1ORAL ERYTHEMA MULTIFORME AS A PARANEOPLASTIC MANIFESTATION

2OF COLON ADENOCARCINOMA. A CASE REPORT

4Paulina Gutierrez, DDS, Valentina Gutierrez MD, Salomon Ramos, DDS,

5Enmanuel Parra, DDS

7Department of Oral and Maxillofacial Surgery. Dentistry Service. University Hospital

8of Maracaibo. 16th Avenue. Zulia, Venezuela.

10

11*Corresponding author: Enmanuel Parra. DDS

12Maracaibo. 19th Avenue. Zulia, Venezuela.

13Phone: +58 424 203 6077

14E-mail: enmanuelparra_04@hotmail.com

15

16Disclosures

17All the authors declare that they have no conflict of interest. In addition, no funding

18was received for conducting this research.

19

20Keywords: erythema multiforme, paraneoplastic manifestation.

21
22ABSTRACT

23

24Erythema multiforme is a vesicular-bullous immune and self-limiting disease, it

25presents acutely affecting skin and mucosa. Unchained by a hypersensitivity reaction

26mediated by the cytotoxic action of T lymphocytes that induce abnormal keratinocyte

27apoptosis. Clinically the lips that become swollen and cracked, bleeding, and crusted;

28intraoral lesions typically on the non-keratinized mucosa and most pronounced in the

29anterior parts of the mouth. Diffuse and widespread macules blister and ulcerate. In

302015, Lee E. and Freer J., included this disease within the paraneoplastic

31dermatological syndromes. Originated because of substances produced by the

32neoplastic tissue. The purpose of this study is to present EM as a paraneoplastic

33manifestation of colon adenocarcinoma.

34

35Keywords: erythema multiforme, paraneoplastic manifestation.

36INTRODUCTION

37

38Erythema multiforme (EM) is a disease of the skin and mucous membranes first

39described by Hebra in the mid-19th century. 1 It is characterized by objective lesions,

40acrally distributed, with a concentric color variation, sometimes accompanied by

41erosions of the oral, genital or ocular mucosa or a combination of them. 2 Several

42studies include EM on the list of paraneoplastic syndromes, manifestations of cancer

43not directly related to the mass effect. 3 All types of cancer can trigger paraneoplastic

44syndromes, including colon cancer, one of the most common types of cancer

45worldwide; this is a group that includes colon adenocarcinoma, which is the most

46common malignant process of the digestive tract, representing 10% of all cancer

47deaths.5 We present the case of EM, which appears before the diagnosis of colon

48adenocarcinoma in a 64-year-old patient. We turn to a discussion about the

49importance that should be given to EM as an early clinical expression of the

50underlying internal malignancy.

51

52CASE DESCRIPTION AND RESULTS

53A 64-year-old woman presented to the Emergency of University Hospital of

54Maracaibo, Venezuela, in February 2019 referring abdominal pain, nausea and

55vomiting at the time of admission. She was diagnosed with Acute Obstructive

56Abdomen. Her medical history was relevant for hypertension and erosive gastritis.

57She was admitted to the general surgery department and referred to the Oral and

58Maxillofacial Surgery Unit because of multiple ulcerative lesions throughout the oral

59cavity with a 2-week course of evolution that did not respond to endovenous

60antifungal therapy. The extraoral clinical examination revealed an ulcerative zone in

61the anterior mucosa of the lower lip, with areas in the crusting phase (Fig. 1). At the

62intraoral clinical examination multiple, convergent, painful and extensive ulcerative

63lesions were observed, covered by non-detachable white plaques, with indefinite,

64irregular and erythematous edges (Fig. 2).

65These lesions were present in the bilateral labial and buccal mucosa, as well as the

66alveolar ridges, hard and soft palate, tongue and floor of the mouth. Due to the

67clinical characteristics of the lesions, and after ruling out other diseases like Steven

68Johnson’s syndrome, pemphigus or blister erosive lichen planus, the patient was

69managed with a diagnosis of Oral Erythema Multiforme. The protocol to follow once

70the diagnosis was established was the use of oral rinses twice a day with

71bicarbonated water in order to modify the oral pH and a topical solution containing

72lidocaine and benzidamine (0.15%), antihistamine, antacid and steroid in equal parts

73(15ml each) three times a day.

74On the fourth day of her admission, an exploratory laparotomy was performed for

75biopsy, and the histopathological report revealed a well differentiated and infiltrative

76colon adenocarcinoma. The evolution of the patient with pharmacological therapy

77was very favorable: on the second day of treatment the painful symptoms diminished

78almost until their disappearance and the crusts at the level of the lips decreased

79considerably. The erythematous plaques distributed throughout the non-keratinized

80mucosa also began to involute from the fifth day until their resolution.

81

82DISCUSSION

83Erythema multiforme (EM) occurs predominantly in young adults, with a slight female

84preponderance and without racial predilection. The literature has linked numerous

85factors to the development of this disease. It includes infections, medication use,

 86malignancy, autoimmune disease and radiation. 2 The most common mucosa

87involved is the oral mucosa, which can be involved in up to 70% of patients. EM is a

88vesicular-bullous immune and self-limiting disease triggered by a hypersensitivity

89reaction mediated by the cytotoxic action of T lymphocytes that induce abnormal

90keratinocyte apoptosis. Clinically, the lips become swollen and cracked, bleeding,

91and crusted; intraoral lesions are typically on the non-keratinized mucosa and most

92pronounced in the anterior parts of the mouth. 6 Several studies include EM in the list

93of paraneoplastic syndromes, which are uncommon manifestations of cancer not

94directly related to mass effect or to a substance normally produced by the cancerous

95tissue or organ. They are often classified by the affected organ system and may

96present before or after the diagnosis of cancer. 3

97

98Among the studies that include EM in the list of paraneoplastic syndromes, the one

99conducted by Ghosh et al. mentions the presence of this pathology in relation to the

100recurrence of breast cancer in a 57-year-old patient. It is also important to highlight

101the case report of Tzovaras et al., where a 66-year-old man presents with a

102persistent EM that manifests long before his diagnosis of underlying extrahepatic

103cholangiocarcinoma. Once the chemotherapeutic treatment for cancer was initiated,

104EM and cholangiocarciona disappeared. But when the neoplasia reoccurred, EM

105also reappeared.7,8

106EM is a rare cutaneous manifestation of malignant tumors. The pathogenesis of

107paraneoplastic dermatoses is associated with unknown factors derived from

108malignant tumors, producing an immunological reaction, which in the case of EM, is

109the result of a continuous stimulation by antigenic tumor material. 9,10

110We present, for the first time in the literature, a case of EM as a paraneoplastic

111syndrome in a patient with colon adenocarcinoma, this malignant gastrointestinal

112neoplasm is the most common in its class. The accumulated evidence indicates that

113adenocarcinoma of the colon develops due to genetic alterations and is a

114complicated disease.9 This pathology has an approximately equal distribution

115throughout the colon. In the proximal colon they grow as polypoid exophytic masses

116that extend through the wall of the cecum and the ascending colon, some areas of

117great caliber; These tumors rarely cause obstruction. In contrast, carcinomas in the

118distal colon tend to be annular lesions that produce constrictions and luminal

119stenosis, sometimes to the point of obstruction. These tumors are formed by tall

120cylindrical cells that resemble the dysplastic epithelium found in adenomas. The

121invasiveness of the components of these tumors causes an important desmoplastic

122response in the stroma that is responsible for its firm consistency. Some poorly

123differentiated tumors form few glands, others produce abundant mucin that

124accumulates within the intestinal wall and is associated with an unfavorable

125prognosis.5 In our patient, the diagnosis of oral EM was documented days before the

126diagnosis of colon adenocarcinoma; and there was no other obvious etiological factor

127that could have led to the manifestation of the oral lesion. It is important to recognize

128the presence of Erythema multiforme as a paraneoplastic manifestation when no

129obvious etiological agents are considered, and therefore to focus on the underlying

130search for malignant neoplasms that are not very evident. This being of vital

131importance for the early detection of cancer and their timely treatment.

132
133REFERENCES

134

1351. Jawetz R, Elkin A, Michael L, Jawetz S and Shin H. Erythema Multiforme Limited

136to the Oral Mucosa in a Teenager on Oral Contraceptive Therapy. J Pediatr Adolesc

137Gynecol. 2007; 20:309-313.

1382. Sokumbi O, Wetter D. Clinical features, diagnosis, and treatment of erythema

139multiforme: a review for the practicing dermatologist. International Journal of

140Dermatology. 2012; 51, 889–902.

1413. Lee E, Freer J. Paraneoplastic Syndromes. Hosp Med Clin. 2015; 4:368–420.

1424. Jiang H, Du J, Gu J, Jin L, Pu Y and Fei B. A 65-gene signature for prognostic

143prediction in colon adenocarcinoma. Int J Mol Med. 2018; 4: 2021–2027.

1445. Kumar V, Abbas A, Aster J. Elsevier/Saunders. Robbins and Cotran Pathologic

145Basis o f Disease. Ninth edition. Philadelphia, , 2015. p 810-813.

1466. Wetter D. Recurrent erythema multiforme: clinical characteristics, etiologic

147associations, and treatment in a series of 48 patients at Mayo Clinic, 2000–2007. J

148Am Acad Dermatol 2010; 62: 45–53.

1497. Ghosh I, Pahwa P, Dinda A, Raina V, Khanna N. Erythema Multiforme Associated

150with Metastatic Breast Cancer. Indian J Dermatol. 2013; 58: 485–486.

1518. Tzovaras V. Persistent Erythema Multiforme in a Patient with Extrahepatic

152Cholangiocarcinoma. Oncology 2007; 73:127–129.

153
1549. Samim F, Auluck A, Zed C, Williams M. Erythema Multiforme A Review of

155Epidemiology, Pathogenesis, Clinical Features, and Treatment. Dent Clin N Am.

1562013; 57:583–596.

15710. Kurzrock R, Cohen PR: Cutaneous paraneoplastic syndromes in solid tumors.

158Am J Med. 1995; 99: 662–671.

159FIGURES

160

161Figure 1. Ulcerative zone in the anterior mucosa of the lower lip, with areas in the

162crusting phase.

163Figure 2. Intraoral view of multiple lesions in the bilateral labial and buccal mucosa,

164alveolar ridges, hard and soft palate, tongue and floor of the mouth.

165