Introduction: Neuroendocrine neoplasms encompass well-differentiated tumors (NETs) and poorly differentiated carcinomas (neuroendocrine carcinomas [NECs]), which are distinguished by their clinical behavior and molecular characteristics. They can cause paraneoplastic syndromes, such as ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS), necessitating prompt recognition and management due to severe hypercortisolism. Case Presentation: A 66-year-old patient with a 3-year history of metastatic mixed neuroendocrine-non-neuroendocrine neoplasm with a NEC and adenocarcinoma component originating from the vulva presented to the emergency department with dyspnea and fatigue. Upon clinical examination, we found widespread hyperpigmentation, a moon-face appearance, hirsutism, buffalo hump, and muscle atrophy. Laboratory investigations revealed severe hypokalemia (2.3 mmol/L), elevated serum cortisol (1,726 nmol/L) and ACTH (194 ng/L) levels. Urinary free cortisol measurement was 21-fold the upper limit of the reference range (3,614.0 nmol/24 h), and cortisol concentration did not decrease after 1mg-dexamethasone suppression test (1,812 nmol/L for an expected value <50 nmol/L), confirming the ACTH-dependent CS. Thoracoabdominal computed tomography (CT) scan demonstrated progressive neoplastic disease in the liver, kidney, lymph nodes, peritoneum, and lungs. Brain magnetic resonance imaging indicated multifocal metastatic infiltration but no evidence of pituitary adenoma. Interestingly, despite a previously negative 68Ga-DOTATATE positron emission tomography (PET)/CT performed 1 year prior, there was moderate somatostatin receptor (SSTR) expression in lymphatic, pulmonary, peritoneal, and bone tissues, suggesting the presence of a component with redifferentiation and re-expression of the SSTR. After the workup, the patient was admitted to a supportive care facility. Hypercortisolism symptoms were effectively managed with an adrenal enzyme inhibitor (ketoconazole) in combination with somatostatin analogs. Unfortunately, the patient was too frail to benefit from peptide receptor radionuclide therapy (PRRT). Conclusion: This redifferentiation phenomenon in neuroendocrine tumors should be further investigated as patients might be, under certain conditions, eligible for PRRT. Therefore, we suggest that newly occurring paraneoplastic syndromes in patients with NEC should always be evaluated using 68Ga-DOTATATE PET/CT.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies arising from different anatomic sites. In the latest WHO guidelines 2019, NENs are separated into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) as these two types of NENs differ substantially in their clinical behavior, evolution, management, and molecular underpinnings [1, 2].

Furthermore, NETs are graded as G1, G2, or G3 based on the mitotic rate and Ki-67 labelling index [2]. NECs have a relatively high Ki-67 index, greater than 20% in essentially all cases and commonly above 50% in the large cell variant and close to 90% in the small cell variant [3, 4].

NENs of varying anatomical locations can cause paraneoplastic syndromes like ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing’s syndrome (CS) (EAS). EAS is caused by unregulated ACTH and/or CRH secretion by NENs.

EAS is a rare form of ACTH-dependent CS. It is estimated that approximately 10% of endogenous CS cases are of paraneoplastic origin, with around 50% of these attributed to lung NETs [5]. Prevalence of EAS with thoracic and gastroenteropancreatic neuroendocrine tumors is estimated to be 3%. EAS can be due to either well-differentiated tumors, grade I and II NETs with a favorable prognosis, or to more aggressive grade III NET and NEC with a worse prognosis.

The 5-year survival rate for EAS patients is shorter compared to non-EAS patients, with a median overall survival of 41.4 months for EAS patients and 61.2 months for non-EAS thoracic and gastroenteropancreatic neuroendocrine tumor patients [6]. These ectopic ACTH-secreting tumors typically lead to severe hypercortisolism and require complex treatment strategies [7‒10]. Early recognition and rapid management are crucial due to the severity of hypercortisolism that can be present. Unfortunately, given the rarity and heterogeneity of the disease, there are no established evidence-based recommendations [11, 12]. We present an exceptionally rare case of a 66-year-old patient without any notable medical history, presenting with a paraneoplastic EAS, emerging 3 years following the initial diagnosis of a MiNEN with a NEC and adenocarcinoma component. The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540707).

History of the Neoplastic Disease

In July 2020, a 62-year-old patient, without any notable medical history, apart from anticoagulated atrial fibrillation, developed a lesion on her right vulva. Subsequently, a partial right vulvectomy with sentinel lymph node biopsy was performed.

An anatomopathological examination showed a MiNEN composed predominantly of a neuroendocrine component, with a 35% adenocarcinoma component. The neuroendocrine component expressed keratin 7 and 20 weakly, and focal expression of chromogranin, synaptophysin, and CD56 was observed. The neuroendocrine component was poorly differentiated. Ki-67 index was not performed on the sample. The adenocarcinoma component exhibited expression of keratin 7, CDX2, and P16. There was no expression of GATA3 or P63 in the entire tumor. Furthermore, lymph node metastases from the adenocarcinoma component were observed.

Next-generation sequencing on the tumor tissue revealed a mutation in the neurofibromatosis type I (NF1) gene (F250Lfs*31) but also CDK8 amplification, CKS1B amplification, FLT3 amplification, MCL1 amplification, NTRK1 amplification, RB1 loss exons 4–5, and TP53 R333fs*12. The tumor was microsatellite stable, and the tumor mutational burden was estimated at 2 Muts/Mb.

After surgery, the patient received four cycles of adjuvant cisplatin/etoposide chemotherapy, followed by radiotherapy administered to the vulva and the inguinal-pelvic region, completed in January 2021. In August 2021, a recurrence was detected in the lungs and the lower pole of the left kidney. This lesion was biopsied in October 2021, confirming the diagnosis of an undifferentiated NEC with a Ki-67 index at 90% expressing chromogranin and synaptophysin.

From November 2021 to August 2022, the patient was treated with carboplatin AUC 2 combined with etoposide 100 mg a day with disease progression after ten cycles. From September 2022, the patient received then capecitabine 625 mg/m2 with temozolomide 100 mg/m2 followed on November 2022 by everolimus 5 mg a day. Subsequently, a therapy with fluorouracil at a dose of 2,400 mg/m2 and irinotecan at 180 mg/m2 every 3 weeks was initiated, with the first cycle administered in February 2023. After five cycles of chemotherapy, on June 2023, the patient was transitioned to metronomic capecitabine while awaiting inclusion in a phase I clinical trial.

In August 2023, the patient went to the emergency department for worsening dyspnea, fatigue, and abdominal pain. She reported experiencing a gradual increase in fatigue over the past month and worsening difficulty in walking due to muscle weakness. Additionally, she described an exacerbation of dyspnea accompanied by a dry cough.

Clinical Examination

Upon clinical examination, we found widespread hyperpigmentation of the skin, a moon-face appearance, hirsutism, and the presence of a buffalo hump. Furthermore, muscle atrophy was evident, along with a slight lower extremity edema (Fig. 1).

Fig. 1.

Thoraco-abdominal CT. In the thoracic region, we did not find a pulmonary embolism. There was a clear progression of pulmonary metastases. a There was an almost complete involvement of the right lower lobe and the left upper lobe (arrow). b Minor pleural effusions appeared (arrow). In the abdominal region, a known left renal metastasis and retroperitoneal lymph nodes were progressing. c There was also progression in previously identified hepatic metastases (arrow). d Progression was observed in retroperitoneal para-aortic adenopathy and in the left renal metastasis (arrow), invading the local retroperitoneal fat.

Fig. 1.

Thoraco-abdominal CT. In the thoracic region, we did not find a pulmonary embolism. There was a clear progression of pulmonary metastases. a There was an almost complete involvement of the right lower lobe and the left upper lobe (arrow). b Minor pleural effusions appeared (arrow). In the abdominal region, a known left renal metastasis and retroperitoneal lymph nodes were progressing. c There was also progression in previously identified hepatic metastases (arrow). d Progression was observed in retroperitoneal para-aortic adenopathy and in the left renal metastasis (arrow), invading the local retroperitoneal fat.

Close modal

Laboratory Investigations

Based on the clinical examination of the patient, we suspected a CS and sought to confirm the diagnosis with additional biological tests. Laboratory investigations (Table 1) revealed severe hypokalemia (2.3 mmol/L [normal value, NV: 3.4–4.4 mmol/L]), increased urinary potassium excretion, elevated serum cortisol (1,726 nmol/L [NV: 63–535 nmol/L]) and ACTH (194 ng/L [NV: 0–47 ng/L]) levels. Urinary free cortisol (UFC) was markedly elevated (3,614.0 nmol/24 h [NV: 30–145 nmol/24 h]). Cortisol concentration was not decreased after 1 mg-dexamethasone suppression test (1,812 nmol/L for an expected value <50 nmol/L).

Table 1.

Laboratory investigations

Laboratory investigations 
 Hemoglobin, g/dL 14.5 12–16 
 Platelets, /µL 143,000 150,000–440,000 
 White blood cells, /µL 11,470 3,500–11,000 
 Lymphocytes, /µL 530 1,200–3,500 
 C-reactive protein, mg/L 68.8 <5 
 Kalium, mmol/L 2.3 3.4–4.4 
 Chlorine, mmol/L 91 98–107 
 Natrium, mmol/L 139 136–145 
 Urea, mg/dL 29.9 16.6–48.5 
 Creatinine, mg/dL 0.76 0.5–0.9 
 g-GT, Ui/L 544 6–42 
 Lactate dehydrogenase, Ui/L 507 135–214 
 Total bilirubin, mg/dL 0.7 <1.2 
 Serum cortisol (morning), nmol/L 1,764 63–535 
 ACTH (morning), ng/L 194 0–47 
 Serum cortisol (after 1 mg dexamethasone), nmol/L 1,812 63–535 
Arterial blood gas analysis 
 pH 7.55 7.35–7.45 
 pCO2, mm Hg 50 32–45 
 pO2, mm Hg 44 75–104 
 Natrium, mmol/L 138 136–145 
 Kalium, mmol/L 2.6 3.4–4.4 
 Chlorine, mmol/L 86 136–145 
 Glucose, mg/dL 318 70–100 
 Lactate, mmol/L 1.5 0.7–2.0 
 Oxygen saturation, % 84 95–98% 
Urinary investigations 
 Urinary potassium, mmol/g creatinine 159 8–129 
 UFC, nmol/24 h 3,614.0 30–145 
Laboratory investigations 
 Hemoglobin, g/dL 14.5 12–16 
 Platelets, /µL 143,000 150,000–440,000 
 White blood cells, /µL 11,470 3,500–11,000 
 Lymphocytes, /µL 530 1,200–3,500 
 C-reactive protein, mg/L 68.8 <5 
 Kalium, mmol/L 2.3 3.4–4.4 
 Chlorine, mmol/L 91 98–107 
 Natrium, mmol/L 139 136–145 
 Urea, mg/dL 29.9 16.6–48.5 
 Creatinine, mg/dL 0.76 0.5–0.9 
 g-GT, Ui/L 544 6–42 
 Lactate dehydrogenase, Ui/L 507 135–214 
 Total bilirubin, mg/dL 0.7 <1.2 
 Serum cortisol (morning), nmol/L 1,764 63–535 
 ACTH (morning), ng/L 194 0–47 
 Serum cortisol (after 1 mg dexamethasone), nmol/L 1,812 63–535 
Arterial blood gas analysis 
 pH 7.55 7.35–7.45 
 pCO2, mm Hg 50 32–45 
 pO2, mm Hg 44 75–104 
 Natrium, mmol/L 138 136–145 
 Kalium, mmol/L 2.6 3.4–4.4 
 Chlorine, mmol/L 86 136–145 
 Glucose, mg/dL 318 70–100 
 Lactate, mmol/L 1.5 0.7–2.0 
 Oxygen saturation, % 84 95–98% 
Urinary investigations 
 Urinary potassium, mmol/g creatinine 159 8–129 
 UFC, nmol/24 h 3,614.0 30–145 

It is noteworthy that the patient did not use any exogenous corticosteroids (nasal or intra-articular) and did not use contraceptives. Given the confirmation of a severe biological hypercortisolism (UFC: 21-fold ULN) requiring rapid initiation of treatment, we did not carry out any further dynamic investigations.

Radiological Investigations

After confirming the presence of a severe endogenous ACTH-dependent CS by biological testing, we conducted a noninvasive diagnostic strategy to determine its etiology [13, 14]. The history of MiNEN strongly suggested an ectopic source of ACTH hypersecretion, leading to the development of the CS. Brain MRI revealed multifocal metastatic infiltration with no evidence of pituitary adenoma, reasonably ruling out a Cushing’s disease in the particular clinical setting of a known MiNEN.

Thoraco-abdominal CT scan (Fig. 2) demonstrated progressive neoplastic disease in the liver, kidney, lymph nodes, peritoneum, and an important progression of pulmonary metastases, including nearly complete infiltration of the right lower lobe and full involvement of the left upper lobe. No lesions were found in the adrenal glands. The CT angiography ruled out the presence of a pulmonary embolism.

Fig. 2.

68Ga-DOTATATE PET/CT and clinic of the patient. a Negative 68Ga-DOTATATE PET/CT scan in July 2022, 1 year before hospital admission, with the patient not showing any signs of Cushing syndrome. b In August 2023, upon hospital admission, there was a reappearance of low to moderate SSTR expression at the lymphatic, pulmonary, peritoneal, and osseous levels (arrow), suggesting the presence of a differentiated neuroendocrine component. At this moment, the patient exhibited all the signs of Cushing syndrome.

Fig. 2.

68Ga-DOTATATE PET/CT and clinic of the patient. a Negative 68Ga-DOTATATE PET/CT scan in July 2022, 1 year before hospital admission, with the patient not showing any signs of Cushing syndrome. b In August 2023, upon hospital admission, there was a reappearance of low to moderate SSTR expression at the lymphatic, pulmonary, peritoneal, and osseous levels (arrow), suggesting the presence of a differentiated neuroendocrine component. At this moment, the patient exhibited all the signs of Cushing syndrome.

Close modal

Interestingly, despite a previously negative 68Ga-DOTATATE PET/CT scan performed 1 year prior (Fig. 1), there was moderate somatostatin receptor (SSTR) expression in the lymphatic, pulmonary, peritoneal, and bone regions, suggesting the presence of a differentiated neuroendocrine component (Fig. 1). Her overall condition and dyspnea, which necessitated oxygen support during the workup, did not allow for any biopsy of the lesions that re-expressed SSTR.

Management

Considering all these findings and specially the UFC >10-fold ULN in the setting of a known MiNEN progressing on imaging, we concluded to a diagnosis of ectopic ACTH-dependent CS of rapid clinical course and life threatening [15]. As the patient’s clinical condition required rapid treatment, we stopped further investigations and started treatment with ketoconazole, a fast-acting inhibitor of adrenal steroidogenesis, as a curative surgical excision of the causative secretory lesions was not an option, nor was bilateral adrenalectomy. Ketoconazole was gradually increased to 200 mg three times per day with good tolerability and biological response (Table 2). The main aim of this treatment was to control cortisol hypersecretion syndrome.

Table 2.

ACTH and cortisol monitoring during treatment titration

DateTimepoint, daysKetoconazole (dosage)ACTH (NV: 0–47), ng/LMorning plasma cortisol (NV: 63–535), nmol/LUFC (NV: 30–145), nmol/24 h
January 23, 2023  411 
August 02, 2023  190 1,762 
August 05, 2023 D-0 200 mg 1x/j Initiation of treatment with ketoconazole 
August 08, 2023 D-3 200 mg 1x/j 3,614 
August 14, 2023 D-9 200 mg 1x/j 210 1,020 
August 21, 2023 D-15 200 mg 2x/j 1,265 
August 27, 2023 D-16 200 mg 2x/j 182 911 
August 27, 2023 D-22 200 mg 3x/j 1,253 
August 28, 2023 D-23 200 mg 3x/j 209 681 
September 01, 2023 D-27 200 mg 3x/j Initiation of treatment with SST analogs 
September 04, 2023 D-30 200 mg 3x/j 239 
DateTimepoint, daysKetoconazole (dosage)ACTH (NV: 0–47), ng/LMorning plasma cortisol (NV: 63–535), nmol/LUFC (NV: 30–145), nmol/24 h
January 23, 2023  411 
August 02, 2023  190 1,762 
August 05, 2023 D-0 200 mg 1x/j Initiation of treatment with ketoconazole 
August 08, 2023 D-3 200 mg 1x/j 3,614 
August 14, 2023 D-9 200 mg 1x/j 210 1,020 
August 21, 2023 D-15 200 mg 2x/j 1,265 
August 27, 2023 D-16 200 mg 2x/j 182 911 
August 27, 2023 D-22 200 mg 3x/j 1,253 
August 28, 2023 D-23 200 mg 3x/j 209 681 
September 01, 2023 D-27 200 mg 3x/j Initiation of treatment with SST analogs 
September 04, 2023 D-30 200 mg 3x/j 239 

NV, normal value.

In addition to controlling symptoms associated with CS, the patient received somatostatin analogs based on the presence of moderate SSTR expression demonstrated by 68Ga-DOTATATE PET/CT as these also provide control of tumor growth. The frail clinical condition of the patient was a serious drawback to consider PRRT as an additional therapeutic modality. The general condition of the patient also did not allow a new line of chemotherapy.

Therefore, the only therapeutic option was to treat the patient symptomatically. After effective management of the hypercortisolism symptoms, the patient was admitted to a supportive care facility to continue the ketoconazole titration to optimize further the control of hypercortisolism. Upon transfer to palliative care, the patient was administered 200 mg of ketoconazole three times daily.

In addition, a dose of 20 Gy was delivered to the brain in 5 sessions using 6 MV photon beams from the linear accelerator, with a palliative intent. Unfortunately, due to her progressive disease, the patient died several weeks later. The patient refused an autopsy, limiting our ability to conduct further anatomopathological investigations on the lesions that re-expressed SSTR.

Interestingly, in this case is that the patient initially presented with a MiNEN containing a NEC component, which typically does not express SSTR in contrast to well-differentiated NET [16]. In our case, the tumor has been biopsied twice, and we found twice an undifferentiated NET with an elevated Ki-67 index that was estimated at 90% at the second biopsy. Unfortunately, the Ki-67 index has not been described for the first biopsy. Additionally, underlying genomic alterations in RB1 and TP53 are typical of poorly differentiated NEC and are generally not found in well-differentiated NET G3.

Regarding the NF1 mutation, due to the high allelic frequency of this mutation (65%), we sought to exclude a germline mutation linked to neurofibromatosis type 1 (NF1) syndrome. NF1 syndrome is a germline condition that predisposes individuals to several types of cancer including glioma, melanoma, lung cancer, ovarian cancer, breast cancer, colorectal cancer, and hematologic malignancies [17]. We had no access to blood DNA, so we investigated the presence of this mutation in the normal tissue surrounding the tumor. Ultimately, we excluded a germline mutation by not detecting the mutation in the normal tissue. Somatic NF1 mutations are critical drivers in multiple cancers. The identification of a high frequency of somatic NF1 mutations in sporadic tumors indicates that neurofibromin likely plays a role in development far beyond its evident involvement in the tumor predisposition linked to NF1 syndrome [18].

NETs do not typically transform into poorly differentiated NECs or vice versa. Once a specific NEN is diagnosed, recurrences or metastases usually exhibit the same histological characteristics (NET or NEC) as the primary tumor [19]. However, progression from a lower grade (G1 or G2) NET to a NET G3 can be seen within an individual tumor or between topographically or temporally separate metastasis [20, 21]. Yang et al. [22] presented a study where Ki-67 labelling indices of metastatic well-differentiated NETs were assessed; they concluded that nearly half of all tumors showed intertumoral heterogeneity sufficient to change the grade from low to intermediate.

The natural history of NETs involves a genome-wide loss of DNA methylation as an epigenetic event, accompanied by an increase in the Ki-67 index, which plays an essential role in tumor development and progression [20]. Progression might be characterized in certain instances by an increase in the rate of cell proliferation or other alterations like nuclear abnormalities and the emergence of notable necrosis [21]. After chemotherapy treatments, NET and NEC can change their Ki-67 index and even become hypermutated [23, 24].

Vyas et al. [25] highlighted that chemotherapy can cause treatment-related alterations in NEC, occasionally leading to a decrease in the Ki-67 index, resulting in a Ki-67 index below 10%, either locally or diffuse (probably related to a cytotoxic effect toward the most aggressive part of the disease) stressing out that this reduction in proliferative rate is of uncertain clinical significance and should not be taken as evidence of a lower grade NET component of the neoplasm. Besides, several case reports have described the re-expression of SSTRs in patients exposed to everolimus and capecitabine/temozolomide. However, these cases were observed in NET patients [25‒28].

Furthermore, it has also been demonstrated that certain medications such as valproic acid, azathioprine, and others can enhance SSTR expression following exposure [29]. This is probably due to epigenetic events [30]. The effects of demethylating agents on the increase in SSTR expression have been investigated not only in mouse and cell models or observed in case reports but are also under investigation in the LANTANA study (NCT0517869), where patients receive demethylating agents prior to PRRT [31].

Curiously, in our case report, the patient was also treated after the first 68Ga-DOTATATE PET/CT with capecitabine/temozolomide, followed by everolimus. One could hypothesize that both phenomena described above have occurred. First, the most aggressive part of the NEC, more sensitive to chemotherapy, has been eradicated, leading to the emergence of a less aggressive NET. Then, capecitabine/temozolomide and everolimus induced a re-differentiation with re-expression of SSTR. A significant limitation of this case report is the absence of anatomopathological samples from the lesions that re-expressed SSTR, due to the patient’s refusal of an autopsy and inability to undergo biopsies during the work-up, due to her overall condition.

To the best of our knowledge, this is the first case of re-expression of SSTR in a NEC that has been described, occurring on the later stages of the disease course. This redifferentiation phenomenon in NEC should be further investigated, as patients might be, under certain conditions, eligible for PRRT. This is particularly significant because, according to the NETTER-1 and more recently NETTER-2 study presented at ASCO 2024, PRRT is likely to become a first-line treatment for NET in near future [32, 33]. Additionally, we suggest that newly paraneoplastic syndromes occurring in NEC patients should always be evaluated for SSTR expression by 68Ga-DOTATATE PET/CT.

This redifferentiation phenomenon in NETs should be further investigated, as patients might, under, be eligible for PRRT. Therefore, we recommend that new-onset paraneoplastic syndromes in patients with NEC be consistently assessed with 68Ga-DOTATATE PET/CT to enable precision medicine.

Written informed consent was obtained from the patient and from their next of kin for publication of this case report and any accompanying images. No patient-identifying information is included in this study. This research was conducted in accordance with the World Medical Association Declaration of Helsinki. This retrospective review did not require ethical approval in accordance with local guidelines.

The authors have no conflicts of interest to declare.

The authors had no funding to declare. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Michel Meyers wrote the article, took the picture, and created the tables. Ahmad Awada is the head of the medical oncology department and was the patient’s medical oncologist. Natacha Driessens was the patient’s endocrinologist for the treatment of ectopic ACTH secretion. Ioannis Karfis performed and interpreted the 68Ga-DOTATATE PET/CT. Daphné t’Kint de Roodenbeke conducted the genetic investigations. Hugo Couvert, Charlotte Hanssens, and Alain Hendlisz helped to write the discussion. All authors discussed the results together, proposing modifications at all stages. The final version of the manuscript was approved by all authors. Natacha Driessens, Ioannis Karfis, Daphné t’Kint de Roodenbeek, and Alain Hendlisz are members of ENETS group ULB.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.

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