Association Between Esophageal Leiomyomatosis and p53 Mutation
Olga Kazarin, MD, Eugene Vlodavsky, MD, PhD, Ludmilla Guralnik, MD, Ran Kremer, MD, Jesse Lachter, MD, and Gil Bar-Sela, MD
Departments of Oncology, Pathology, Diagnostic Radiology, Thoracic Surgery, and Gastroenterology, Rambam Health Care Campus and Technion-Israel Institute of Technology, Haifa, Israel
Li-Fraumeni syndrome is a cancer predisposition syn- drome associated with a variety of neoplasms, mainly soft tissue sarcoma, premenopausal breast cancer, brain tumors, adrenocortical carcinoma, and leukemia. Esophageal leiomyomatosis involves the presence of several rare benign neoplastic lesions composed of proliferating smooth muscle cells in the esophageal wall. The current case report presents a patient with recurrent diffuse leiomyomas of the esophagus and confirmed p53 mutation with clinical criteria of Li- Fraumenilike syndrome.
(Ann Thorac Surg 2013;95:1429-31) @ 2013 by The Society of Thoracic Surgeons
L i-Fraumeni syndrome is a cancer predisposition syn- drome associated with soft tissue sarcoma, osteosar- coma, premenopausal breast cancer, brain tumors, adre- nocortical carcinoma, leukemia, and a variety of other neoplasms [1]. It is genetically associated with a detect- able germline mutation in the TP53 tumor suppressor gene that codes a transcription factor (p53) involved in cell cycle regulation and activation of DNA repair [1, 2]. Two forms of the syndrome are recognized: historical, clinically defined, classic Li-Fraumeni syndrome (LFS); and Li-Fraumenilike (LFL) syndrome, which shares some but not all of the features of LFS [1, 2].
Esophageal leiomyomatosis involves having several benign, neoplastic lesions composed of proliferating smooth muscle cells in the esophageal wall. Most cases of leiomyomatosis were reported to occur in Alport syn- drome (hematuric nephropathy, visceral leiomyomatosis,
Accepted for publication Aug 20, 2012.
Address correspondence to Dr Bar-Sela, Division of Oncology, Rambam Health Care Campus, POB 9602, Haifa 31096, Israel; e-mail: g_barsela@ rambam.health.gov.il.
deafness, ocular lesions), and other cases to occur in a familial pattern [3], but no cases were reported in LFL syndrome. We present a patient with LFL syndrome with esophageal leiomyomatosis, together with abdominal leiomyosarcoma.
This 55-year-old woman with no disease, medications, or surgery in her medical history presented to our emer- gency department in May 2010 owing to abdominal pain exacerbated in the last few days before admission. She had a family history of several malignancies, including her mother and two sisters with breast carcinoma, a grandmother with lung carcinoma, and cousins with brain tumor, sarcoma, and breast carcinoma. Her physi- cal examination was unremarkable. Whole-body com- puted tomography scan showed a 37-mm diameter mass of the mid esophageal wall extending into the mediasti- num (Fig 1), an 87-mm abdominal mass probably origi- nating from the mesenterium (Fig 2), and a pulmonary nodule of 14 mm in the left lower lobe. Positron emission tomography-fluorodeoxyglucose scan showed pathologic uptake only in the abdominal mass. Upper gastrointesti- nal endoscopy showed signs of inflammation and exter- nal compression of the mid esophagus by the known mass. Fine-needle aspirations from the esophageal mass and the lung nodule showed no evidence of malignancy. The esophageal mucosa showed hyperplasic muscularis mucosa (not sufficient for the diagnosis of leiomyoma owing to the small sample size). Laparoscopic biopsy from the abdominal mass showed high grade leiomyo- sarcoma (Fig 3).
In July 2010, the patient underwent resection of the abdominal mass with part of the small intestine. Pathol- ogy analysis revealed a 120-mm mass that invaded the small bowel serosa, with the same histology as found preoperatively; operative margins and 18 lymph nodes were free of tumor. The patient refused a recommenda- tion to receive radiotherapy to the tumor bed. Four months later, hybrid positron emission tomography- fluorodeoxyglucose/computed tomography scan showed pathologic uptake in the esophageal mass. Fine-needle aspiration-guided endoscopic ultrasonography and cy- tology revealed suspected sarcoma cells. Right thoracot- omy with resection of the esophageal mass showed a 35-mm encapsulated mass completely resected. Final histology was benign leiomyoma (Fig 4).
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@ 2013 by The Society of Thoracic Surgeons Published by Elsevier Inc
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Six months after the thoracotomy, upper endoscopy performed for mild dysphagia found two submucosal pro- trusions in the middle esophagus. Leiomyomas were sus- pected, and the patient planned to continued endoscopic follow-up, without resection of the lesions. Four months later, she complained of worsening dysphagia and a sensa- tion of progressive dyspnea. Another upper endoscopy found a 12-mm round, hard, submucosal esophageal lesion 20 cm from the teeth, and biopsy revealed a leiomyomatosis tumor of uncertain malignant potential. In March 2012, she underwent endoscopic excision of this encapsulated sub- mucosal leiomyoma. Follow-up with chest and abdominal computed tomography scan showed no difference in the size of the lung lesion.
Genetic consultation led to testing for p53 mutation. Molecular testing of a DNA sample examining the bases sequences of the exon TP53 showed significant changes of gene sequencing of exon 10. These changes have been
reported in the literature to be responsible for Li- Fraumeni syndrome [1]. Furthermore, additional changes of exon 4 were localized, and these changes were re- ported in different databases as a genetic polymorphism increasing the susceptibility to the development of ma- lignancies such as breast cancer [4].
Comment
Li-Fraumeni syndrome is inherited as an autosomal domi- nant disorder, linked to germline mutations of the tumor suppressor gene p53 (TP53). The most commonly used clinical diagnostic criteria of classical LFS include a proband with a sarcoma diagnosed before the age of 45 years, a first-degree relative with any cancer before age 45, and a first- or second-degree relative with any cancer before age 45 or a sarcoma at any age [1, 2]. Genetic testing of our patient showed a mutation in the TP53 gene, along with a family history of sarcoma and other malignancies at young ages, all compatible with LFS. However, the proband pa- tient was diagnosed with leiomyosarcoma at the age of 55; thus, she belongs to the group of LFL patients as described by Birch and Eeles [2] in 1995, who characterized LFL as “having features of the Li-Fraumeni syndrome but did not fulfill all of the strict definition criteria.” It is estimated that 70% of persons with LFS and 8% to 22% of persons with LFL syndrome have detectable TP53 mutations [1].
Leiomyomas are one of the most common types of benign esophageal neoplasms; conversely, diffuse esoph- ageal leiomyomatosis is a rare benign pathologic entity. Only a few cases of multiple leiomyomatosis have been reported. Seremetis and coworkers [3] found 2.4% cases of diffuse esophageal leiomyomatosis in 838 reviewed cases of esophageal leiomyoma.
The characteristic lesion of diffuse esophageal leio- myomatosis is composed of a proliferation of smooth muscle that leads to marked circumferential thickening in a large portion of the esophagus [5]. Microscopic examination of our pathology specimen showed predom-
inant hypertrophy of the inner circular layer of the muscularis propria with lesser involvement of the outer longitudinal layer and the muscularis mucosa.
In the presented case, endoscopic findings appeared as submucosal protrusions compromising the esophageal lu- men, but covered with normal mucosa. Histopathology examination of the two esophageal lesions showed hyper- plastic muscularis mucosa, compatible with the diagnosis of leiomyomatosis. In approximately two thirds of the re- ported cases of esophageal leiomyomatosis, patients were younger than 30 years, and most cases (more than 70%) seemed to be associated with Alport’s syndrome [3]. An increased incidence of multiple esophageal leiomyomas was also reported in association with mutations in the MEN1 tumor suppressor gene [6, 7].
Benign tumors are rarely described in association with p53 mutations, but Kmet and associates [8] reported cases of benign epithelial ovarian tumors associated with a p53 mutation. To the best of our knowledge, an association of recurrent diffuse leiomyoma of the esophagus and con- firmed p53 mutation with clinical criteria of LFL has not been reported yet. Clinicians should be aware of this rare association, and patients with a family history of several malignancies should be tested for p53 mutations.
References
1. Varley JM, Evans DG, Birch JM. Li-Fraumeni syndrome-a molecular and clinical review. Br J Cancer 1997;76:1-14.
2. Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li- Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009;27:1250-6.
3. Seremetis MG, Lyons WS, de Guzman VC, Peabody JW. Leiomyomata of the esophagus. An analysis of 838 cases. Cancer 1976;38:2166-77.
4. Martin AM, Kanetsky PA, Amirimani B, et al. Germline TP53 mutations in breast cancer families with multiple primary can- cers: is TP53 a modifier of BRCA1? J Med Genet 2003;40:e34.
5. Ray S, Saluja SS, Gupta R, Chattopadhyay TK. Esophageal leiomyomatosis-an unusual cause of pseudoachalasia. Can J Gastroenterol 2008;22:187-9.
6. McKeeby JL, Li X, Zhuang Z, et al. Multiple leiomyomas of the esophagus, lung and uterus in multiple endocrine neoplasia type 1. Am J Pathol 2001;159:1121-7.
7. Choi H, Kim S, Moon JH, et al. Multiple endocrine neoplasia type 1 with multiple leiomyomas linked to a novel mutation in the MEN1 gene. Yonsei Med J 2008;49:655-61.
8. Kmet LM, Cook SLS, Magliocco AM. A review of p53 expression and mutation in human benign, low malignant potential, and invasive epithelial ovarian tumors. Cancer 2003;97:389-404.
Anterior Mediastinal Angiomyolipoma
Fatih Candaş, MD, Ufuk Berber, MD, Akin Yildizhan, MD, Nurettin Yiyit, MD, Rauf Görür, MD, and Turgut Işitmangil, MD
Departments of Thoracic Surgery and Pathology, GATA Haydarpasa Teaching Hospital, Istanbul, Turkey
Angiomyolipomas are benign, solitary, noninvasive mes- enchymal tumors. They most often arise in the kidney.
Extrarenal presentations of these tumors are in skin, orophaynx, abdominal wall, gastrointestinal tract, heart, lung, liver, uterus, penis, and spinal cord. Angiomyoli- poma of the mediastinum is extremely rare and is composed of an admixture of fat, smooth muscle cells, and tortuous, thick-walled, small to medium sized blood vessels. We present a surgically confirmed case of anterior mediastinal angiomyolipoma incidentally diagnosed in an asymptomatic patient.
(Ann Thorac Surg 2013;95:1431-2) @ 2013 by The Society of Thoracic Surgeons
A ngiomyolipomas are benign, solitary, and noninva- sive mesenchymal tumors. They most often arise in the kidney [1, 2]. Extrarenal presentations of these tu- mors are in skin, orophaynx, abdominal wall, gastroin- testinal tract, heart, lung, liver, uterus, penis, and spinal cord [1]. Angiomyolipoma of the mediastinum is ex- tremely rare and is composed of an admixture of fat, smooth muscle cells, and tortuous, thick-walled, small to medium sized blood vessels [1-3]. We present a surgi- cally confirmed case of anterior mediastinal angiomyoli- poma incidentally diagnosed in an asymptomatic patient.
A 22-year-old man presented to our clinic with a large mass located in the anterior mediastinum. The mass was incidentally detected on a chest roentgenogram. There was no relevant previous medical history. At admission, the patient complained of slight fatigue and dyspnea on exercise. Standard laboratory values were within normal ranges. Chest roentgenogram showed a 11 × 7 cm well-defined mass in the upper paravertebral area. Com- puted tomography (CT) scanning of the thorax showed a large circumscribed tumor with focal fatty area in the anterior mediastinum (Fig 1). Percutaneous transthoracic needle biopsy was performed under CT guidance. His- tologic examination revealed that the interstitial stroma contained smooth muscle cells and focal fat cells. We considered the possibility of lymphoma and mediastinal liposarcoma. The patient electively underwent a video- assisted thoracic biopsy. The frozen section was not diagnostic. At the same operation, the patient underwent a right thoracotomy. The operative findings revealed no evidence of invasion to pleura or other mediastinal tissues. The tumor was easily dissected free from the surrounding structures (aorta, pulmonary artery, vagal nerve), except the phrenic nerve. The phrenic nerve was involved by the tumor but there was doubtful evidence of diaphragmatic paralysis. After dissection, the mass was resected with the phrenic nerve. Macroscopically, the tumor seemed totally removed. Histologic exami- nation showed interstitial stroma containing smooth muscle cells, focal fat cells, and conglomerated blood vessels (Fig 2).
Accepted for publication July 16, 2012.
Address correspondence to Dr Candas, Department of Thoracic Surgery, GATA Haydarpasa Teaching Hospital, 34668 Uskudar, Istanbul, Turkey; e-mail: fhcandas@yahoo.com.