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 : tatjana.peros-golubicic@zg.htnet.hr
KEY WORDS:
Intrathoracic, multiple neoplasms
ABSTRACT
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.
KEY WORDS:
Intrathoracic, multiple neoplasms
INTRODUCTION
Multiple primary neoplasms in a single patient have been reported as early as the end
of the 19th century (1), and since then numerous works concerning the
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 (4).
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).
CASE REPORT
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.
DISCUSSION
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
neoplasms.
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.
TABLE 2.
REPORTS OF MULTIPLE MALIGNANT NEOPLASMS
Authors
Ref
Primary
neoplasm
Second primary
neoplasms
Multiple primary
neoplasms
Mesothelioma,
NHL- Bcell
Tondini
10
/
/
Habal
13
Colon
adenocarcinoma
Carcinoid
/
Demandante
14
/
/
Ureteral/bladder/urethral
transitional cell
carcinoma, prostatic
adenocarcinoma
Antakli
16
Lung cancer
Lung cancer –
second primary
/
Keshishian
17
Tonsillar
squamous
carcinoma
Gerstle
19
Gastrointestinal
carcinoid
Takabe
20
Mesothelioma
Lung
adenocarcinoma
Esophagus and
tongue squamous
carcinoma
Malignant
neoplasms of
gastrointestinal or
other localisations
NHL – B cell
/
/
/
TABLE 2. (nova)
REPORTS OF MULTIPLE PRIMARY MALIGNANT NEOPLASMS
Authors
Ref
Multiple primary neoplasms
No. of
patients
Year
Carey
22
Lung cancers
19
1993.
Ferguson
30
Lung cancers
117
1993.
Tondini
10
Mesothelioma
NHL- B cell
Case
report
1994.
Antakli
16
Lung cancers
54
1995.
Gerstle
19
Gastrointestinal carcinoid
Malignant neoplasms of
gastrointestinal or other
localisations
32
1995.
Takabe
20
Mesothelioma
NHL – B cell
Case
report
1997.
Keshishian
17
Tonsillar squamous carcinoma
Lung adenocarcinoma
Esophagus and tongue squamous
carcinoma
Case
report
1998.
Habal
13
Colon adenocarcinoma
Carcinoid
Case
report
2000.
Beshay
31
Pulmonary typical carcinoids
Case
report
2003.
10
TABLE 1.
SOME ETIOPATHOGENETIC FACTORS OF MULTIPLE PRIMARY
NEOPLASMS IN A SINGLE PATIENT (5)
Mechanisms of
carcinogenesis
_____________________________________________________________
Chemical
Tobacco
Tobacco+alcohol
Asbestos
Cadmium
Nickel
Arsenic
Lungs, upper respiratory tract
Larynx, lungs, upper digestive tract
Mesothelioma, lungs
Prostate, kidneys, lungs
Lungs, parnasal sinuses
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
_____________________________________________________________
11
REFERENCES
1. Billroth T. Die Allgemeine Chirurgische Pathologie and Therapie. In: Reimer
G. Vorlesungen-Ein Handbuch fur Studierende and Artze, 14, Berlin:Auflage,
1889.
2. Waren S, Gates O. Multiple primary malignant tumors: a survey of literature
and statistical study. Am J Cancer 1932; 16:1358-14.
3. Wang Xi, Christiani DC, Mark JE, et al. Carcinogen exposure, p53 alteration,
and K-ras mutation in synchronous multiple primary lung canrcinoma. Cancer
1999; 85:1734-9.
4. Matzkin H, Brafs Z. Multiple primary malignant neoplasms in the
genitourinary tract: occurrence and etiology. J Urology 1989; 142:1-12.
5. Awada A, Klastersky A. Neoplasies multiples: problemes etiologiques et
possibilities preventives. Rev Med Brux 1992; 13:239-242.
6. Rudan I, Ranzani GN, Strnad M, et al. Surname as “cancer risk “ in extreme
isolates: example from island Lastovo, Croatia. Coll Antropol 1999;
23(2):557-569.
7. Rudan I, Campbell H, Ranzani GN, et al. Cancer incidence in eastern Adriatic
isolates, Croatia: examples from island Krk, Cres, Lošinj, Rab and Pag. Coll
Antropol 1999; 23(2):547-556.
8. Sozzi G, Miozzo M, Pastorino U, et al. Genetic evidence for an independent
origin of multiple preneoplastic and neoplastic lung lesions. Cancer Res 1995;
55:135-140.
12
9. Shimiziu S, Yatabe Y, Koshikowa T, et al. High frequency of clonally related
tumors in cases of multiple synchronous lung cancers as revelaed by molecular
diagnosis. Clin Cancer Res 2000; 6:3994-3999.
10. Tondini M, Rocco G, Travaglini M, et al. Pleural mesothelioma associated
with non-Hodgkin`s lymphoma. Thorax 1994; 49:1269-1270.
11. Green DM, Hyland A, Barcos MP, et al. Second malignant neoplasms after
treatment for Hodgkin`s disease. J Clin Oncol 2000; 18:1492-1499.
12. Leone G, Mele L, Pulsoni A, et al. Incidence of secondary leukemias.
Haematologica 1999; 84:937-945.
13. Habal N, Sims C, Bilchik AJ. Gastrointestinal carcinoid tumors and second
primary malignancies. J Surg Oncol 2000; 75:306-310.
14. Demandante CGN, Troyer DA. Multiple Primary Neoplasms. Case Report and
a Comprehensive Review of Literature. Am J Clin Oncol 2003; 26:79-83.
15. Bumpers HL, Natesha RK, Barnwell SP, Hoover EL. Multiple and distinct
primary cancers: a case report. J Natl Med Assoc 1994; 86(5):387-388.
16. Antakli T, Schaefer RF, Rutherford JE et al. Second primary lung cancer. Ann
Thorac Surg 1995; 59:863-867.
17. Keshishian A, Sarkar FH, Kucyj G, Just-Viera JO. Four multiple primary
neoplasms of the aerodigestive tract. Ann Thorac Surg 1998; 65:252-254.
18. Van Rees BP, Clenton-Jansen AM, Cense HA et al. Molecular evidence of
field cancerization in a patient with 7 tumors of the aerodigestive tract. Human
Path 2000; 31:269-271.
19. Gerstle J, Gordon L, Kauffman GL, Koltun WA. The incidence, management
and outcome of patients with gastrointestinal carcinoids and secondary
primary malignancies. J Am Coll Surg 1995; 180:427-432.
13
20. Takabe K, Tsukada Y, Shimizu T, et al. Malignant lymphoma involving the
penis following malignant pleural mesothelioma. Intern Med 1997; 36:712715.
21. Martini N, Melamed MR. Multiple primary lung cancers. J Thorac Cardiovasc
Surg 1975; 70:606-612.
22. Carey FA, Donnelly SC, Walker WS, et al. Synchronous primary lung
cancers: prevalence in surgical material and clinical implications. Thorax
1993; 48:344-346.
23. Zachariae H, Thestrup-Pedesen K. Interferon alpha and etretinate combination
treatment of cutaneous T-cell lymphoma. J Invest Dermatol 1990; 95:206-208.
24. Vilon P, Fiche M, Maugars Y, et al. Parosteal sarcoma of radius in the course
of etretinate therapy. Rev Rheum Mal Osteoartic 1991; 58:825-827.
25. Hajdu SI, Hajdu EO. Multiple primary malignant tumors. J Am Geriatr Soc
1968; 16:16-26.
26. Berge T, Cederqvist L, Schonebeck J. Multiple primary malignant tumors: an
autopsy study of a circumscribed population. Acta Pathol Microbiol Scand
1969; 76:171-183.
27. Haddow AJ, Boyd JF, Graham AC. Multiple primary neoplasms in the
Western Hospital Region, Scotland: a survey based on cancer registration data.
Scott Med J 1972; 17:143-152.
28. Lee TK, Myers RT, Scharyj M. Multiple primary malignant tumours (MPMT):
study of 68 autopsy cases (1963-1980). J Am Gerietr Soc 1982; 30:744-753.
29. Aydiner A, Karadeniz A, Uygun K, et al. Multiple primary neoplasms at a
single institution: differences between synchronous and metasynchronous
neoplasms. Am J Clin Oncol 2000; 23:364-370.
14
30. Ferguson MK. Synchronous Primary Lung Cancers. Chest 1993; 103:398S400S.
31. Beshay M, Roth T, Stein R, Schmid RA. Synchronous bilateral typical
pulmonary carcinoid tumors. Eur J Cardiothorac Surg 2003; 23:251-253.