Fever of unknown origin as the first manifestation of colonic pathology

Discussion

The series published by Peterson and Beeson in 1961¹ and Larson et al in 1982¹¹ show a certain variability with regard to the importance of different types of neoplasms in FUO. However, in most published series, haematological neoplasms are more common than solid tumours, with an approximate ratio of 2:1. Kazanjian et al report an incidence of neoplasms that reaches 24% of all cases, with Hodgkin's disease as the first cause and colon cancer as the most common solid tumor.¹² However, other authors, such as Hirschmann,¹³ do not describe any cases of colon cancer, and Hirschmann's study includes only one case of kidney cancer. With regard to fever-inducing solid cancers, most are located in the abdominal cavity.¹¹ The global incidence of colon cancer in case series with FUO ranges from 0% to 5%.^9,10 Fever associated with neoplastic processes is due to the production of tumour-induced pyrogens, necrosis of large masses, hypothalamic involvement and infection, as well as secondary causes derived from the neoplastic process, such as blastic crises, paraneoplastic phlebitis, etc. The presence of FUO in patients with a known neoplasm is estimated to be due to an infectious concomitant cause in 50% of cases; it is related to an immunodepressed state and/or the rupture of mucous membranes, which, in most cases, implies an advanced stage of disease.¹³ Colon cancer-induced FUO results from the same pathophysiological mechanisms underlying other tumours. Rupture of the mucous barrier facilitates invasion by intestinal bacteria.¹⁰

The fever pattern in our patients was bacteraemic in all cases: spikes in fever were lacking a stable periodicity and so could not be predicted and disappeared spontaneously or after antibiotic therapy.¹¹ In a previous series study of 23 patients with recurrent fever, the authors observed that 8.6% presented with colorectal cancer.¹⁰ For this reason, we must point out that a recurrent or spiking fever may be the first and only manifestation of a hidden colon neoplasm.¹⁰

Although the literature usually describes negative blood cultures (due to the use of antibiotic therapy or the fact that the fever is caused by temporary bacteraemia), our study found positive results in 45% of patients in whom blood culture tests were performed. With regard to bacteraemia associated with colon cancer, two bacteria stood out: Streptococcus bovis^14,15 and Clostridium septicum.^16,17 The degree of association between the bacteraemias caused by these bacteria and colon cancer is so high that their presence makes it necessary to rule out colon cancer.¹⁶ In addition, Bacteroides fragilis and Escherichia coli may cause bacteraemias in patients with colon tumours, although they do not have such a direct relation with colonic tumour pathologies as S. bovis and C. septicum.¹⁰ In our case study, ‘classic’ germs were found in four patients (S. bovis in two; E. coli in two). According to the central line-associated bloodstream infection (CLABSI) criteria,¹⁸ our series had a remarkably high number of cases with positive results for coagulase-negative staphylococci (n=5; 25% of all blood cultures and 55.6% of all positive blood cultures). Bacteraemia caused by these germs is generally associated with the iatrogenic context of intravenous catheters, but this was not the case in any of our 20 patients who underwent blood culture tests. We did not observe similar data in other studies,^19,20 and, to the best of our knowledge, an association of coagulase-negative staphylococci bacteraemia with colon cancer has not been described. However, the number of cases included in our study is not large and we cannot rule out the possibility that this is a ‘chance finding’.

Apart from bacteraemia, other infectious disorders may lead to fever in patients with non-disseminated colon cancer, including appearance of a fistula; intra-abdominal infections¹⁶ such as peritonitis; perilesional abscesses; distant infections such as empyema, endocarditis (4.3% of patients in our series) and arthritis;²¹ urinary infections (secondary to colovesical fistulas; 6.4% of patients in our series);¹⁶ extensions of other infections; necrotising cellulitis; and gaseous gangrene.^17,22 In our series, 17.4% of patients had hepatic metastases; none of these had a tumour fever pattern (a continuous and stable fever that does not respond to antibiotics), which is explained by the systemic inflammatory reaction in a disseminated disease caused by liver metastases, tumour-induced pyrogens, necrosis of the tumour itself or central involvement.²³

In an analysis of time between symptom onset and diagnosis, we must highlight that fever lasted for ≥6 months in almost 40% of patients. This would suggest that fever is not a sign that practitioners associate immediately with the presence of colonic pathology. Whenever there is no initial clinical suspicion, invasive endoscopic tests are postponed to a second or third stage of the investigation pathway. The spiked fever pattern probably contributes to this fact, because it suggests an infectious pathology. In our patients, therefore, we found different initial suspected diagnoses, such as endocarditis, fistula and intra-abdominal abscesses (data not shown).

Ninety per cent of patients who underwent an FOB test showed a positive result. Although the number of patients in this situation was small (n=9), this fact may suggest the usefulness of a simple, inexpensive and non-invasive test in the rational and staged study of a patient with FUO.

Finally, we observed a high number of analytical tests (tumour markers and autoimmunity studies) and radiological tests (ultrasound imaging and abdominal computed tomography) in patients who presented with fever as a first symptom (data not shown).

In conclusion, fever secondary to colon neoplasms, both benign and malignant, usually presents with a bacteraemic pattern, with positive results from blood-culture tests in a high percentage of cases.