Tumor genomic profiling represents a promising tool in diagnosis and management of cancer of unknown primary. We report our experience on the impact of genomic profiling in elucidating primary tumor site, correlation with pathologic findings and patient management. Tissue or cytology specimens from 22 cancers of unknown primary were referred for genomic profiling. Reports were available to review in 18 cases; 3 samples were inadequate for analysis. Of the remaining 15 cases, primary tumor site was suggested in 12 cases (80%), whereas it remained indeterminate in 3 (20%). Of the 12 cases, molecular profiling was concordant with light microscopy findings in 3 patients, whereas in 2 cases molecular testing identified a sarcoma, contradicting light microscopy and immunohistochemistry findings. The suggested primary was confirmed by additional immunohistochemistry in 1 case and by endoscopic biopsy in another. In 5 cases, follow-up biopsy or additional testing were not considered necessary for patient management. Three patients received palliative care and 12 received various chemotherapy regimens. Five patients died within a year, whereas 9 were alive more than a year after diagnosis, 3 of who were alive >3 years after diagnosis. In conclusion, genomic profiling helped confirm the original diagnosis and suggested primary sites in two third of our cases. Although many patients may be at a disease stage too advanced to withstand further investigations or underg aggressive therapy, molecular testing improves diagnostic accuracy and may thus assist in selection of the most appropriate therapy.

BACKGROUND Infection with Histoplasma capsulatum ( H. capsulatum ) can lead to disseminated disease involving the gastrointestinal tract presenting as diffuse abdominal pain and diarrhea which may mimic inflammatory bowel disease (IBD). CASE SUMMARY We report a case of 12-year-old boy with presumptive diagnosis of Crohn disease (CD) that presented with several months of abdominal pain, weight loss and bloody diarrhea. Colonoscopy showed patchy moderate inflammation characterized by erythema and numerous pseudopolyps involving the terminal ileum, cecum, and ascending colon. Histologic sections from the colon biopsy revealed diffuse cellular infiltrate within the lamina propria with scattered histiocytic aggregates, and occasional non-necrotizing granulomas. Grocott-Gomori’s Methenamine Silver staining confirmed the presence of numerous yeast forms suggestive of Histoplasma spp., further confirmed with positive urine Histoplasma antigen (6.58 ng/mL, range 0.2-20 ng/mL) and serum immunoglobulin G antibodies to Histoplasma (35.9 EU, range 10.0-80.0 EU). Intravenous amphotericin was administered then transitioned to oral itraconazole. Follow-up computed tomography imaging showed a left lower lung nodule and mesenteric lymphadenopathy consistent with disseminated histoplasmosis infection. CONCLUSION Gastrointestinal involvement with H. capsulatum with no accompanying respiratory symptoms is exceedingly rare and recognition is often delayed due to the overlapping clinical manifestations of IBD. This case illustrates the importance of excluding infectious etiologies in patients with “biopsy-proven” CD prior to initiating immunosuppressive therapies. Communication between clinicians and pathologists is crucial as blood cultures and antigen testing are key studies that should be performed in all suspected cases of histoplasmosis to avoid misdiagnosis and inappropriate treatment.