Four primary tumors of lung, bladder, prostate, and breast in a male patient.

Abstract: We present a very rare case of quadruple cancers in a 65-year-old male patient. It is a case of both synchronous and meta-chronous primary malignant neoplasms occurring in four different organs. Immunohistochemical stains showed tumor cell nuclei to be negative for p53 over-expression. To our knowledge, this is the first documented case with this combination of primary tumors. The tumors included an adenosquamous cell carcinoma of the lung, transitional cell carcinoma of the urinary bladder, and adenocarcinomas of the prostate and the breast. We also review the medical literature for the possible causes of multiple primary malignant neoplasms.

Key Words: multiple primary malignant neoplasms, lung, bladder, prostate, breast, p53

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Multiple primary malignant neoplasms (MPMN) in a single patient have been documented in the literature over the past hundred years, and they were first described by Billroth in 1889. (1) The lesions can be limited to a single organ or involve multiple organ systems. The majority of MPMN occurring in multiple organs are metachronous, while the synchronous lesions are less frequent. (2)

We present a very rare case of quadruple cancers in a male patient. Our patient had four primary neoplasms with three different histologies. The tumors included an adenosquamous cell carcinoma of the lung, transitional cell carcinoma of the urinary bladder, and adenocarcinomas of the prostate and the breast. Immunohistochemical stains showed tumor cell nuclei to be negative for p53 over-expression. To our knowledge, this is the first documented case of MPMN of the lung, bladder, prostate, and breast in a male patient. Little mention has been made of both synchronous and metachronous primary neoplasms in four different organs occurring in a single patient, as shown in this case.

Case Report

Our patient, a heavy smoker for 50 years, is a 65-year-old man who presented to our institution in September 1999 with an episode of hematuria. He also reported having dysuria and intermittent urinary retention of a few weeks' duration. He had no respiratory or gastrointestinal complaints, and he denied any weight loss. He had a history of lung adenosquamous carcinoma diagnosed in 1988 and was treated outside our institution with left pneumonectomy and adjuvant chemotherapy and radiotherapy. His family history was negative for malignancies.

His physical examination was nonrevealing. His laboratory tests were within normal limits except for the urine cytology which was positive for malignant cells. Cystoscopy with biopsy of the prostate revealed a high grade transitional cell carcinoma (TCC) of the bladder infiltrating the prostate. CT scan of abdomen and pelvis showed local infiltration of the perivesical area with small retroperitoneal adenopathy. The patient underwent radical cystectomy with ileal pouch diversion in late September. Pathology revealed moderately differentiated TCC, high grade stage B1 JEWETT-T2 UICC with extension in situ carcinoma to the ureters and the prostatic urethra and metastasis to one of nine lymph nodes. In addition, the patient had a 0.5 cm well-differentiated adenocarcinoma of the right lobe of the prostate (Gleason 3).

The patient received two cycles of vinblastine, methotrexate, and cisplatin. He did well, remaining free of disease until 2001 when his treating physician noticed a retraction in his left nipple. On physical examination he had a small 2 X 1 cm retroareolar mass. Open biopsy done in late March revealed an infiltrating ductal carcinoma, grade 2/3 (Modified Scarff-Bloom-Richardson) with associated intraductal carcinoma, comedo-type. The tumor was present at the surgical margin. Around 40% of tumor cells stained positive with antibody to the estrogen receptor, and 30% stained positive with antibody to the progesterone receptor. HER-2/neu was not over-expressed. Immunohistochemical stain for prostate specific antigen was negative and the findings were most suggestive of a breast primary. In late April 2001, the patient underwent left modified radical mastectomy with level I and II axillary lymph node dissection that showed residual tumor with metastasis to 1 of 10 axillary lymph nodes. He was given radiotherapy to the left chest and axilla and was put on tamoxifen.

In May of 2001, the patient had bloody urethral discharge. Cytology of urethral wash was positive for high grade carcinoma. He underwent total urethrectomy, and the pathology showed high grade TCC. In November 2001, CT scan of abdomen and pelvis showed retroperitoneal and para-aortic adenopathy. Fine needle aspirate (FNA) of para-aortic lymph node revealed metastatic poorly-differentiated carcinoma with necrosis. A bone scan showed multiple areas of increased uptake involving the upper thoracic spine from D1 to D4 as well as D8, and the appearance was consistent with metastatic disease. He received five cycles of Gemzar and cisplatin for the recurrent bladder tumor with good response. In February 2002, the patient presented with septic shock, and he ultimately died after being hospitalized for several weeks. Immunohistochemical stains for p53 were done later on the available tissues (bladder, prostate, and breast) and were found to be negative (Fig. 1).

Discussion

Different authors may use different criteria to define a case of multiple primary malignancies. (3) To establish definitely a diagnosis of multiple neoplasms, one must adhere to the criteria set by Warren and Gates in 1932. (4) Each of the tumors must present a definite picture of malignancy; each is distinct; and the probability of one being a metastasis of the other must be excluded. Synchronous tumors are defined as two or more primary tumors that are diagnosed within 6 months of the first primary tumor; metachronous tumors are defined as those that are detected after an interval of more than 6 months. Our patient had four such multiple primary neoplasms. The adenosquamous lung carcinoma was treated with pneumonectomy, chemotherapy, and radiotherapy. Synchronous different cell carcinomas of the bladder (transitional cell carcinoma) and prostate (adenocarcinoma) followed 11 years later. The patient did not have symptoms that might suggest a prostate cancer, and his small tumor volume suggests that this may be a clinically insignificant prostate cancer. His prostate specific antigen levels were not checked preoperatively as this was not a clinically suspected tumor. Adenocarcinoma of the left breast developed 13 years after the initial radiotherapy to the left lung cancer.

[FIGURE 1 OMITTED]

The incidence of multiple primary neoplasms may increase, due to a combination of different factors, including improved diagnostic modalities and therapeutic protocols leading to more patients with cancer surviving long enough to develop second cancers. (5) The incidence of cancer rises with age, including the occurrence of MPMN. (6,7) As the survival rates improve and the population ages, the frequency of individuals with multiple cancers will increase. (8) Spratt and Hoag (9) concluded that, empirically, persons living to extreme age can expect to have multiple cancers with greater frequency. Chance alone is likely to explain the occurrence of a large proportion of second tumors, especially in older populations. (10)

The occurrence of a first malignancy is a risk for a second in that individual, and a review of the medical literature supports this idea. In his review of 1,300 primary malignant tumors in 1932, Warren et al concluded that these patients have an increased risk for the development of a second primary tumor. (4) This may be reasonable, because the first neoplasm was probably initiated by factors and agents that are still capable of initiating a second neoplasm. Numerous autopsy series have reported a 1.8 to 11% incidence of multiple primary cancers. (11) The Mayo Clinic reported a 5.1% incidence of multiple primary tumors in more than 3,700 patients. (12) Cleary et al described 30 patients with three or more primary malignancies over a 20-year period. (13)

There is sufficient evidence to establish a causal association between cigarette smoking and cancer of the aerodigestive system, lungs, stomach, liver, kidney, uterine cervix, and urinary bladder. (14) Our patient was a heavy smoker, and he had two smoking-related cancers (lung and bladder).

Radiotherapy and chemotherapy are also associated with an increased risk of developing a second malignant neoplasm in childhood. (15) One of the late sequelae of a successful treatment is the development of a second malignant tumor. (10) Our patient received radiotherapy for his lung cancer. Thirteen years later he developed breast cancer, which may have been in the radiation field of the first tumor. The contribution of radiotherapy to the occurrence of breast cancer cannot be ignored especially when we know that there is a particularly high risk of radiation-induced breast cancer in women treated for Hodgkin disease at young ages. (16)

The relationship of blood type to multiple malignancies has been studied and has produced controversial opinions. Several studies of blood groups with multiple malignancies have found an excess of Type A in patients with multiple primary neoplasms when compared with control groups of women. (17, 18) The patient in the present report was Type O. The p53 protein is the most common gene mutated in human cancers. (19) More than half of all neoplasms in humans are thought to have mutation of the p53 protein. (20) The protein coded by the p53 gene functions in cell cycle regulation is involved with cell apoptosis. (21) Although the mutated p53 gene has been postulated to induce immunohistochemically-detectable p53 protein, reports regarding the relationship between p53 mutation and p53 protein expression have been contradictory. (22) Immunohistochemical stains done on the available tissues (bladder, prostate, and breast) showed tumor cell nuclei to be negative for p53 (Fig. 1). The age of onset of all four cancers is consistent with the average age of sporadic cancer diagnosis of the respective type. This fact makes a hereditary cancer syndrome less likely.

Of the four cancers that this patient had, male breast cancer is the least common. Male breast cancer is rare, accounting for approximately 1% of all breast cancer cases. BRCA2 mutations constitute a significant proportion of the genetic factors associated with an increased risk of breast cancer for men. Other genetic factors include AR gene mutations, CYP17 polymorphism, Cowden syndrome, and CHEK2. (23) The patient had no family history of malignancy. However, genetic testing was not done for the patient or his family, and so the absence of these mutations in the family can not be confirmed.

Aggressive treatment and close surveillance follow up of patients with MPMN may help to control the disease for long periods of time and may possibly improve the prognostic outlook for these patients. Appropriate cytogenetic and molecular studies should be developed to improve preventive strategies in the detection of MPMN. Still, the realistic longterm prognosis depends principally on the clinical staging of each tumor.

Conclusion

We presented a case of quadruple cancer in a male patient. The diagnosis of MPMN should be properly made. Many factors may affect the occurrence of MPMN in the same patient. These patients should be closely followed up.

References

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15. Kony SJ, de Vathaire F, Chompret A, et al. Radiation and genetic factors in the risk of second malignant neoplasms after a first cancer in childhood. Lancet 1997;350:91-95.

16. Horwich A, Swerdlow AJ. Second primary breast cancer after Hodgkin's disease. Br J Cancer 2004;90:294-298.

17. Fadhli HA, Dominguez R. ABO Blood groups and multiple cancers. JAMA 1963;185:757-759.

18. Tsukada Y, Moore RH, Bross ID, et al. Blood groups in patients with multiple cancers. Cancer 1964;17:1229-1232.

19. Culotta E. Koshland Jr DE. p53 sweeps through cancer research. Science 1994;264:16.

20. Ireland AP, Clark TR, DeMeester GW. Barrett's esophagus. The significance of p53 in clinical practice. Ann Surg 1997;225:17-30.

21. Doussis-Anagnostopoulou I, Remadi S. Kaklamanis L, et al. Detection of p53 in Hodgkin's disease using the monoclonal antibody PAb248. J Pathol 1996;178:170-172.

22. Gao JP, Uchida T, Wang C, et al. Relationship between p53 gene mutation and protein expression: clinical significance in transitional cell carcinoma of the bladder. Int J Oncol 2000;16:469-475.

23. Weiss JR, Moysich KB, Swede H. Epidemiology of male breast cancer. Cancer Epidemiol Biomarkers Prev 2005;14:20-26.

An expert is a person who has made all the mistakes that can be made in
a very narrow field.
--Niels Bohr

Zaher K. Otrock, MD, Rami A.R. Mahfouz, MD, and Ziad M. Salem, MD

From the Departments of Internal Medicine and Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

Reprint requests to Ziad M. Salem, MD, Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon. PO Box: 11-0236. Email: [e-mail]

Accepted April 19, 2005.

RELATED ARTICLE: Key Points

* The diagnosis of multiple primary neoplasms is made following definite criteria.

* The incidence of multiple primary neoplasms is influenced by environmental, genetic, or some combination of factors.

* Patients with multiple primary neoplasms should be closely monitored as they have a high incidence of other cancers or recurrence of their primaries.