Spontaneous Occurrence of Gangrene Due to Clostridium septicum in a Patient With Advanced Endometrial Carcinoma

Background: We report the first known case of spontaneous, atraumatic Clostridium septicum gangrene occurring in a patient with recurrent endometrial adenocarcinoma. Case: A 63-year-old white female undergoing chemotherapy for recurrent endometrial adenocarcinoma presented with right “arthritis-like” shoulder pain. She denied fever, chills, or shoulder trauma. The patient was afebrile and her blood pressure was 100/50. Her right shoulder and upper extremity were remarkable for an area of dark blue discoloration with crepitus. The white blood cell (WBC) count was 8,200/μl with left shift. Serum creatinine, platelet count, and coagulation studies were normal. Computed tomography revealed gas in the right shoulder tissues. A Gram stain of fluid aspirated from the shoulder demonstrated gram-positive spore-forming rods. She declined surgical intervention and expired within hours of admission. Cultures of the right shoulder eventually grew Clostridium septicum. Conclusion: It is imperative to consider clostridial gangrene in the differential diagnosis for any patient with cancer and a fever of unknown origin.

first modern description is credited to Joseph Jones, a surgeon in the Confederate Army. 2 During the Civil War 2,642 soldiers developed gangrene in battlefield wounds with a mortality of 46%.
Necrotizing soft tissue infections may be classi- fied as clostridial or nonclostridial. 3Nonclostridial infections are polymicrobial and are believed to evolve through synergy between facultative and anaerobic bacteria. 4Clostridial infections are usu- ally monomicrobial, with Clostridium welchii (also known as C. perfringens) the most common isolate.C. septicum accounts for one third of all cases.
Clostridial infections range from simple wound contaminationsorganisms found in devitalized tissues without actual tissue invasionto life-threat- ening rnyonecrosis (gangrene) characterized by in- vasion into and destruction of otherwise healthy tissues.Gangrene is often preceded by trauma such as crush injuries, penetrating wounds, compound fractures, or prolonged interruptions in arterial per- fusion.Spontaneous, atraumatic cases of clostridial gangrene have recently been reported, s '6 The presence of C. septicum in necrotizing soft tissues infections, particularly the atraumatic type, may be increasing in incidence. 7Of particular in- terest is the association between C. septicum gan- grene and malignant disease. 8We report herein the first known case of spontaneous, atraumatic C. septicum gangrene occurring in a patient with recur- vent endometrial adenocarcinoma, emphasizing the clinical manifestations and management of clostrid- ial myonecrosis.

CASE REPORT
A 63-year-old white female with recurrent endo- metrial adenocarcinoma presented for evaluation of right shoulder pain.Three weeks prior to admis- sion she became easily fatigued with normal daily activity.On the day prior to admission, the patient noted a dull, aching, nonradiating pain in her right shoulder described as an "arthritis-like" pain.The patient applied ice to her shoulder and took 50 mg of oxycodone without relief.On the morning of admission the pain was worse with the development of paresthesias and edema of the right shoulder.The patient's daughter noted a large black-blue discoloration on the right shoulder.Upon further questioning, she denied fever, chills, or trauma to the shoulder.
Her medical history was pertinent for uterine cancer.Six years ago, she presented with postmeno- pausal bleeding and dilatation and curettage re- vealed the presence of a poorly differentiated en- dometrial adenocarcinoma.She underwent a total abdominal hysterectomy and bilateral salpingo- oophorectomy with pelvic washings.Pathology demonstrated a poorly differentiated adenocarci- noma with loci of clear cell differentiation and penetration through one third of the myometrium.Pelvic cytology was positive for malignant cells.Pelvic radiation therapy was administered in 180 cGy daily fractions to a total dose of 5,040 cGy followed by daily oral medroxyprogesterone.She remained without evidence for cancer until 8 months before admission when on follow-up exam- ination a 2-cm vaginal apex lesion proved to be recurrent disease.The patient received 5 courses of cisplatinum and doxorubicin.Disease progression was confirmed prior to the 6th treatment course when pelvic examination showed the vaginal mass to be increasing in size.The patient was started on tamoxifen and the 1st course of ifosfamide/mesna chemotherapy was given month before admis- sion.
Physical examination at time of admission re- vealed an ill-appearing, cachectic elderly woman supporting her right arm.She was afebrile and her blood pressure was 100/50.Her right shoulder and upper extremity were remarkable for an area of dark blue discoloration with crepitus (Fig. 1).There was a drastic decrease in the range of motion of the right shoulder and the patient was unable to grip with her right hand.Pulses were diminished in the left arm and absent in the right upper ex- tremity.
Fluid was aspirated from the shoulder and sub- mitted for Gram stain and culture.To distinguish between a primary vascular occlusion and nontrau- matic myonecrosis, we ordered an angiogram which demonstrated diffuse narrowing of the arteries of the right upper extremity and diffuse soft tissue gas and edema consistent with gangrene.The Gram stain of the shoulder aspirate demonstrated gram- positive spore-forming rods with many polymor- phonuclear leukocytes.
After contemplating her recurrent cancer and end-stage condition, the patient declined surgical intervention.She expired within hours of admis- sion.Cultures of the right shoulder eventually grew C. septicum.

INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 35 DISCUSSION
Since the legalization of induced abortion, reports of clostridial myonecrosis/gangrene have become sparse in the gynecologic literature.Braverman and colleagues 9 reported a case of traumatic C. septicum uterine infection following curettage for endome- trial cancer.A spontaneous case of C. welchii infec- tion was reported by Lacey and colleagues 1 in a patient undergoing chemotherapy for choriocarci- noma.In both cases, cancer was the common de- nominator.
There were about a dozen cases of C. septicum infections reported to the National Communicable Disease Center between 1940 and 1967 vs. 27 cases between 1963 and 1968. 8The prevalence of C. septicum in atraumatic cases of gangrene also seems to be increasing, s '7'11 Reasons for the increasing incidence and prevalence of life-threatening C. sep- ticum infections are unknown but may include bet- ter screening for the organism. 11C. septicum is believed to be normal colonic flora; however, this is controversial due to the difficulty in isolating the organism from the stool of normal persons.Clostridial species (including C. septicum) can be isolated from the vaginal secretions of 5-10% of asymptomatic women. 12Therefore, C. septicum may be an opportunistic pathogen.
Associations between C. septicum infections and malignancy are increasingly recognized.Between 1977 and 1979, 7 patients were treated at Massachusetts General Hospital for either C. septicum bacteremia or gangrene and all had associated ma- lignancies.13 Alpern and Dowell reported that 23/27 (85%) patients with C. septicum septicemia had malignant disease.The more common cancers associated with C. septicum infections include gas- trointestinal, genitourinary, and hematologic ma- lignancies.Tumors may provide direct portals for entry.C. septicum produces 4 exotoxins leading to necrosis of surrounding tissues.Upon penetrating normal tissue barriers, bacteria may enter the co- elomic cavity or the bloodstream.In colon cancers, interruptions in colonic mucosal integrity provide an avenue for the intestinal organisms.Cancer che- motherapy may also be a predisposing factor for C. septicum infection.In one series, 14/23 (61%) pa- tients with C. septicum infections complicating can- cer were undergoing chemotherapy and 6 other patients had tumors involving the colon.In leuke- mias, necrotizing enterocolitis during episodes of drug-induced neutropenia has been reported. 14hemotherapy may directly facilitate the entry of C. septicum through patchy necrosis of epithelial cells leading to interruptions in the colonic mucosa, or indirectly through damage resulting form mu- cosal hemorrhage during periods of drug-induced thrombocytopenia.14 Prior to this report, only 4 other cases of clostridial sepsis in association with gynecologic cancers have been reported and all fol- lowed either surgical instrumentation or chemo- therapy. 9,1he rapid clinical deterioration of our patient with spontaneous C. septicum myonecrosis is a hall- mark of the disease.Mortality from clostridial sep- ticemia ranges from 67 to 100%.s'll'ls Bretzke and coworkers 16 showed that the mortality rate as- sociated with C. septicum infections is 3 times higher than that associated with all other clostridial infec- tions.The relative severity of C. septicum infections may be due to the greater aerotolerance of this organism, s Successful treatment is dependent upon early di- agnosis due to the rapid progression of the dis- ease.17 Pertinent symptoms and signs include the sudden onset of severe pain in a wound, often with a nonpurulent exudate, and localized edema.Dif- fuse bronzing of the skin, crepitus, cutaneous gan- grene, or hemorrhagic bullae indicate advanced disease and therefore are poor prognostic signs.Tachycardia is a common systemic manifestation.Fever is often absent.The presence of hypotension portends impending cardiovascular collapse.
After diagnosis, the treatment plan includes 1) aggressive operative debridement; 2) adequate an- tibiotic therapy; and 3) supportive measures in- cluding fluid resuscitation and cardiovascular sup- port.C. septicum is sensitive to large doses of penicillin G. Chloramphenicol or clindamycin may be used in the penicillin-allergic patient.Antibiot- ics are an adjunct, not a replacement for aggressive surgical debridement of devitalized tissues.Hyperbaric oxygen therapy prevents bacterial exotoxin production and may improve the clinical outcome.The effectiveness of polyvalent gangrene antitoxin is under investigation.
The link between malignant disease and C. septi- cure myonecrosis is recognized but poorly under- stood.Knowing that this association exists, one must consider clostridial gangrene in the differential di- agnosis for any patient with cancer and a fever of unknown origin.

Fig
Fig. I. Two areas of discoloration are seen involving the right shoulder and represent cutaneous gangrene.Both le- sions were crepitant to palpation.
3(a INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY