Genetic alteration in carcinoid tumors of the lung.

Surgically resected specimens of 13 carcinoid tumors of the lung including nine typical carcinoids and four atypical carcinoids, and eight salivary gland type carcinomas (six mucoepidermoid carcinomas and two adenoid cystic carcinomas) were analyzed regarding p53 expression, loss of heterozygosity (LOH) in chromosome 3p, 9p, and K-ras mutation. The overexpression of p53 was identified in four atypical carcinoid tumors, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma, however, none of typical carcinoids showed p53 immunoreactivity. LOH in 3p14 was demonstrated in three of seven informative cases in all tumors. LOH in 9p was demonstrated in two of five informative cases in all tumors. Two of three cases with LOH at 3p14 had a poor prognosis, one of which also had LOH at 9p. No mutation of the K-ras gene was observed in any of these tumors. These data thus indicate that p53 overexpression might distinguish atypical carcinoid tumors from typical tumors and might therefore be useful as an adjunct modality in the differential diagnosis of pulmonary carcinoid tumors. The presence of LOH at 3p14 or 9p may thus help to identify lung cancer patients with a poor prognosis.     

Bronchial adenoma: review of 18-year experience at the Brompton Hospital.

Continued uncertainty about the prognosis for patients with bronchial adenomata led to a review of the experience of this condition in the Brompton Hospital. Of 72 patients seen between January 1955 and December 1972, 39 were women and 33 men, mean age 45 years, range 9-73 years. The commonest presenting symptoms were haemoptysis, cough, sputum, and repeated chest infections. Positive bronchoscopic biopsy occurred in 35 of 43 cases; five of these were originally reported as carcinomata, of oat-cell type in four. Plain chest film abnormality occurred in 69 patients. Seventy-three operative procedures comprised two endoscopic removals, two wedge resections, six bronchotomies, five pneumonectomies, and 58 lobectomies (seven with sleeve resection). Recurrence in three of six bronchotomies--two with adenoid cystic carcinomata (cylindromata)--necessitated further surgery. Lobectomy and lymph node dissection is usually the operation of choice. Histology confirmed 67 carcinoids (eight with atypical histology or lymph node metastases), two adenoid cystic carcinomata, one muco-epidermoid, and two mucous gland adenomata. Prolonged follow-up is especially indicated in patients with adenoid cyst carcinoma and in those with atypical or metastatic carcinoid histology. Although such pathology is not incompatible with long survival, of 10 patients in these categories, all five late deaths were probably related to the tumour. However, of 57 patients considered to have had typical carcinoid histology and adequate removal of the tumour, there has to date been no tumour-related death, but one patient developed radiosensitive atypical carcinoid tracheal tumours nine years later. The actuarially assessed survival of 71 patients undergoing surgery for bronchial adenomata was 75% at 15 years. Specific tumour types should replace the term bronchial adenoma.     

Bronchial adenoma.

Thirty-three patients with bronchial adenoma have been treated in U.S. Army hospitals. These included 27 with carcinoid, 3 with mucoepidermoid carcinoma, and 3 with adenoid cystic carcinoma. No deaths could be directly related to the adenomas during an average follow-up of 14.5 years.     

Bronchial carcinoids: a review of 60 patients

Sixty patients with a bronchial carcinoid underwent surgical treatment. Preoperative fiberoptic bronchoscopy revealed a characteristic pink, smooth, bleeding tumor in 71.4% of the patients with a typical carcinoid and 16.7% of those with an atypical carcinoid (p less than 0.05). Eight pneumonectomies, seven bilobectomies, 34 lobectomies, three lobectomies with bronchoplasty, six bronchotomies with bronchoplasty, and two segmental resections were performed. All patients entered follow-up, and 47 were followed for more than 5 years. Ten-year survival was 89.6% for patients with a typical carcinoid and 60% for those with an atypical carcinoid. Ten-year survival was 88.1% for patients with carcinoids without lymph node involvement. All patients with lymph node involvement died within 5 years. Overall, 5 of the 8 patients having pneumonectomy died of acute cardiorespiratory failure. We conclude that a limited surgical resection with or without bronchoplasty and systematic lymphadenectomy is the procedure of choice in patients with typical carcinoids. On the other hand, atypical carcinoids are comparable to well-differentiated malignancies of the lung. Whenever possible, pneumonectomy should be avoided in favor of bronchial sleeve resection.     

Bronchial carcinoid tumors: nodal status and long-term survival after resection

BACKGROUND: Bronchial carcinoid tumors show a favorable outcome. We sought to determinate the variables influencing the long-term survival of patients treated for bronchial carcinoid tumors. METHODS: We conducted a retrospective single institutional review of 163 patients surgically treated from January 1990 to April 2002. According to 1999 World Health Organization criteria, cases were segregated into typical (<2 mitoses per 2 mm, no necrosis) and atypical carcinoids (2 to 10 mitoses per 2 mm or necrosis). RESULTS: There were 86 men and 77 women with a mean age of 49.5 +/- 11 years. Symptoms were present in 89 patients (54.6%). Operations included 145 formal lung resections (89%), 9 wedge resections (5.52%), 8 sleeve lobectomies (4.9%), and 1 segmental resection (0.61%) plus radical mediastinal lymphadenectomy in all cases. No operative mortality was reported. Histologic examination showed 121 (74.2%) typical carcinoids (107 N0 and 14 N1), and 42 (25.8%) atypical carcinoids (15 N0, 18 N1, 9 N2). All patients were included in a follow-up (median, 54 months; mean, 58 months; range, 4 to 150 months), which included total body computed tomographic scan and bronchoscopy every year. Overall 5-year survival was 90.3% with a mean survival time of 139 months (95% confidence interval, 133 to 145). In N0 patients with either typical or atypical carcinoid tumors, no disease-related mortality was reported (100% 5-year survival). In N1 patients, 5-year survival was 90.0% for those with typical carcinoids, and 78.8% for those with atypical carcinoids (p = 0.394). In atypical carcinoids with N2 disease, 5-year survival was 22.2%. CONCLUSIONS: Prognosis in bronchial carcinoid tumors is more related to nodal status than to histologic subtype. In N0 and N1 patients no statistical significant difference has been found between typical and atypical subtype. However, N2 bronchial carcinoid tumors show a dismal prognosis.     

Bronchial carcinoids. Our experience with 35 cases

BACKGROUND: The aim of this study was to review personal experience regarding bronchial carcinoids. METHODS: This study investigated retrospectively 35 patients with bronchial carcinoids treated in our institution (Unit of General and Thoracic Surgery, University of Bologna) in 20 years (from 1978 to 1997). RESULTS: The m/f rate was 0.6, the average age 42.5 years and the smokers' percentage 42.8. The patients were symptomatic in 88.6% of cases. The carcinoid was located in the right lung in 17 patients (48.5%) and central in 29 patients (82.8%). Surgical treatment included pneumonectomy (6), lobectomy (17), bilobectomy (3), sleeve lobectomy (2), sleeve bilobectomy (1), sleeve resection of main bronchus (1), bronchotomy and tumorectomy (3) and wedge parenchymal resection (2). Thirty patients (85.7%) presented a typical carcinoid and five (14.3%) atypical carcinoid. Peribronchial and/or hilar lymphonodal metastases were present at surgery in 2 cases (5.7%), both centrally located and atypical. The typical carcinoids showed a real 5 years survival rate of 95.8% (with only one death, not related to the neoplasm), while that of the atypical carcinoids was 80% (one patient died of multiple metastases). CONCLUSIONS: The conclusions is drawn that although the carcinoid tumours are a distinct group of neuroendocrine lung neoplasms with a good prognosis in the majority of the cases, lobectomy and sleeve lobectomy are still the standard resection procedure for the majority of carcinoids. For atypical carcinoids lobectomies are the minimal oncologic surgical treatment.     

Primary tracheal tumors: experience with 14 resected patients.

OBJECTIVE: Primary tracheal tumors are rare. Management includes interventional endoscopy, surgery and radiotherapy. METHODS: Between 1987 and 1996, 14 patients treated by resection and reconstruction of the trachea and bifurcation for primary tracheal tumors were retrospectively analyzed. RESULTS: The most common histological finding was adenoid cystic carcinoma (n=7), followed by a squamous cell carcinoma (n=2), a mucoepidermoid carcinoma (n=2), a carcinoid tumor (n=1) and two benign tumors (xanthogranuloma, pleomorphic adenoma). Various reconstruction techniques were used and one prosthesis was implanted. Eight of the patients required preoperative Nd-YAG laser recanalisation. Six were treated by postoperative external beam radiotherapy, in three cases combined with endoluminal brachytherapy. Two major postoperative wound-healing impairment at the anastomosis occurred. Four minor wound-healing disorders were successfully treated by interventional endoscopy. Two patients died postoperatively with mediastinitis respectively with bilateral pneumonia. A local recurrence was observed in only two cases. At the last follow-up in January 1998, nine patients were still alive. We observed five long-term survivors (>6 years) with an adenoid cystic carcinoma or mucoepidermoid carcinoma. CONCLUSIONS: Extensive segmental resection of the trachea is the treatment of choice for primary malignant and occasionally for benign tracheal tumors. Interventional endoscopy is a part of modern tracheal surgery.     

支气管K细胞癌临床行为的观察

目的 了解支气管Ｋ细胞癌的恶性度、间表现及预后等差异。方法 回顾性分析了经光镜电镜或免疫组化检查确诊的支气管典型类癌２４例,在典型类癌１９例和小细胞肺癌３２５例资料。结果 小细胞肺癌男性多,典型、非典型类癌女性多;典型类癌病人平均年龄小于非典型类癌和小细胞肺癌者,且平均病程长,而小细胞肺癌病程短,非典型类癌者居中;镜下典型类癌息肉样病变多,非典型类癌和小细胞肺癌菜花病变多;典型类癌活检阳性率低于非     

Bronchial carcinoid tumours. A clinicopathologic study of 82 cases

A clinical and "blind" histologic review of 82 cases of bronchial carcinoid tumour is presented. The malignant potential of the tumours was only partly predictable from their histologic appearance. Histologically 65 of the tumours were typical benign carcinoids. Regional metastases were found at operation in two of these patients. Fatal carcinoid syndrome with regional and distant metastases appeared in two patients about 1 and 3 years postoperatively. One of the patients with regional metastases at operation is clinically free from carcinoid 12 years later. Malignancy was histologically suspected in 17 cases, in ten of which regional metastases were found at operation. Three of these ten patients are alive 6 to 16 years postoperatively, but two without regional metastases at operation died of local recurrence and distant metastases after 3 to 4 years. Carcinoid syndrome was not seen in these 17 patients. There was one peroperative death. Altogether ten patients (12%) died of recurrence. Among the cases judged at the "blind" histologic review to be suspectedly malignant, the corresponding figure was 50%. For typical carcinoids, conservative resection, including lymph-node metastases, is the treatment of choice. Wedge or sleeve resection with or without pulmonary resection were employed in ten cases. Suspectedly malignant carcinoid tumours may require more extensive surgery.     

Surgical treatment of other bronchial tumors

Bronchial gland tumors (bronchial carcinoids, adenoid cystic carcinoma, mucoepidermoid carcinoma are the most common), benign tumors and other rare primary malignant neoplasms present as endobronchial tumors. This article discusses the surgical treatment of each of these tumors individually.     

The malignancy of bronchial adenoma.

The literature on bronchial adenoma has been reviewed and controversy found to exist about certain aspects of these tumors, particularly their malignancy. A retrospective study of 79 cases managed in Edinburgh since 1946 is presented. Seventy-one were of the carcinoid type, 7 were adenoid cystic carcinomas, and there was a single example of mucoepidermoid carcinoma. All types show a definite malignant potential, greatest in the rare mucoepidermoid tumor and least in the common carcinoid variety. Adenoid cystic carcinoma occupied an intermediate position in frequency and malignancy.     

Bronchoplastic procedures for central carcinoid tumors: clinical experience

Objective: To evaluate the short-term and the long-term results of bronchoplastic resections (BR) performed for central carcinoid tumors (CCT). Methods: Retrospective study of patients who underwent BR for a CCT between 1966 and 2003. Results: BRs were performed in 25 patients out of 92 (27%) who were resected for CCT. Median age was 37 years. All patients were symptomatic. Preoperative bronchoscopy was diagnostic in 15 patients. The bronchoplasties performed were: 11 sleeve lobectomies, 1 sleeve segmentectomy, 8 wedge lobectomies, 4 flap lobectomies and 1 wedge segmentectomy. There were 22 typical and 3 atypical carcinoids without nodal metastasis. No major complications or mortality occurred. One patient with a typical carcinoid developed pretracheal metastatic adenopathy 19 years after resection. No recurrence or stenosis has occurred at the sites of bronchoplasty so far. Three patients died of unrelated disease. Overall the 10-, 15- and 20-year survival rates were 100, 100 and 71%. Conclusions: Bronchoplastic resections are the treatment of choice for CCT. Short- and long-term results are excellent. Life-long follow-up is necessary, however, due to the possibility of late recurrence.     

胸腺类癌外科治疗的长期结果

目的探讨胸腺类癌的临床表现,分类与预后的关系,以及手术方式及术后辅助治疗特点,以提高对该病的认识。方法回顾性分析北京协和医院1980年1月至2006年1月18例胸腺类癌的外科治疗和随诊结果。开胸探查活检2例,姑息性切除2例,完整切除14例,包括2例上腔静脉系统切除移植人工血管。采用寿命表法计算生存率,用Cox单因素回归模型分析胸腺类癌预后的影响因素。结果2例行开胸探查患者分别于术后1年和2年死亡;2例姑息性切除术后患者症状暂时缓解;完整切除患者除1例合并柯兴综合征术后2周死于败血症,其余13例术后完全恢复,随诊5个月至15年良好。全组3年、5年、10年生存率分别为72.6%、60.5%和40.3%。经Cox单因素分析结果:纵隔淋巴结转移(P=0.047)、病理类型(P=0.000)、手术方式(P=0.000)和术后综合治疗(P=0.018)是影响预后的因素。结论胸腺类癌不同于胸腺瘤、胸腺癌,临床诊断困难;病理学分典型和不典型胸腺类癌,两者临床表现和预后明显不同。不典型类癌恶性程度高,切除后容易复发和转移,预后较差。彻底切除肿瘤以及受侵的组织和器官,可以明显提高长期生存率。术后放疗、化疗有一定辅助作用。     

Long-term outcome after resection for bronchial carcinoid tumors.

OBJECTIVES: We sought to determine the long-term survival of patients treated for bronchial carcinoid tumors and whether lesser resections have had an effect on outcomes. METHODS: We conducted a retrospective, multi-institutional review of patients treated surgically for primary bronchial carcinoid tumors since 1980. Operative approach, pathologic stage, histology, surgical complications, tumor recurrence, and long-term survival were assessed. RESULTS: There were 50 men and 89 women with a mean age of 52.2+/-17.4 and 58.9+/-13.3 years, respectively (P=0.021). Men were more likely to be current or former smokers than were women. Operations included lobectomy or bilobectomy in 110, pneumonectomy in four, wedge resection in 22, and bronchial sleeve resection only in three patients; resection was performed thoracoscopically in six patients. One patient died postoperatively. Stages were I, 121; II, nine; III, six; and IV, three. Typical carcinoid tumors were stage I in 100 and more advanced (stages II-IV) in nine, whereas atypical carcinoid tumors were stage I in 18 and more advanced in eight (P=0. 002). Median follow-up was 43 months (range 1-149) during which 21 (15%) patients died (four from recurrent cancer) and 19 patients (14%) were lost to follow-up. Recurrent cancer developed in 2/98 patients with typical and 5/25 patients with atypical subtypes (P<0. 001; log-rank test). The likelihood of recurrence was related to histological subtype (relative risk 7.9 for atypical carcinoid; 95% confidence interval 1.4-43.5). Five-year survival was 88% for stage I patients and was 70% for patients with more advanced stages. When stratified by stage, survival was related to age (relative risk=1.9 for a 10 year increase in age; 95% confidence interval 1.2-2.9) and possibly to the histological subtype, but not to patient gender, year of operation, or type of operation performed. CONCLUSIONS: Either major lung resection or wedge resection is appropriate treatment for patients with early stage typical bronchial carcinoid tumors. Survival is favorable for early stage tumors regardless of histological subtype. Local recurrence is more common among patients with atypical subtypes, suggesting that a formal resection may improve long-term outcome.     

Diagnosis and staging of "other bronchial tumors"

Unusual bronchial tumors represent 4% to 6% of all lung tumors. These lesions include hamartomas, bronchial carcinoids, adenoid cystic carcinoma, mucoepidermoid carcinoma, and other more rare tumors. In the majority of patients these lesions are diagnosed using transthoracic FNA and different bronchoscopic biopsy techniques such as bronchial lavage, bronchial brushing, endobronchial biopsy, transbronchial biopsy, and transbronchial needle aspiration. Thoracoscopic wedge biopsy is diagnostic in the remainder of cases. Occasionally, because of tumor location, thoracoscopically-guided FNA or thoracoscopic ultrasound are helpful in obtaining a diagnosis. Staging of these lesions is assessed after proper resection; however, mediastinoscopy should be performed if preoperative mediastinal adenopathy is appreciated.     

Carcinoids of lungs]

The analysis of the results of the examination and treatment of 29 patients with carcinoids of the lungs has been carried out for 1984-1995. Peripheral carcinoids were detected in 59% of cases, of the tumor in the main and lobar bronchi was revealed in 41% of cases. The analysis showed that there are no symptoms, pathognomonic for carcinoids of the lungs; carcinoid syndrome was not detected in any patient. The examination (roentgenography and CT of the lungs, bronchoscopy) has not provided any objective, differential diagnostic criteria for carcinoids, cancer and benign tumors of the lungs. Morphological examination of the removed tumors allowed all the carcinoids to be divided in two types: typical (benign neuroendocrine tumor) and atypical (well differentiated neuroendocrine carcinoma). The final differentiation is possible only after conduction of thorough histological, electron microscopy and immunohistochemical examination. The principal method of carcinoids treatment is surgical one. The optimal surgical procedure is pneumonectomy or lobectomy with lymphadenectomy. Atypical resection of the lung without lymphadenectomy in peripheral location of the tumor is justified only in early stages of the disease and in cases of morphological verification of benign character of neuroendocrine tumor. Late results were followed up in 27 patients. In the group of patients with atypical carcinoids in terms of 6 to 12 months 3 patients died from progressing of the main disease. There were neither lethal outcomes nor signs of relapse of the disease in the group of patients with typical carcinoid. The terms of follow up were from 1 year to 12 years.     

Radiotherapy for adenoid cystic carcinoma of the palate

This is an analysis of 16 patients with adenoid cystic carcinoma of the palate who were treated with curative intent by radiotherapy alone (9) or surgery and radiotherapy (7). No patient received adjuvant chemotherapy. Follow-up ranged from 3 years to 19 years with 69% of the patients having follow-up of more than 5 years. Two patients in the radiotherapy alone group developed local recurrences, and both have had long-term surgical salvage. No local failures were seen in the combined therapy group. Twelve patients (75%) are alive and disease-free. Two patients died with distant disease, one within each treatment group. One patient in the combined therapy group is alive at 8 years with distant metastases, while one in the radiotherapy alone group died of intercurrent disease at 12 years. No significant complications were seen in either treatment group. The role of radiotherapy in the treatment of adenoid cystic carcinoma of the palate is reviewed.     

Ovarian mucinous carcinoids including some with a carcinomatous component: a report of 17 cases

Only rare primary mucinous (goblet cell) carcinoids of the ovary have been reported, and their clinicopathologic features have not been well delineated. The authors studied 17 examples from patients 14 to 74 years of age. The clinical presentations were similar to those of ovarian neoplasms in general. The tumors ranged from 0.8 to 30 cm in diameter. In six cases the tumor was in the wall of a mature cystic teratoma, appearing grossly as solid nodules or areas of thickening in four of them, six tumors were entirely solid, and five were solid associated with other types of cystic tumor. The tumors were divided into three groups on the basis of their microscopic features. Six neoplasms, designated "well differentiated," were composed of small glands, many of which floated in pools of mucin. The glands were lined by goblet cells and columnar cells, some of which were of neuroendocrine type. Three tumors, designated "atypical," were characterized by crowded glands, some of which were confluent, small islands with a cribriform pattern, and scattered microcystic glands. The glands were lined by cuboidal to columnar cells, some of them neuroendocrine, admixed with goblet cells. Eight tumors, designated "carcinoma arising in mucinous carcinoid," contained islands and larger nodules of tumor cells, or closely packed glands, as well as single cells, mainly of the signet ring cell type. Most of the cells were devoid of mucin and were severely atypical with marked mitotic activity. Necrosis was present in all eight tumors. Seven of the eight tumors with a carcinomatous component contained at least minor foci of well-differentiated mucinous carcinoid; the eighth contained only foci of atypical mucinous carcinoid. The neuroendocrine nature of a variable proportion of the cells in all three groups was demonstrated by staining for neuroendocrine markers. The mucinous nature of other cells was confirmed by mucicarmine or Alcian blue stains. The ovary contained an intrinsic component of trabecular and insular carcinoid, and of strumal carcinoid in one case each, an adjacent mature cystic teratoma in six cases, mucinous cystadenocarcinoma in three cases, and borderline mucinous cystic tumor, borderline Brenner tumor, and epidermoid cyst in one case each. Fifteen tumors were stage I, one was stage II, and one was stage III. The last two tumors had a carcinomatous component. Follow-up data were available for 15 patients; 12 were alive and free of tumor 2.3 to 14 years (average, 4.7 years) after the ovarian tumor was excised. One patient, whose tumor had a carcinomatous component, died 3 years postoperatively of unrelated causes. Two patients, both of whom had a carcinomatous component in their tumor, died 9 and 12 months postoperatively. Primary mucinous carcinoids must be distinguished from metastatic mucinous carcinoid tumors from the appendix or elsewhere. Features supporting an ovarian origin are the additional presence in the specimen of teratoma or an ovarian surface epithelial tumor, an absence of blood vessel or lymphatic space invasion, and confinement to a single ovary. Similar features help to distinguish mucinous carcinoids from Krukenberg tumors. Mucinous carcinoids should also be distinguished from strumal carcinoids, which can contain mucinous glands, and insular carcinoid tumors that arise rarely in the wall of a mucinous cystic neoplasm. Although the number of cases in this series is small, the follow-up data suggest that the degree of differentiation, particularly the presence of frank carcinoma, is an important prognostic factor.     

Head and neck large cell neuroendocrine carcinoma should be separated from atypical carcinoid on the basis of different clinical features, overall survival, and pathogenesis

According to the 2005 World Health Organization classification of head and neck tumors, neuroendocrine tumors can be subdivided into typical carcinoid, atypical carcinoid, and small cell carcinoma. Similar tumors diagnosed as large cell neuroendocrine carcinomas (LCNECs) in the lung are diagnosed as atypical carcinoids in the head and neck region. We studied neuroendocrine tumors and analyzed whether LCNEC should be separated from atypical carcinoid in the head and neck region. Twenty-three cases of primary head and neck neuroendocrine tumors were included and subdivided into typical carcinoid, atypical carcinoid, and small cell carcinoma according to the 2005 World Health Organization guidelines, and then LCNECs were separated from atypical carcinoids according to modified criteria using the Ki-67-labeling index and mitotic count. Clinical information and survival data were obtained, and immunohistochemical studies for p53 were conducted. The 5-year survival rates for the 2 typical carcinoids, 7 atypical carcinoids, 7 LCNECs, and 7 small cell carcinomas were 100.0%, 83.3%, 21.4%, and 20.8%, respectively (P=0.032). The LCNEC patients were older (mean age, 61 vs. 41 y; P=0.038), more commonly in advanced stage (stages III and IV 100% vs. 28.6%, P=0.01), with a poorer prognosis (5-year survival 21.4% vs. 83.3%, P=0.03), and more commonly had tumors overexpressing p53 (85.7% vs. 0%, P=0.005) as compared with atypical carcinoid patients. LCNECs should be separated from atypical carcinoids as a new entity of neuroendocrine carcinoma in the head and neck region. The new classification may provide better risk stratification and useful information for proper treatment.     

Tracheal stenosis. A study of 100 cases

A series of 100 cases of tracheal stenoses, 66 non-neoplastic and 34 neoplastic, are reviewed; tracheal resection was performed in 28 inflammatory stenoses and in five tumours. A T-tube stent was used in 12 patients. Results were good in 81% of resections for non-neoplastic stenoses; two out of three resections for adenoid cystic carcinoma are alive after ten years and the third died after two years with metastases; two patients who received a tracheal resection for epidermoid carcinomas died after three and four years with metastases. Inflammatory tracheal stenoses treated using T-tube achieved good results only in one third of cases. Pre-operative preparation is the most important factor to obtain good results: end-to-end anastomosis requires a healthy mucosa without infection or ulcers.