Multiple primary malignancies in a single patient are relatively rare but have increase in frequency in recent decades. This may be a result of medical advancements in diagnostic and therapeutic strategies, a possible effect of new carcinogens in the industrial environment, and longer life span allowing another primary cancer to develop. Among those with multiple primary malignancies, double cancer is commonly seen, while triple cancers occur in 0.5% of patients, and quadruple or quintuple cancers occur in only less than 0.1% of the population.1 This report describes a rare case of a patient with five metachronous primary malignancies. The time interval between each of the malignancies is more than 2 years. Literatures about at least four primary malignancies are also discussed.
A 74-year-old woman visited our gastroenterology department in March 2006 for mild abdominal pain, dizziness, and passage of tarry stool for 2 days. The patient was a carrier for hepatitis B virus and had hypertension, for which she took amlodipine and furosemide for decades. She denied tobacco usage or alcohol consumption. She worked as a cook for several decades. No specific cancer history was recorded on her pedigree.
The patient had a past history of colon cancer, the first of her cancers, which was curatively resected in April 1991. The pathological report showed well-differentiated adenocarcinoma, Duke's B2 (Figure 1A). The tumor staging was T3N0M0, stage II. In 1993, a stomach tumor, which was her second cancer, was noted in a routine follow-up visit in which upper gastroenterological panendoscopy (PES) was performed. The patient underwent gastrectomy with BII anastomosis in July of that year. The pathologic report disclosed low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) (Figure 1B). The patient has had cough with blood-tinged sputum for 2 months and received broncoscopy in July 1996. The biopsy showed adenocarcinoma (Figure 1C) and she received explored thoracotomy with left lobectomy and mediastinal lymph node dissection on during the same month. A solitary tumor of 5 cm×5 cm×5 cm was resected. All the regional lymph nodes were negative for malignancy. The findings at operation were T2N0M0, stage IB. This was the patient's third malignancy. Her postoperative course was non-eventful and she received short-term clinic follow-up for several months. In February 1999, a palpable mass over the left breast was noted and the patient visited the general surgery service. Biopsy showed malignancy and she received modified radical mastectomy with level II lymph node dissection on February 12. A 2.5 cm×2.0 cm×2.0 cm mass was resected. The pathologic report showed infiltrating ductal carcinoma with free resection margin (Figure 1D). The lymph nodes were negative for cancer. The findings at operation were T2N0M0, stage IIA, and this was her fourth malignancy.
The patient received regular follow-up for being an HBV carrier and sonograms since 1996 showed liver cirrhosis. Cholecystopathy and splenomegaly secondary to liver cirrhosis were noted since 2003. She was admitted to the hospital due to bleeding from esophageal varices twice in 2006 and was successfully treated with ligation of the varices. Sonography showed no liver masses.
Abdominal distension with unstable vital signs was noted on June 11, 2007. Abdominal CT scan showed severe cirrhosis of the liver and a 4.7-cm, solitary, and bulging mass in the subcapsule of the hepatic S8 dome with massive bloody ascites (Figure 2A and 2B). The enhancement was heterogenous, and primary hepato-cellular carcinoma with rupture was suspected. Imaging studies did not reveal other metastatic lesions. Alpha-fetoprotein (AFP) level was 21.1 ng/ml, and carcinoembronic antigen was 3.8 ng/ml. No further pathological confirmation was performed due to the patient's poor condition. Palliative care was administered. The patient's general condition deteriorated and she expired on July 15, 2007.
Multiple primary malignancies in a single patient were first reported by Billroth in 1879. He hypothesized that each tumor must have a different histologic appearance, must arise in different locations, and must produce its own metastasis. These criteria were too strict, as pointed out by other authors.2 Warren and Gates3 modified the diagnostic criteria for multiple primary malignancies in 1932, due to the increasing occurrence of this situation. Their criteria included the following: (1) each tumor must present a definite picture of malignancy; (2) each tumor must be histologically distinct; and (3) the possibility that one is a metastasis of another must be excluded.
When tumors form synchronously in different organs, they are diagnosed as multiple primary malignant tumors. In 1977 Moertel defined metachronous neoplasm as the time interval of two primary lesions of more than 6 months, which is currently a widely accepted classification.4
In reviews of the literature regarding multiple primary malignancies, several common points can be concluded. First, the Japanese population seems to have a higher likelihood of developing multiple primary malignancies. Yamamoto et al5 reported that approximately 15% to 20% of Japanese patients with colorectal carcinoma developed multiple primary malignancies. This might be caused by gene susceptibility, longer average life span, or medical advancement in chemotherapy and radiotherapy. Second, most cases with at least four primary malignancies are geriatric. The mechanisms explaining the association of cancer and aging include: (1) time length of carcinogenesis (the longer a person lives the more likely it is that carcinogenesis will be completed and cancer will develop); (2) molecular changes of age (older tissues are susceptible to environmental carcinogenesis and undergo molecular changes similar to carcinogenesis); and (3) changes in the environment (aging is associated with molecular changes in DNA signaling and body environment that may favor the development of cancer).6 Third, among those multiple primary malignancies, smoking-related cancers, prostate cancers, and renal cell carcinoma are more commonly associated.7 Fourth, head and neck cancer survivors are at an increased risk for another cancer of the respiratory or digestive tract.8 A “field cancerization effect” was assumed to explain this phenomenon that carcinogens to which the organ has been exposed may initiate the proliferation of many clones of cells.9 Carcinogenic insults, such as tobacco and alcohol, would increase the likelihood of multiple independent malignant foci developing in the mucosa epithelium.
The patient described in this report never smoked tobacco or drank alcohol, but she had been a cook in Taiwan for decades and may have been exposed to carcinogenic smoke. All of the five neoplasms were not in the head and neck region. The patient did not receive chemotherapy or radiotherapy for her first four primary cancers. The first four neoplasms were pathologically proved, but the fifth lacked a definitive tissue specimen due to the patient's poor clinical condition and her family's refusal of aggressive management. We recognized the fifth one as primary instead of metastatic cancer for some reasons. The time interval between the fourth and fifth neoplasm is as long as 100 months to make it less likely to be a metastatic lesion without the evidence of a residual primary cancer. The abdominal CT scan also presents characteristics of primary hepatocellular carcinoma, including severe liver cirrhosis, solitary and bulging mass, and massive hemoperitoneum caused by tumor bleeding. Spontaneous rupture and hemoperitoneum in metastatic liver cancers are very rare in comparison with primary ones.10 The AFP level was elevated. Although it is unremarkable, studies includes one investigating the Chinese population had showed that around 40% of hepatic cell carcinoma has normal levels of AFP.11 Among the cases of five primary malignancies reported in literatures (Table), at least two lesions are in the same origin, such as gastrointestinal tract.12-15 In our patient, the five malignancies were all derived from different organs and in different regions.
Cases with four primary malignancies have been reported more often in the recent literature. However, it is still rare to have patients with five primary malignancies, especially metachronous and in the Chinese population. It is important to perform a thorough examination to rule out a new lesion as another's metastasis. But clinicians should keep in mind that the prevalence of multiple primary malignancies is increasing. The assumption of a new lesion in a patient with a previous history of cancer as metastasis could possibly change the treatment strategies and delay the management of a curable neoplasm. In addition, long-term follow-up and screening strategies are important in patients with curatively resected malignancies.
In summary, the longer a patient lives, the more predisposed he or she is to developing additional malignancies. Aging is an inevitable problem in many industrialized countries, including Taiwan. The early detection of additional primary malignancies will enable prompt management and will increase the cure rate of disease. Multiplicity of primary malignancies itself does not necessarily indicate a poor prognosis as long as adequate diagnosis and management are performed.
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