Perianal Infections in Patients With Hematologic Malignancy: The Risk of Fournier’s Gangrene Leading to Mortality and Irreversible Organ Damage

Perianal infections have a wide spectrum of clinical manifestations that range from local cellulitis to sepsis. Historically, the incidence of such infection was underestimated, as often patients were thought to have another proctologic disease or their data were improperly recorded. Although imaging is performed in select cases, typically the diagnosis is based on anamnesis and physical examination. Perianal infection arises in 7.3% to 9% of patients with acute leukemia, and diagnosis is a clinical challenge.^1-3 In patients at high risk of neutropenia, a rectal examination cannot be performed because of the need to prevent passage of intestinal microorganisms from the damaged mucosa into the surrounding tissue.

Moreover, since the inflammatory response is suppressed owing to neutropenia, the absence of pus causes false-negative results on digital examination. Delayed diagnosis and resulting lack of treatment may result in progression of perianal infection to Fournier’s gangrene (FG), a form of necrotizing fasciitis of the perineal, perianal, and genital region that originates from genitourinary, colorectal, and dermal diseases.⁴ Although FG bears the name of J. A. Fournier, FG was first reported by Baurienne⁵ in 1764. Mortality resulting from FG is primarily dependent on the timing of medical care and the extent of the infection; delay in treatment and inadequate surgical debridement are factors that contribute to morbidity (including amputation and organ failure) and mortality.⁶

In patients with hematologic malignancy, perianal infection presents diagnostic challenges and therapeutic controversy. The efficacy of surgical intervention is not well established. Although the findings reported herein represent a case series without a comparator, they may be of value to physicians because as of this writing and to the author’s knowledge, no randomized or prospective studies have been done on the management of perianal infection in patients with hematologic malignancy. It was hypothesized that surgical treatment might reduce mortality and morbidity in cases in which inflammation extended beyond the perianal region, in cases with abscess formation, and in cases that showed no improvement with medical therapy. It was also supposed that a diverting ostomy might improve survival rates in the setting of FG.

Study design

This was a retrospective case series.

Patient selection

The data of patients with FG who were operated on at the general surgery department in a tertiary care hospital between January 2010 and December 2018 were retrospectively reviewed. Inclusion criteria were as follows: (1) patients older than 18 years, and (2) patients with hematologic malignancies who developed perianal infection progressing to FG. Exclusion criteria were as follows: (1) patients younger than 18 years, (2) patients without hematologic malignancies, (3) patients without FG, and (4) insufficient data.

Outcomes measures

The primary outcome was mortality, and the secondary was morbidity (including amputation and irreversible organ damage). The clinical status of the patients and management were assessed for their association with mortality and morbidity.

Diagnosis of Fournier’s gangrene

Diagnosis was based on surgical findings when the gray-black, foul-smelling, gangrenous tissue with dishwater-gray exudate was revealed and confirmed by histopathologic examination, if available.

Management

A broad-spectrum antibiotic regimen was administered as an initial empiric therapy at onset of fever and de-escalated based on the culture results and clinical response. Both surgical debridement and antibiotic therapy were applied for all patients when FG occurred. Diverting ostomy was performed in 3 patients. In 1 patient, a split-thickness skin graft was used for wound healing.

Statistical analysis

Data were analyzed using SPSS, version 17 (IBM). Demographic characteristics were analyzed using descriptive analysis and expressed as n (%) and mean ± standard deviation.

Ethics

Because of the retrospective design and small case number, no institutional review board approval was necessary. All patients were informed that their data could be used for research, and informed consent was obtained from all patients before surgery.

In a previous study, 86 cases of FG were identified during the same period (between January 2010 and December 2018), with 20 deaths (23.3%).⁶ Of these 86 patients, 4 had a hematologic malignancy and perianal infection was the leading precipitating event causing FG. One of the 4 patients died of overwhelming sepsis (25%). In 1 patient, orchiectomy was inevitable owing to necrosis (25%). The effect of treatment modalities on mortality and irreversible organ damage (orchiectomy) is shown in the Figure. All 4 patients were male, with a mean age of 36.75 years ± 13.1 (range, 23–52 years). Fournier’s gangrene was diagnosed approximately 8.75 days ± 6.94 (range, 3–17 days) after onset of anal pain and 13.5 days ± 12.2 (range, 3–31 days) after onset of fever. The mean length of hospitalization was 45.75 days ± 24.25 (range, 23–78 days).

Case 1

A 23-year-old male with acute myeloblastic leukemia (AML) and a duodenal myeloid sarcoma reported fever and dull anal pain during treatment consisting of chemotherapy (CT) and bone marrow transplantation (BMT). He did not have diabetes mellitus (DM). The patient had other risk factors, however, such as smoking and neutropenia. The onset of fever (38.5°C) and anal pain occurred on day 5 and day 10, respectively, of the BMT. On examination performed by infectious disease specialists, the patient was comfortable, and there were no abnormal physical signs. The patient had pancytopenia, and the C-reactive protein (CRP) level was 25.5 mg/L. A broad-spectrum antibiotic regimen was administered as an initial empiric therapy at the onset of fever. Surgical consultation was requested 2 days after the onset of the anal pain. A small, erythematous, subcutaneous mass near the anal orifice was present. The patient underwent surgical debridement for FG on day 13 of BMT. Antibiotic therapy was de-escalated based on the culture results (Klebsiella pneumoniae). Unfortunately, the patient died of overwhelming sepsis on day 23 of BMT (Table).

Case 2

A 29-year-old male with acute lymphocytic leukemia reported fever (38.7°C) and dull anal pain on day 10 of CT. He was a smoker but did not have DM. He was comfortable and had no abnormal physical signs, with the exception of perineal and scrotal edema and erythema. Laboratory values were as follows: white blood cell (WBC) count, 11.6 × 10⁹/L; hematocrit (HCT), 36%; CRP level, 18.5 mg/L; and biochemical values, in the normal range. Based on clinical and scrotal ultrasonography findings, a broad-spectrum antibiotic regimen was administered as initial empiric therapy for epididymitis. The FG was diagnosed on day 22. The patient underwent surgical debridement; in the second debridement, a diverting ostomy was performed. Antibiotic therapy was de-escalated based on the culture results (Escherichia coli and K pneumoniae). A split-thickness skin graft was used for wound healing, and the patient was discharged on day 50 (Table).

Case 3

A 52-year-old male with a transformation of chronic lymphocytic leukemia (CLL) into AML reported fever (38.8°C) and dull anal pain on day 14 of CT. He also had nausea and vomiting. The patient did not have a history of smoking or DM. The patient was comfortable and had no abnormal physical signs, with the exception of scrotal-perineal-inguinal edema and erythema. He had bicytopenia, and the CRP level was 24.1 mg/L. A broad-spectrum antibiotic regimen was administered as an initial empiric therapy. Onset of FG occurred on day 17. The patient underwent surgical debridement; during the third debridement, a diverting ostomy was performed. Antibiotic therapy was de-escalated based on the culture results extended-spectrum ß-lactamases (ESBL) positive and carbapenemase positive E coli). The patient was discharged on day 32 (Table).

Case 4

A 43-year-old male with AML reported fever and dull anal pain during the course of CT. He did not have a history of smoking or DM. The onset of fever (38°C) and anal pain occurred on day 8 and day 22, respectively, of therapy. The patient was comfortable, and there were no abnormal physical signs. Laboratory results were as follows: WBC count, 6.4 × 10⁹/L; HCT, 34.9%; and CRP level, 46.5 mg/L. A broad-spectrum antibiotic regimen was administered as an initial empiric therapy at onset of fever. Surgical consultation was requested when the patient developed anal pain. On examination, a spontaneously draining perianal abscess was detected. Perianal edema had extended to the scrotum. Based on clinical and scrotal ultrasonography findings, the antibiotic regimen was continued for epididymitis. Pelvic magnetic resonance imaging (MRI) revealed the presence of seminoma. Following spontaneous drainage of the scrotal abscess, FG arose on day 39. The patient underwent surgical debridement and orchiectomy for necrosis. During the same session, a diverting ostomy was performed. Antibiotic therapy was de-escalated based on culture results (ESBL positive E coli). The patient was discharged on day 78 (Table).

Perianal infection arises in 7.3% to 9% of patients with acute leukemia, and clinical diagnosis is challenging.^1-3 The type of hematologic malignancy does not affect the frequency of perianal infection. However, the side effects of the CT regimen used in AML, increase the risk of neutropenia and mucositis.^7,8 Thus, patients with AML are at increased risk of recurrence of perianal infection.^7,8 The absence of sufficient pus (as a consequence of an inefficient neutrophil count to produce inflammation) might obscure the clinical status of the patients, resulting in a delay in diagnosis. Three patients in this study had AML, 1 had a transformation of CLL into AML, and 2 of 3 patients with AML had severe neutropenia. The American Society of Colon and Rectal Surgeons has advocated using computed tomography and MRI for select patients to guide management.⁹

Diagnosis of perianal infections in the patient with hematologic malignancy is challenging, and collaborative communication between health care providers in different subspecialties may improve the diagnostic process. This study reveals that mortality and/or morbidity is inevitable if subspecialty consultations are not well-directed, and promptly, to the appropriate department. In case 1, a surgical consultation was requested 2 days after the onset of anal pain. Ultrasonography was performed in 4 patients and MRI was performed in 1, following the onset of perianal pain. However, the scheduling of radiologic appointments was inefficient.

Controversies exist concerning managing perianal infections in patients with hematologic malignancy, and there is no consensus as to the treatment protocol. Although some authors consider surgical treatment to be necessary for patients with neutropenia,^1,10-12 others think surgical treatment causes an increase in mortality compared to medical treatment.¹³ It has been reported that 37% to 58% of these patients were treated surgically,¹³ and the neutrophil count has been reported to be an important factor in treatment and diagnosis.^2,3,12,13 Some authors have concluded that surgical interventions could bring good results when they are performed for a well-bordered and fluctuant abscess, which is a sign of efficient neutrophil function.^2,3,14 Additionally, 30% to 88% of patients with neutropenia but without a well-bordered and fluctuant abscess reportedly were successfully treated with medical therapy alone.¹³ In the current study, all patients were treated by medical therapy until onset of FG. Unfortunately, medical treatment was not effective. Fournier’s gangrene occurred within approximately 8.75 days ± 6.94 (range, 3 days–17 days) of onset of anal pain. Although 2 patients had neutropenia (cases 1 and 3), abscess formation (case 1) and severe inflammation extending to the perineal-scrotal-inguinal region (case 3) were also detected. The spread of inflammation over the perineum and scrotum was misinterpreted as epididymitis in cases 2 and 4, although a spontaneously draining perianal abscess was observed in case 4. Moreover, testicular necrosis owing to FG was misinterpreted as seminoma in case 4. Perianal infections spread insidiously through tissues because they were not treated efficiently. Along with abscess formation, the spread of inflammation beyond the perianal region, which is a sign of failed treatment, may require surgical intervention.

In all cases, surgical debridement for FG was inevitable. A diverting ostomy was performed in all patients except case 1. The patient in case 1 died of overwhelming sepsis. That patient had received CT and undergone BMT and had pancytopenia. Underlying diseases and side effects of CT and BMT weakened the ability of the patient’s immune system to combat infection, as stated in a previous study.¹² In contrast to typical cases of FG, microorganisms were monomicrobial in origin, and gram-negative isolates were the most common. A significant number of antibiotic-resistant, gram-negative isolates supported the fact that continuous enteral contamination could cause treatment failure. Diverting ostomy may be a surgical option to prevent fecal contamination and should be considered when planning surgical intervention for FG in this specific patient population.

This was a small case series without a comparator. No standardized approach was used for perianal infections in patients with hematologic malignancy. Only patients with hematologic malignancy who underwent surgery for FG were included. Fournier’s gangrene was the last step in disease progression, at which point surgery was inevitable. Thus, results of this study cannot be used to draw conclusions about management strategy regarding medical or surgical treatment.

The diagnosis and management of perianal infection are quite difficult in patients with hematologic malignancy. Clinical suspicion may effectively reduce mortality by allowing early intervention and close monitoring, especially in the patient with fever accompanied by anal pain. Collaborative communication between subspecialists may aid in diagnosis. Surgery may improve the prognosis for patients with perianal inflammation spreading beyond the perianal region, those with abscess formation, those who show no improvement with medical therapy, and those who develop FG. Diverting ostomy may be a surgical option to improve survival rates when FG arises.

Author: Arife Simsek, MD

Affiliations: Inonu University, School of Medicine, Department of General Surgery, Malatya, Turkey

Correspondence: Arife Simsek, MD, Inonu University, School of Medicine, Department of General Surgery, Malatya 44100 Turkey; draksimsek@yahoo.com.tr

Disclosure: The author discloses no financial or other conflicts of interest.