-7. 2. Bang G. Acanthosis nigricans maligna. ORAL SURG ORAL MED ORAL PATHOL 1970;29:370-5.
3. Pollitzer S. Acanthosis nigricans: a symptom of a disorder of the abdomen. JAMA 1909;53: 1369-73. 4. Fladung G, Heite HJ. Haufigkeitsanalytische Untersuchungen zur Frage der symptomatologischen Abgrenzung verschiedener Formen der Acanthosis nigricans. Arch Klin Exp Dermatol 1957;205:282-3 11. 5. Masson JC, Montgomery H. Relationship of acanthosis nigricans to abdominal malignancy: report of cases, in which
Volume 68 Number 1
Improvement of oral lesions of malignant
the primary growth was in the pelvis. Am J Obstet Gynecol 1936;32:716-26. 6. Mostofi RZ, Hayden NP, Soltani K. Oral malignant acanthosis nigricans. ORAL SURG ORAL MED ORAL PATHOL 1983; 561372-4. I. Curth HO. Dermatoses and malignant internal tumors. Arch Dermatol Syphilol 1955;71:95-107. 8. Kahn RC. Flier JS. Bar RS. et al. The svndromes of insulin resistance’ and acanthosis nigricans. N Engl J Med 1976; 294~73945. 9. Kahn CR. Insulin resistance, insulin sensitivity, and insulin unresponsiveness:a necessary distinction. Metabolism 1978; 27:1893-902. 10. Flier JS, Eastman RC, Minaker KL, Matteson D, Rowe JW. Acanthosis nigricans in obesewomen with hyperandrogenism. Characterization of an insulin-resistance state distinct from the type A and B syndromes. Diabetes 1985;34:101-7. 11. Gorin RJ, Pindborg JJ, Cohen Jr MM. Syndromes of the head and neck. 2nd ed. New York: McGraw-Hill Co, 1976: 1-8. 12. Jakhi SA, Parekh BK. Acanthosis nigricans: a case report. J Oral Med 1982;37:18-20. 13. MSller H, Erikson S, Waldenstrom JP. Complete reversibility of paraneoplastic acanthosis nigricans after operation. Acta Med Stand 1978;203:245-6.
acanthosis nigricans
79
14. Brown J, Winkelman RK. Acanthosis nigricans: a study of 90 cases. Medicine 1968;47:33-51. 15. Waisman M. Dermatomyositis, calcinosis cutis, acanthosis nigricans, and exogenous hypercortisonism. Arch Dermatol 1970;102:572-4. 16. Sturner RA, Denning S, Marchase P. Acanthosis nigricans and autoimmunoreactivity. JAMA 1981;246:763-5. 17. Urushizaki I. Immunosuppression associated with cancer. Clin Immunol 1971;11:491-501. (in Japanese with English abstract). 18. Shibata Y, Tamura K, Ishida N. In vivo analysis of the suppressoreffect of immunosuppressive acidic protein, a type of q-acid glycoprotein, in connection with its high level in tumor-bearing mice. Cancer Res 1983;43:2889-96. 19. Hodson ME, Turner-Warwick M. Autoantibodies in patients with bronchial carcinoma. Thorax 1975;30:367-70. Reprint requests to:
Dr. Noboru Matsuda Department of Oral Surgery, School of Medicine Gunma University 3-39-15, Showa-machi, Maebashi, Japan 371