MULTIPLE PRIMARY INTRATHORACIC NEOPLASMS:
CASE REPORT AND A REVIEW OF THE LITERATURE
Tatjana Peroš-Golubičić, Silvana Smojver-Ježek, Marijan Gorečan, Njetočka
Gredelj,, Jasna Tekavec-Trkanjec, Marija Alilović,
Doc dr. sc. Tatjana Peroš-Golubičić University Clinic for Lung Diseases
10 000 Zagreb, Jordanovac 104, CROATIA
Tel. + 385 1 23 85 142, Fax. + 385 1 23 48 345
E-mail : email@example.com
Intrathoracic, multiple neoplasms
Multiple neoplasms in a single patient, synchronous or metasynchronous is not a rare
event, the incidence varies from 1% to 11% of all the neoplasms. They can be
hereditary, connected with some environmental agents or previous therapies. The
incidence of multiple neoplasms rises with age. We report an extremely rare case of
multiple intrathoracic neoplasms (mesothelioma, carcinoid and B-cell lymphoma) in a
71-year old man previously treated for cutaneous T-cell lymphoma. The left upper
lobectomy was performed and was followed by 6 courses of chemotherapy and the
irradiation of the sternum. He was stable two years later.
Intrathoracic, multiple neoplasms
Multiple primary neoplasms in a single patient have been reported as early as the end
th century(1), and since then numerous works concerning the of the 19
etiopathogenesis, diagnosis and prognosis of such cases have been performed. The
pathologic criteria of multiple neoplasms was summarised by Warren and Gates (2);
tumors are considered to be arising independently if they exhibit different histology
characteristics indicative of a subtype or degree of differentiation, if they are located
in different lobes and are not accompanied by tumors of other organs. Molecular
markers including the pattern of DNA ploidy, chromosome 3 p depletion, K-ras and
p53 mutational pattern also have been used to identify the independent origin of
multiple tumors (3).
Multiple neoplasms could be defined, concerning their appearance in time, as
synchronous or metasynchronous; the latter are defined as second and
metasynchronous if they appear 6 months or latter following the first neoplasm
Etiopathogenesis of multiple neoplasms(5) includes hereditary aspects (familial
occurrence with increased incidence, but also the influence of the “protective” factors)
(6,7). It also includes the influence of external factors (tobacco, combined effects of
tobacco and alcohol, asbestos, nutritional factors, viruses, the loss of immunity)
(8,9,10) and the effects of previous therapies (especially with cytotoxic agents and
hormones, immunosuppressants and irradiation) (11,12) or influance of tumour
producing hormons (secretin, gastrin, bombesin, cholecystokinin, vasoactive intestinal
peptide)(13)(Table 1.). From review of the recent literature it would appear that
incidence of multiple neoplasms rises with age (14).
A 71-year old man was admitted to the hospital with a month history of chest pain, dry cough, dispnoa and malasia. Five years before he was treated for biopsy proven mycosis fungoides with etretinate for six months with a considerable success. The chest auscultation showed diminished breath sounds in the left lung. Routine laboratory findings were normal except for sedimentation rate of 130. The chest radiograms showed hyperinflation of the parenchyma in the supradiaphragmal and retrosternal region, a pathological process of the anterior upper mediastinum, an infiltration of the peripheral lingula 3 cm in the diameter and smaller one in the apicoposterior subsegment of the left upper lobus (Fig.1.a, 1.b.). Fiberbronhoscopy showed a tumor with smooth surface in the subsegmental bronchus of the left upper lung lobe. Bronchial brushing cytology (Fig.2.a.) and pathohistological analyses of the tumor biopsy proved that the tumor was carcinoid. The transthoracic fine needle aspiration of mediastinal mass did not reveal its aetiology.
The patient underwent an operation, left upper lobectomy and mediastinal biopsy were performed. During the operation the node in the lingula was seen fixed to the pericardium. The intraoperative imprint cytology of the infiltrate in the lingula and pericardium revealed a malignant tumor. The tumor was firm, grey-white, 2.5x2 cm in
size, composed of pleomorphic atypical epithelial cells in tubulopapilary formations and desmoplastic stroma (Fig.2.b.). The immunohistochemistry showed NSE and BerEP4 negative, EMA and cytokeratin positive tumor cells. Pathohistological diagnosis was a malignant mesothelioma. A similar infiltrate was found in the upper lobus of the left lung, 0.4x4 cm in size. In the apicoposterior subsegmental bronchus of the left upper lobe a sharply demarcated, smooth, soft, fleshy tumor was found, 0.8
cm in diameter, composed of uniform cells with eosinophilic cytoplasms in acinar formations, NSE and cytokeratin positive, EMA negative. The diagnosis was typical carcinoid. The mediastinal tumor was white, homogenous, 4 x 2 x 0,6 cm in size, composed of atypical small lymphoid cells – lymphoplasmocytoid type, B
immunophenotype. The conclusion was non-Hodgkin lymphoma of
lymphoplasmocytoid type/ immunocytoma. In two of the synchronous tumors –
immunocytoma and mesothelioma, overexpression of the p53 tumor suppressor gene product was found.
During the postoperative period a painful tumor of the sternum arose. The chest CT showed mediastinal mass with ventral, thoracic border, which was not sharp but irregular, suggesting the infiltrative growth. (Fig.1.c.) The fine needle aspiration showed the cells of non-Hodgkin lymphoma. (Fig.2.c.) The patient underwent six courses of chemotherapy (protocol CHOP: adriamycin, ciclophosphamide, oncovin and metilprednisolon) and the irradiation of the sternum. Two years later the patient was without symptoms, conventional chest radiogram and CT scan showed only a fibrous residue and there were no signs of local or distant spreading of any of the tumors.
This is a case of multiple intrathoracic neoplasms: mesothelioma, carcinoid and B-cell lymphoma, in a patient who has been treated for cutaneous T-cell lymphoma. Similar case has not been reported previously.
Multiple primary neoplasms in a single individual are extremely rare when more then three distinct lesions are considered (15). The incidence of multiple primary lung cancer ranges from 0,5% to 10% (16).
In clinical reports patients with multiple primary cancer of upper aerodigestive tract have been described (17,18), as well as combination of other malignant neoplasms and patients with multiple primary lung cancer.
(10,13,16,17,19,20,22,30,31). (Table 2.) It would appear that patients who have developed one neoplasm of aerodigestive tract might be at greater risk of developing a second primary tumor, particularly with alcohol consumption and
smoking habits. when they used alcohol and are heavy smokers.
In the case of lung cancer the occurrence of a metachronous primary lung tumors has been over 10% for patients surviving more then 3 years. Criteria of multiple lung neoplasms modified from Martini and Melamed (21) include demonstration of tumors with different histology and proof that tumors, if histologically similar, arise from separate and distinct endobronchial foci. Many authors exclude cases in which there is more than one tumor of given histological type, arguing that the second tumor cannot be distinguished from intrapulmonary metastasis (22). We reported patient with three intrathoracal malignant tumors from different origins. Our patient had carcinoid, tumor from neuroendocrine origin, mesothelioma, malignant mesenchymal tumor, intrathoracic B-cell lymphoma and cutaneous T-cell lymphoma.
Etretinate is a monoaromatic retinoid used in the treatment of keratinising skin disorders and cutaneous T-cell non-Hodgkin lymphomas (23). Teratogenic potential
has been described, as well as the induction of different skeletal alterations, even the
perosteal osteosarcoma (24). Etretinate has been administered to our patients for 6
months, five years before diagnosis of multiple second malignancies and we cannot
affirm the connection between those events.
No specific hereditary syndrome could be identified from the patient's pedigree or the
environmental causative agents responsible for the development of multiple
malignancies. Individuals with history of multiple neoplasms should have a complete
family history evaluation and follow-up for development of subsequent primary
Several studies have shown increased risk of multiple neoplasms for older patients,
especially for those earlier treated with aggressive anticancer drugs. The percent of
patients older than 50 years who developed multiple neoplasms varies from 71% to
94% in different series (25-29). The reason for increased incidence of multiple
neoplasms could be generally older population, and on the other hand more effective antitumorous therapy that prolongs patients lives and increases risk for other primary
neoplasms. Our patient, as reported, has been treated efficiently for another malignancy.
REPORTS OF MULTIPLE MALIGNANT NEOPLASMS
Primary Second primary Multiple primary Authors Ref neoplasm neoplasms neoplasms
Mesothelioma, Tondini 10 / / NHL- Bcell
Colon Habal 13 Carcinoid / adenocarcinoma
transitional cell Demandante 14 / / carcinoma, prostatic
Lung cancer – Antakli 16 Lung cancer / second primary
Keshishian 17 squamous Esophagus and /
carcinoma tongue squamous
Gastrointestinal neoplasms of Gerstle 19 / carcinoid gastrointestinal or
Takabe 20 Mesothelioma NHL – B cell /
TABLE 2. (nova)
REPORTS OF MULTIPLE PRIMARY MALIGNANT NEOPLASMS
No. of Authors Ref Multiple primary neoplasms Year patients Carey 22 Lung cancers 19 1993. Ferguson 30 Lung cancers 117 1993.
Mesothelioma Case Tondini 10 1994. NHL- B cell report Antakli 16 Lung cancers 54 1995.
Malignant neoplasms of Gerstle 19 32 1995. gastrointestinal or other
Mesothelioma Case Takabe 20 1997. NHL – B cell report
Tonsillar squamous carcinoma
Lung adenocarcinoma Case Keshishian 17 1998. Esophagus and tongue squamous report
Colon adenocarcinoma Case Habal 13 2000. Carcinoid report
Case Beshay 31 Pulmonary typical carcinoids 2003. report
SOME ETIOPATHOGENETIC FACTORS OF MULTIPLE PRIMARY
NEOPLASMS IN A SINGLE PATIENT(5)
Tobacco Lungs, upper respiratory tract
Tobacco+alcohol Larynx, lungs, upper digestive tract
Asbestos Mesothelioma, lungs
Cadmium Prostate, kidneys, lungs
Nickel Lungs, parnasal sinuses
Arsenic Skin, lungs
endocrine Breasts, corpus uteri, ovaries, colon
Viral Burkitt's lymphoma, non-Hodgkin lymphoma
Immunodefficiency Thymoma, skin cancer, non-Hodgkin lymphoma
Following the therapy for Hodgkin's disease,
lymphomas and Kaposi sarcomas in AIDS