FUO is challenging and frustrating for both physicians and patients because the diagnostic work-up frequently involves multiple modalities including invasive procedures that often do not clearly explain the origin of the fever. From prolonged febrile illness to FUO, at least one-fifth to one-third of the cases, the diagnosis is not able to be made[1,3,4]
. Vanderschueren, et al. quite reasonably have proposed to consider etiologic possibility of malignancy in patients with FUO as malignancies occupy a sizable proportion of FUO (15.1%) and further, are the major cause of FUO-related deaths
. Though the major cancer associated with FUO involves the reticuloendothelial system, solid tumors with FUO, such as hepatocellular carcinoma, hypernephroma and atrial myxoma, have also been reported. However, colorectal cancer, as observed in these two cases, has not been previously reported to be the likely cause of FUO in Chinese patients. For example, in a study of 78 Chinese adult patients with FUO, there were no cases of colorectal carcinoma
. The most extensive evaluation has occurred in Caucasian populations in Denmark. A population-based study using a cancer registry noted an association at least between colorectal cancer and FUO. While the association does not necessarily mean that the cancer was causing the FUO, it does justify investigation for colorectal cancer in the work-up of patients with FUO
If the relationship is causal, the mechanism could be infectious or non-infectious. Recurrent infection in the ulcerated mucosa may play a role. Some organisms, such as Streptococcus bovis (S. bovis) or Escherichia coli,
may invade mucosa or express themselves as metastatic infections, especially among immune compromised hosts with colorectal cancer[6,7]
.There is a well-established relationship between S. bovis
bacteremia (SBB) and colorectal cancer, but this association is merely about causal sequence, not that FUO is likely accompanied by colorectal cancerconcomitantly
. As a matter of fact, since S. bovis
is just one of the normal flora of the digestive tract, it is not surprising that some patients with SBB have concomitant bowel diseases. In a report with three colon cancer patients who complained of fever for over three weeks to six months of time, none of them had specific digestive symptoms; interestingly, those surgical specimens appeared involving the whole muscular wall and pericolic fat, with abscess formation in the pericolic fat. As pathologic evaluation of the tumor tissues demonstrated a severe organized inflammatory process forming abscesses in the pericolic fat, along with microcytic anemia and high erythrocyte sedimentation rate (ESR), they speculated it was more likely to be associated with infection
. In our first case, gastrointestinal symptoms were absent, the cancer involved the entire colonic wall and pericolic tissue, and abscesses containing about 5-10 ml of pus inside were found. The nature of bacteria associated with these abscesses was not evaluated.
The cause of the FUO related colon cancer may be explained by a non-infectious background. Tumors cause recurrent fever by intermittent necrosis with subsequent phagocytosis and cytokine production
. In certain kinds of tumors, it was speculated that interleukin I (IL-1) and tumor necrosis factor (TNF) were the major endogenous pyrogens identified. Circulating IL-1 and TNF centrally act on the thermoregulatory center of the hypothalamus[9,10]
. However, since there are no data on whether carcinoma of the colon can produce IL-1 and TNF, this paraneoplastic mechanism for FUO remains speculative.
Currently, the evidence-based approach to investigating patients with FUO recommends a diagnostic spiral CT of the abdomen[1,8]
. It should be one of the initial investigations in FUO, since it has a high diagnostic yield and is likely to identify two of the most common causes of FUO: intra-abdominal abscesses and histiocytic or lymphoproliferative disorders. Since various types of malignancies could accompany fever, CT of the abdomen should be a very useful tool to search for an origin of hidden malignancy with FUO
. In fact, many published cases of carcinoma of the colon with FUO, including our first case, have shown CT scans to reveal masses associated with the colon[7,11]
. However, as its accuracy and sensitivity varies, it is complementary to theclinical assessment of the patient and to the use of other diagnostic modalities[12,13]
. Thus, as an early investigation in patients with FUO, expectations of abdominal CT should be limited. This was illustrated by both our cases where the initial CT was negative. In the first case, the pelvis was not scanned and the tumor may have been picked up there. In the second case, the tumor was not readily visible on CT earlier in the patient’s course. The presence of iron deficiency may have prompted earlier colonoscopy, but chronic systemic inflammation is often associated with iron deficiency due to poor iron absorption. It is well known that CT scanning is not the investigation of choice for detecting colon cancer. Therefore, it isreasonable to suggest that clinicians should seriously consider performing colonoscopy in patients with FUO, undiagnosed after a conventional work-up including abdominal CT scan. Colonoscopy is an essential investigation because both colon cancer and Crohn’s disease are classic causes of recurrent FUO[14,15]
. Colonoscopy definitely has a better yield than barium enema as the small sizes of tumor might be missed and it has the added advantage of providing tissue confirmation
In summary, we have described 2 patients who had fever for years: the first unequivocally related to carcinoma of the colon and the second likely to be causally related. Neither patient had gastrointestinal symptoms. We conclude that in patients presenting with FUO where standard investigations including a CT scan of the abdomen have failed to reveal a cause, colonoscopy should be considered to search for colorectal cancer.