Fulminant cryptosporidiosis after near-drowning: a human Cryptosporidium parvum strain implicated in invasive gastrointestinal adenocarcinoma and cholangiocarcinoma in an experimental model

Abstract

In the present work, we report the characterization of a Cryptosporidium parvum strain isolated from a patient who nearly drowned in the Deule River (Lille, France) after being discharged from the hospital where he had undergone allogeneic stem cell transplantation. After being rescued and readmitted to the hospital, he developed fulminant cryptosporidiosis. The strain isolated from the patient's stools was identified as C. parvum II2A15G2R1 (subtype linked to zoonotic exposure) and inoculated into SCID mice. In this host, this virulent C. parvum isolate induced not only severe infection but also invasive gastrointestinal and biliary adenocarcinoma. The observation of adenocarcinomas that progressed through all layers of the digestive tract to the subserosa and spread via blood vessels confirmed the invasive nature of the neoplastic process. These results indicate for the first time that a human-derived C. parvum isolate is able to induce digestive cancer. This study is of special interest considering the exposure of a large number of humans and animals to this waterborne protozoan, which is highly tumorigenic when inoculated in a rodent model.

Fig 1

Gastric and hepatic neoplastic lesions in SCID mice infected with C. parvum IIaA15G2R1 isolated from an HSCT recipient patient. (A) High-grade intraepithelial neoplasia in the antropyloric region of a Dex-treated SCID mouse 51 to 60 days postinfection (p.i.) showing important cellular atypias and presence of numerous parasites (arrows) inside the glands. Stain, hematoxylin and eosin. Bar, 50 μm. (B) Intramucosal adenocarcinoma in the stomach of a Dex-treated SCID mouse 51 to 60 days p.i. showing architectural distortion, gland fusion with buds of the glandular epithelium into the lamina propia, and loss of the basement membrane. Stain, Volgens-Gomori. Bar, 50 μm. (C) Well-differentiated adenocarcinoma in the gastric region of a Dex-treated SCID mouse 51 to 60 days p.i. showing major cellular atypias (arrow) and numerous mitoses. Stain, hematoxylin and eosin. Bar, 100 μm. (D) Well-differentiated gastric adenocarcinoma invading (arrow) through the muscularis (m) in a Dex-treated SCID mouse 61 to 70 days p.i. Stain, hematoxylin and eosin. Bar, 100 μm. (E) Well-differentiated bile duct adenocarcinoma of the hepatohilar region of the liver (l) in a Dex-untreated SCID mouse 90 days p.i. Proliferation of glands disposed in desmoplastic stroma was observed. Stain, hematoxylin and eosin. Bar, 400 μm. (F) Well-differentiated bile duct adenocarcinoma of the hepatohilar region in a Dex-untreated SCID mouse 90 days p.i. showing cellular atypias, architectural distortion, and parasites (arrow) in the lumen of the glands. Stain, hematoxylin and eosin. Bar, 100 μm.

Fig 2

Ileocecal lesions of SCID mice infected with C. parvum IIaA15G2R1 isolated from an HSCT recipient patient. (A) Intramucosal adenocarcinoma in a Dex-treated SCID mouse 40 to 50 days PI. The mucosa is irregularly thickened, with intraluminal budding in an adenomatous fashion around the entire circumference of the cecum. Stain, hematoxylin and eosin. Bar, 1,500 μm. (B) Well-differentiated adenocarcinoma in a Dex-treated SCID mouse 51 to 60 days PI. Architectural distortion of glands and loss of gland differentiation with epithelial atypias consisting of loss of normal polarity, nuclear stratification, prominent nucleoli, and irregularly scattered chromatin were observed. The presence of parasites (arrows) inside the glands is shown. Stain, hematoxylin and eosin. Bar, 50 μm. (C) Dex-treated SCID mouse 40 to 50 days PI. Volgens-Gomori stain shows architectural distortion, fusion of glands, loss of the basal membrane, and presence of the neoplastic cells in the lamina propria. Bar, 50 μm. (D) Dex-treated SCID mouse 40 to 50 days PI. Interruption (arrows) of the muscularis mucosae (mm) and invasion into the submucosa (sm) by the neoplastic glands are shown (immunohistochemical stain for alpha smooth muscle actin). Bar, 400 μm. (E) Dex-treated SCID mouse 90 days PI. A well-differentiated adenocarcinoma invading the subserosa (ss) through the muscularis (m) is shown (immunohistochemical stain for cytokeratin). Bar, 200 μm. (F) Dex-treated SCID mouse 51 to 60 days PI. Vascular tumor emboli (arrow) were detected in the submucosa (sm). Stain, hematoxylin and eosin. Bar, 50 μm.