Is Clostridium septicum a Link Between Necrotizing Fasciitis and Colorectal Cancer? 

Clostridial infections are opportunistic, with 1% being due to Clostridium septicum.^1,2C septicum, a rare subgroup of the species, causes spontaneous gas gangrene with over 80% of cases associated with an underlying malignancy.^1–3C septicum is a motile, anaerobic, spore forming, gram-positive rod.⁴ The ileum and cecum are the most common source of C septicum.^5,6 The gastrointestinal mucosa can become damaged, either from neoplastic lesions, cytotoxic drugs, irradiation, or immunosuppressive drugs.^5,7,8 This tissue hypoxia leads to bacterial proliferation. Alpha toxin is the main virulence factor in C septicum, causing intravascular hemolysis, necrosis, and hydrolysis of cell membranes. This allows the bacteria to penetrate the traumatized gastric mucosa, allowing direct spread through the systemic circulation.^9–12
 
The incubation period of C septicum ranges from 6 hours to 3 days with rapid progression towards myonecrosis.^5,13–15 It is able to invade healthy tissues, creating an ischemic environment that precipitates anaerobic fermentation.^10,11,16 Through the actions of alpha toxin, the increase in capillary permeability induces tachycardia and hypotension in the patient. Bacterial proliferation and fermentation lead to dark-colored bullae formation with malodorous fluid secondary to soft tissue necrosis.^3,5,17
 
Clostridium septicum is part of the normal GI flora, but in the setting of colon cancer it has been associated with the development of bacteremia and gas gangrene with an estimated mortality rate of 79% within the first 48 hours of discovery, given the progressed presentation of the underlying colorectal pathology discovered. C septicum typically only becomes prevalent after significant tumor invasion allows the bacteria to translocate from the colon via mucosal ulceration. However, this organism is not considered a causative agent for malignancy but is thought to be happenstance secondary to a symbiotic relationship with the environment.
 
Necrotizing fasciitis requires early clinical diagnosis. The mortality rate of C septicum infections ranges from 56% to 60%, with most deaths happening within the first 24 hours without prompt treatment.^1,4,10 The Laboratory Risk Indicator for Necrotizing Fasciitis score (LRINEC score) was developed as a clinical decision-making tool to diagnose necrotizing fasciitis by Wong et al.¹⁸ It includes white blood cell (WBC) count, hemoglobin, sodium, glucose, creatinine, and C-reactive protein. With a maximum score of 13, a score of ≥6 is suspicious of necrotizing fasciitis with a probability of 50 to 75%, whereas a score of ≥8 is strongly predictive of necrotizing fasciitis with a probability of more than 75%.^18,19 Research has found mixed results of this diagnostic criteria.^19–21 One prospective cohort study revealed a LRINEC score ≥6 with a sensitivity of 43% and specificity of 83%.¹⁹ However, other studies have insinuated that the LRINEC score has good diagnostic performance.^19,22,23 

Patient Presentation and Treatment

The patient is a 67-year-old male with past medical history of coronary arterial disease, congestive heart failure, hypertension, hyperlipidemia, and type 2 diabetes mellitus who presented to Crozer-Chester Medical Center in spring 2021 with a two-day history of shortness of breath. In the emergency department, the patient was found to be septic with a heart rate of 135 beats per minute, respiratory rate of 39 breaths per minute, and WBC count of 42,600. Of note, the patient was also found to have an elevated troponin to 15.95 and a lactic acid of 18.3. The patient was directly admitted to the ICU with a diagnosis of acute myocardial infarct with plans for heart catheterization the same day, which yielded 40–50% stenosis of a prior coronary bypass graft.
 
The patient was noted to have an acute kidney injury following heart catheterization. Nephrology was consulted and suggested the patient was likely experiencing acute tubular necrosis in the setting of myocardial infarct. The patient’s creatinine would continue to rise, and the patient would begin dialysis during admission. An ultrasound of the abdomen yielded a mass on the left border of the liver.
 
On day 5 of admission, nursing noted newfound blisters (Figure 1 and Figure 2) to the right plantar and lateral heel. Vascular surgery was consulted and believed the blisters to be associated with pressure injuries. Of note, there were no wounds noted to the lower extremities at admission from ED staff.
 
Podiatry was then consulted for local wound care of the suspected pressure wounds. Upon inspection, the blisters were deroofed, yielding classic dishwater drainage with frank malodor and underlying dusky skin changes. Given the patient’s continued elevated LRINEC score and pain out of proportion to the right heel area, the patient was taken to the operating room for an emergent incision and drainage with suspected necrotizing fasciitis. His LRINEC score was noted to be 12 based on the initial operative day’s laboratory values.
 
Intraoperative findings yielded marked fatty necrosis and malodor to the underlying wound areas with no direct bone exposure or deep abscesses noted. Wound culture was taken intraoperatively yielding Clostridium septicum upon speciation. Infectious disease was then consulted for IV antibiotic recommendations and upon speciation of the infecting organism they recommended further GI workup given the high correlation of Clostridium septicum with colon cancer reported in literature. GI recommended colonoscopy; however, the first colonoscopy was tainted with excessive GI bleeding and a repeat colonoscopy was scheduled for 2 weeks later. Oncology was consulted regarding liver mass, and biopsy was planned for outpatient procedure.
 
The patient underwent a second wound debridement (Figure 3 and Figure 4) following further necrotic demarcation that yielded a right plantar and lateral heel wound down to the level of calcaneus with exposed extensor digitorum longus tendons to the lateral midfoot. Negative pressure wound therapy and Santyl (Smith + Nephew) were started for additional local wound care measures with hopes for regranulation.
 
The patient was discharged to a skilled nursing facility and underwent a repeat colonoscopy two months later that revealed a fungating partially obstructive large mass in the cecum involving 2/3 of the lumen circumference which was biopsied and revealed invasive adenocarcinoma.
 
The patient presented to the hospital three months after initial presentation with fibronecrotic right foot wounds with fifth metatarsal and plantar calcaneal osteomyelitis having started chemotherapy (Figure 5 and Figure 6). His positron emission tomography (PET) scan, performed 3 months after initial presentation, yielded abnormal uptake cecal mass from known malignancy, with abnormal extensive multifocal hepatic uptake and ill-defined porta hepatis lymph node from metastasis (Figure 7). The right foot wound remained stable but was deemed unsalvageable given the patient's comorbidities. The patient will undergo right below knee amputation upon finishing his current round of chemotherapy.

The Connection Between Diabetic Foot Infection and Abdominal Malignancy

Necrotizing fasciitis is still considered a rare disease process in the United States with the Centers for Disease Control and Prevention only reporting 500–1000 cases annually. Given the condition’s rarity, a missed diagnosis is reported in more than 85% of cases.²⁴ Although necrotizing fasciitis is most commonly reported in the case of trauma, the present study reveals the implication of developing necrotizing fasciitis from a malignant source as well. The patient's reported presentation was consistent with that reported in the literature as he was noted to first have leg swelling, which transitioned to pain out of proportion, bullae formation, and development of subcutaneous emphysema.²⁵  
 
Due to the destructive and potentially deadly complications of necrotizing fasciitis, the differential diagnosis should always stand in the presence of newfound pain out of proportion, redness, and swelling especially in the presence of bullae formation, crepitus, and an elevated LRINEC score. Surgical debridement is considered a mandatory step for controlling progression of infection, reducing bacterial load, and preventing further destruction and is to be completed until the surgical margins are noted to have adequate bleeding from subcutaneous and underlying muscular tissues.²⁴ As in this case, additional debridement is often necessary and many patients may need additional skin grafting or hyperbaric oxygen therapy for ultimate wound healing.
 
Cancers to the cecum only account for ~20% of colon cancers. Literature yields that given the high correlation of malignancy in the presence of Clostridium septicum infections, a thorough colorectal cancer screening should be conducted when this organism is isolated.²⁶ Other organisms to be wary of for possible colorectal pathology correlation are Enterococcus faecalis, Streptococcus bovis, Bacteroides fragilis, Helicobacter pylori, Escherichia coli, and Fusobacterium species.²⁷ Research has shown that Clostridium septicum exhibits an alpha-toxin that yields necrosis and has a propensity for hematogenous spreading via causing cell hemolysis, making it easier to obtain seeding through the bloodstream. C septicum has also been reported to have an ability to selectively cause apoptosis of neutrophils to interfere with the normal immune response.²⁶
 
This report yields an unusual connection between a diabetic foot infection and an abdominal malignancy, while also revealing the speed at which necrotizing fasciitis can develop from a limb lacking an open wound. Clostridium septicum’s correlation to colon cancer is well documented; however, only isolated instances of necrotizing fasciitis associated with the lower extremity have been reported. Most cases concerning Clostridium septicum and necrotizing fasciitis are found more central to the bacteria secreting abdominal lesion in question.

In Conclusion

Patient education is important when dealing with long-term care following any extensive surgical debridement. Necrotizing fasciitis is likely to yield an extensive recovery period, regardless of a patient’s comorbidities, for an attempt at limb salvage given the extent of wide surgical debridement necessary to control the infectious process. Although the infection was controlled in this case study, the limb was considered non-salvageable with chronic osteomyelitis developing to the base of the fifth metatarsal and plantar calcaneus and a below knee amputation is necessary for complete surgical cure and an attempt at improved quality of life. As seen in this report, keeping an open mind to a broader differential diagnosis can lead to more direct and beneficial therapies in the setting of diabetic limb salvage.
 
Alex Pilkinton, DPM, is a second-year resident affiliated with Crozer-Chester Medical Center in Upland, PA.
 
Aurora Oliva, DPM, is a first-year resident affiliated with Crozer-Chester Medical Center in Upland, PA.
 
Frank Adamo, DPM, is an attending physician affiliated with Crozer-Chester Medical Center in Upland, PA.
 
Disclosures and Conflicts of Interest: The listed authors have no financial disclosures or conflicts of interest to report pertaining to the following case study.

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