Complete and Sustained Remission of Hypercortisolism With Pasireotide Treatment of an Adrenocorticotropic Hormone (Acth)-Secreting Thoracic Neuroendocrine Tumour: an N-Of-1 Trial

Posted on February 7, 2023 by MaryO
Abstract

N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing’s Syndrome (CS).

Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation.

This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.

 

Filed under: adrenal, Cancer, Clinical trials, Cushing's, Rare Diseases, Treatments | Tagged: , , , , , , , | Leave a comment »

An Aggressive Case of Adrenocortical Carcinoma Complicated by Paraneoplastic Cushing’s Syndrome

Posted on February 4, 2023 by MaryO

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Surgical resection may be curative if localized disease is identified, although recurrence is common. Research shows that the use of adjuvant therapeutic regimens such as EDP-M (combination of mitotane, etoposide, doxorubicin, and cisplatin) in high-risk patients has survival benefits.

A 75-year-old female was incidentally found to have a right adrenal heterogeneous internal enhancement measuring 5.0 x 3.7cm. The workup confirmed autonomous adrenal production of corticosteroids and she was referred to surgery for an adrenalectomy. A T2 ACC with positive margins and lympho-vascular invasion was resected, following which she was started on external beam radiation followed by four cycles of carboplatin and etoposide. Despite initial treatments, she was diagnosed with refractory metastatic disease at subsequent follow-ups. Pembrolizumab immunotherapy was started, but disease progression continued, and she was eventually transitioned to mitotane 1g twice daily. She continued to worsen and was eventually transitioned to hospice care.

The management of ACC remains diagnostically challenging, especially because most patients do not present until an advanced stage of disease. Surgery is commonly employed with a curative intent, and opinions regarding adjuvant cytotoxic therapy and/or radiotherapy remain mixed.

Introduction

Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with an annual incidence of 0.5-2.0 cases per million persons [1]. ACC is associated with an unsatisfactory prognosis with an estimated median survival of about three to four years. The five-year survival is 60-80% for tumors confined to the adrenal space, 35-50% for locally advanced disease, and 0% to 28% in cases of metastatic disease [2].

Surgical en-bloc resection is commonly employed and is recommended for locoregional disease. There is no standard of care for the management of ACC although cytotoxic cisplatin-based regimens such as EDP-M (a combination of mitotane, etoposide, doxorubicin, and cisplatin) may be employed as adjuvant therapy in those with very high recurrence risk. Mitotane is recommended for patients with a high risk of recurrence (stage III disease, R1 resection margins, or Ki67 >10%) although its routine use for low/moderate risk disease is controversial [3]. Despite complete resection of early-stage disease, recurrence rates in ACC are still very high and appropriate management remains a challenge.

We demonstrate a patient with a limited-stage T2 ACC who, despite receiving primary surgery, adjuvant chemotherapy and radiotherapy, progressed to metastatic disease.

Case Presentation

A 75-year-old female was evaluated by endocrinology for an incidentally discovered adrenal mass. A week prior, she was hospitalized for chest pain. A CT angiogram to exclude aortic dissection revealed a large right adrenal lesion with foci of heterogeneous internal enhancement measuring 5.0 cm x 3.7 cm (Figure 1).

Computed-tomography-(CT)-scan-of-the-abdomen-demonstrating-incidentally-noted-adrenal-mass.
Figure 1: Computed tomography (CT) scan of the abdomen demonstrating incidentally noted adrenal mass.

White circle: Large irregular right-sided adrenal mass with foci of heterogenous internal enhancement noted

She was initially asymptomatic, and denied constitutional symptoms such as fatigue or unexplained loss of weight. However, she had a history of hypertension and anxiety, which raised concern for a pheochromocytoma. She otherwise denied unexplained bruising, palpitations, muscle aches, tremors, and heat/cold intolerance.

Aside from hypertension and anxiety, she had a history of type II diabetes mellitus managed on metformin alone. Her family history was remarkable for a brother who also had a left adrenal lesion which was found to be a non-functional adenoma following adrenalectomy.

Her vitals were normal except for a blood pressure of 150/90. Examination showed a well-nourished female with no obvious Cushingoid features, such as increased dorsocervical fat pad, axillary or abdominal striations, or unexplained extremity bruising. Cardiac and respiratory exams were within normal limits, and no lymphadenopathy was appreciated.

She was scheduled for further workup of her adrenal incidentaloma and was found to have an elevated serum cortisol level. An overnight low-dose dexamethasone suppression test was non-suppressed, and adrenocorticotropic hormone (ACTH) level was found to be low (Table 1). These findings confirmed autonomous adrenal production of corticosteroids, and she was referred to surgery for adrenalectomy.

Investigation (units) Value (initial) Value (repeat) Reference range
24-hour urinary epinephrine (mcg/24hr) <1.4 – <21
24-hour urinary norepinephrine (mcg/24hr) 28 – 15-80
24-hour urinary metanephrines (mcg/24hr) <29 – 30-180
24-hour urinary normetanephrines (mcg/24hr) 211 – 148-560
Plasma renin activity (ng/mL/hr) 0.2 – 0.2-1.6
Serum aldosterone (ng/dL) 4.1 – 2-9
Serum cortisol (ug/dL) 22.2 54.1 2.7-10.5 (for 6-8PM)
24-hour urinary cortisol (mcg/day) 22.9 1347 <45
ACTH level (pg/mL) 3.2 – 7.2-63.3
Table 1: Investigations performed in the workup of the patient’s incidentaloma. Repeat values for select investigations are presented a year later after she presented with metastatic disease.

ACTH: adrenocorticotropic hormone

She successfully underwent surgery without complications. A surgical pathology report showed a high-grade adrenocortical carcinoma with positive surgical margins. Small vessel lymphovascular invasion was noted, but regional lymph nodes could not be assessed. The primary tumor was staged T2, with a mitotic rate of 22/50 high power fields that marked it as high grade histologically (Figure 2).

Hematoxylin-&-eosin-stain-of-a-section-of-tissue-from-pathologic-biopsy-under-high-power-microscopy.-Noted-are-the-increased-number-of-mitotic-figures,-increased-nuclear:cytoplasmic-ratio,-and-abnormal-mitotic-figures-typical-for-a-high-grade-malignancy,
Figure 2: Hematoxylin & eosin stain of a section of tissue from pathologic biopsy under high power microscopy. Noted are the increased number of mitotic figures, increased nuclear:cytoplasmic ratio, and abnormal mitotic figures typical for a high-grade malignancy,

She was subsequently referred to oncology for further evaluation, and proceeded with external beam radiation therapy for a total dose of 4500 cGy over 25 fractions, followed by adjuvant therapy with four cycles of carboplatin and etoposide. Dose reduction was needed after cycle two for worsening fatigue and neuropathy, but she otherwise tolerated the treatments well.

Nearly a year later, a regular surveillance CT demonstrated multiple sub-centimeter pulmonary nodules with patchy ground-glass abnormalities concerning for metastatic disease. In view of her disease progression, she started pembrolizumab immunotherapy.

Repeat imaging, in the setting of worsening fatigue and anorexia, confirmed enlargement of her multiple lung nodules with a new soft tissue mediastinal mass also being found (Figure 3). She developed worsening lower extremity edema and required hospitalizations for recurrent hypokalemia with hypertension. Endocrinologic evaluation revealed grossly elevated 24-hour urinary free cortisol and elevated serum cortisol levels consistent with severe Cushing’s syndrome, and she was started on high-dose ketoconazole.

CT-of-the-chest-demonstrating-multiple-nodules-in-the-lungs-consistent-with-metastatic-disease-progression.
Figure 3: CT of the chest demonstrating multiple nodules in the lungs consistent with metastatic disease progression.

Green lines: Identified lung parenchymal nodules measuring 2.60 cm (panel 1) and 2.24 cm (panel 2) in greatest diameter.

Despite six months of immunotherapy, repeat imaging showed substantial increase in size of both her multiple bilateral lung nodules. Extensive mediastinal and hilar adenopathy was also noted. Her treatment regimen was switched once more to mitotane 1g twice daily. She also had multiple subsequent hospitalizations for severe hypokalemia complicated by atrial fibrillation with rapid ventricular response.

She continued to clinically deteriorate, with increasing shortness of breath, fatigue, and chest pain. A goals of care discussion was held in view of her aggressive disease course and multiple lines of failed therapy. She was then transitioned to hospice care, and her mitotane was stopped.

Discussion

Although overall adrenal tumors are common in the population, affecting about 3-10% of people, most of these are benign. ACC on the other hand is rare, and approximately 40-60% of ACCs are found to be functional tumors that produce hormones. Fifty to 80% of these functional ACCs secrete cortisol [4]. A surprising percentage of these may even be picked up incidentally, with one multicentric and retrospective evaluation of 1096 cases demonstrating that 12% of adrenal incidentalomas are ACCs [2]. Despite improved detection rates, however, this has not translated to earlier detection and treatment of ACC [5].

The first proposed TNM staging classification scheme for ACC in 2003 by the International Union Against Cancer (UICC) had notable shortcomings, including similar outcomes for both stage II and III disease [6]. A study of 492 patients in a German ACC registry found that disease-specific survival (DSS) did not significantly differ between stage II and stage III ACC (hazard ratio, 1.38; 95% confidence interval, 0.89-2.16) and furthermore, patients who had stage IV ACC without distant metastases had an improved DSS compared with patients who had metastatic disease (P = .004) [7]. The American Joint Committee of Cancer (AJCC), and the European Network for the Study of Adrenal Tumors (ENSAT) consequently developed revised staging systems that better reflect patient prognosis.

The most important predictors of survival in patients with ACC are tumor grade, tumor stage, and surgical treatment. For patients after surgical resection, the administration of adjunctive therapy is guided by the risk of recurrence. Despite early-stage resection, disease recurrence rates in ACC are very high. Besides the EDP-M regimen, no others have been successfully evaluated in large, randomized trials [4]. Whenever possible, it is still recommended that patients be referred to a clinical trial on an individual basis.

The ADJUVO clinical trial consisted of 91 low-recurrence-risk ACC patients who were randomly assigned to either observation or adjuvant mitotane therapy after surgical resection. Low recurrence risk is defined as Ki67<10%, stage I-III according to ENSAT classification, and microscopically complete resection. Adjuvant mitotane treatment failed to demonstrate statistically significant differences in disease-free survival, recurrence-free survival and overall survival between these patient groups [8]. Our case seems to suggest that even limited-stage disease may need to be managed aggressively not just with primary surgery, but also adjuvant chemoradiotherapy, especially with a high histologic grade.

PD-1 blockade in adrenocortical carcinoma was evaluated in a phase II study of 39 participants, with a progression-free survival of 2.1 months independent of mismatch repair deficiency status being reported [9]. Despite switching to pembrolizumab in our patient, disease progression continued unabated, calling into question the clinical benefit of PD-1 blockade in ACC.

A small study on the use of metyrapone with EDP-M in three advanced ACC patients with Cushing’s syndrome displayed a good safety profile with minor drug-drug interactions and appears to be a good option in combination with mitotane and other cytotoxic chemotherapies [10]. Ketoconazole is often less effective than metyrapone and requires regular monitoring of liver function tests, although it also inhibits androgen production.

Conclusions

This case demonstrates the unfortunate prognosis of many patients with ACC. Although patients may present with classical symptoms of hypercortisolism or hyperandrogenism, many patients do not present with symptoms until the disease has advanced. Surgery may be employed with curative intent, although the evidence for adjuvant radiotherapy is mixed. The management for patients with ACC continues to remain a challenge due to the lack of evidence for optimal therapeutic management. In view of the aggressive nature of ACC, patients with high-grade histology despite limited-stage disease require adjuvant chemoradiation in addition to primary surgery to maximize the chances of progression-free survival. Also, although the use of PD-1 blockade has revolutionized cancer care in several other tumor types, evidence of clear benefit in ACC is lacking, as our case demonstrates.

References

  1. Kerkhofs TM, Verhoeven RH, Van der Zwan JM, et al.: Adrenocortical carcinoma: a population-based study on incidence and survival in the Netherlands since 1993. Eur J Cancer. 2013, 49:2579-86. 10.1016/j.ejca.2013.02.034
  2. Else T, Kim AC, Sabolch A, et al.: Adrenocortical carcinoma. Endocr Rev. 2014, 35:282-326. 10.1210/er.2013-1029
  3. Survival Rates for Adrenal Cancer. (2022). https://www.cancer.org/cancer/adrenal-cancer/detection-diagnosis-staging/survival-by-stage.html.
  4. Fassnacht M, Dekkers OM, Else T, et al.: European Society of Endocrinology Clinical Practice Guidelines on the management of adrenocortical carcinoma in adults, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2018, 179:G1-G46. 10.1530/EJE-18-0608
  5. Kebebew E, Reiff E, Duh QY, Clark OH, McMillan A: Extent of disease at presentation and outcome for adrenocortical carcinoma: have we made progress?. World J Surg. 2006, 30:872-8. 10.1007/s00268-005-0329-x
  6. Fassnacht M, Wittekind C, Allolio B: [Current TNM classification systems for adrenocortical carcinoma]. Pathologe. 2010, 31:374-8. 10.1007/s00292-010-1306-1
  7. Fassnacht M, Johanssen S, Quinkler M, et al.: Limited prognostic value of the 2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer. 2009, 115:243-50. 10.1002/cncr.24030
  8. Berruti A, Fassnacht M, Libè R, et al.: First randomized trial on adjuvant mitotane in adrenocortical carcinoma patients: the Adjuvo Study. J Clin Oncol. 2022, 40:1. 10.1200/JCO.2022.40.6_suppl.001
  9. Raj N, Zheng Y, Kelly V, et al.: PD-1 blockade in advanced adrenocortical carcinoma. J Clin Oncol. 2020, 38:71-80. 10.1200/JCO.19.01586
  10. Claps M, Cerri S, Grisanti S, et al.: Adding metyrapone to chemotherapy plus mitotane for Cushing’s syndrome due to advanced adrenocortical carcinoma. Endocrine. 2018, 61:169-72. 10.1007/s12020-017-1428-9

From https://www.cureus.com/articles/135058-an-aggressive-case-of-adrenocortical-carcinoma-complicated-by-paraneoplastic-cushings-syndrome#!/

Filed under: adrenal, Cancer, Cushing's, symptoms | Tagged: , | Leave a comment »

Recurrent Neuroendocrine Tumor of the Cervix Presenting With Ectopic Cushing’s Syndrome

Posted on November 28, 2022 by MaryO

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Abstract

Neuroendocrine carcinomas (NEC) of the cervix are a rare disease entity and account for only 1-2% of cervical carcinomas. The small-cell variant is the most common, with a worse prognosis and a higher rate of lymphatic and hematogenous metastases when compared with other subtypes of NEC. The diagnosis is usually made when the extra-pelvic disease is already apparent. Cushing’s syndrome due to adrenocorticotropic hormone (ACTH)-secreting tumors of the cervix is exceedingly rare. To date, there have been no reported cases in the literature of Cushing’s syndrome induced by the recurrence of metastases years after the initial diagnosis. This is a case of recurrent small-cell neuroendocrine carcinoma of the cervix presenting with Cushing’s syndrome five years after her original diagnosis. We present here the workup, management, and follow-up of this patient, including multisystemic, coordinated medical care.

Introduction

Neuroendocrine carcinomas (NECs) are heterogenous groups of tumors derived from neuroendocrine cells. NECs of the cervix are rare and account for 1-2% of all cervical carcinomas, with the small-cell variant being the most common [1,2]. Small-cell NECs have a high rate of lymphatic and hematogenous metastasis even when the carcinoma is limited to the cervix. Patients usually present at a late stage, with the extra-pelvic disease being apparent at the time of diagnosis [2]. Among the different histologic variants of NEC of the cervix, the small-cell variant has the highest rate of recurrence [3]. Adrenocorticotropic hormone (ACTH)-secreting tumors of the cervix are rare [4]. We present a case of recurrent metastatic NEC of the cervix five years after the original diagnosis of NEC of the cervix, now presenting with Cushing’s syndrome [1,2].

Case Presentation

A 39-year-old female with a history of recurrent small-cell cervical cancer presented to the emergency department (ED) of our hospital with complaints of weight gain, generalized facial edema, lightheadedness, tingling sensation of her entire face, bilateral leg edema, and abdominal distention.

Her problems started a month prior to her ED visit, when she started to complain of abdominal distention. She had a computed tomography (CT) abdomen with contrast, which revealed evidence of metastatic disease, including multiple large liver lesions (Figure 1). Subsequently, she had a positron emission tomography (PET) scan, which confirmed the presence of hypermetabolic lesions in the right peritonsillar tissue, liver, right lower quadrant of the abdomen, and bilateral pulmonary nodules with lymphadenopathy in the left hilum (Figure 2). A liver biopsy was done, with the final pathology consistent with recurrent NEC of the cervix. She was started on cisplatin, etoposide, and atezolizumab by gynecologic oncology but started to develop facial swelling and progressive abdominal distention, prompting this ED consult and subsequent admission.

Abdomial-CT-with-contrast-done-one-month-prior-showed-evidence-of-metastatic-disease-including-multiple-large-liver-lesions.
Figure 1: Abdomial CT with contrast done one month prior showed evidence of metastatic disease including multiple large liver lesions.
PET/CT-demonstrated-the-presence-of-hypermetabolic-lesions-in-the-liver-and-right-lower-quadrant-of-the-abdomen.
Figure 2: PET/CT demonstrated the presence of hypermetabolic lesions in the liver and right lower quadrant of the abdomen.

She had a significant medical history of being diagnosed with cervical cancer (FIGO stage 1B2 NEC) five years prior by gynecologic oncology, at which time she underwent concurrent chemo-radiation followed by surgical assessment of her pelvic lymph nodes with robotic pelvic lymph node dissection and bilateral ovarian transposition to avoid premature menopause. She was subsequently treated with cisplatin and pelvic radiation. She had a follow-up cervical biopsy several months after chemotherapy, which showed persistent NEC, but her PET scan showed no evidence of metastatic disease. After undergoing a robotic total laparoscopic hysterectomy, the final pathology showed a persistent microscopic focus of NEC of the cervix with negative margins. She received adjuvant chemotherapy with cisplatin and etoposide for six cycles with regular follow-up pap smears and annual PET scans, with no evidence of recurrence for five years.

On admission, her vital signs were: blood pressure = 129/79 mm Hg, pulse rate = 85/min, respiratory rate = 18/min, and temperature = 98.5 °F (36.9 °C). Her physical examination was notable for moon facies (a noticeable change from her pictures as recent as two months prior), supraclavicular and dorsocervical fat pads, multiple bruises on her arms, edema of her face and legs, acne of her face and neck, and hair growth of her chin area. No purple striae were seen on the abdomen.

Laboratory tests revealed leukopenia and thrombocytopenia (which were attributed to her chemotherapy), recently diagnosed diabetes (occasional hyperglycemia and HbA1c 7.7%), and electrolyte imbalances (hypokalemia and hypophosphatemia) (Table 1).

Sodium 142 mEq/L (135–145 mEq/L)
Potassium 2.0 mEq/L (3.5–5.0 mEq/L)
Chloride 98 mEq/L (98–108 mEq/L)
CO2 35 mEq/L (21–32 mEq/L)
Anion gap 9 mEq/L (8–16 mEq/L)
BUN 14 mg/dL (7–13 mEq/L)
Creatinine 1.13 mg/dL (0.6–1.1 mg/dL)
Glucose 460 mg/dL (74–100 mg/dL)
Calcium 7.8 mg/dL (8.5–10.1 mg/dL)
Phosphorous 1.0 mg/dL (2.5–4.5 mg/dL)
Albumin 2.5 mg/dL (3.1–4.5 mg/dL)
AST 43 U/L (15–27 U/L)
ALT 76 U/L (12–78 U/L)
White blood cell count 0.6 k/cmm (4.5–10.0 k/cmm)
Red blood cell count 3.55 million cells/μL (3.7–5 × 2)
Hemoglobin 11.9 g/dL (12.0–16.0)
Hematocrit 34.3% (35.0–47.0)
Platelet 45 k/cmm (150–440 k/cmm)
Table 1: Initial laboratory work showed leukopenia, thrombocytopenia, hyperglycemia, hypokalemia, and hypophosphatemia.

AST: aspartate aminotransferase, CO2: carbon dioxide, BUN: blood urea nitrogen, ALT: alanine aminotransferase.

Her chest X-ray showed bilateral pleural effusions. Magnetic resonance imaging (MRI) of the brain showed no evidence of pituitary masses, abnormalities, or metastatic disease in the brain. A CT of the chest showed new bilateral non-calcified lung nodules when compared to the previous PET scan, pathologic-sized left hilar adenopathy, and multiple peripherally enhancing hepatic nodules and masses (Figure 3). The adrenal glands were unremarkable. Workup for facial swelling and bilateral leg edema showed no evidence of superior vena cava (SVC) syndrome on both her chest CT and transthoracic echocardiogram.

Contrast-enhanced-chest-CT-showing-bilateral-noncalcified-lung-nodules.
Figure 3: Contrast-enhanced chest CT showing bilateral noncalcified lung nodules.

She was admitted to the intensive care unit (ICU) and started on empiric antibiotics and filgrastim for neutropenia. Replacement therapy for both hypokalemia and hypophosphatemia was given. After both electrolytes were normalized, the patient was started on basal-bolus insulin therapy.

Based on her clinic presentation of excessive weight gain, new-onset hyperglycemia, hypertension with hypokalemia, and a history of NEC, suspicion of Cushing’s syndrome was high. Further workup showed elevated serum cortisol after 1 mg overnight dexamethasone suppression, elevated 24-hour urine cortisol, and elevated midnight salivary cortisol, which confirmed Cushing’s syndrome (Table 2). ACTH was also elevated, but dehydroepiandrosterone sulfate (DHEAS) was normal. Thyroid function tests showed a slightly low free thyroxine, but this was attributed to an acute illness.

HgbA1C 7.7% (4.0-6.0%)
ACTH 1207 pg/mL (7.2–63.3 pg/mL)
24-hour urine cortisol 7070 μg/24 hr (6–42 μg/24 hr)
Salivary cortisol >1.000 μg /dL (0.025–0.600 μg/dL)
Serum cortisol after 1 mg overnight dexamethasone suppression 143.0 μg/dL (3.1–16.7 μg/dL)
Total testosterone 77 ng/dL (14–76 ng/dL)
DHEAS 250.0 μg/dL (57.3–279.2 μg/dL)
Chromogranin A 970.9 ng/mL (0.0–101.8 ng/mL)
TSH 0.572 mIU/L (0.358–3.74mIU/L)
Free T4 0.70 ng/dl (0.76–1.46) ng/dl
Table 2: Work up showed elevated ACTH, elevated 24-hour urine cortisol, elevated salivary cortisol, and elevated serum cortisol after 1 mg overnight dexamethasone suppression test.

HgbA1C: hemoglobin A1C; ACTH: adrenocorticotropic hormone; DHEAS: dehydroepiandrosterone sulfate; TSH: thyroid stimulating hormone; free T4: free thyroxine.

A diagnosis of Cushing’s syndrome due to metastatic small-cell neuroendocrine carcinoma of the cervix was assumed. A bilateral adrenalectomy, which is the definitive treatment of hypercortisolism when surgical removal of the source of excess ACTH is done, was not done because gynecologic oncology wanted to treat her with chemotherapy urgently due to her metastases and the nature of the disease and felt that surgery and recovery would delay the start of chemotherapy. Ketoconazole was felt to be a poor choice in the setting of liver metastases with worsening liver function tests. The patient was thus started on mifepristone 300 mg daily, as it is indicated for hypercortisolism secondary to endogenous Cushing’s syndrome with diabetes. Nephrology was consulted, and potassium supplementation was transitioned to oral potassium chloride 40 meq tablets four times a day; spironolactone 50 mg twice daily was added for the hypokalemia and hypertension, which occurred after the patient started bevacizumab. Hypokalemia is a common side effect of mifepristone therapy due to the glucocorticoid receptor blockade, which leads to cortisol’s spillover effect on unopposed mineralocorticoid receptors. She was discharged home with a basal-bolus insulin regimen.

Her posthospitalization course was complicated by compression fractures of her lumbar spine one week after discharge with no history of falls. An MRI of the spine showed chronic compression fractures of the T11-L3 vertebral bodies with no evidence of osseous metastatic disease. Dual-energy X-ray absorptiometry (DXA) scan interpretation demonstrated osteoporosis. Vertebral fracture assessment showed morphometric fractures in the lower thoracic and upper lumbar vertebrae. She was subsequently treated with IV administration of 5 mg of zoledronic acid. She was also readmitted multiple times after her initial admission due to the patient’s developing neutropenic fever, which was treated with filgrastim and antibiotics.

After starting mifepristone, her glycemic control improved to the point that insulin therapy could be subsequently discontinued. Her liver enzymes normalized, and ketoconazole was subsequently added for adjunct therapy to treat hypercortisolism, but the dose could not be optimized due to persistently elevated liver function tests. Hypokalemia management and resistant hypertension were additional challenges encountered by this patient.

At her follow-up visits, she had notably lost weight with the improvement of her leg edema. She continued to follow up with a nephrologist on an outpatient basis, and her normal potassium levels were normal on 40 meq of oral potassium chloride tablets four times a day and spironolactone 150 mg twice a day. She was followed up closely by her gynecologic oncologist and was on bevacizumab, topotecan, and paclitaxel before her unfortunate demise a few months later.

Discussion

Cushing’s syndrome due to ectopic ACTH secretion only represents 9-18% of cases. Most primary endocrine tumors responsible for ectopic ACTH secretion are located in the chest [5]. Abdominal and retroperitoneal neuroendocrine tumors are the second- and third-most reported sites [5]. Neuroendocrine tumors of the cervix are incredibly rare [6-9].

A unique feature of this case is that the patient presented with Cushing’s syndrome due to neuroendocrine tumor metastases found five years after the primary site of the tumor was resected. For this patient, a biopsy of the liver confirmed a metastatic neuroendocrine tumor, but it is unknown if the other sites of metastases are implicated in the production of excess ACTH.

The management of this disease focuses on controlling hypercortisolism, consequent hyperglycemia, and hypokalemia. Surgical excision of ACTH-secreting neuroendocrine tumors is the most effective, but in cases where that is not possible, bilateral adrenalectomy and medical treatment are the next best treatments for this disease entity [10]. For this patient, bilateral adrenalectomy was not done as gynecologic oncology wanted to treat her with chemotherapy urgently due to the metastases and nature of the disease and felt that surgery and recovery would delay the start of chemotherapy.

We provided medical management for the patient’s hypercortisolism. Pharmacological therapy for hypercortisolism can be categorized into immediate-acting steroidogenesis inhibitors (metyrapone, ketoconazole, and etomidate), slow-acting cortisol-lowering drugs (mitotane), and glucocorticoid receptor antagonists (mifepristone) [5]. We initially chose mifepristone because it is indicated in patients with type 2 diabetes mellitus and could be given safely despite the patient’s worsening liver function levels [11].

As demonstrated, the management of recurrent hypokalemia proved challenging in this patient. The phenomenon is well known to be induced by ectopic ACTH. Several mechanisms contribute to this. Activation of renal tubular type 1 (mineralocorticoid) receptors by cortisol is thought to be the mechanism that applies mainly to patients with severe hypercortisolism due to ectopic ACTH secretion. Additionally, there may also be an increase in the production of renin substrate from the liver. The high serum cortisol concentrations may not be completely inactivated by 11β-hydroxysteroid dehydrogenase type 2 in the kidney and overwhelm its ability to convert cortisol to cortisone, resulting in activation of mineralocorticoid receptors resulting in potassium loss in the distal tubules [12]. Hypokalemia may also result from adrenal hypersecretion of mineralocorticoids, such as deoxycorticosterone and corticosterone. This can also be amplified by mifepristone, as it is a glucocorticoid receptor antagonist that increases circulating cortisol levels [12].

Complications such as hypokalemia, hyperglycemia, acute respiratory distress syndrome, infections, muscle wasting, hypertension, and bone fractures can occur and can arise at any time throughout the course of the disease when urine-free cortisol is fivefold or more above the upper limit of normal [5]. Ketoconazole was initially considered for medical treatment, but due to mildly elevated liver enzymes during the initial presentation, we decided to use mifepristone instead. A small cohort study showed that severe hypercortisolism and increased baseline transaminase levels could be due to cortisol-induced hepatic steatosis [13]. Later in her course, ketoconazole was added to her mifepristone therapy to decrease adrenal cortisol production. Unfortunately, her dose could not be increased due to the patient’s persistently elevated liver enzymes.

Recurrent pancytopenia due to chemotherapy contributed to the protracted nature of this patient’s clinical course. Due to cortisol’s immunosuppressive and anti-inflammatory effects, opportunistic infections can arise [14]. Since her initial hospitalization, she has been readmitted several times due to neutropenic fever, which was treated with filgrastim and antibiotics.

Conclusions

Ectopic Cushing’s syndrome due to metastatic neuroendocrine small-cell carcinoma is a rare condition with a poor prognosis. The options for treatment are few and not necessarily curative. There needs to be increased awareness of this serious and rare complication. Managing the condition can be a challenge and requires a multidisciplinary team approach to improve outcomes.

References

  1. Cohen JG, Kapp DS, Shin JY, et al.: Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients. Am J Obstet Gynecol. 2010, 203:347.e1-6. 10.1016/j.ajog.2010.04.019
  2. Salvo G, Gonzalez Martin A, Gonzales NR, Frumovitz M: Updates and management algorithm for neuroendocrine tumors of the uterine cervix. Int J Gynecol Cancer. 2019, 29:986-95. 10.1136/ijgc-2019-000504
  3. Stecklein SR, Jhingran A, Burzawa J, Ramalingam P, Klopp AH, Eifel PJ, Frumovitz M: Patterns of recurrence and survival in neuroendocrine cervical cancer. Gynecol Oncol. 2016, 143:552-7. 10.1016/j.ygyno.2016.09.011
  4. Chen J, Macdonald OK, Gaffney DK: Incidence, mortality, and prognostic factors of small cell carcinoma of the cervix. Obstet Gynecol. 2008, 111:1394-402. 10.1097/AOG.0b013e318173570b
  5. Young J, Haissaguerre M, Viera-Pinto O, Chabre O, Baudin E, Tabarin A: Management of Endocrine Disease: Cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion. Eur J Endocrinol. 2020, 182:R29-58. 10.1530/EJE-19-0877
  6. Hashi A, Yasumizu T, Yoda I, et al.: A case of small cell carcinoma of the uterine cervix presenting Cushing’s syndrome. Gynecol Oncol. 1996, 61:427-31. 10.1006/gyno.1996.0168
  7. Iemura K, Sonoda T, Hayakawa A, et al.: Small cell carcinoma of the uterine cervix showing Cushing’s syndrome caused by ectopic adrenocorticotropin hormone production. Jpn J Clin Oncol. 1991, 21:293-8.
  8. Barghouthi N, Perini J, Cheng J: Ectopic adrenocorticotropic hormone production: a case of neuroendocrine cervical small cell carcinoma presenting as Cushing syndrome. AACE Clin Case Rep. 2018, 4:e367-e369. 10.4158/ACCR-2018-0080
  9. Di Filippo L, Vitali G, Taccagni G, Pedica F, Guaschino G, Bosi E, Martinenghi S: Cervix neuroendocrine carcinoma presenting with severe hypokalemia and Cushing’s syndrome. Endocrine. 2020, 67:318-20. 10.1007/s12020-020-02202-x
  10. Ilias I, Torpy DJ, Pacak K, Mullen N, Wesley RA, Nieman LK: Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the National Institutes of Health. J Clin Endocrinol Metab. 2005, 90:4955-62. 10.1210/jc.2004-2527
  11. Biller BM, Grossman AB, Stewart PM, et al.: Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab. 2008, 93:2454-62. 10.1210/jc.2007-2734
  12. Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross 😄 Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab. 2012, 97:2039-49. 10.1210/jc.2011-3350
  13. Young J, Bertherat J, Vantyghem MC, Chabre O, Senoussi S, Chadarevian R, Castinetti F: Hepatic safety of ketoconazole in Cushing’s syndrome: results of a Compassionate Use Programme in France. Eur J Endocrinol. 2018, 178:447-58. 10.1530/EJE-17-0886
  14. Sarlis NJ, Chanock SJ, Nieman LK: Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin. J Clin Endocrinol Metab. 2000, 85:42-47. 10.1210/jcem.85.1.6294

 

From https://www.cureus.com/articles/111698-recurrent-neuroendocrine-tumor-of-the-cervix-presenting-with-ectopic-cushings-syndrome

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Filed under: Cancer, Cushing's, Rare Diseases, symptoms, Treatments | Tagged: , , , | Leave a comment »

Challenging Case of Ectopic ACTH Secretion from Prostate Adenocarcinoma

Posted on May 2, 2022 by MaryO

Abstract

Cushing’s syndrome (CS) secondary to ectopic adrenocorticotrophic hormone (ACTH)-producing prostate cancer is rare with less than 50 cases reported. The diagnosis can be challenging due to atypical and variable clinical presentations of this uncommon source of ectopic ACTH secretion. We report a case of Cushing’s syndrome secondary to prostate adenocarcinoma who presented with symptoms of severe hypercortisolism with recurrent hypokalaemia, limb oedema, limb weakness, and sepsis. He presented with severe hypokalaemia and metabolic alkalosis (potassium 2.5 mmol/L and bicarbonate 36 mmol/L), with elevated 8 am cortisol 1229 nmol/L. ACTH-dependent Cushing’s syndrome was diagnosed with inappropriately normal ACTH 57.4 ng/L, significantly elevated 24-hour urine free cortisol and unsuppressed cortisol after 1 mg low-dose, 2-day low-dose, and 8 mg high-dose dexamethasone suppression tests. 68Ga-DOTANOC PET/CT showed an increase in DOTANOC avidity in the prostate gland, and his prostate biopsy specimen was stained positive for ACTH and markers for neuroendocrine differentiation. He was started on ketoconazole, which was switched to IV octreotide in view of liver dysfunction from hepatic metastases. He eventually succumbed to the disease after 3 months of his diagnosis. It is imperative to recognize prostate carcinoma as a source of ectopic ACTH secretion as it is associated with poor clinical outcomes, and the diagnosis can be missed due to atypical clinical presentations.

1. Introduction

Ectopic secretion of adrenocorticotropic hormone (ACTH) is responsible for approximately 10–20% of all causes of Cushing syndrome [1]. The classic sources of ectopic ACTH secretion include bronchial carcinoid tumours, small cell lung carcinoma, thymoma, medullary thyroid carcinoma (MTC), gastroenteropancreatic neuroendocrine tumours (NET), and phaeochromocytomas [2]. Ectopic adrenocorticotropic syndrome (EAS) is diagnostically challenging due to its variable clinical manifestations; however, prompt recognition and treatment is critical. Ectopic ACTH production from prostate carcinoma is rare, and there are less than 50 cases published to date. Here, we report a case of ectopic Cushing’s syndrome secondary to prostate adenocarcinoma who did not present with the typical physical features of Cushing’s syndrome, but instead with features of severe hypercortisolism such as hypokalaemia, oedema, and sepsis.

2. Case Presentation

A 61-year-old male presented to our institution with recurrent hypokalaemia, lower limb weakness, and oedema. He had a history of recently diagnosed metastatic prostate adenocarcinoma, for which he was started on leuprolide and finasteride. Other medical history includes poorly controlled diabetes mellitus and hypertension of 1-year duration. He presented with hypokalaemia of 2.7 mmol/L associated with bilateral lower limb oedema and weakness, initially attributed to the intake of complementary medicine, which resolved with potassium supplementation and cessation of the complementary medicine. One month later, he was readmitted for refractory hypokalaemia of 2.5 mmol/L and progression of the lower limb weakness and oedema. On examination, his blood pressure (BP) was 121/78 mmHg, and body mass index (BMI) was 24 kg/m2. He had no Cushingoid features of rounded and plethoric facies, supraclavicular or dorsocervical fat pad, ecchymoses, and no purple striae on the abdominal examination. He had mild bilateral lower limb proximal weakness and oedema.

His initial laboratory findings of severe hypokalaemia with metabolic alkalosis (potassium 2.5 mmol/L and bicarbonate 36 mmol/L), raised 24-hour urine potassium (86 mmol/L), suppressed plasma renin activity and aldosterone, central hypothyroidism, and elevated morning serum cortisol (1229 nmol/L) (Table 1) raised the suspicion for endogenous hypercortisolism. Furthermore, hormonal evaluations confirmed ACTH-dependent Cushing’s syndrome with inappropriately normal ACTH (56 ng/L) and failure of cortisol suppression after 1 mg low-dose, 2-day low-dose, and 8 mg high-dose dexamethasone suppression tests (Table 2). His 24-hour urine free cortisol (UFC) was significantly elevated at 20475 (59–413) nmol/day.

Table 1 
Investigations done during his 2nd admission.
Table 2 
Diagnostic workup for hypercortisolism.

To identify the source of excessive cortisol secretion, magnetic resonance imaging (MRI) of the pituitary fossa and computed tomography (CT) of the thorax, abdomen, and pelvis were performed. Pituitary MRI was unremarkable, and CT scan showed the known prostate lesion with extensive liver, lymph nodes, and bone metastases (Figure 1). To confirm that the prostate cancer was the source of ectopic ACTH production, gallium-68 labelled somatostatin receptor positron emission tomography (PET)/CT (68Ga-DOTANOC) was done, which showed an increased DOTANOC avidity in the inferior aspect of the prostate gland (Figure 2). Immunohistochemical staining of his prostate biopsy specimen was requested, and it stained positive for ACTH and markers of neuroendocrine differentiation (synaptophysin and CD 56) (Figures 3 and 4), establishing the diagnosis of EAS secondary to prostate cancer.

Figure 1 
CT thorax abdomen and pelvis showing prostate cancer (blue arrow) with liver metastases (red arrow).
Figure 2 
Ga68-DOTANOC PET/CT demonstrating increased DOTANOC avidity seen in the inferior aspect of the right side of the prostate gland (red arrow).
Figure 3 
Hematoxylin and eosin staining showing acinar adenocarcinoma of the prostate featuring enlarged, pleomorphic cells infiltrating as solid nests and cords with poorly differentiated glands (Gleason score 5 + 4 = 9).
Figure 4 
Positive ACTH immunohistochemical staining of prostate tumour (within the circle).

The patient was started on potassium chloride 3.6 g 3 times daily and spironolactone 25 mg once daily with normalisation of serum potassium. His BP was controlled with the addition of lisinopril and terazosin to spironolactone and ketoconazole, and his blood glucose was well controlled with metformin and sitagliptin. To manage the hypercortisolism, he was treated with ketoconazole 400 mg twice daily with an initial improvement of serum cortisol from 2048 nmol/L to 849 nmol/L (Figure 5). Systemic platinum and etoposide-based chemotherapy was recommended for the treatment of his prostate cancer after a multidisciplinary discussion, but it was delayed due to severe bacterial and viral infection. With the development of liver dysfunction, ketoconazole was switched to intravenous octreotide 100 mcg three times daily as metyrapone was not readily available in our country. However, the efficacy was suboptimal with marginal reduction of serum cortisol from 3580 nmol/L to 3329 nmol/L (Figure 5). The patient continued to deteriorate and was deemed to be medically unfit for chemotherapy or bilateral adrenalectomy. He was referred to palliative care services, and he eventually demised due to cancer progression within 3 months of his diagnosis.

Figure 5 
The trend in cortisol levels on pharmacological therapy.

3. Discussion

Ectopic ACTH secretion is an uncommon cause of Cushing’s syndrome accounting for approximately 9–18% of the patients with Cushing’s syndrome [3]. Clinical presentation is highly variable depending on the aggressiveness of the underlying malignancy, but patients typically present with symptoms of severe hypercortisolism such as hypokalaemiaa, oedema, and proximal weakness which were the presenting complaints of our patient [4]. The classical symptoms of Cushing’s syndrome are frequently absent due to the rapid clinic onset resulting in diagnostic delay [5].

Prompt diagnosis and localisation of the source of ectopic ACTH secretion are crucial due to the urgent need for treatment initiation. The usual sources include small cell lung carcinoma, bronchial carcinoid, medullary thyroid carcinoma, thymic carcinoid, and pheochromocytoma. CT of the thorax, abdomen, and pelvis should be the first-line imaging modality, and its sensitivity varies with the type of tumour ranging from 77% to 85% [6]. Functional imaging such as 18-fluorodeoxyglucose-PET and gallium-68 labelled somatostatin receptor PET/CT can be useful in localising the source of occult EAS, determining the neuroendocrine nature of the tumour or staging the underlying malignancy [3, 6]. As prostate cancer is an unusual cause of EAS, we proceeded with 68Ga-DOTANOC PET/CT in our patient to localise the source of ectopic ACTH production.

The goals of management in EAS include treating the hormonal excess and the underlying neoplasm as well as managing the complications secondary to hypercortisolism [3]. Prompt management of the cortisol excess is paramount as complications such as hyperglycaemia, hypertension, hypokalaemia, pulmonary embolism, sepsis, and psychosis can develop especially when UFC is more than 5 times the upper limit of normal [3]. Ideally, surgical resection is the first-line management, but this may not be feasible in metastatic, advanced, or occult diseases.

Pharmacological agents are frequently required with steroidogenesis inhibitors such as ketoconazole and metyrapone, which reduce cortisol production effectively and rapidly [3, 6], the main drawback of ketoconazole being its hepatic toxicity. The efficacy of ketoconazole is reported to be 44%, metyrapone 50–75%, and ketoconazole-metyrapone combination therapy 73% [3, 7]. Mitotane, typically used in adrenocortical carcinoma, is effective in controlling cortisol excess but has a slow onset of action [3, 8]. Etomidate infusion can be used for short-term rapid control of severe symptomatic hypercortisolism and can serve as a bridge to definitive therapy [9]. Mifepristone, a glucocorticoid receptor antagonist, is indicated mainly in difficult to control hyperglycaemia secondary to hypercortisolism [8]. Somatostatin analogue has been proposed as a possible pharmacological therapy due to the expression of somatostatin receptors by ACTH secreting tumours [8, 10]. Bilateral adrenalectomy should be considered in patients with severe symptomatic hypercortisolism and life-threatening complications who cannot be optimally managed with medical therapies, especially in patients with occult EAS or metastatic disease [3, 8]. Bilateral adrenalectomy results in immediate improvement in cortisol levels and symptoms secondary to hypercortisolism [11]. However, surgical complications, morbidity, and mortality are high in patients with uncontrolled hypercortisolism [8], and our patient was deemed by his oncologist and surgeon to have too high a risk for bilateral adrenalectomy. For the treatment of prostate carcinoma, platinum and etoposide-based chemotherapies have been used, but their efficacy is limited with a median survival of 7.5 months [4, 12]. The side effects of chemotherapy can be severe with an enhanced risk of infection due to both cortisol and chemotherapy-mediated immunosuppression. Prompt control of hypercortisolism prior to chemotherapy and surgical procedure is strongly suggested to attenuate life-threatening complications such as infection, thrombosis, and bleeding with chemotherapy or surgery as well as to improve prognosis [3, 13].

There are rare reports of ectopic ACTH secretion from prostate carcinoma. These tumours were predominantly of small cell or mixed cell type, and pure adenocarcinoma with neuroendocrine differentiation are less common [4, 5]. There is a strong correlation between the prognosis and the types of malignancy in patients with EAS, and patients with prostate carcinoma have a poor prognosis [4]. These patients had metastatic disease at presentation, and the median survival was weeks to months despite medical treatment, chemotherapy, and even bilateral adrenalectomy [4], as seen with our patient who passed away within 3 months of his diagnosis.

In conclusion, adenocarcinoma of the prostate is a rare cause of EAS. The diagnosis and management are complex and challenging requiring specialised expertise with multidisciplinary involvement. The presentation can be atypical, and it is imperative to suspect and recognise prostate carcinoma as a source of ectopic ACTH secretion. Prompt initiation of treatment is important, as it is a rapidly progressive and aggressive disease associated with intense hypercortisolism resulting in high rates of mortality and morbidity.

Data Availability

The data used to support the findings of this study are included within the article.

Conflicts of Interest

The authors declare that there are no conflicts of interest.

Acknowledgments

The authors would like to thank the Pathology Department of Changi General Hospital for their contribution to this case.

References

  1. I. Ilias, D. J. Torpy, K. Pacak, N. Mullen, R. A. Wesley, and L. K. Nieman, “Cushing’s syndrome due to ectopic corticotropin secretion: twenty years’ experience at the national institutes of health,” Journal of Clinical Endocrinology & Metabolism, vol. 90, no. 8, pp. 4955–4962, 2005.View at: Publisher Site | Google Scholar
  2. J. Newell-Price, P. Trainer, M. Besser, and A. Grossman, “The diagnosis and differential diagnosis of cushing’s syndrome and pseudo-cushing’s states,” Endocrine Reviews, vol. 19, no. 5, pp. 647–672, 1998.View at: Publisher Site | Google Scholar
  3. J. Young, M. Haissaguerre, O. Viera-Pinto, O. Chabre, E. Baudin, and A. Tabarin, “Management of endocrine disease: cushing’s syndrome due to ectopic ACTH secretion: an expert operational opinion,” European Journal of Endocrinology, vol. 182, no. 4, pp. R29–R58, 2020.View at: Publisher Site | Google Scholar
  4. M. S. Elston, V. B. Crawford, M. Swarbrick, M. S. Dray, M. Head, and J. V. Conaglen, “Severe Cushing’s syndrome due to small cell prostate carcinoma: a case and review of literature,” Endocrine Connections, vol. 6, no. 5, pp. R80–R86, 2017.View at: Publisher Site | Google Scholar
  5. O. M. Alshaikh, A. A. Al-Mahfouz, H. Al-Hindi, A. B. Mahfouz, and A. S. Alzahrani, “Unusual cause of ectopic secretion of adrenocorticotropic hormone: cushing syndrome attributable to small cell prostate cancer,” Endocrine Practice, vol. 16, no. 2, pp. 249–254, 2010.View at: Publisher Site | Google Scholar
  6. A. Sundin, R. Arnold, E. Baudin et al., “ENETS consensus guidelines for the standards of care in neuroendocrine tumors: radiological, nuclear medicine and hybrid imaging,” Neuroendocrinology, vol. 105, no. 3, pp. 212–244, 2017.View at: Publisher Site | Google Scholar
  7. J.-B. Corcuff, J. Young, P. Masquefa-Giraud, P. Chanson, E. Baudin, and A. Tabarin, “Rapid control of severe neoplastic hypercortisolism with metyrapone and ketoconazole,” European Journal of Endocrinology, vol. 172, no. 4, pp. 473–481, 2015.View at: Publisher Site | Google Scholar
  8. L. K. Nieman, B. M. K. Biller, J. W. Findling et al., “Treatment of cushing’s syndrome: an endocrine society clinical practice guideline,” Journal of Clinical Endocrinology & Metabolism, vol. 100, no. 8, pp. 2807–2831, 2015.View at: Publisher Site | Google Scholar
  9. T. B. Carroll, W. J. Peppard, D. J. Herrmann et al., “Continuous etomidate infusion for the management of severe cushing syndrome: validation of a standard protocol,” Journal of the Endocrine Society, vol. 3, no. 1, pp. 1–12, 2019.View at: Publisher Site | Google Scholar
  10. K. Von Werder, O. A. Muller, and G. K. Stalla, “Somatostatin analogs in ectopic corticotropin production,” Metabolism, vol. 45, pp. 129–131, 1996.View at: Publisher Site | Google Scholar
  11. N. Klomjit, D. J. Rowan, A. G. Kattah, I. Bancos, and S. J. Taler, “New-onset resistant hypertension in a newly diagnosed prostate cancer patient,” American Journal of Hypertension, vol. 32, no. 12, pp. 1214–1217, 2019.View at: Publisher Site | Google Scholar
  12. R. Nadal, M. Schweizer, O. N. Kryvenko, J. I. Epstein, and M. A. Eisenberger, “Small cell carcinoma of the prostate,” Nature Reviews Urology, vol. 11, no. 4, pp. 213–219, 2014.View at: Publisher Site | Google Scholar
  13. F. A. Collichio, P. D. Woolf, and M. Brower, “Management of patients with small cell carcinoma and the syndrome of ectopic corticotropin secretion,” Cancer, vol. 73, no. 5, pp. 1361–1367, 1994.View at: Google Scholar

Copyright © 2022 Wanling Zeng and Joan Khoo. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

From https://www.hindawi.com/journals/crie/2022/3739957/

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Treatment for Rare Cancer May Help Cushing’s Patients

Posted on February 5, 2021 by MaryO

The cancer medicine bexarotene may hold promise for treating Cushing’s disease, a study suggests.

The study, “Targeting the TR4 nuclear receptor with antagonist bexarotene can suppress the proopiomelanocortin signalling in AtT‐20 cells,” was published in the Journal of Cellular and Molecular Medicine.

Cushing’s disease is caused by a tumor on the pituitary gland, leading this gland to produce too much adrenocorticotropic hormone (ACTH). Excess ACTH causes the adrenal glands to release too much of the stress hormone cortisol; abnormally high cortisol levels are primarily responsible for the symptoms of Cushing’s.

Typically, first-line treatment is surgical removal of the pituitary tumor. But surgery, while effective in the majority of cases, does not help all. Additional treatment with medications or radiation therapy (radiotherapy) works for some, but not others, and these treatments often have substantial side effects.

“Thus, the development of new drugs for CD [Cushing’s disease] treatment is extremely urgent especially for patients who have low tolerance for surgery and radiotherapy,” the researchers wrote.

Recent research has shown that a protein called testicular receptor 4 (TR4) helps to drive ACTH production in pituitary cancers. Thus, blocking the activity of TR4 could be therapeutic in Cushing’s disease.

Researchers conducted computer simulations to screen for compounds that could block TR4. This revealed bexarotene as a potential inhibitor. Further biochemical tests confirmed that bexarotene could bind to, and block the activity of, TR4.

Bexarotene is a type of medication called a retinoid. It is approved to treat cutaneous T-cell lymphoma, a rare cancer that affects the skin, and available under the brand name Targretin.

When pituitary cancer cells in dishes were treated with bexarotene, the cells’ growth was impaired, and apoptosis (a type of programmed cell death) was triggered. Bexarotene treatment also reduced the secretion of ACTH from these cells.

In mice with ACTH-secreting pituitary tumors, bexarotene’s use significantly reduced tumor size, and lowered levels of ACTH and cortisol. Cushing’s-like symptoms also eased; for example, bexarotene treatment reduced the accumulation of fat around the abdomen in these mice.

Additional cellular experiments suggested that bexarotene specifically works on TR4 by changing the location of the protein. Normally, TR4 is present in the nucleus — the cellular compartment that houses DNA — where it helps to control the production of ACTH.

But with bexarotene treatment, TR4 tended to go outside of the nucleus, leading to lower ACTH production. The researchers noted that other mechanisms may also be involved in the observed effects of bexarotene.

“In summary, our work demonstrates that bexarotene is a potential inhibitor for TR4. Importantly, bexarotene may represent a new drug candidate to treat CD,” the researchers concluded.

From https://cushingsdiseasenews.com/2021/02/05/bexarotene-cancer-drug-t-cell-lymphoma-acth-production/?preview_id=39289

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