Immunohistochemical and ultrastructural review of six cases previously diagnosed as null cell PitNETs

Pituitary neuroendocrine tumors (PitNETs) lacking lineage affiliation are termed "null cell" PitNETs (NCTs). NCTs are characterized as being immunonegative for pituitary hormones as well as transcription factors. We analyzed the ultrastructure and immunohistochemistry of six hormone-negative and transcription factor (TPIT, PIT1, SF1)-negative PitNETs, with less than 1% immunoreactive cells. Histologically, three cases presented a perivascular pattern and pseudorosettes; the other three showed a solid pattern with oncocytic changes. Electron microscopic examination revealed poorly differentiated tumor cells with sparsely scattered secretory granules and intracellular organelles in all null cell tumors when compared with hormone-positive PitNETs. Two cases harbored a honeycomb Golgi (HG) structure, and three oncocytic tumors showed mitochondrial accumulation. The two HG cases were immunopositive for newly obtained TPIT (CL6251) and showed some adrenocorticotropic hormone-positive cells, while the remaining four were diffusely immunopositive for GATA3, with two SF1-positive cases identified in subsequent immunostaining. Thus, these six cases may be classified as two sparsely granulated corticotroph PitNETs, two gonadotroph PitNETs with SF1 re-staining, and two likely gonadotroph PitNETs with GATA3 immunostaining. No "true NCT" was detected among 1071 PitNETs, demonstrating the importance of precise diagnosis following the most recent criteria to improve therapeutic success.