Question

A 60-year-old male with a medical history of HIV (updated CD4 count of 30) presented to the emergency department with headaches, disorientation, and acute onset vision loss. He was found to have an increasing number of skin lesions on the face for the past 3 weeks. Multiple well-demarcated, eroded papulonodules were seen on the nose and forehead (Figure 1). A punch biopsy of the dorsal nose showed the findings on hematoxylin and eosin in Figure 2.

Based on the clinical presentation and biopsy findings, which three stains would be most useful to highlight the underlying pathology?

1. Verhoeff-Van Gieson
2. Thioflavin T
3. Periodic acid-Schiff
4. Von Kossa
5. Fontana- Masson
6. Masson trichrome
7. Toluidine blue
8. Mucicarmine
9. Fite
10. HHV-8

Correct Answer

Correct Answers: Correct Answer: 3, 5, 8

Explanation

In the setting of AIDS (CD4 count less than 50), the scattered, umbilicated, and eroded papules and nodules across the head and neck distribution (Figure 1) are suspicious for opportunistic infections. Even within just the infectious category, the differential diagnoses are broad, including molluscum, tuberculosis, leishmaniasis, monkeypox, cat scratch, secondary syphilis, and various mycoses. Histoplasma, Cryptococcus, Coccidioides, and Talaromyces are among the deep fungal infections that fit this clinical morphology.¹

Figure 2 shows a dermal infiltrate on high power, with innumerable fungal yeasts of different sizes within clear spaces of circular capsules. Yeasts of variable size and shape clustered within capsules are distinctly characteristic of Cryptococcus, particularly in the context of central nervous system (CNS) symptoms and molluscoid cutaneous findings.² Consequently, a fungal stain like PAS (answer choice C) can help highlight the yeasts.² Although Fontana-Masson is typically used to highlight melanin and the absence of melanin in vitiligo, the pleomorphic cryptococcal yeasts stain yellow-brown to black with Fontana-Masson (answer choice E).^2,3 Mucicarmine (answer choice H) stains pink the organism’s classic polysaccharide capsule,² which serves as the antiphagocytic virulence factor.

Cryptococcus is an encapsulated fungus found in bird droppings, with human transmission occurring through inhalation of the yeasts.⁴ The fungus then lies dormant in the hilar lymph nodes and lungs, walled off with granulomatous inflammation.⁴ During periods of immunocompromise, the fungus proliferates and disseminates throughout the body, including to the brain, bone, and skin.⁴ Cryptococcus demonstrates a tropism for the skin and brain,^5,6 so dermatologists must recognize cutaneous cryptococcal infection both clinically and under histopathology. Meningoencephalitis drives mortality in disseminated cryptococcal infection, so the CNS symptoms seen in this patient case must raise suspicion for disseminated Cryptococcus. ⁷

The HIV pandemic led to a spike in incidence in many opportunistic infections, including cryptococcosis.⁸ Now with an estimated global incidence of 1 million cases per year,⁴ cryptococcosis must be on the differential for umbilicated papules and nodules, particularly in patients with immunocompromise. Additional settings of immunocompromise include patients with chronic corticosteroid use, solid organ transplants, and chronic tumor necrosis factor inhibitor use.⁵ Skin-limited disease from traumatic inoculation has been described but is rare.⁷ If Cryptococcus is identified in the skin, investigation for systemic involvement, especially in the CNS and lungs, is crucial. ⁷

Incorrect stains in answer choices: Verhoeff-Van Gieson (choice 1) – elastic fibers stain black. Example conditions: pseudoxanthoma elasticum, anetoderma, cutis laxa. Thioflavin T (choice 2) – amyloid stains yellow-green under fluorescence. Von Kossa (choice 4) – calcium salts stain black. Example conditions: calciphylaxis, calcinosis cutis, pseudoxanthoma elasticum. Masson trichrome (choice 6) – Mature collagen stains blue-green whereas smooth muscle stains red. Example conditions: scar vs. leiomyoma. Toluidine blue (choice 7) – mast cell granules and mucin stain purple. Example conditions: urticaria pigmentosa, connective tissue disease. Fite (choice 9) – partially acid-fast organisms such as Nocardia and atypical mycobacteria stain pink. HHV-8 (choice 10) – Kaposi sarcoma stains brown.

References

1. Elewski BE, Hughey LC, Hunt KM, Kay RJ. Chapter 77 – Fungal Diseases. In: Dermatology. 5th Edition. Elsevier; 1343-1375. 2. Elston DM. Chapter 18 – Fungal infections. In: Dermatopathology. 3rd Edition. Elsevier; 306-320. 3. Ferringer T, Ko CJ. Chapter 1 - The basics. In: Dermatopathology. 3rd Edition. Elsevier; 1-35. 4. Meya DB, Williamson PR. Cryptococcal disease in diverse hosts. N Engl J Med. 2024 May 2;390(17):1597-1610. PMID: 38692293. 5. Maziarz EK, Perfect JR. Cryptococcosis. Infect Dis Clin North Am. 2016 Mar;30(1):179-206. PMID: 26897067. 6. Moe K, Lotsikas-Baggili AJ, Kupiec-Banasikowska A, Kauffman CL. The cutaneous predilection of disseminated cryptococcal infection in organ transplant recipients. Arch Dermatol. 2005 Jul;141(7):913-4. PMID: 16027320. 7. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis. 2010 Feb 1;50(3):291-322. PMID: 20047480. 8. Durden FM, Elewski B. Cutaneous involvement with Cryptococcus neoformans in AIDS. J Am Acad Dermatol. 1994 May;30(5 Pt 2):844-8. PMID: 8169258.