Clinical, Laboratory, and Treatment Profiles of Silent Corticotroph Adenomas That Have Transformed to the Functional Type: A Case Series With a Literature Review.

Guangyao Zheng,Huabing Zhang,Hui You,Xu Sun,Lin Lu,Ming Feng,Zhaolin Lu,Yong Yao,Huijuan Zhu,Congxin Dai,Renzhi Wang,Xiaohai Liu

doi:10.3389/fendo.2020.558593

Abstract

Purpose: Silent corticotroph adenoma (SCA) is clinically non-functional pituitary adenoma with expression of corticotropin or Tpit. To further understand the characteristics of this rare type of SCA transforming to a functional SCA, we retrospectively reviewed SCAs that converted to typical Cushing's syndrome at a tertiary medical center and the relevant literature.Methods: Patients were identified based on the diagnosis of pituitary adenoma without symptoms of hypercortisolism at the initial visit with positive Immunohistochemical (IHC) staining for corticotropin or Tpit after surgery and subsequent transformation to functional SCAs during the follow-up period from March 1990 to January 2020 at Peking Union Medical College Hospital and in the literature. The characteristics of the clinical manifestations, biochemical results, imaging findings, pathology findings and outcome were analyzed.Results: Altogether, 16 patients were included in the study with an average age of 42.0 ± 12.48 (18–65) years at the first visit. Females were slightly predominant (F:M = 1.3:1). The median time of conversion from the nonfunctional to the functional type was 30 (13.0, 68.3) months. Once a functional SCA developed, the adrenocorticotropic hormone (ACTH) level and 24-h urine free cortisol were increased 3.8- (2.6, 12.9) and 5.3- (2.6, 19.3) fold, respectively, above the normal range. Approximately 50% of the patients had macrocystic changes on pituitary MRI. All 16 patients experienced 1–5 surgeries with a median of 2.5 (2.0, 4.0) surgeries. The proportion of patients with Ki-67 ≥ 3% increased from 22.2% (2/9) at the beginning to 50% (7/14) at the time of functional SCA diagnosis. Thirteen patients received radiotherapy, and 4 patients (30.8%) achieved remission. Four patients with refractory functional SCAs received temozolomide treatment with the normalization of cortisol in 4 cases and reduced tumor volume in 3 cases.Conclusion: In this study, all cases that transformed to functional SCAs were macroadenomas. Hypercortisolism was more severe in functional SCA patients. The tumors tended to have frequent recurrence and were highly invasive. Temozolomide could be a promising treatment for refractory functional SCA cases. Long-term follow-up is needed for nonfunctional SCAs since some cases have the potential to transform to clinical Cushing's syndrome.

Highlights

Pituitary adenomas originate from the pituitary gland and are slow-growing and benign in most cases
The clinical data of patients who were initially diagnosed with non-functional pituitary adenoma (NFPA) and presented later with typical Cushing’s syndrome and abnormal hormone tests during long-term follow-up were collected at Peking Union Medical College Hospital from March 1990 to December 2019
Seven silent corticotroph adenomas (SCAs) patients initially diagnosed with NFPAs met the enumerated inclusion/exclusion criteria and had transformation to typical Cushing’s syndrome during the follow-up period

Summary

Introduction

Pituitary adenomas originate from the pituitary gland and are slow-growing and benign in most cases. There were some special cases of “clinically silent but pathological active” pituitary adenomas among the NFPAs; they were called “silent pituitary adenomas,” which indicated that these pituitary adenomas had immunohistochemical (IHC) expression of one or more anterior pituitary hormones but no relevant clinical symptoms. It was recommended that, in addition to the expression of hormone levels, transcription factors should be measured to define the actual lineage of the tumor according to the 2017 WHO classification of pituitary adenomas. Further evaluation of hormonenegative adenomas showed that 95% (n = 116) of those tumors expressed transcription factors as follows: gonadotroph adenomas (SF-1 positive, 66.4%), SCAs (Tpit positive, 26.9%), etc. The SCAs, distinguished by integrating IHC staining for hormones with transcription factors, were the second most common (16.1%, 83/516) of the above mentioned clinically silent NFPAs

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