High-Grade Progression, Sarcomatous Transformation, and/or Metastasis of Pituitary Neuroendocrine Neoplasms (PitNENs): The UCSF Experience

Abstract

Pituitary neuroendocrine tumors (PitNET) that metastasize comprise ~ 0.2% of adenohypophyseal tumors are aggressive and are challenging to treat. However, many non-metastatic tumors are also aggressive. Herein, we review 21 specimens from 13 patients at UCSF with metastatic PitNETs (CSF or systemic, N = 7 patients), high-grade pituitary neuroendocrine neoplasms (HG-PitNEN, N = 4 patients), and/or PitNETs with sarcomatous transformation (PitNET-ST, N = 5 patients). We subtyped cases using the World Health Organization (WHO) and International Agency for Research on Cancer (IARC) criteria for neuroendocrine neoplasms (NENs). Lineage subtypes included acidophil stem cell, null cell, thyrotroph, corticotroph, lactotroph, and gonadotroph tumors. The median Ki-67 labeling index was 25% (range 5-70%). Lack of p16 was seen in 3 cases, with overexpression in 2. Strong diffuse p53 immunopositivity was present in 3 specimens from 2 patients. Loss of Rb expression was seen in 2 cases, with ATRX loss in one. Molecular analysis in 4 tumors variably revealed TERT alterations, homozygous CDKN2A deletion, aneuploidy, and mutations in PTEN, TP53, PDGFRB, and/or PIK3CA. Eight patients (62%) died of disease, 4 were alive at the last follow-up, and 1 was lost to the follow-up. All primary tumors had worrisome features, including aggressive lineage subtype, high mitotic count, and/or high Ki-67 indices. Additional evidence of high-grade progression included immunohistochemical loss of neuroendocrine, transcription factor, and/or hormone markers. We conclude that metastatic PitNET is not the only high-grade form of pituitary NEN. If further confirmed, these histopathologic and/or molecular features could provide advanced warning of biological aggressiveness and be applied towards a future grading scheme.

Keywords: Grading; Metastasis; Neuroendocrine neoplasms; Pituitary carcinoma; Pituitary neuroendocrine carcinoma; Pituitary neuroendocrine tumor; Pituitary sarcoma.

Fig. 1

Examples of neuroimaging features on intracranial MRI (a, d) and spinal DOTATATE PET scan and MRI (e). a Separate infundibular enhancing nodule in patient 3 (white arrow). b Leptomeningeal enhancing nodule, representing CSF dissemination in patient 5 (black arrow). c Cavernous sinus invasion and expansion in patient 6 (red arrow). d Clival invasion in patient 11 (yellow arrow). e Two separate drop metastases representing CSF dissemination in case 13 (yellow and white arrows)

Fig. 2

Examples of high-grade progression in cases 11 (a–c) and 6 (d–l). Case 11b showed similar features to a conventional gonadotroph tumor, but with up to 19 mitoses per 2 mm² (a), less SF1 positivity than most (b), and a Ki-67 labeling index of roughly 40% (c). Case 6a initially presented as a silent corticotroph tumor with up to 8 mitoses per 2 mm.² (d), diffuse ACTH expression (not shown), a Ki-67 labeling index of ~ 5% (not shown), and extensive TPIT positivity (e). At recurrence (Case 6b), there were similar areas to the original tumor, but focal areas showed a marked increase in mitotic count (f), loss of ACTH positivity (g, right half), and markedly increased Ki-67 labeling (h, right half). A subsequent resection (Case 6d) from a site of intracranial CSF dissemination showed brain invasion (i), markedly elevated Ki-67 labeling (j), lack of ACTH expression (not shown), partially retained TPIT positivity (k), and loss of Rb expression (l, note positivity in endothelial cells)

Fig. 3

Examples of sarcomatous transformation in cases 2 and 10. Case 2a included both areas of conventional gonadotroph PitNET (a, b left half), and sarcomatous transformation (b right half, c). The latter showed p53 overexpression (d) and lack of p16 expression in tumor cells (e, note staining of endothelial cells). Case 10a started off as a gonadotroph tumor with scattered spindle-shaped rhabdomyoblastic cells (f, g), the latter of which were myogenin-positive (h). In subsequent recurrences, the rhabdomyosarcomatous component became increasingly predominant (i, j), as evidenced by both myogenin (k) and desmin (l) immunostains

Fig. 4

Examples of metastatic PitNET from cases 1 and 13. Case 1a was an acidophil stem cell tumor with marked cytologic atypia (a), patchy prolactin staining (not shown), and extensive positivity on the antimitochondrial antigen (AMA) stain (b). The p16 stain showed that the primary sellar tumor was negative (c, note internal positive control in blood vessels). A subsequent cervical lymph node resection showed similar histology (d) and patchy prolactin positivity (e) similar to the primary tumor. Case 13a was a silent corticotroph tumor with 5 mitoses per 2 mm.² (not shown), a Ki-67 labeling index of 19% (not shown), and scattered immunoreactivity for ACTH (f) and TPIT (not shown). A subsequent bone metastasis specimen from the cervical vertebral body showed classic cytologic features of PitNET (g), but lack of any ACTH or TPIT expression (not shown). An immunostain for ATRX showed loss of expression in tumor cells (h, note staining of endothelial cells)