- Email: [email protected]
CASE REPORTS: Quadruple cancer in a single patient: a report of four cases
614
Case reports
importance of adjuvant therapy in perianal Paget’s disease.7 Combined chemoradiotherapy may be considered as primary treatment for perianal Paget’s disease in those medically unfit for surgery, or as an alternative to further surgery for recurrence after surgery, and for anyone wishing to avoid mutilating surgery.6,15–17 It is still in need of further clinical trials to determine its role in the treatment of perianal extramammary Paget’s disease. A staging classification for perianal extramammary Paget’s disease was proposed by Shutze and Gleysteen14 (Table 1) showing the description of each stage and the recommended therapy. The prognosis for this disease must be guarded and varies with its spectrum. However, the prognosis of the patients with an underlying carcinoma of the anorectum is reported to be much poorer than for patients with Paget’s disease restricted to the skin and adnexa.11,14,18 Perianal extramammary Paget’s disease has a high rate of local recurrence. Therefore, patients who are affected should be kept under a strict follow-up programme. Long-term follow up is necessary to exclude recurrence and development of an associated cancer.11 Bech et al.11 and Jensen et al.19 suggested a follow-up programme which includes at least a complete physical examination, proctosigmoidoscopy and a random biopsy of the perianal region once a year. Colonoscopy is performed at 2–3 yearly intervals. In conclusion, this rare disease continues to pose problems in diagnosis and treatment. It should be remembered when confronted with a ‘therapy resistant perianal eczema’.
5. 6.
7. 8. 9. 10. 11. 12. 13.
14. Acknowledgement The author is grateful to Ms Anita M. Choco for editing this manuscript.
15.
16.
References 1. Paget J. On disease of the mammary areola preceding cancer of the mammary gland. St Bartholomew Hospital Research London 1874; 10: 87–9. 2. Berardi RS, Lee S, Chen HP. Perianal extramammary Paget’s disease. Surg Gynecol Obstet 1988; 167: 359–65. 3. Crocker HR. Paget’s disease affecting the scrotum and penis. Trans Pathol Soc London 1889; 40: 187–91. 4. Darier J, Coulillad P. Sur un cas de maladie de Paget de la
17.
18.
re´gion pe´rine´a-anale et scrotale. Ann de Dermatol and de Syph 1893; 4: 25–31. Tjandra J. Perianal Paget’s disease: report of three cases. Dis Col Rect 1988; 31: 462–6. Thirlby RC, Hammer CJ, Galagan KA, Travaglini JJ, Picazzi VJ. Perianal Paget’s disease: successful treatment with combined chemoradiotherapy, report of a case. Dis Col Rect 1990; 33: 150–2. Sarmiento JM, Wolff BG, Burgart LJ, Frizelle FA, Ilstrup DM. Paget’s disease of the perianal region—an aggressive disease? Dis Col Rect 1997; 40: 1187–94. Lock MR, Katz DR, Parks Sir A, Thomson JPS. Perianal Paget’s disease. Postgrad Med J 1977; 53: 768–72. Butler JD, Hershman MJ, Wilson CA, Bryson JR. Perianal Paget’s disease. JR Soc Med 1997; 90: 688–9. Goldman S, Ihre T, Logerstedt U, Svensson C. Perianal Paget’s disease: report of five cases. Int J Colorectal Dis 1992; 7: 167–9. Beck DE, Fazio VW. Perianal Paget’s disease. Dis Col Rect 1987; 30: 263–6. Herzog U, Flue M, Roche R, Curschellas E. Perianal extramammary Paget’s disease: report of two cases. Eur J Surg Oncol 1993; 19: 469–73. Murakami K, Tanimura H, Ishimoto K, Yamaue H, Yamade N, Shimamoto T. Reconstruction with bilateral gluteus maximum myocutaneous rotation flap after wide local excision for perianal extramammary Paget’s disease: report of two cases. Dis Colon Rectum 1996; 39: 227–31. Shutze WP, Gleysteen JJ. Perianal Paget’s disease: classification and review of management—report of two cases. Dis Colon Rectum 1990; 33: 502–7. Secco GB, Lapertosa G, Sertoli MR, Scarpati D, Riboli EB. Perianal Paget’s disease: case report of an elderly patient treated with polychemotherapy and radiotherapy. Tumor 1984; 70: 381–3. Besa P, Rich TA, Delclos L, Edwards CL, Ota DM, Wharton JT. Extramammary Paget’s disease of the perineal skin: role of radiotherapy. Int J Radiot Oncol Biol Phys 1992; 24: 73–8. Voight H, Basserman R, Nathrath W. Cytoreductive combination chemotherapy for regionally advanced unresectable extramammary Paget carcinoma. Cancer 1992; 70: 704–8. Williams SL, Rogers LW, Quan SH. Perianal Paget’s disease: report of seven cases. Dis Col Rect 1976; 19: 30–40.
Accepted for publication 26 January 2000
doi:10.1053/ejso.2000.0958, available online at http://www.idealibrary.com on
Quadruple cancer in a single patient: a report of four cases S. Mussari, M. Amichetti and L. Tomio Department of Radiation Oncology, S. Chiara Hospital, Trento, Italy
Multiple primary neoplasia was once considered a rare curiosity but is now a well recognized phenomenon. Only a few papers have been published in the English literature with regard to occurrence of four or more primary malignancies in a single patient. We report four cases of quadruple cancer; a review of the literature about this topic is discussed. Key words: multiple neoplasms; quadruple cancer.
2000 Harcourt Publishers Ltd
615
Case reports Table 1. Patients with quadruple cancer treated in the Radiotherapy Department of Trento, Italy (1984–1997) Location of tumors Case
Age (years)
Gender
1st
2nd
3rd
4th
1 2 3 4
47 48 55 60
Male Male Male Male
Anus Lung Oral cavity Oral cavity
Oesophagus Stomach Oropharynx Larynx
Lung Rectum Oesophagus NHL
Oral cavity Lung Melanoma Oesophagus
Table 2. The cases of quadruple cancer reported in the English literature between 1980 and 1997, all curatively treated Location of carcinoma Reference
Year 9
Bjerrum et al. Craig et al.10 Abe et al.11 Murata et al.12 Mori et al.13 Fukamoto et al.14 Sakashita et al.15 Koide et al.16 Keshishian et al.17 Nakayama et al.6
Age (years) Gender
1984 1986 1991 1994 1994 1995 1996 1997 1998 1999
61 60 45 71 64 63 69 56 39 62
Female Male Male Male Male Male Male Male Male Female
1st
2nd
3rd
4th
Rectum Oral cavity Stomach Skin Bladder Stomach Stomach Stomach Oropharynx Breast
Breast Lung Colon Stomach Skin Lung Lip Oesophagus Oesophagus Breast
Uterus Larynx Ureter Colon Larynx Hypopharynx Oral cavity Gastric remnant Lung Vater’s papilla
Colon Oral cavity Rectum Larynx Liver Maxillary sinus Oral cavity Pancreas Oral cavity Bladder
Introduction The occurrence of multiple primary malignancies (MPMs) in a single patient has increased in the past few decades, favoured also by the progress in techniques for early detection and treatment of cancers.1 The incidence of MPMs has been carried out by cancer registries of several countries.2–4 Recently, in three Italian population-based cancer registries a second primary cancer has occurred in 2.4% of the 19 252 cancer patients analysed; in this study primary head and neck cancer patients were not included.5 The incidence of quadruple cancer, which also includes autopsy cases, is extremely low (<0.1%).6 Cases report The charts of the patients treated at the Department of Radiation Oncology of S. Chiara Hospital, Trento, Italy, between 1984 and 1997 were reviewed searching for the cases of multiple primaries. For the purpose of this report, the cases with double or triple tumours were excluded from the analysis. We observed four cases of quadruple cancers, all curatively treated. A brief description of the patients is reported in Table 1. Discussion MPMs have long passed the stage of pathological curiosity to become an established medical problem. Warren and Gates7 defined MPMs as follows: (1) each tumour must present a definite picture of malignancy, (2) each tumour must be histologically distinct and (3) the possibility that one is a metastasis of the other must be excluded. The majority of the patients with quadruple cancer present with breast and upper aero-digestive tumours.1 In our patients the most Correspondence to: Dr Salvatore Mussari, U.O. Radioterapia Oncologia, Ospedale S. Chiara, Largo Medaglie d’Oro, 38100 Trento, Italy. Fax: +39-461-903139; E-mail: [email protected]
common pattern of association was between oesophageal cancer and head and neck cancer (three out of four patients); this association is also common in the North-East of Italy among tobacco and alcohol abusers.8 Using a Net-Scape Advanced Med-line (www.ncbi.nlm.nih.gov), we found 10 studies of clinical quadruple cancer published in the English literature from 1980 to 1999 (Table 2). The majority of these were reported by Japanese authors, while no Italian reports were found. The majority of MPMs occur as a result of random chance.18 Nonetheless, different mechanisms have been considered to be involved in MPMs, such as the intense exposure to carcinogens, the effects of chemo- and/or radiotherapy and the influence of genetic predisposition. The most typical examples of the first situation are the tobaccorelated cancers.19,20 Head and neck cancer survivors are at increased risk for another cancer of the respiratory and upper digestive system. A possible explanation of this phenomenon is the ‘field cancerization effect’.21 According to this theory, carcinogens to which the organ has been exposed may initiate the proliferation of many clones of cells; the subsequent promotion of their growth along carcinogenesis may lead to the formation of multifocal tumours. In our report, patients 1, 3 and 4 were heavy drinkers and smokers, thus they support this hypothesis. Many malignancies are treated with chemotherapy and/or radiotherapy. Both of them have been shown to be carcinogenic in several reports.22–24 The main problem in proving a correlation between antineoplastic therapies and secondary cancer may be attributable to detection bias rather than to carcinogenic therapy.25 In our cases all the patients received potential carcinogenic therapy (i.e. radiotherapy to the site which develops metachronous tumour). Therefore, for instance, the lung cancer which occurred in patient 1 could be attributed to carcinogenic effect of the previous radiotherapy for oesophageal cancer. The occurrence of two or more cancers in a particular person might be a result of genetic susceptibility. Recent studies have revealed that the same gene, Rb1, was deleted in osteosarcoma, a frequent second tumour in retinoblastoma patients.26 Another disorder of this type is the Li–Fraumeni cancer family syndrome,
616
Case reports
which includes soft tissue sarcomas, breast cancer and lung cancer as well as other cancers.27 Unfortunately, no genetic evaluation was performed in our patients. In addition to these risk factors, the occurrence of MPMs may be favoured, as in our cases, by the early stage of each tumour, the curative effect of therapies and the young age of the patients at onset. The occurrence of MPMs is a rare but increasingly frequently reported event. Many theories have been proposed to explain MPMs, but none have been proven, even though the key risk factors appear to be smoking and family history. In the future chemoprevention, more intensive surveillance and appropriate cytogenetic and molecular studies should be developed in order to improve preventive strategies in the detection of MPMs. Additionally, multidisciplinary treatment and conservative strategies are important to ameliorate quality of life and survival rate in patients with MPMs.
12.
13.
14. 15. 16. 17.
References 1. Schottenfeld D. In: Schottenfeld D, Fraumeni JF Jr (eds) Cancer Epidemiology and Prevention. New York: Oxford University Press, 1996: 1370–87. 2. Levi F, Randibison L, Te VC, Rolland-Portal I, Franceschi S, La Vecchia C. Multiple primary cancers in the Vaud Cancer Registry, Switzerland, 1974–1981. Cancer 1993; 67: 391–5. 3. Coleman MP. Multiple primary malignant neoplasms in England and Wales, 1971–1981. Yale J Med Biol 1986; 59: 517–31. 4. Tsukuma H, Fujimoto I, Hanai A, Hiyama A, Kitagawa T, Kinoshita N. Incidence of second primary cancers in Osaka residents, Japan, with special reference to cumulative and relative risk. Jpn J Cancer 1994; 85: 339–45. 5. Buiatti E, Crocetti E, Acciai S, Grafa` L, Falcini F, Milandri C, La Rosa M. Incidence of second primary cancer in three Italian population-based cancer registries. Eur J Cancer 1997; 33: 1829–34. 6. Nakayama H, Masuda H, Ugajin W, Nakamura Y, Akiyama K. Quadruple cancer including bilateral breasts, Vater’s papilla, and urinary bladder: a report of a case. Surg Today 1999; 29: 276–9. 7. Warren S, Gates O. Multiple primary malignant tumors: a survey of the literature and statistical study. Am J Cancer 1992; 16: 1358–414. 8. Franceschi S, Bidoli E, Baron AE, Barra S, Talamini R, Serraino D, La Vecchia C. Nutrition and cancer of the oral cavity and pharynx in north-east of Italy. Int J Cancer 1991; 47: 20–5. 9. Bjerrum OW, Gjedde S, Bendtzen K, Enke C, Pedersen BK, Munch-Petersen B, Platz P, Wulf HC. An unusual case of multiple malignancy in an adult. Tumori 1984; 70: 575–7. 10. Craig DM, Triedman LJ. Four primary malignant neoplasms in a single patient. J Surg Oncol 1986; 32: 8–10. 11. Abe Y, Nakada T, Kawamura S, Adachi M, Kubota Y, Kakizaki H, Watanabe H, Yamaguchi T, Watanabe M. A case of
18. 19.
20.
21. 22.
23.
24. 25. 26.
27.
quadruple carcinoma with special reference to ureteral cancer. Int Urol Nephrol 1991; 23: 325–31. Murata K, Iwazawa T, Takayama T, Yamashita K, Okagawa K. Quadruple cancer including Bowen’s disease after arsenic injections 40 years earlier: report of a case. Surg Today 1994; 24: 1115–8. Mori T, Nakase K, Tsuji K, Nagaya S, Ikeda T, Tanigawa M, Tamaki S, Miyanishi E, Kita K, Shirakawa S. Quadruple cancer in a human T-cell leukemia virus type 1 carrier. Intern Med 1994; 33: 155–7. Fukamoto K, Nakamura S, Takahashi A, Kono N, Ichikawa G. A case with quadruple primary cancers of head and neck. Gan To Kagaku Ryoho 1995; 22 (Suppl. 3): 215–20. Sakashita H, Miyata M, Miyamoto H, Kurumaya H. A case of quadruple cancer, including triple cancers in the head and neck region. J Oral Maxillofac Surg 1996; 54: 501–4. Koide N, Yazawa K, Koide S, Adachi W, Amano J. Oesophageal cancer associated with other primary cancers: a study of 31 patients. J Gastroenter Hepatol 1997; 12: 690–4. Keshishian A, Sarkar FH, Kucyj G, Just-Viera JO. Four multiple primary malignant neoplasms of the aerodigestive tract. Ann Thorac Surg 1998; 65: 252–4. Neugut AI, Robinson E. Multiple primary neoplasms. Cancer J 1992; 5: 245–8. Schottenfeld D, Gant RC, Wynder EL. The role of alcohol and tobacco in multiple primary cancers of the upper digestive system, larynx and lung—a prospective study. Prev Med 1974; 3: 277–93. Berg JW, Schottenfeld D. Incidence of multiple primary cancers. III. Cancers of the respiratory and upper digestive system as multiple primary cancers. J Natl Cancer Inst 1970; 44: 264–74. Slaughter DP, Soutwick HW, Smejkal W. ‘‘Field cancerization’’ in oral stratified squamous epitelium. Clinical implications of multicentric origins. Cancer 1953; 6: 693–8. Curtis RE, Boice JD Jr, Stovall M, Bernestein L, Greenberg RS, Flannery JT, Schwartz AG, Weyer P, Moloney WC, Hoover RN. Risk of leukemia after chemotherapy and radiation for breast cancer. N Eng J Med 1992; 326: 1745–51. Valagussa P, Santoro A, Fossati-Bellani F, Fossati-Bellani F, Banfi A, Bonadonna G. Second acute leukemia and other malignancies following treatment for Hodgkin’s disease. J Clin Oncol 1986; 4: 830–7. List AF, Foll DC, Greco FA. Lung cancer and Hodgkin’s disease, association with previous radiotherapy. J Clin Oncol 1985; 3: 215–21. Craig SL, Feinstein AR. Antecedent therapy versus detection bias as causes of neoplastic multimorbidity. Am J Clin Oncol 1999; 22: 51–6. Hansen MF, Koufos A, Gallie BL, Phillips BA, Fodstad O, Bragger A, Gedde-Dahl T, Cavanee WK. Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisponition. Proc Natl Acad Sci USA 1985; 82: 6216–20. Li FP, Fraumeni JF Jr. Prospective study of a family cancer syndrome. J Am Med Assoc 1982; 247: 2892–4.
Accepted for publication 26 January 2000
Case reports
importance of adjuvant therapy in perianal Paget’s disease.7 Combined chemoradiotherapy may be considered as primary treatment for perianal Paget’s disease in those medically unfit for surgery, or as an alternative to further surgery for recurrence after surgery, and for anyone wishing to avoid mutilating surgery.6,15–17 It is still in need of further clinical trials to determine its role in the treatment of perianal extramammary Paget’s disease. A staging classification for perianal extramammary Paget’s disease was proposed by Shutze and Gleysteen14 (Table 1) showing the description of each stage and the recommended therapy. The prognosis for this disease must be guarded and varies with its spectrum. However, the prognosis of the patients with an underlying carcinoma of the anorectum is reported to be much poorer than for patients with Paget’s disease restricted to the skin and adnexa.11,14,18 Perianal extramammary Paget’s disease has a high rate of local recurrence. Therefore, patients who are affected should be kept under a strict follow-up programme. Long-term follow up is necessary to exclude recurrence and development of an associated cancer.11 Bech et al.11 and Jensen et al.19 suggested a follow-up programme which includes at least a complete physical examination, proctosigmoidoscopy and a random biopsy of the perianal region once a year. Colonoscopy is performed at 2–3 yearly intervals. In conclusion, this rare disease continues to pose problems in diagnosis and treatment. It should be remembered when confronted with a ‘therapy resistant perianal eczema’.
5. 6.
7. 8. 9. 10. 11. 12. 13.
14. Acknowledgement The author is grateful to Ms Anita M. Choco for editing this manuscript.
15.
16.
References 1. Paget J. On disease of the mammary areola preceding cancer of the mammary gland. St Bartholomew Hospital Research London 1874; 10: 87–9. 2. Berardi RS, Lee S, Chen HP. Perianal extramammary Paget’s disease. Surg Gynecol Obstet 1988; 167: 359–65. 3. Crocker HR. Paget’s disease affecting the scrotum and penis. Trans Pathol Soc London 1889; 40: 187–91. 4. Darier J, Coulillad P. Sur un cas de maladie de Paget de la
17.
18.
re´gion pe´rine´a-anale et scrotale. Ann de Dermatol and de Syph 1893; 4: 25–31. Tjandra J. Perianal Paget’s disease: report of three cases. Dis Col Rect 1988; 31: 462–6. Thirlby RC, Hammer CJ, Galagan KA, Travaglini JJ, Picazzi VJ. Perianal Paget’s disease: successful treatment with combined chemoradiotherapy, report of a case. Dis Col Rect 1990; 33: 150–2. Sarmiento JM, Wolff BG, Burgart LJ, Frizelle FA, Ilstrup DM. Paget’s disease of the perianal region—an aggressive disease? Dis Col Rect 1997; 40: 1187–94. Lock MR, Katz DR, Parks Sir A, Thomson JPS. Perianal Paget’s disease. Postgrad Med J 1977; 53: 768–72. Butler JD, Hershman MJ, Wilson CA, Bryson JR. Perianal Paget’s disease. JR Soc Med 1997; 90: 688–9. Goldman S, Ihre T, Logerstedt U, Svensson C. Perianal Paget’s disease: report of five cases. Int J Colorectal Dis 1992; 7: 167–9. Beck DE, Fazio VW. Perianal Paget’s disease. Dis Col Rect 1987; 30: 263–6. Herzog U, Flue M, Roche R, Curschellas E. Perianal extramammary Paget’s disease: report of two cases. Eur J Surg Oncol 1993; 19: 469–73. Murakami K, Tanimura H, Ishimoto K, Yamaue H, Yamade N, Shimamoto T. Reconstruction with bilateral gluteus maximum myocutaneous rotation flap after wide local excision for perianal extramammary Paget’s disease: report of two cases. Dis Colon Rectum 1996; 39: 227–31. Shutze WP, Gleysteen JJ. Perianal Paget’s disease: classification and review of management—report of two cases. Dis Colon Rectum 1990; 33: 502–7. Secco GB, Lapertosa G, Sertoli MR, Scarpati D, Riboli EB. Perianal Paget’s disease: case report of an elderly patient treated with polychemotherapy and radiotherapy. Tumor 1984; 70: 381–3. Besa P, Rich TA, Delclos L, Edwards CL, Ota DM, Wharton JT. Extramammary Paget’s disease of the perineal skin: role of radiotherapy. Int J Radiot Oncol Biol Phys 1992; 24: 73–8. Voight H, Basserman R, Nathrath W. Cytoreductive combination chemotherapy for regionally advanced unresectable extramammary Paget carcinoma. Cancer 1992; 70: 704–8. Williams SL, Rogers LW, Quan SH. Perianal Paget’s disease: report of seven cases. Dis Col Rect 1976; 19: 30–40.
Accepted for publication 26 January 2000
doi:10.1053/ejso.2000.0958, available online at http://www.idealibrary.com on
Quadruple cancer in a single patient: a report of four cases S. Mussari, M. Amichetti and L. Tomio Department of Radiation Oncology, S. Chiara Hospital, Trento, Italy
Multiple primary neoplasia was once considered a rare curiosity but is now a well recognized phenomenon. Only a few papers have been published in the English literature with regard to occurrence of four or more primary malignancies in a single patient. We report four cases of quadruple cancer; a review of the literature about this topic is discussed. Key words: multiple neoplasms; quadruple cancer.
2000 Harcourt Publishers Ltd
615
Case reports Table 1. Patients with quadruple cancer treated in the Radiotherapy Department of Trento, Italy (1984–1997) Location of tumors Case
Age (years)
Gender
1st
2nd
3rd
4th
1 2 3 4
47 48 55 60
Male Male Male Male
Anus Lung Oral cavity Oral cavity
Oesophagus Stomach Oropharynx Larynx
Lung Rectum Oesophagus NHL
Oral cavity Lung Melanoma Oesophagus
Table 2. The cases of quadruple cancer reported in the English literature between 1980 and 1997, all curatively treated Location of carcinoma Reference
Year 9
Bjerrum et al. Craig et al.10 Abe et al.11 Murata et al.12 Mori et al.13 Fukamoto et al.14 Sakashita et al.15 Koide et al.16 Keshishian et al.17 Nakayama et al.6
Age (years) Gender
1984 1986 1991 1994 1994 1995 1996 1997 1998 1999
61 60 45 71 64 63 69 56 39 62
Female Male Male Male Male Male Male Male Male Female
1st
2nd
3rd
4th
Rectum Oral cavity Stomach Skin Bladder Stomach Stomach Stomach Oropharynx Breast
Breast Lung Colon Stomach Skin Lung Lip Oesophagus Oesophagus Breast
Uterus Larynx Ureter Colon Larynx Hypopharynx Oral cavity Gastric remnant Lung Vater’s papilla
Colon Oral cavity Rectum Larynx Liver Maxillary sinus Oral cavity Pancreas Oral cavity Bladder
Introduction The occurrence of multiple primary malignancies (MPMs) in a single patient has increased in the past few decades, favoured also by the progress in techniques for early detection and treatment of cancers.1 The incidence of MPMs has been carried out by cancer registries of several countries.2–4 Recently, in three Italian population-based cancer registries a second primary cancer has occurred in 2.4% of the 19 252 cancer patients analysed; in this study primary head and neck cancer patients were not included.5 The incidence of quadruple cancer, which also includes autopsy cases, is extremely low (<0.1%).6 Cases report The charts of the patients treated at the Department of Radiation Oncology of S. Chiara Hospital, Trento, Italy, between 1984 and 1997 were reviewed searching for the cases of multiple primaries. For the purpose of this report, the cases with double or triple tumours were excluded from the analysis. We observed four cases of quadruple cancers, all curatively treated. A brief description of the patients is reported in Table 1. Discussion MPMs have long passed the stage of pathological curiosity to become an established medical problem. Warren and Gates7 defined MPMs as follows: (1) each tumour must present a definite picture of malignancy, (2) each tumour must be histologically distinct and (3) the possibility that one is a metastasis of the other must be excluded. The majority of the patients with quadruple cancer present with breast and upper aero-digestive tumours.1 In our patients the most Correspondence to: Dr Salvatore Mussari, U.O. Radioterapia Oncologia, Ospedale S. Chiara, Largo Medaglie d’Oro, 38100 Trento, Italy. Fax: +39-461-903139; E-mail: [email protected]
common pattern of association was between oesophageal cancer and head and neck cancer (three out of four patients); this association is also common in the North-East of Italy among tobacco and alcohol abusers.8 Using a Net-Scape Advanced Med-line (www.ncbi.nlm.nih.gov), we found 10 studies of clinical quadruple cancer published in the English literature from 1980 to 1999 (Table 2). The majority of these were reported by Japanese authors, while no Italian reports were found. The majority of MPMs occur as a result of random chance.18 Nonetheless, different mechanisms have been considered to be involved in MPMs, such as the intense exposure to carcinogens, the effects of chemo- and/or radiotherapy and the influence of genetic predisposition. The most typical examples of the first situation are the tobaccorelated cancers.19,20 Head and neck cancer survivors are at increased risk for another cancer of the respiratory and upper digestive system. A possible explanation of this phenomenon is the ‘field cancerization effect’.21 According to this theory, carcinogens to which the organ has been exposed may initiate the proliferation of many clones of cells; the subsequent promotion of their growth along carcinogenesis may lead to the formation of multifocal tumours. In our report, patients 1, 3 and 4 were heavy drinkers and smokers, thus they support this hypothesis. Many malignancies are treated with chemotherapy and/or radiotherapy. Both of them have been shown to be carcinogenic in several reports.22–24 The main problem in proving a correlation between antineoplastic therapies and secondary cancer may be attributable to detection bias rather than to carcinogenic therapy.25 In our cases all the patients received potential carcinogenic therapy (i.e. radiotherapy to the site which develops metachronous tumour). Therefore, for instance, the lung cancer which occurred in patient 1 could be attributed to carcinogenic effect of the previous radiotherapy for oesophageal cancer. The occurrence of two or more cancers in a particular person might be a result of genetic susceptibility. Recent studies have revealed that the same gene, Rb1, was deleted in osteosarcoma, a frequent second tumour in retinoblastoma patients.26 Another disorder of this type is the Li–Fraumeni cancer family syndrome,
616
Case reports
which includes soft tissue sarcomas, breast cancer and lung cancer as well as other cancers.27 Unfortunately, no genetic evaluation was performed in our patients. In addition to these risk factors, the occurrence of MPMs may be favoured, as in our cases, by the early stage of each tumour, the curative effect of therapies and the young age of the patients at onset. The occurrence of MPMs is a rare but increasingly frequently reported event. Many theories have been proposed to explain MPMs, but none have been proven, even though the key risk factors appear to be smoking and family history. In the future chemoprevention, more intensive surveillance and appropriate cytogenetic and molecular studies should be developed in order to improve preventive strategies in the detection of MPMs. Additionally, multidisciplinary treatment and conservative strategies are important to ameliorate quality of life and survival rate in patients with MPMs.
12.
13.
14. 15. 16. 17.
References 1. Schottenfeld D. In: Schottenfeld D, Fraumeni JF Jr (eds) Cancer Epidemiology and Prevention. New York: Oxford University Press, 1996: 1370–87. 2. Levi F, Randibison L, Te VC, Rolland-Portal I, Franceschi S, La Vecchia C. Multiple primary cancers in the Vaud Cancer Registry, Switzerland, 1974–1981. Cancer 1993; 67: 391–5. 3. Coleman MP. Multiple primary malignant neoplasms in England and Wales, 1971–1981. Yale J Med Biol 1986; 59: 517–31. 4. Tsukuma H, Fujimoto I, Hanai A, Hiyama A, Kitagawa T, Kinoshita N. Incidence of second primary cancers in Osaka residents, Japan, with special reference to cumulative and relative risk. Jpn J Cancer 1994; 85: 339–45. 5. Buiatti E, Crocetti E, Acciai S, Grafa` L, Falcini F, Milandri C, La Rosa M. Incidence of second primary cancer in three Italian population-based cancer registries. Eur J Cancer 1997; 33: 1829–34. 6. Nakayama H, Masuda H, Ugajin W, Nakamura Y, Akiyama K. Quadruple cancer including bilateral breasts, Vater’s papilla, and urinary bladder: a report of a case. Surg Today 1999; 29: 276–9. 7. Warren S, Gates O. Multiple primary malignant tumors: a survey of the literature and statistical study. Am J Cancer 1992; 16: 1358–414. 8. Franceschi S, Bidoli E, Baron AE, Barra S, Talamini R, Serraino D, La Vecchia C. Nutrition and cancer of the oral cavity and pharynx in north-east of Italy. Int J Cancer 1991; 47: 20–5. 9. Bjerrum OW, Gjedde S, Bendtzen K, Enke C, Pedersen BK, Munch-Petersen B, Platz P, Wulf HC. An unusual case of multiple malignancy in an adult. Tumori 1984; 70: 575–7. 10. Craig DM, Triedman LJ. Four primary malignant neoplasms in a single patient. J Surg Oncol 1986; 32: 8–10. 11. Abe Y, Nakada T, Kawamura S, Adachi M, Kubota Y, Kakizaki H, Watanabe H, Yamaguchi T, Watanabe M. A case of
18. 19.
20.
21. 22.
23.
24. 25. 26.
27.
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Accepted for publication 26 January 2000