Answer: leishmaniasis, presenting as atypical perianal and rectal wart-like lesions (see below for patient follow up)
As Anon and Florida Fan mention, the differential of small intracellular objects in the 2-5 micron range includes leishmania amastigotes, small yeasts (primarily Histoplasma capsulatum), microsporidia spores, and Toxoplasma gondii tachyzoites.
We can exclude Histoplasma capsulatum, other yeasts, and microsporidia based on the negative GMS stain, thereby leaving Toxoplasma and Leishmania in our differential. These two organisms are differentiated by morphologic features: Toxoplasma gondii tachyzoites are arc-shaped with a small eccentric nucleus (see case 284), while Leishmania sp. amastigotes are oval and have an eccentric nucleus AND a rod-shaped kinetoplast. Although it can be challenging to appreciate morphology in formalin-fixed, paraffin-embedded sections, this case actually allowed us to see some good examples of a kinetoplast (arrow) next to the nucleus (arrowhead):
Therefore, we can say that the patient most likely has leishmaniasis, although the unusual presentation of wart-like peri-anal and rectal lesions raises the question of whether this represents atypical cutaneous disease or visceral disease involving the GI tract and extending to the perianal skin.
To help solve this mystery, we needed additional information, and it turns out, an additional procedure needed to be performed. The patient was from Nicaragua, where cutaneous, mucocutaneous, and visceral disease has been described. He has been in the U.S. for approximately 6 years and hasn't traveled outside of the U.S. since.
To evaluate for visceral involvement, a bone marrow biopsy was then performed, which confirmed the presence of amastigotes. Therefore, this case represents an unusual presentation of visceral leishmaniasis, masquerading as anal warts!
Material from the bone marrow biopsy has now been sent to the CDC for species determination.
Many thanks to Bryan Schmitt for the interesting case!