Highly Aggressive and Radiation-Resistant, “Atypical” and Silent Pituitary Corticotrophic Carcinoma: A Case Report and Review of the Literature

Background: Pituitary tumors typically remain silent unless interaction with nearby structures occurs. Rare subsets of pituitary tumors display aggressive phenotypes: highly mitotic, locally invasive, metastatic, chemotherapy and radiation resistant, etc. Disease progression and response to therapy is ill-defined in these subtypes, and their true prognostic potential is debated. Thus, identifying tumor characteristics with prognostic value and efficacious treatment options remains a challenge in aggressive pituitary tumors. Case Presentation: A 45-year-old female presented with a nonfunctioning corticotropic pituitary macroadenoma with biomarkers suggestive of an “atypical” subtype: Ki-67 of 8–12%, increased mitosis, and locally invasive. Despite resections and radiation, growth continued, eventually affecting her vision. Although histologically ACTH positive, the patient remained clinically asymptomatic. Twelve months later, an episode of Cushing’s disease-induced psychosis prompted a PET-CT scan, identifying sites of metastasis. Temozolomide was added to her medical regimen, and her metastatic liver lesions and boney metastases were treated with radiofrequency ablation and stereotactic body radiation therapy, respectively. Systemic treatment resulted in a drop in her ACTH levels, with her most recent scans/labs at 12 months following RFA suggesting remission. Conclusions: This is a unique presentation of a pituitary tumor, displaying characteristics of both clinically silent corticotropic and “atypical” macroadenoma subtypes. Although initially ACTH positive while clinically silent, the patient’s disease ultimately recurred metastatically with manifestations of Cushing’s disease and psychosis. With the addition of temozolomide to her treatment plan, her primary and metastatic sites have responded favorably to radiation therapy. Thus, the addition of temozolomide may be beneficial in the treatment of aggressive pituitary tumors.

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Clinical, Biological, Radiological Pathological and Immediate Post-Operative Remission of Sparsely and Densely Granulated Corticotroph Pituitary Tumors: A Retrospective Study of a Cohort of 277 Patients With Cushing’s Disease

Frontiers in Endocrinology ◽

10.3389/fendo.2021.672178 ◽

2021 ◽

Vol 12 ◽

Author(s):

Beata Rak ◽

Maria Maksymowicz ◽

Monika Pękul ◽

Grzegorz Zieliński

Keyword(s):

Cushing’S Disease ◽

Pituitary Tumors ◽

Signs And Symptoms ◽

Cortisol Concentration ◽

Cushing's Disease ◽

Ki 67 ◽

Remission Status ◽

Multiple Data ◽

The Mean ◽

Corticotroph Adenomas

PurposeCushing’s disease is the most common cause of endogenous hypercortisolemia due to a corticotroph pituitary tumor. Up-to-date there is no reliable biomarker of invasiveness among corticotroph tumors, while it is well established in the literature that sparsely granulated somatotroph tumors are characterized by poorer prognosis. The aim of the study was to correlate multiple data including clinical, biochemical, radiological, and pathological findings (including granulation pattern) as well as immediate post-operative remission status among patients operated on due to corticotroph tumors.MethodsWe enrolled all patients consecutively operated on for planned transsphenoidal neurosurgery due to corticotroph PitNETs in years 2010–2018. We excluded from analysis silent corticotroph tumors, plurihormonal PitNETs, and the Crooke’s cell adenomas.ResultsWe recorded 348 hormonally active corticotroph PitNETs. The results of the analysis showed the female predominance 79.88% (n = 278), with the mean age of Cushing’s disease occurrence 43.27 years of age. The mean time from the first signs and symptoms to the operation was 2 years. The women were diagnosed earlier (20–40 years of age vs. 50–60 years of age among men). We performed a detailed analysis of 277 cases classified by granularity pattern as DG or SG corticotroph PitNETs. Densely granulated tumors (DG) occurred four times more frequently than sparsely granulated (SG) (n = 225 vs. n = 52), at similar age (mean 42.94; median 40 vs. mean 45.46; median 45.5; p = 0.3896), but were characterized by lower Knosp’s scale grades (p = 0.0147*), smaller preoperative tumors’ volumes measured at MRI, and more commonly exhibited lower Ki-67 labeling index (<3%) (p = 0.0168*). What is more, DG adenomas more frequently achieved an immediate remission status (measured as postoperative cortisol concentration <2 µg/dl; p = 0.0180*), and the mean postoperative cortisol concentration in DG group was lower than in SG group (mean 5.375 µg/dl vs. 10.47 µg/dl; median 2.49 µg/dl vs. 6.52 µg/dl; p = 0.0028**).ConclusionsOur study indicates that DG corticotroph adenomas occurred at younger age, more commonly were microadenomas as compared to SG tumors, less frequently had invasive features in comparison to SG corticotroph adenomas (p = 0.0019**), and more commonly achieved an immediate postsurgical hormonal remission (p = 0.0180*). We highlight the need for an accurate differentiation of DG and SG subtypes in the pathomorphological diagnosis of corticotropic tumors, especially in invasive PitNETs.

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Abstract #19: Resolution of Cushing's Disease with Empty Sella Syndrome After Radiation Therapy: Case Report and Literature Review

Endocrine Practice ◽

10.1016/s1530-891x(20)43867-4 ◽

2003 ◽

Vol 9 ◽

pp. 7

Author(s):

Vanessa Rodríguez ◽

Rakesh Patel ◽

Steve Lieberman

Keyword(s):

Radiation Therapy ◽

Case Report ◽

Literature Review ◽

Cushing’S Disease ◽

Empty Sella ◽

Cushing's Disease ◽

Empty Sella Syndrome

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Bilateral adrenalectomy in Cushing's disease: Altered long-term quality of life compared to other treatment options

Annales d Endocrinologie ◽

10.1016/j.ando.2018.01.002 ◽

2019 ◽

Vol 80 (1) ◽

pp. 32-37 ◽

Cited By ~ 9

Author(s):

Pauline Sarkis ◽

Muriel Rabilloud ◽

Jean-Christophe Lifante ◽

Anna Siamand ◽

Emmanuel Jouanneau ◽

...

Keyword(s):

Quality Of Life ◽

Cushing’S Disease ◽

Treatment Options ◽

Bilateral Adrenalectomy ◽

Cushing's Disease

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Role of Hypofractionated Radiation Therapy in a Multidisiplinary Approach to Treat Persistent Cushing’s Disease

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2018.07.1025 ◽

2018 ◽

Vol 102 (3) ◽

pp. e333-e334

Author(s):

R. Meral

Keyword(s):

Radiation Therapy ◽

Cushing’S Disease ◽

Cushing's Disease ◽

Hypofractionated Radiation Therapy ◽

Hypofractionated Radiation

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Cushing’s disease: radiation therapy

Pituitary ◽

10.1007/s11102-008-0117-3 ◽

2008 ◽

Vol 12 (1) ◽

pp. 11-14 ◽

Cited By ~ 18

Author(s):

Mary Lee Vance

Keyword(s):

Radiation Therapy ◽

Cushing’S Disease ◽

Cushing's Disease

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Immunochistochemical characteristics of blood vessels in non-visualized and visualized on MRI pituitary adenoma in patients with Cushing’s disease

Problems of Endocrinology ◽

10.14341/probl201662565-66 ◽

2016 ◽

Vol 62 (5) ◽

pp. 65-66

Author(s):

Patimat M. Khandaeva ◽

Iya A. Voronkova ◽

Zhanna E. Belaya ◽

Lyudmila Y. Rozhinskaya ◽

Aleksandr V. Vorontsov ◽

...

Keyword(s):

Pituitary Adenoma ◽

Blood Vessels ◽

Cushing’S Disease ◽

Pituitary Tumor ◽

Pituitary Tumors ◽

Average Diameter ◽

Cushing's Disease ◽

Retrospective Evaluation ◽

Acth Secreting ◽

Microvessels Density

Backgraund. Regardless of improvements in MRI, up to 20% of ACTH-secreting pituitary tumors are only identified at surgical exploration.Aim: to estimate whether there is any difference in blood vessels and the subsequent ability to uptake contrast agent in visualized microadenoma as compared to non-visualized on MRI ACTH-secreting pituitary tumors.Materials and methods. retrospective evaluation of ACTH-positive pituitary tumors from patients with Cushing’s disease (n=39) with either non-visualized pituitary tumor on MRI (n=17) or pituitary tumor less then 25 mm (n=22). MRI was performed using Siemens Magnetom Harmony 1.0T with gadolinium. Selected tumors were stained with anty-СD34 antibody (clone QBEnd/10, RTU, Leica) and anty-D2-40 antibody (clone D2-40, RTU, Dako). We evaluated the microvessels density and measured the diameter of larger and smaller vessel.Results. The microvessels density were not different in subject with visualized (123 [77;136]) and non-visualized (112 [110,0;126,5]) pituitary adenomas as well as number of slit-shaped vessels (32 [5;50] in visualized vs 25 [5;50] in non-visualized pituitary adenoma). The diameter of these vessels also did not differ: the diameter of the largest vessels in patients without visualization 53 µm [32,5;63,5] vs 33 µm [30,0;51,5], the average diameter of the blood vessels 15 µm [14,5-26,0] against 13 µm [12;14].Conclusions. The diameter and microvessels density in ACTH-producing pituitary adenoma does not affect the visualization of adenoma on MRI in patients with Cushing 's disease.

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Intraoperative ultrasound-directed resection of pituitary tumors

Journal of Neurosurgery ◽

10.3171/jns.1995.83.2.0225 ◽

1995 ◽

Vol 83 (2) ◽

pp. 225-230 ◽

Cited By ~ 41

Author(s):

Zvi Ram ◽

Thomas H. Shawker ◽

Mary H. Bradford ◽

John L. Doppman ◽

Edward H. Oldfield

Keyword(s):

Mr Imaging ◽

Cushing’S Disease ◽

Intraoperative Ultrasound ◽

Pituitary Tumors ◽

Thyroid Stimulating Hormone ◽

Cushing's Disease ◽

Content Type ◽

Normal Pituitary Gland ◽

Intraoperative Localization ◽

Fine Print

✓ Microadenomas of the pituitary vary in size, particularly those related to Cushing's disease. They are often not visualized on preoperative magnetic resonance (MR) imaging and may be difficult to find during surgical exploration of the pituitary. To enhance intraoperative localization of pituitary adenomas, we assessed the feasibility of using ultrasound to detect and localize pituitary tumors. Intraoperative ultrasound (IS) in the axial and sagittal planes was performed with an Intrascan system using a 12-MHz mechanically oscillating, end-firing transducer. Interpretation of the scans was performed by two individuals, who were usually blinded to the results of preoperative MR imaging or petrosal sinus sampling. Twenty-eight patients were examined. Eighteen of these patients had microadenomas (1.5–7 mm), all with Cushing's disease; nine had macroadenomas (10–20 mm), three of which were adrenocorticotropic hormone—secreting, three growth hormone—secreting, two thyroid-stimulating hormone—secreting, and one nonfunctioning; and one patient had an intrasellar craniopharyngioma. Normal sellar and parasellar structures, such as intrapituitary cysts, the intracavernous carotid arteries, and the diaphragma sella were easily visualized. Twenty-three of the 28 tumors, including 13 of the 18 microadenomas, were detected on IS (82% sensitivity). Tumors were seen as hyperechoic masses in 19 patients, mixed echogenicity in three, and isoechoic in one. In most macroadenomas IS allowed visualization of the interface between the tumor and the normal pituitary gland. These results indicate the potential of IS to aid the intraoperative localization and definition of pituitary tumors.

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Cyproheptadine-Induced Remission of Cushing's Disease Due to Pituitary Basophil Adenoma

Drug Intelligence & Clinical Pharmacy ◽

10.1177/106002808201601213 ◽

1982 ◽

Vol 16 (12) ◽

pp. 962-965 ◽

Cited By ~ 3

Author(s):

J. Jimenez-Alonso ◽

J. Munoz-Avila ◽

L. Jaimez ◽

F. Pérez-Jimenez ◽

C. Bellido ◽

...

Keyword(s):

Cushing’S Disease ◽

Pituitary Tumors ◽

Corticotropin Releasing Factor ◽

Cushing's Disease ◽

Patient Support ◽

Acth Secretion ◽

Hypothalamic Regulation ◽

Potent Antagonist ◽

Factor Secretion ◽

Acth Release

Serotonin is involved in the control of ACTH secretion, possibly by stimulating corticotropin releasing factor secretion from the hypothalamus. Cushing's disease seems to be due to defective hypothalamic regulation of ACTH release from the pituitary gland. Cyproheptadine is a potent antagonist of serotonin and has been used successfully in some patients with Cushing's disease, although, generally, in women without radiological evidence of pituitary tumors. We report the successful use of cyproheptadine in a 54-year-old man with Cushing's disease due to pituitary basophil adenoma. Significant clinical and biochemical improvement was noted 45 days after treatment began. The results in this patient support our findings that cyproheptadine can be effective in patients with Cushing's disease due to pituitary tumors, as well as in preparing very ill patients for surgery or managing such patients until radiotherapy takes effect.

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