Measuring TSH Levels Could Improve Diagnosis for Cushing’s Syndrome

Measuring the variation in thyroid stimulating hormone blood levels between midnight and morning may be better for diagnosing Cushing’s syndrome than current approaches, a study suggests. 

The study, “TSH ratio as a novel diagnostic method for Cushing’s syndrome,” was published in the Endocrine Journal. 

Cushing’s syndrome (CS) is a condition characterized by excess cortisol in the blood, which can lead to a variety of issues, including obesity, high blood pressure, abnormal lipid levels, osteoporosis, depression, and cognitive impairments.

In some cases, patients have high cortisol levels, but lack the typical physical features of Cushing’s syndrome. These patients are considered to have subclinical Cushing’s syndrome (SCS), and are at higher risk for cardiovascular disease.

Being able to properly diagnose CS and SCS is of utmost importance for proper intervention and treatment of these patients.

Current methods of diagnosis rely on dexamethasone suppressing tests or late-night salivary and blood cortisol tests, as well as measurements of cortisol in urine. However, because cortisol is a stress-hormone, it can be elevated in cases of mental or physical stress, leading to false positive results on these tests. 

Researchers in this study examined if another hormone, called the thyroid stimulating hormone (TSH), could be used to diagnose Cushing’s syndrome with better accuracy.

TSH is a hormone that stimulates the thyroid gland and whose secretion is affected by the body’s circadian rhythm. Its highest levels in the blood are usually seen in the late evening or early morning. However, patients with CS or SCS lack this nocturnal increase in TSH levels, which could be useful as a new diagnostic approach.

The study recruited 142 patients with suspected CS and SCS, and 21 patients with depression, being treated at the Osaka University Hospital in Japan.

Patients received the ordinal screening tests for Cushing’s syndrome, along with measurements of their midnight-to-morning TSH levels.

After taking the tests, only 20 patients were diagnosed as having Cushing’s, including 12 with over (normal) Cushing’s syndrome and 10 with subclinical Cushing’s syndrome.

Patients with Cushing’s had significantly lower midnight TSH levels than non-Cushing’s patients. No differences were seen in morning levels between the groups. Of note, TSH ratio was maintained in patients with depression, suggesting TSH levels could be used to diagnose Cushing’s in patients with depression.

Researchers observed that serum TSH ratio had powerful diagnostic accuracy. Among patients identified as having Cushing’s, 90% actually had the disease. And among patients excluded for Cushing’s, 95% did not have the condition. These sensitivity and specificity rates were better than with current diagnostic approaches.

However, when considering this test, patients with a severe TSH deficiency must be taken into account.

Overall, these results suggest that the midnight-to-morning serum TSH ratio is a potential new way to diagnose both CS and SCS with a higher specificity than the current diagnostic methods

“The strength of our current survey is its prospective design and the evaluation of not only overt CS but also SCS. The limitation is the relatively small number of CS group patients, especially overt CD,” the researchers wrote.

“New prospective studies will be needed with a larger number of patients in order to further clarify the optimal TSH ratio in the diagnosis of CS,” the study concluded. 

From https://cushingsdiseasenews.com/2018/06/28/measuring-tsh-levels-may-improve-cushings-syndrome-diagnosis-study/

Tumors in Cushing’s Patients Have Distinct Genetic Profiles

A study examining the genes expressed in pituitary tumors of Cushing’s disease patients found that these tumors may be grouped into three distinct subsets.

The finding suggests that different biological processes contribute to the development of each subset, an insight that may aid in developing targeted therapies.

The study, “Gene expression profiling in human corticotrope tumors reveals distinct, neuroendocrine profiles,” was published in the Journal of Neuroendocrinology.

In Cushing disease, a pituitary tumor producing excess amounts of the adenocorticotropic hormone causes the body to produce too much cortisol.

Pituitary tumors respond differently to modulators of ACTH secretion, and patients have different disease manifestations, but what makes them differ from one another is unknown.

To determine if the genetic profile of tumors could explain the clinical diversity reported in these patients, Italian researchers evaluated 40 benign, ACTH-secreting pituitary tumors removed from patients with Cushing’s disease.

Of the 20,815 genes examined in the study, 1,259 were significantly elevated in the pituitary tumors. These were mostly involved in pathways that kept the neuroendocrine cell profile.

Based on their genetic profile, researchers were able to cluster tumors into three distinct subgroups. Samples in group A had four specific genes, associated with tumor-related processes, that were overly active. In group B, there were 313 overly active genes, involved in many of the mechanisms of hormone-secreting adenomas.

Group C had 29 highly active genes, all involved in calcium influx and cell growth – mechanisms that are important for the development of ACTH-secreting adenomas.

“It appears that these tumors present a neuroendocrine cell profile but, at the same time, clearly distinct gene expression patterns [are seen] in individual subgroups,” the researchers wrote.

Looking at clinical characteristics that correlated with each subgroup, the researchers found that most group A patients  had macroadenomas (large tumors) that had invaded the sella – the compartment where the pituitary gland resides at the base of the brain. These patients were also older than those in the other two subgroups.

Some patients in group B also had macroadenomas, but no such tumors were seen in group C. However, researchers found no association between the groups and the hormonal values, clinical findings, or surgical outcomes.

Collectively, the findings add new clues to the molecular mechanisms involved in the progression of benign pituitary tumors. They also provide new ground for developing targeted therapies, the researchers said.

From https://cushingsdiseasenews.com/2018/06/22/tumors-in-cushing-disease-patients-show-distinct-genetic-profiles-study-reports/

Cushing’s Patients at Risk of Life-threatening Pulmonary Fungal Infection

Cushing’s disease patients who exhibit nodules or masses in their lungs should be thoroughly investigated to exclude fungal infection with Cryptococcus neoformans, a study from China suggests.

While rare, the infection can be life-threatening, showing a particularly worse prognosis in patients with fluid infiltration in their lungs or with low white blood cell counts in their blood.

The study, “Cushing’s disease with pulmonary Cryptococcus neoformans infection in a single center in Beijing, China: A retrospective study and literature review,” was published in the Journal of the Formosan Medical Association.

Cortisol, a hormone that is produced in excess in Cushing’s disease patients, is a kind of glucocorticoid that suppresses inflammation and immunity. Consequently, subjects exposed to cortisol for long periods, much like immuno-compromised patients, are at high risk for infections.

In Cushing’s patients, the most common infections include Pneumocystis jiroveci, Aspergillus fumigatus, and Cryptococcosis — 95 percent of which are caused by C. neoformans.

But while “Cushing’s disease patients are susceptible to C. neoformans, the association between pulmonary C.neoformans and [Cushing’s disease] is poorly explored,” researchers said.

In an attempt to understand the clinical characteristics of Cushing’s patients who develop C.neoformans infections, researchers in Beijing, China, reviewed the clinical records of six patients at their clinical center.

Their analysis also included six other patients whose cases had been reported in previous publications.

Patients had a mean age of 44 and 10 were diagnosed initially with high blood pressure. Seven also had diabetes mellitus.

All patients had elevated cortisol levels in their urine and high levels of the adrenocorticotropic hormone (ACTH). Ultimately, all patients were found to have masses in their pituitary glands, causing the high cortisol and ACTH levels.

Patients complained of lung symptoms, including shortness of breath after physical activity, cough, and expectoration. But they had no fever or signs of blood in the lungs, which could suggest lung infection.

A CT scan of the chest then revealed lung nodules in four patients, and lung masses in five patients. Four patients, including one with a lung mass, also had lung air spaces filled with some material (pulmonary consolidation), which was consistent with pulmonary infection.

After analyzing lung nodule/mass biopsies, lung fluids, or blood samples, all patients were diagnosed with C. neoformans pulmonary cryptococcosis.

For their infection, patients received anti-fungal drugs, including amphotericin-B, fluconazole, flucytosine, and liposomal amphotericin. Cushing’s disease, however, was treated with surgery in 10 patients and ketoconazole in two patients.

Despite the treatments, five patients died during follow-up, including four who experienced co-infections or spreading of the cryptococcal infection and one patient with extensive bleeding after surgical removal of the gallbladder.

Among them, two patients had significantly low white blood cell levels and elevated cortisol levels, and four had infiltration in their lungs, suggesting these are markers of poor prognoses.

Researchers also noted that the patients who received ketoconazole died during in the reviewed studies. They attribute this to ketoconazole’s anti-fungal properties, which may interfere with its ability to manage Cushing’s symptoms.

Given the high susceptibility of Cushing’s disease patients to C. neoformans infections, “pulmonary nodules or masses should be aggressively investigated to exclude” this potentially fatal opportunistic infection, the researchers suggested.

“The infiltration lesions in chest CT scan and lymphopenia seem to be potential to reflect the poor prognosis,” they said.

From https://cushingsdiseasenews.com/2018/06/15/pulmonary-fungal-infection-threatens-cushings-disease-patients-study/

Cushing’s syndrome caused by ACTH-producing thymic typical carcinoid with local invasion and regional lymph node metastasis: a case report

  • Wakako Fujiwara Email author View ORCID ID profile,
  • Tomohiro Haruki,
  • Yoshiteru Kidokoro,
  • Takashi Ohno,
  • Yohei Yurugi,
  • Ken Miwa,
  • Yuji Taniguchi and
  • Hiroshige Nakamura
Surgical Case Reports20184:55

https://doi.org/10.1186/s40792-018-0459-7

Received: 28 March 2018

Accepted: 31 May 2018

Published: 11 June 2018

Abstract

Background

Ectopic ACTH-producing thymic carcinoid tumors are rare, but often behave aggressively with local invasion and distant metastasis. We herein report a case of ACTH-producing thymic typical carcinoid tumor with lymph node metastasis treated by surgery and postoperative radiation therapy.

Case presentation

A 61-year-old woman was admitted to be evaluated for hypoglycemia and hypokalemia. Laboratory data revealed elevation of serum cortisol and ACTH levels. Overnight administration of 8 mg dexamethasone did not suppress plasma ACTH. Chest CT demonstrated a tumor of 30 mm in diameter and enlargement of the lymph node at the anterior mediastinum. Ectopic ACTH syndrome was suspected and total thymectomy and lymph node dissection were performed. The histopathological examination indicated typical carcinoid tumor and mediastinal lymph node metastasis, and immunohistochemical staining was positive for ACTH. The plasma ACTH level decreased immediately after surgery. She received postoperative radiation therapy of 60 Gy.

Conclusion

Ectopic ACTH-producing thymic typical carcinoid tumors are rare, and it is important to consider this disease and perform appropriate treatment.

Keywords

Thymic carcinoid ACTH Cushing’s syndrome Total thymectomy

Background

Among adrenocorticotrophic hormone (ACTH)-dependent Cushing’s syndrome, 10–20% is due to nonpituitary tumors termed ectopic ACTH syndrome (EAS). The most common cause of EAS is small cell lung cancer, followed by thymic carcinoids. Thymic carcinoids are very rare neuroendocrine tumors that often complicate endocrine disorders. Although previously assumed to be variants of bronchopulmonary carcinoid tumors, they are generally more aggressive and difficult to treat. It is widely accepted that surgical resection is the only curative treatment for localized lesions, and the efficacy of chemotherapy and radiotherapy has not been well established.

We herein report a case of EAS caused due to a thymic typical carcinoid tumor successfully treated by surgery followed by radiation.

Case presentation

A 61-year-old woman visited her primary care doctor because of general malaise, face edema, skin pigmentation, insomnia, and polyuria. Blood examination revealed marked hypokalemia and impaired glucose tolerance. Bilateral adrenal enlargement was observed on abdominal ultrasonography, and she was referred to our hospital for further examination. Endocrine examination showed both elevated plasma cortisol (107.7 pg/mL) and ACTH levels (1100 pg/mL), and increased urinary excretion of free cortisol (6650 mcg/day) and 17-ketogenic steroids (78.7 mg/day). Plasma cortisol and ACTH levels were elevated without any diurnal rhythm. Plasma cortisol was not suppressed by the overnight 8-mg dexamethasone suppression test. There was no response of plasma ACTH or cortisol to exogenous corticotropin-releasing hormone (CRH). Other hormones of the pituitary, thyroid, and adrenal medulla were all in normal ranges. Thus, ectopic ACTH syndrome was strongly suggested.

Chest computed tomography (CT) demonstrated a tumor of approximately 30 mm in diameter and enlargement of the lymph node in the anterior mediastinum (Fig. 1). High accumulation of 18-fluorodeoxyglucose in the anterior mediastinum tumor (maximum standardized uptake value [SUV] 2.48) but not in the lymph node was observed on positron emission tomography (PET)/CT. Somatostatin receptor scintigraphy also revealed mild uptake in the tumor. Collectively, these data were consistent with a diagnosis of EAS caused by an anterior mediastinum tumor, possibly thymic carcinoid tumor. There was no abnormal finding indicating multiple endocrine neoplasia (MEN).

Figure 1
Fig. 1

Chest CT image. A tumor (30 × 30 × 14 mm) without invasion localized in the anterior mediastinum (a). Enlargement of lymph node (b)

Before the operation, we administered 500 mg/day of metyrapone, and both ACTH and cortisol levels decreased to 68.5 pg/mL and 3.02 mcg/mL respectively. After 2 months of medical treatment, her symptoms were relieved and bilateral adrenal enlargement decreased. Under open thoracotomy by median sternotomy, she underwent total thymectomy, pericardial partial resection, dissection of the anterior regional and the right paratracheal lymph nodes, and sampling of the subcarinal lymph node. Histopathologically, the tumor consisted of round to spindle-shaped cells with high nucleus/cytoplasm ratios containing finely granular chromatin. Necrosis was absent, and mitotic figures were infrequent, with less than two per ten high-power fields (HPF). Tumor cells were positive for chromogranin A, synaptophysin, CD-56, and ACTH on immunohistochemistry (Fig. 2). The tumor had invaded the pericardium, and mediastinal lymph nodes were positive for metastasis. The final diagnosis was stage IVA (pT2N1M0) ACTH-producing thymic typical carcinoid tumor. The plasma ACTH level decreased to 14.8 pg/mL, less than normal, immediately after surgery (Fig. 3). Hydrocortisone was administered during the perioperative period and was gradually tapered, and finished 4 months after surgery. She received postoperative radiation therapy of 60 Gy. At 8 months after surgery, she showed no sign of Cushing’s syndrome or recurrence of the tumor without any medications.

Figure 2
Fig. 2

HE staining (a) indicated typical carcinoid tumor. Tumor cells were positive for synaptophysin (b), CD-56 (c), and ACTH (d) on immunostaining

Figure 3
Fig. 3

Changes in plasma ACTH levels during the clinical course

Discussion

Ectopic ACTH-producing thymic carcinoid tumor is an extremely rare clinical condition, comprising 29% of all thymic carcinoids and 5–42% of all ectopic ACTH-producing syndrome [1, 2]. It has been reported that radical surgical resection of the ACTH source is the only effective treatment [3]. Prior to surgery, medication therapy should be done to prevent perioperative complications and perform surgery when hormone values and symptoms are controlled. Furthermore, there is a risk of postoperative adrenal insufficiency; strict perioperative management is desirable.

Unlike pulmonary and other carcinoid tumors, thymic carcinoids often behave aggressively as an advanced disease with local invasion, lymph node metastasis, and distant metastasis because of the high proportion of atypical carcinoid tumors. Regarding ACTH-producing thymic tumors, Neary et al. reported three cases of well-differentiated ACTH-producing thymic neuroendocrine carcinomas, and the patients had no lymph node metastasis, recurrence, or death. On the other hand, nine cases of moderately differentiated ACTH-producing thymic neuroendocrine carcinomas almost had lymph node metastasis, and all patients had recurred [4]. However, our case was a typical carcinoid tumor with lymph node metastasis and local invasion.

As a surgical procedure, a median sternotomy approach is generally recommended because this enables excision of the entire thymus, perithymic fat, other affected mediastinal structure, and aggressive lymph node dissection. However, there is no standard for lymph node dissection in thymic epithelial tumors even though lymph node metastasis is an important prognostic factor. Hwang et al. recommended right paratracheal node dissection in addition to anterior regional lymph node dissection for TNM clinical stage II or higher diseases because they are crucial stations on the lymphatic pathway of thymic malignancies [5]. In the present case, we performed total thymectomy, followed by lymph node dissection of the anterior regional and right paratracheal nodes, and sampling of subcarinal lymph node via median sternotomy. The anterior mediastinal lymph nodes were positive for metastasis. Consequently, we considered the extent of lymph node dissection to be adequate, and radical resection was completed because the postoperative plasma ACTH level was successfully decreased. Although a good prognosis is expected by combined surgery and radiation, relatively high malignancy characteristics are observed compared with typical carcinoids, and strict follow-up is needed.

Conclusion

We report a rare case of ectopic ACTH-producing thymic typical carcinoid with local invasion and regional lymph node metastasis. Surgical resection was effective to control Cushing’s syndrome in this case, and nodal staging may help to guide adjuvant treatment, but systemic nodal dissection/sampling is yet to be standardized.

Abbreviations

ACTH: 

Adrenocorticotrophic hormone

CRH: 

Corticotropin-releasing hormone

CT: 

Computed tomography

SUV: 

Standardized uptake value

PET: 

Positron emission tomography

MEN: 

Multiple endocrine neoplasia

HPF: 

High-power fields

CD-56: 

Cluster of differentiation-56

Declarations

Acknowledgements

The authors thank Dr. Nosaka and Dr. Umekita for diagnostic assessment of this case.

Availability of data and materials

The dataset supporting the conclusions of this article is included within the article.

Authors’ contributions

WF and YT were the attending doctors for the patient. WF, YK, KM, YT, and HN performed the operation. WF, TH, and HN drafted this manuscript. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

No applicable.

Consent for publication

This patient consented to the reporting of this case in a scientific publication.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

References

  1. Yoshikawa T, Noguchi Y, Matsukawa H, et al. Thymus carcinoid producing parathyroid hormone (PTH)-related protein: report of a case. Surg Today. 1994;24:544–7.View ArticlePubMedGoogle Scholar
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  3. Zhou X, Hnag J, Che J, et al. Surgical treatment of ectopic adrenocorticotropic hormone syndrome with intra-thoracic tumor. J Thorac Dis. 2016;8:888–93.View ArticlePubMedPubMed CentralGoogle Scholar
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Copyright

© The Author(s). 2018

Radiation to the Whole Pituitary Compartment Effective at Controlling Cushing’s

Radiation therapy targeting the entire sella — the compartment where the pituitary gland resides at the base of the brain — is effective at controlling Cushing’s disease and should be considered for patients with suspected invasive adenoma tumors, a new study shows.

The study, “Technique of Whole-Sellar Stereotactic Radiosurgery for Cushing’s Disease: Results from a Multicenter, International Cohort Study,” was published in the journal World Neurosurgery.

In patients with Cushing’s disease, excess cortisol levels are caused by a kind of pituitary tumor (adenoma)  that secretes too much adrenocorticotropic hormone (ACTH).

Removing the adenoma using the transsphenoidal approach — a minimally invasive procedure performed through the nose to remove pituitary tumors — remains the first-line treatment for patients with newly diagnosed Cushing’s syndrome. For patients who fail surgery and medical management, stereotactic radiosurgery (SRS) may be used.

SRS is not a surgery in the traditional sense, as it does not require an incision. Instead, SRS uses many focused radiation beams to treat tumors and other problems in the brain, neck and other parts of the body.

While surgery may achieve very good remission rates in patients with an identifiable adenoma, as many as 50 percent of Cushing’s disease patients have no identifiable adenoma on magnetic resonance imaging (MRI) scans. In such cases, surgeons can opt for SRS targeting the entire sella, a procedure called whole-sellar SRS. However, the outcomes of whole-sellar SRS are not fully known.

Researchers conducted an international, retrospective study to analyze the outcomes of Cushing’s disease patients who received whole-sellar SRS.

The study enrolled 68 patients, including 52 who received the procedure for persistent disease, nine whose disease returned after surgery, and seven as their initial treatment.

Patients underwent a type of SRS known as gamma knife radiosurgery (GKRS), which uses small beams of gamma rays to target and treat brain tumors. They were then followed for a mean of 5.3 years.

Whole-sellar SRS was effective at controlling the disease, researchers found. In the five years after receiving the treatment, 75.9 percent of patients achieved a remission. Of those, 86% remained recurrence-free for five or more years.

The mean volume of area targeted using whole-sellar SRS was 2.6 cm3. Researchers discovered that treatment volumes greater than 1.6 cm3 were associated with a shorter time to remission, indicating that targeting a larger portion is more beneficial.

Also, statistical analysis revealed that a reduced dose of radiation was linked to recurrence, suggesting that a higher dose is more advantageous.

Regarding adverse events, 22.7% of patients who underwent whole-sellar SRS developed loss of one or more pituitary hormones.

Researchers also compared outcomes of patients who underwent whole-sellar SRS to those who received adenoma-targeted SRS, of which the latter involves irradiating only the tumor.

Interestingly, there were no differences in remission rate, time to remission, recurrence-free survival, or new endocrine disease development between both groups.

“Whole-sellar GKRS is effective at controlling [Cushing’s disease] when an adenoma is not clearly defined on imaging or when an invasive adenoma is suspected at the time of initial surgery,” the researchers concluded.

From https://cushingsdiseasenews.com/2018/05/25/precise-radiation-pituitary-sella-effective-control-cushings-study/

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