By Nancy Foster,2014-06-26 20:47
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    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 :


    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.



    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


    Tonsillar adenocarcinoma

    Keshishian 17 squamous Esophagus and /

    carcinoma tongue squamous



    Gastrointestinal neoplasms of Gerstle 19 / carcinoid gastrointestinal or

    other localisations

    Takabe 20 Mesothelioma NHL B cell /

TABLE 2. (nova)


    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.

    Gastrointestinal carcinoid

    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





Mechanisms of




    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

Nutritional and/or

    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


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