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Dermatopathology: Practical & Conceptual

October – December 2010 | Volume 16, No. 4

Disseminated cutaneous nodules—What a wart!

Jayaseelan, Elizabeth; Mathias, Rohini

Report of a patient

A 51-year-old South Indian male presented to us with a 30-year history of multiple painless, warty, and ulcerated nodules over the face, trunk, and extremities, some of which bled on touch. The lesions initially started over the cheeks and then spread to other areas. There was a history of recurrence after previous excisions. Accompanying these were larger asymptomatic subcutaneous nodules over the neck and limbs. He gave a history of bathing in local ponds, was a chronic alcoholic, and had multiple unprotected exposures with commercial sex workers. Repeated testing for HIV had been negative. He had been treated with intermittent courses of dapsone for three years, but did not respond favorably to it.

Cutaneous examination revealed multiple, nontender papules and nodules, most of them with a verrucous surface in sizes ranging from 0.3 x 0.3 cm to 7 x 7 cm, predominantly distributed over the face with fewer such lesions over the trunk and limbs. The larger lesions showed surface ulceration and bled on touch. Larger nontender, subcutaneous, mobile nodules, cystic in consistency, were present over the neck and extremities (Figs. 1A-C).

Fig. 1A-C

(A) Multiple verrucous nodules over the face, trunk and upper limbs with subcutaneous nodules over the neck, forearms and hand. (B) Closer view of the nodules on the face show ulceration and hemorrhage. A large subcutaneous nodule is seen on the neck. (C) Verrucous and subcutaneous nodules over the left leg.

His blood work revealed severe anemia with a hemoglobin of 4.3 gm with a microcytic hypochromic picture on peripheral smear and erythroid hyperplasia on bone marrow analysis. His chest x-ray was normal, and testing for HIV and syphilis was negative.

Histopathology

Sections of a biopsy of a verrucous nodule stained with H&E clinched the diagnosis (Figs. 2A-C). What is your diagnosis?

Fig. 2A-C

Histopathology. What is your diagnosis?

Answer and explanation

Disseminated cutaneous rhinosporidiosis

The epidermis shows acanthosis and papillomatosis with areas of focal thinning and ulceration. The dermis has a typical “Swiss cheese” appearance (Fig. 2A) made up of numerous spherical cystic structures (sporangia) of varying sizes and stages of development. A dense mixed inflammatory cell infiltrate that consists of lymphocytes and histiocytes, neutrophils, and plasma cells is accompanying. The cysts are surrounded by a thick eosinophilic wall and contain numerous large spores (endospores). Eosinophilic thick-walled sporangia containing numerous endospores together with a ruptured sporangium are depicted in Figure 2B. Immature sporangia with thinner walls containing endospores are shown in Figure 2C.

Rhinosporidiosis also referred to as “dermosporidiosis,” [1] is an enigmatic chronic granulomatous infection characterized by slow growing polypoid masses usually of the nasal or conjunctival mucosa of humans and animals. The etiological agent previously designated as Rhinosporidium equi, R. ayyari, R. kinealyi, and R. amazonicum is now believed to represent the same species: Rhinosporidium seeberi, [2] whose taxonomical classification was uncertain for over a century. First identified by Malbran in 1892, who regarded it as a sporozoan, it was subsequently thought to be a protozoan by Seeber and a fungus (phycomycete) by Ashworth. [3] It has been postulated that it could be the cyanobacterium, Microcystis aeruginosa [4] or just carbohydrate containing bodies derived from cellular lysosomes rather than true micro-organisms. [5] Based on molecular biology techniques, however, it is currently classified into a new clade, Mesomycetozoea, [6] a group of protists which include fish and amphibian parasites formerly belonging to the DRIP clade.

The life cycle of R. seeberi has several stages. In the earliest stage it is a 5-10µ sphere with a thin membrane containing a single nucleus in a granular cytoplasm (juvenile sporangium). It begins to grow as it penetrates tissue and passes through the immature and intermediate stages [2] transforming into a mature sporangium 50-200µ in size with a double membrane and one operculum or germinal pore. It turns into a cyst of over 300µ, undergoes nuclear divisions, and then contains up to 20,000 trophozoites. The mature cyst expels the trophozoites through the operculum, restarting the cycle. [7] Trauma is a predisposing factor to acquire the infection. [8] The infective spores enter through the traumatized nasal mucosa and multiply in the submucosa, forming the sporangia which get filled with spores. The extruded spores incite a reactive hyperplasia leading to the formation of polypoid vascular masses.

Natural hosts are fish and other aquatic animals. The intermediate hosts include cattle, horses, mules, goats, dogs, wild ducks, and geese, which transmit the infective spores through their feces polluting the air, and more commonly, the water in ponds. The infection is acquired by man by contact with stagnant water containing the spores or by inhaling the spores. The observation that the nose and eyes are the most common sites involved suggests that the usual reservoirs could be water, dust, mud, or soil.[9] Man is the dead-end host, as no case of human-to-human transmission has been documented. Within the host, autoinoculation and hematogenous dissemination are the modes of spread, but dissemination via the lymphatics has also been suggested.

The only host factor that has been studied is the blood group of patients. In an Indian study the occurrence of rhinosporidiosis was found to be highest among those with O+ blood group, followed by AB+ blood group, despite the latter group being a relative rarity in the general population. [10] Studies involving larger series have been suggested. [2] Some individuals are more prone to develop this infection due to unknown host factors.

Rhinosporidiosis occurs more commonly in males between 15 and 40 years old. Although having a diverse geographic occurrence, it is more common in the tropics and is particularly prevalent in Southern India and Sri Lanka.

The nose and nasopharynx is involved in 70% of cases. Unilateral nasal obstruction, epistaxis, nasal discharge, and itching are the usual symptoms. Patients present with red or purple friable, vascular, and soft polyps studded with whitish flecks corresponding to mature cysts, displaying a “strawberry-like” appearance. They may arise from the anterior part of the septum, the floor of the nasal cavity, or the inferior/middle turbinate. Rarely, it grows backwards and presents in the oropharynx or oral cavity. The conjunctiva, usually the palpebral part, is the next common site. The bulbar conjunctiva, limbus, lacrimal apparatus, and canthus are less often involved. Ocular mucosal involvement is seen in 15% cases. Rarely, other sites such as the maxillary antrum, epiglottis, larynx, trachea, bronchus, ear, scalp, rectum, external genitalia or skin are involved. Osteolytic bone lesions have also been reported. [11]

Skin involvement may be of three types: (1) primary cutaneous lesions without internal organ involvement as a result of direct inoculation; (2) satellite lesions around the nasal polyps due to contiguous spread or autoinoculation; or (3) disseminated lesions due to hematogenous spread. [12] Generalized rhinosporidiosis with cutaneous and visceral involvement is a rarity.

Clinical presentations of dermosporidiosis are varied and include verrucous plaques, [12-15] which are most common, polypoid growths, [12] subcutaneous nodules (tumoral rhinosporidiosis/ rhinosporidioma), [16,17] granulomatous, furunculoid, [18] ecthymatoid, [8] and cutaneous hornlike lesions. [18] Subcutaneous nodules indicate hematogenous dissemination. Cutaneous rhinosporidiosis in the setting of HIV infection has also been described. [19]

Complications of rhinosporidiosis include dissemination to vital organs, such as the brain, lungs, kidney, liver and spleen, hemorrhage, secondary bacterial infection, recurrence, and death. [20]

Clinical differential diagnosis for nasal lesions includes polyps of allergic origin. Vaginal and penile lesions may mimic condylomas. Rectal lesions may resemble prolapsed internal hemorrhoids. [8] Subcutaneous nodules must be differentiated from lipomas, epidermal cysts, soft tissue sarcomas, and disseminated phaeohyphomycosis. Verrucous plaques may masquerade as hyperkeratotic lupus vulgaris, tuberculosis verrucosa cutis, verrucous carcinoma, and deep mycoses.

The diagnosis of rhinosporidiosis can be confirmed on histopathological examination. The epithelium is hyperplastic with papillomatosis and deep invaginations, some of which form pseudocysts. Globular cysts of varying shape, representing sporangia in different stages of development, give the dermis a distinctive “Swiss cheese” appearance. The sporangia have a thick eosinophilic wall and contain numerous spores. Rupture of the sporangia through a pore leads to release of the spores into neighbouring tissue. The organisms stain with PAS at all the stages, but GMS and mucicarmine stains are not effective for organisms less than 100µ in diameter. There is surrounding dense mixed inflammatory infiltrate with lymphocytes and histiocytes, including occasional giant cells, plasma cells, neutrophils and eosinophils. [21] Though the developmental stages can be readily identified by special fungal stains, such as the Gomori methenamine silver, Giemsa, and the PAS stains, identification of the stages can also be made with the routine hematoxylin and eosin even without special stains. [7]

The primary histological differential diagnosis is coccidiodomycosis which has a different clinical presentation. Histologically, the sporangia and endospores of Coccidiodes immitis are much smaller in size (60µ and 2-5µ respectively) and the endospores, fewer in number. Arthroconidia and hyphae may also be seen. Only the empty sporangia of R. seeberi might be confused with those of C. immitis. [21] Mycospherulosis, an iatrogenic lipogranuloma, histologically mimics rhinosporidiosis and has been referred to as a distant cousin of rhinosporidiosis, though it does not stain positive with GMS stain. In adiaspiromycosis, the sporangial walls of Chrysosporium parvum var. crescens are much thicker with large adiaconidia. [2]

Aspiration cytology from a cystic subcutaneous nodule mounted with 10% potassium hydroxide or stained with Giemsa will also reveal the presence of sporangia with endospores. R. seeberi has not been successfully cultured in artificial media so far.

Electrocautery or CO2 laser for smaller lesions and surgical excision with electrocautery of the base is the preferred treatment modality albeit high recurrence rates due to incomplete excision or spillage of spores with subsequent autoinoculation. Extensive growths, such as those on the penis, might require amputation. Dapsone (100-200 mg/day for several months), which acts by arresting the maturation of the sporangia and inducing a granulomatous response with subsequent fibrosis, [22,23] antifungals like ketoconazole, [24] itraconazole, griseofulvin, amphotericin B [25] and antibiotics, such as ciprofloxacin, have shown varied results. Potassium iodide was not found to be beneficial. However, medical management best serves as an adjunct to surgical modalities. Rare instances of spontaneous regression have been documented.

Summary

Background: Rhinosporidiosis caused by Rhinosporidium seeberi is a chronic granulomatous infection of the nasal and conjunctival mucosa which rarely infects the skin. It has a distinctive histopathology characterized by large thick-walled sporangia with multiple large endospores. Objectives: To delineate the varying manifestations of cutaneous rhinosporidiosis and to demonstrate its diagnostic histopathology. Patients/ Methods: A 51- year-old male presented with a 30-year history of asymptomatic verrucous cutaneous nodules, as well as cystic subcutaneous indolent nodules over the face, trunk and extremeties. Histopathology of a verrucous nodule revealed numerous large thick-walled sporangia containing endospores within the dermis, some of them showing rupture along with a mixed cell infiltrate. Conclusion: Though cutaneous rhinosporidiosis is a rare entity, it has a classic histopathology and must be diagnosed at the earliest, as it is a therapeutic challenge once the lesions are disseminated.

Rohini Mathias, M.D. and Elizabeth Jayaseelan, D.N.B. are from the Department of Dermatology, Venereolgy and Leprology, St. John’s Medical College in Bangalore, India. This article was reviewed by Almut Böer, M.D. Contact corresponding author via email: dr.rohinimathias@gmail.com

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