A case of sporotrichosis infection mimicking pyoderma gangrenosum and the role of tissue culture in diagnosis: A case report

Abstract

Sporotrichosis infections may cause cutaneous lesions mimicking other infectious or non-infectious causes such as pyoderma gangrenosum. We present a case of cutaneous sporotrichosis misdiagnosed as pyoderma gangrenosum and treated with immunosuppressants for 17 months leading to exacerbation and atypical morphology mimicking Histoplasma organisms on biopsy. Exclusion of infection prior to diagnosing pyoderma gangrenosum is important to prevent iatrogenic immunosuppression, demonstrating the challenges with application of the updated pyoderma gangrenosum diagnostic criteria.

Introduction

Cutaneous sporotrichosis infections can be difficult to visually distinguish from other ulcerative or infiltrative lesions. The differential for ulcerative lesions includes infectious and non-infectious causes such as malignancies, vascular disorders, and inflammatory disorders. Sporotrichosis lesions have been misdiagnosed as ulcerative pyoderma gangrenosum (PG) due to similar clinical appearance or lack of positive culture or histological stains.^1–8 Weenig et al. ¹ found that 11/64 (17%) lesions misdiagnosed as PG were caused by primary cutaneous infections, with the pathogen being Sporothrix schenckii in 5/11 cases. As immunosuppressive therapies are standard of care for treating PG, exclusion of infectious etiology is especially important prior to starting therapy. Updated ulcerative PG diagnostic criteria require a biopsy demonstrating neutrophilic inflammation, making diagnosis of PG no longer purely a diagnosis of exclusion. ⁹ This case highlights the importance of exclusion of infection as a diagnostic criterion.

Here, we report a case of cutaneous sporotrichosis misdiagnosed and treated for 17 months as ulcerative PG, leading to exacerbation and atypical morphology mimicking Histoplasma organisms on re-biopsy.

Case report

A 78-year-old male presented with a non-healing left arm ulcer in June 2017 (Figure 1). A 5-mm punch biopsy showed extensive neutrophilic inflammation and periodic acid–Schiff (PAS) staining for fungal organisms was reported as negative, and simultaneous tissue culture was not done. The case diagnosis was compatible with PG. Various immunosuppressive treatments were tried for a year leading to worsening progression.

Figure 1.

View of the patient’s left upper arm prior to antifungal treatment showing cribriform ulceration.

The patient presented to our clinic November 2018 and was being treated with IV immunoglobulin (IVIG), prednisone, and ustekinumab for 7 months with severe disease progression. Treatment with cyclosporine and mycophenolate previously failed due to hypertension and leg swelling, and gastrointestinal disturbances, respectively. No risk factors such as environmental exposures, previous occupation, and travel were reported. Lymphangitis and lymph node involvement was not present.

A 4-mm punch biopsy of the ulcer edge showed numerous three- to four-micron intra-cytoplasmic yeasts within histiocytes (Figure 2(a)). Hundreds of intracellular organisms were PAS stain-positive and Grocott’s methenamine silver stain-positive (Figure 2(b) and (c)), ranging from 3 to 12 microns with some budding yeasts. Despite morphological consistency with Histoplasmosis duboisii or capsulatum, tissue cultures led to isolation of S. schenckii species complex, an interesting report in histopathology.

Figure 2.

Biopsy from November 2018. (a) Hematoxylin and eosin stain (magnification 400×) showing intra-histiocytic and extracellular yeasts measuring from 3 to 5 microns, resembling Histoplasma organisms. (b) Periodic acid–Schiff stain (magnification 400×) showing yeasts measuring 3–12 microns in diameter within histiocytes. (c) Grocott’s methenamine silver stain (magnification 400×).

Prednisone was tapered and itraconazole (200 mg/day) was promptly started. Treatment continued for 4 months leading to complete wound regression and healing of the left arm (Figure 3). He received standard wound care.

Figure 3.

View of the patient’s left upper arm 3 months post-treatment.

A second opinion of the initial biopsy in June 2017 reported the rare presence of PAS-positive yeast (Figure 4(a) and (b)) in the original biopsy.

Figure 4.

Biopsy from June 2017. (a) Hematoxylin and eosin stain from the biopsy showing suppurative dermatitis below an ulcer, in which focally a multinucleated histiocyte is visible (magnification 400×). (b) A single PAS-positive yeast organism measuring 4–6 microns found on re-examination (magnification 640×).

Discussion

We report a case of chronic S. schenckii cutaneous infection initially misdiagnosed as PG due to a lack of tissue culture complemented with overlook in identifying PAS-positive organisms. This led to mistreatment and severe exacerbation of the patient’s lesion for 17 months. Re-biopsy showed atypical histologic morphology of S. schenckii as hundreds of intra-cytoplasmic yeasts within histiocytes, mimicking Histoplasmosis organisms. Tissue culture results confirmed S. schenckii infection. This picture is not usually seen in a biopsy of typical sporotrichosis cases and was suspected to be caused by chronic iatrogenic immunosuppression.

S. schenckii is an environmentally ubiquitous thermodimorphic fungus existing worldwide in a filamentous form at 25°C and transforming into yeast-like cells at 35°C–37°C. Common sources of infection to trauma-induced wounds include rose thorns, soil, hay, decaying vegetation, plants, animal feces, and zoonotic transmission from cats. ¹⁰

Cutaneous manifestations of sporotrichosis include lymphocutaneous, fixed cutaneous, and disseminated cutaneous. In cutaneous infections, a papulonodular lesion develops within 2–4 weeks of inoculation, followed by ulceration and purulent discharge. Lymphocutaneous infections occur with subsequent spread to lymphatic channels and accounts for up to 80% of sporotrichosis infections.^11,12 Extracutaneous sporotrichosis manifestations including pulmonary, osteoarticular, mucosal, disseminated, and meningeal sporotrichosis have been reported in immunocompromised individuals.^11,13

An ulcerated lesion may have an infectious or non-infectious differential (Table 1). Wound culture is the diagnostic gold standard, but may take more than 5 days to grow. A PAS-positive stain was reported in only 3.2%–19.7% of sporotrichosis infections due to low fungal burden in early infections.^14,15

Table 1.

Differential diagnosis of cutaneous sporotrichosis.

Infectious causes
Fungal • Histoplasmosis • Cryptococcus • Blastomycosis • Coccidioidomycosis
Bacterial • Cutaneous anthrax (Bacillus anthracis) • Pyodermatitis (Staphylococcus, Streptococcus) • Cutaneous tuberculosis • Cat-scratch disease (Bartonella henselae) • Syphilis (Treponema pallidum) • Tularemia (Francisella tularensis) • Non-tuberculous mycobacteria (Mycobacterium avium complex (MAC), M. marinum M. chelonae, and M. ulcerans) • Cutaneous nocardiosis (Nocardia brasiliensis) • Tertiary syphilis (Treponema pallidum)
Parasitic • Leishmaniasis (Leishmania braziliensis) • Cutaneous amebiasis (Entamoeba histolytica)
Non-infectious causes
• Pyoderma gangrenosum • Osteomyelitis • Cutaneous sarcoidosis • Sweet’s syndrome • Wegener’s granulomatosis

Itraconazole is the first-line treatment for cutaneous sporotrichosis infections, with open treatment trials reporting 90%–100% success rate if continued up to 4 weeks after treatment resolution.^16–18 Liposomal amphotericin B is often used for severe or extracutaneous manifestations.^3,19 Local heat therapy has also been reported to be effective as temperatures >38°C minimize sporotrichosis growth.^6,20

Many reported cases of sporotrichosis misdiagnosed as PG were treated with immunosuppressive treatment leading to exacerbation (Table 2). Delayed diagnosis led to reports of superinfection, disseminated sporotrichosis, and osteoarticular sporotrichosis.^7,8 Because both ulcerative PG and fixed cutaneous sporotrichosis occur in absence of lymphatic involvement, the clinical picture is difficult to distinguish.^3,8 In addition, 50% of sporotrichosis infections are not correlated with a history of trauma, gardening, or rose exposure. ²

Table 2.

Case reports of sporotrichosis infections misdiagnosed as pyoderma gangrenosum.

Author, year	Age and sex	History	Risk factors	Site of lesion	What led to initial diagnosis of PG?	Initial management	Sporotrichosis diagnosis (Method)	Treatment
Byrd et al., 2001 2	59 and F	6 months Hx of ulcerated nodule	Ankle prick by rose thorn	Right leg	Unknown, but was diagnosed as PG after ulceration of lesion	Prednisone, oral antibiotics, azathioprine, and cyclosporine	Cutaneous sporotrichosis (Tissue culture, positive PAS stain)	Itraconazole (200 mg/TID) for 18 months
Yang et al., 2006 3	40 and M	1 year Hx of non-healing ulcer with history of sarcoidosis	Blackberry picking	Left forearm	Two previously nondiagnostic biopsies, negative tissue culture, and history of pulmonary sarcoidosis led to suspicion of ulcerative cutaneous sarcoidosis and pyoderma gangrenosum	Prednisone	Disseminated cutaneous sporotrichosis (Biopsy and culture)	Itraconazole (200 mg/d) for 2 months
Lima et al., 2017 4	39 and F	Incomplete response to itraconazole from 2 years ago	Scratched by sporotrichosis-infected cat	Abdomen progressing to right arm	Incomplete response to itraconazole from 2 years ago led to revision of diagnosis to PG	Corticosteroids, immunosuppressive drugs, infliximab, non-opioid analgesics, and morphine	Disseminated cutaneous sporotrichosis (Biopsy, tissue culture)	Liposomal amphotericin B (400 mg/day) for 6 weeks followed by itraconazole (400 mg/d) for 12 months
Charles et al., 2017 5	57 and F	10 months Hx of three enlarging ulcers after arthropod bite	Trauma	Right arm	Biopsy showed granulomatous reaction, incomplete response to itraconazole, ulcerative characteristic, and severely painful pattern led to presumed diagnosis of PG with secondary infection	Levofloxacin, ceftriaxone, prednisone, penicillin, and topical clobetasol	Cutaneous sporotrichosis (Tissue culture, positive PAS stain)	Itraconazole (200 mg/d) for 3 months followed by 200 mg/BID
Takazawa et al., 2018 6	47 and M	4 months Hx of skin ulcer on leg after fall	Trauma	Right lower leg	Medical history of ulcerative colitis and clinical presentation of skin ulcer	Topical steroid	Fixed cutaneous sporotrichosis (Tissue culture, PAS stain, PCR)	Potassium iodide (500 mg) for 2 weeks followed by 1000 mg for 3 weeks
Saeed et al., 2019 7	35 and F	Fell on right forearm	Cat owner, previously worked as a landscaper	Legs, arm, and abdomen	Negative stains and numerous ulcers	Prednisone doxycycline	Osteoarticular and disseminated sporotrichosis (Tissue culture)	Liposomal amphotericin B for 28 days, itraconazole (200 mg/TID followed by 200 mg/BID). Amphotericin (4 mg/kg/d) for 3 weeks followed by posaconazole (300 mg/d) for 12 months
White et al., 2019 8	62 and M	1 month Hx of thigh lesion after playing golf		Left thigh	Atypical presentation ulcer without lymphocutaneous spread	Cephalexin for group B streptococcus prednisone, cyclosporine, ustekinumab, and IVIG	Disseminated sporotrichosis (Tissue and blood culture)	Liposomal amphotericin B (5 mg/kg IV daily), posaconazole (300 mg/BID followed by 300 mg/d). Itraconazole (200 mg/q8 h × 9 followed by 200 mg/q12 h) for 10 months after discharge; terbinafine (250 mg/d) later added due to wound progression
Present case	78 and M	No relevant history	None	Left arm	Negative PAS stain, and lack of tissue culture	Cyclosporine, mycophenolate, IVIG, prednisone, and ustekinumab	Fixed cutaneous sporotrichosis (Tissue culture)	Itraconazole (200 mg/d) for 4 months

PG: pyoderma gangrenosum; PAS: periodic acid–Schiff; IVIG: IV immunoglobulin; BID: two times a day; TID: three times a day.

In 2018, Maverakis et al. published revised diagnostic criteria for diagnosing ulcerative PG.8 The major diagnostic criterion of histological presence of neutrophilic infiltrate at the ulcer edge must be met along with four other minor diagnostic criteria (Table 3). Under previous diagnostic criteria of exclusion, our case would not have satisfied the PG diagnostic criterion as a proper exclusion of infection was not done. However, under the new diagnostic criteria where exclusion of infectious causes is not required, potential for misdiagnosis and treatment exacerbation increases.

Table 3.

New diagnostic criteria for ulcerative pyoderma gangrenosum.

Major diagnostic criterion—Must be met: Biopsy of ulcer edge demonstrates neutrophilic infiltrate

Minor diagnostic criterion—At least four must be met: Pathergy(ulcer occuring at the site of trauma) Exclusion of infection via histological stains and tissue culture Pathergy a  History (personal or family) of inflammatory bowel disease or inflammatory arthritis History of papule pustule, or vesicle that rapidly ulcerated Peripheral erythema, undermining border, and tenderness at site of ulceration Multiple ulcerations with at least one occurring on anterior lower leg Cribriform or “wrinkled paper” scar(s) at site of healed ulcer Decrease in ulcer size within 1 month of initiating immunosuppressive medication(s)

Source: Modified from Maverakis et al. (2018).

a

Ulcers occurring at trauma sites should extend past the area of trauma.

Ultimately, this case highlights the importance of tissue culture in excluding infectious causes before diagnosing PG and presents an atypical S. schenckii morphology mimicking Histoplasma organisms in chronically immunosuppressed infections.