A Skin Scrape Becomes a Real Headache
by Bruce D. Ragsdale, MD
Western Dermatopathology
Fig. 1. Cell phone photos by the patient's wife.
At presentation to the dermatologist, an 84-year-old male had a relatively asymptomatic but enlarging nodulo-ulcerative lesion on the left proximal forearm of 2.5 months' duration. It had evolved from one of several abrasions to the forearm sustained during a "slip and fall" in the garden in November 2009, as recorded by his wife on her cell phone camera at 5 and 14 days after (Fig. 1). No medical attention was sought at the time. The scrapes were merely cleaned with soap and water and then bandaged with gauze over Polysporin. The scrapes had almost completely healed two weeks after the accident (Fig. 1, right panel). While the scrapes continued to resolve, a single proximal wound enlarged into a 4-cm indurated ulcer. Seventy-six days after the accident continued deterioration of the proximal forearm wound prompted the patient's initial contact with the dermatologist (Fig. 2, upper left).
Fig. 2. Follow up photos by the dermatologist.
A few days later, a rubbery subcutaneous nodule was noticed on the upper-right inner breast. Apart from the elbow ulcer, the patient reported feeling well and had no history of exotic travel or other exposures and no risk factors for immune compromise. A melanoma, 0.2 mm thick, had been excised in 1996 from his back without sequelae. Of current medical concern was a rising PSA level in light of previous treatment for prostate cancer approximately 20 years ago involving radiation and 2 prostate needle biopsies of 12 September 2005 showing carcinoma with a Gleason score of 8/10. Peripheral neuropathy led to a protein electrophoresis in May 2007 revealing an M-spike in the gamma region comprising 1.34 gm% of IgG-kappa. A bone marrow biopsy in June 2007 yielded small populations of kappa-predominant lymphocytes and plasma cells consistent with either low level lymphoplasmacytic lymphoma or monoclonal gammopathy of undetermined significance (MGUS). In July 2007, he began rituximab bimonthly and has remained on it since then. His most recent rituximab dose was in the last week of March 2010. A chest x-ray was unremarkable.
The initial dermatologic impressions were basal or squamous cell carcinoma vs. lymphoma for the enlarging forearm ulcer and angiolipoma for the chest nodule. Biopsies of both lesions (arm and chest) showed similar lymphocyte-rich granulomatous inflammation at both sites favoring infection (backdrop, right figure, above). Birefringent soil contaminants showed up in the initial biopsy of the forearm lesion corroborating the history of an original injury in the garden. Mycobacterial and fungal cultures on material from biopsies of the forearm and chest lesions produced no growth. Empiric treatment was minocycline 100 b.i.d. and Clobex spray, while the forearm ulcer progressed in thickness and diameter (Fig. 2, right).
The brisk granulomatous inflammation displayed in the initial biopsy from forearm (background in Fig. 2) predicted infection. The recommendation to repeat the biopsy of the arm with provision for culture was met, plus a biopsy of the relatively new chest nodule. Again, a brisk, focally necrotic granulomatous inflammation was evident in both while special stains were negative for fungi and mycobacteria as were the cultures. Lacking a specific diagnosis, the indurated ulcer was excised 127 days after the accident (31 March 2010), providing abundant fresh material for microscopic study and culture, again without demonstrable fungi or mycobacteria and sterile for bacterial pathogens, mycobacteria and fungi. Diagnostic frustration motivated Rags on a 2-hour histologic scrutiny since “the answer must be here”.
Fig. 3. Histopathologic field from the excised ulcer (x600).
Your diagnosis is:
- Malakoplakia
- Malignant histiocytosis
- Rosai-Dorfman disease
- Prostatic carcinoma
- Langerhans histiocytosis
- Infection
Diagnosis: Infection, specifically cutaneous amoebiasis as a precursor to Balamuthia encephalitis in a somewhat immunocompromised patient
IMPORTANT FEATURE: Cutaneous presentation of a treatable disease with almost universally fatal outcome, rarely diagnosed before autopsy.
Back to the story... "the answer must be here”. After 2 hours scanning at high magnification, suddenly Rags realized that rare amoebic trophozoites, perhaps 3 – 5 per slide, were situated inconspicuously among the histiocytes (Fig. 3, elongate darker staining "cell" in center). Only toluidine blue in a new round of special stains improved their visibility (Fig. 4, lower right). They extended slender projections which aid in motility (lower center, Gomori green trichrome). Some were encysted (Fig. 4, upper right, lower left and lower right) mimicking fungal spherules (Fig. 4, lower left, GMS). Occasional trophozoites and cysts of Balamuthia can be binucleate (Fig. 4, upper right, Gomori green trichrome).
Fig. 4. Pathogenic ameobae were rare in tissue profiles and difficult to distringuish from histiocytes, even in special stains (x1000).
COMMENT: Amoebas belonging to the genera Naegleria, Acanthamoeba and Balamuthia are free-living, amphizoic and opportunistic protozoa that are ubiquitous in nature. These amoebas are found in soil, water and air samples from all over the world. Human infection due to these amoebas involving brain, skin, lung and eyes has increased significantly during the last ten years (1). Several species of Acanthamoeba and Balamuthia are pathogenic "opportunistic" free-living amoebas which evoke granulomatous reactions, usually seen in debilitated, malnourished individuals, in patients undergoing immunosuppressive therapy for organ transplants, and with the acquired immunodeficiency syndrome (AIDS). The patient here discussed was described as relatively healthy, without risk factors for immune compromise, but on rituximab since 2007 for a nebulous bone marrow dyscrasia and therefore likely to have some immune compromise in addition to being age 84.
Balamuthia mandrillaris amoebas are recognized as a causative agent of granulomatous amoebic encephalitis, a disease that is usually fatal. They were first recognized when isolated from the brain of a mandrill baboon that died in the San Diego Zoo Wild Life Animal Park. Subsequently, the amoebas have been found in a variety of animals, including humans (young and old, immunocompromised and immunocompetent persons), in countries around the world (6).
Cutaneous amebiasis, often a manifestation of disseminated extracerebral disease, is extremely rare. Extracerebral acanthamebiasis, with the exception of contact lens-associated keratitis, is reported but little emphasized in the literature. Often a reflection of disseminated disease, cutaneous acanthamebiasis is an increasingly recognized infection since the emergence of acquired immunodeficiency syndrome (AIDS) and the use of immunosuppressive drugs (2). Infection can result from soil contamination through a break in the skin, as occurred in this patient, or from carriage of cysts on wind-blown soil particles into the respiratory tract. Either way, the amoebas that emerge from the cysts are hematogenously transported to the CNS, where they cause granulomatous encephalitis. Acanthamoeba typically involves the central nervous system and skin by disseminating from a primary focus in the lungs or sinuses.
Cutaneous disease in the absence of CNS involvement is increasingly recognized, especially in the setting of chronic, nonhealing skin lesions in the patient with AIDS. Cutaneous Acanthamoeba infection in patients with AIDS manifests as subcutaneous nodules and mimics other more commonly encountered clinical entities (3). Skin lesions may be the presenting sign of disseminated Acanthamoeba infection in patients with AIDS (4). Any clinical setting for primary cutaneous amebiasis other than this is most unusual. Skin lesions can be the primary manifestations of Acanthamoeba infection. One of two Balamuthia infections successfully treated began in the skin (5).
Amoebae are resistant to many therapeutic agents. The disease portends a poor prognosis if the infection involves the central nervous system (2). Most diagnoses of Balamuthia encephalitis are made at autopsy because of its rarity (about 150 cases of Balamuthia infection are on record) and the challenge of making the histopathologic diagnosis. Treatment is problematic and the optimal microbial therapy has yet to be determined. The central role of macrophages in combating amoebae explains the granulomatous reaction in all specimens from the present patient, skin and brain, and suggests immune modulation as a potential alternative therapeutic mode of treatment for these infections. Granulomatous inflammation is notably absent in immunocompromised patients with severe disease and CNS involvement but is prominent in the present specimens- a hopeful sign as this patient joins a handful of known survivors.
Balamuthia has recently been reported as transmitted through organ transplantation to the recipients (8). Clinicians should be aware of Balamuthia infection as a potentially fatal cause of encephalitis. Organ procurement organizations (OPOs) and transplant centers should be aware of the potential for Balamuthia infection in donors with encephalitis of uncertain etiology, and OPOs should communicate this elevated risk for infection to transplant centers so they can make an informed risk assessment in the decision to accept an organ.
FOLLOW-UP: A few days after excision of the indurated elbow ulcer, the patient was hospitalized. His son indicated that the patient had mental changes in personality over a period of months, nothing acute. A cervical spinal fluid analysis displayed a moderate lymphocytosis without eosinophils. A mild eosinophilia showed in the complete blood count. On 3 April 2010, 4 days after excision of the arm ulcer, a CT of the head displayed mid to posterior basal patterns of moderate size suspicious for vasogenic edema. An hour later, followup CT displayed bilateral areas of abnormal enhancement. In the left medial parieto-occipital lobe, a cystic mass with nodule was suggested. On the right there was moderate gyral enhancement throughout the area of probable vasogenic edema in the temporal posterior parietal lobe.
Fig. 5. MRI displayed bilateral areas of abnormal signal. The background is the granulomatous histology of the brain biopsy (x2000).
Differential diagnosis included inflammation/infection, neoplasm and ischemia/infarct. An MRI of the brain with and without contrast on 5 April 2010 indicated "bilateral rim-enhancing occipital lobe lesions in the cortical/subcortical region. Gyral enhancement is present on the right lesion. The left medial occipital lesion may represent juxtaposed enhancing lesion" (Fig 5).
When Rags called the clinician to report the sighting of amoebae in the skin lesion and heard of the neurologic symptoms, he predicted an amoebic brain abscess. Clinicians still favored metastatic carcinoma from the prostate. A diagnostic and therapeutic brain biopsy was undertaken the next morning. As in prior specimens from this patient's skin lesions, a brisk granulomatous reaction (backdrop in above brain MRI) had been mounted against rare amoebic organisms. To arrive at a more certain identification, specimen material was submitted for amoebic cultures in saline at the time of operation. These came to naught; the preferred method is to place small pieces of lesional tissue on a plate of living tissue culture cells and send this to Centers for Disease Control (CDC). So slides and blocks of elbow ulcer and brain specimen were sent off to the CDC in Atlanta, Georgia where immunohistochemical reactions were be done that distinguished Balamuthia from Acanthamoeba.
Three months after brain surgery, Rags contacted the patient’s wife by phone. She said he was home on antimicrobial medicines, cleaning out his desk and arguing with her about some bills she’d paid. Five months out from brain biopsy, he was out to dinner at a restaurant pleasantly discussing his shrinking brain abscesses as he continues a triple drug regimen of flucytosine, sulfadiazine, and azithromycin. At 9 months, he is still doing well, taking apart a malfunctioning calculator when Rags called.
California's only State Epidemiologist showed up at the door of the patient the other day with a shovel and took away some backyard dirt. The recovery of a Balamuthia amoeba from a soil sample taken from a plant at the home of a child from California, USA, who died of Balamuthia amoebic encephalitis, seems to be the only published link of this kind (6). Urban dust can contain the organism, not just soil (7).
The patient is doing splendidly, one of a handful of survivors.
References
- Martinez AJ, Visvesvara GS. Free-living, amphizoic and opportunistic amebas. Brain Pathol. 1997 Jan;7(1):583-98.
- Paltiel M, et al. Disseminated cutaneous acanthamebiasis: a case report and review of the literature. Cutis. 2004 Apr;73(4):241-8.
- Chandrasekar PH, et al. Cutaneous infections due to Acanthamoeba in patients with acquired immunodeficiency syndrome. Arch Intern Med. 1997 Mar 10;157(5):569-72.
- Torno MS Jr, et al. Cutaneous acanthamoebiasis in AIDS. J Am Acad Dermatol. 2000 Feb;42(2 Pt2):351-4. Review.
- Deetz TR, et al. Successful treatment of Balamuthia amoebic encephalitis: Presentation of 2 cases. CID 2003; 37 (15 November),1304-1312.
- Dunnebacke TH, Schuster FL, Yagi S, Booton GC. Balamuthia mandrillaris from soil samples. Microbiology. 2004 Sep;150(Pt ):2837-42.
- Niyyati M, et al. Isolation of Balamuthia mandrillaris from urban dust, free of known infectious involvement. Parasitol Res. 2009 Dec;106(1):279-81.
- Centers for Disease Control and Prevention (CDC). Balamuthia mandrillaris transmitted through organ transplantation --- Mississippi, 2009. MMWR Morb Mortal Wkly Rep. 2010 Sep 17;59(36):1165-70.