Cushing's Disease

Abstract

In patients with Cushing's disease (CD), prompt diagnosis and treatment are essential for favorable long-term outcomes, although this remains a challenging task. The differential diagnosis of CD is still difficult in some patients, even with an organized stepwise diagnostic approach. Moreover, despite the use of high-resolution magnetic resonance imaging (MRI) combined with advanced fine sequences, some tumors remain invisible. Surgery, using various surgical approaches for safe maximum tumor removal, still remains the first-line treatment for most patients with CD. Persistent or recurrent CD after unsuccessful surgery requires further treatment, including repeat surgery, medical therapy, radiotherapy, or sometimes, bilateral adrenalectomy. These treatments have their own advantages and disadvantages. However, the most important thing is that this complex disease should be managed by a multidisciplinary team with collaborating experts. In addition, a personalized and individual-based approach is paramount to achieve high success rates while minimizing the occurrence of adverse events and improving the patients' quality of life. Finally, the recent new insights into the pathophysiology of CD at the molecular level are highly anticipated to lead to the introduction of more accurate diagnostic tests and efficacious therapies for this devastating disease in the near future.

Keywords: Cushing’s disease; Cushing’s syndrome; USP-8; aggressive pituitary tumor; pasireotide; pituitary carcinoma; pituitary corticotroph tumor; temozolomide; transsphenoidal surgery.

Figure 1

Comparisons of MRI sequences for detecting an adrenocorticotropic hormone (ACTH)-producing micro-tumor (white arrow). The 3D-spoiled gradient-echo (SGE) sequence with 3T-MRI was superior to other conventional MRI sequences in both presented patients.

Figure 2

A patient of Cushing’s disease with negative-MRI⁽¹⁵¹⁾. Extensive MRI studies including 3T MRI failed to demonstrate any findings suggesting tumor but inferior petrosal sinus sampling (IPSS) suggested pituitary origin of ACTH-dependent CD in a 20-year-old woman. A 3-mm diameter micro-tumor was found on the left side of the pituitary as predicted by IPSS. Selective tumorectomy resulted in complete remission of the disease. No abnormal findings were found in preoperative MRI even after review in MRI scans retrospectively comparing them to postoperative MRI findings.

Figure 3

Algorithm of the management of Cushing’s disease. CD: Cushing’s disease.

Figure 4

Surgery for a tumor invading cavernous sinus. Fourty-seven-year old female. Small tumor (5 mm in diameter) was located in the right wing of the pituitary invading into cavernous sinus. The tumor was completely removed with separating and excising the medial wall of the cavernous sinus (CS) with the invading tumor inside of the CS Postoperative ACTH and cortisol levels were reduced to <1.5 pg/mL and 1.2 μg/dL, respectively.

Figure 5

Ectopic pituitary tumor. Thirty-five year-old female. Ectopic micro-tumor (4 mm in maximum diameter) was located in left suprasellar area without any connection with pituitary gland, and the tumor was completely removed via an extended transnasal approach. Postoperative ACTH and cortisol levels are reduced, Table 1 pg/mL and 0.5μg/dL, respectively.

Figure 6

When any reliable tumor is not detected throughout an extensive exploration of the sella, we usually end up hemihypophysectomy of the side suspected by venous sampling results. These two postoperative T1weighted infusion MRIs showing the pituitary after right (left) and left (right) hemihypophysectomy in cases without any definite tumors during surgery.

Figure 7

This 52-year-old lady had undergone transsphenoidal surgery for the treatment of pituitary apoplexy (tumor was large macro-tumor at that time). Several years later she showed Cushing’s syndrome and a detailed examination confirmed Cushing’s disease due to pituitary tumor located in the left side of pituitary which was removed by the first repeat surgery. However, both ACTH (91.3 pg/mL) and cortisol level (13.8 μg/dL) were still high. 11C-methionine PET-CT confirmed active small tumor still remained at the right posterosuperior sellar region which had been separated in the primary surgery and was removed by the 2nd repeat surgery (ACTH and cortisol levels reduced to 7.4 pg/mL and 2.6 μg/dL, respectively).

Figure 8

Mechanism capable of expressing or inhibiting an effect of Temozolomide (TMZ). TMZ exerts its cytotoxic effects through methylation at the O6 position of guanine (G) which gives rise to DNA adducts and consequently, tumor cell apoptosis. In contrast, O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that counteracts the effects of TMZ by removing alkylating adducts from DNA. The mismatch repair (MMR) pathway plays important roles in the removal and maintenance of DNA base mismatches caused by incorrect insertions or deletions arising from DNA replication. Base mismatches are detected by the heterodimers of MSH2 and MSH6, which assist another heterodimeric complex of MLH1 and PMS2. Unrepaired TMZ-induced O6-methyl-guanine (MeG) can pair with cytosine (C) or thymidine (T) and the nucleotide pair of O6-MeG/C or O6-MeG/T is detected by the MMR system. Keeping O6-MeG intact, only newly synthesized strands are excised, and this repair cycle will be repeated. With this useless cycle, MMR pathway stimulates DNA damage-induced G2 checkpoint and apoptosis during DNA synthesis. Therefore, the inactivation of MMR is associated with tolerance to the cytotoxic effects of alkylating agents.

Figure 9

This 33-year-old man was referred to us for seeking repeat surgery with a prior history of one time of transsphenoidal surgery and two craniotomy procedures for the treatment of invasive macro-tumor. Pathology confirmed the tumor was crook’s cell tumor with Ki67 labelling index 4% and O6-methylguanine-DNA methyltransferase was negative. Temozolomide (TMZ) treatment had started after partial removal before radiosurgery because of poor condition of the patient and relatively large residual tumor mass. Not was there a good response from ACTH and cortisol, but the tumor shrunk well to TMZ. TMZ was terminated after 24 cycles and complete remission has continued for 8 years with panhypopituitarism, although cyberknife radiosurgery was performed one year after TMZ start.

Figure 10

Forty-two-year-old lady with macro-tumor. Local radiation (total 56 gray) was administered after surgery. Her ACTH, cortisol levels have decreased to normal range along with shrinkage of residual tumor mainly located in the outer compartment of cavernous sinus. The patient still continues complete remission 18 years after surgery and radiotherapy.

Figure 11

Left two rows showing a typical micro-tumor consisting of densely granulated corticotroph tumor. In contrast, right two rows showing MRI and histology of a Crooke’s cell tumor composed of tumor cells with Crooke’s hyaline change. Ring-like cytokeratin expression is typical with the ACTH expression dislocated to the cell periphery and juxtanuclear region. By electron microscopy, the cytoplasm is filled with intermediate filaments and secretory granules are displaced to the subplasmalemmal area.

Figure 12

The histology of a micro-tumor showing densely granulated corticotroph tumor. Tumor cells are basophilic in hematoxylin and eosin stains (HE) that are diffusely and strongly positive for ACTH and TPIT. In addition, somatostatin receptor (SSTR) 2 was negative whereas SSTR5 was strongly positive in almost all cells in this case.