*Medical Synopsis: Shresthvi Havelia, 23 years / Female* *1. Past Medical History* 1. *PCOD*: Diagnosed age 13. Treated with Yamini since Jan 2021. Switched to Yamini LS Jan-Mar 2022, then back to Yamini. _Note: All PCOD symptoms resolved post first NET surgery 2022_ 2. *Cholecystectomy*: 2017 for gall stones *2. Oncologic History: Malignant Neuroendocrine Tumor with Metastatic/Cushing’s Presentation* **Timeline** **Event / Finding** **May 2022, UK** Acute presentation: Vomiting, bilateral leg edema. Admitted RUH Bath. Found: Right adrenal hemorrhage, Probable IVC thrombus, Bilateral segmental PE, Anterior mediastinal mass. Started on LMWH Dalteparin → Apixaban 10mg BD → 5mg BD **May-Jun 2022, India** PET-CT at Max Delhi → Histobiopsy + FNAC: **Malignant Neuroendocrine Tumor**. DOTA PET done **21st July 2022** VATS resection of mediastinal NET by Dr. Deshpande. Post-op histopath confirms NET **Jul 2022 - Jul 2023** Continued Apixaban **2023-2024** Surveillance: CT Dec 2023, DOTA June 2024, Blood tests June 2024 **29th July 2024** Recurrence on DOTA → Sternotomy resection by Dr. Deshpande. Post-op histopath + discharge **Jan-Apr 2025** Rising Chromogranin A. April DOTA: Recurrent disease. FDG PET April 8 2025 **Apr 2025 - Aug 2025** Started **Sandostatin LAR 30mg IM monthly**. 5 doses given. During this period: weight gain, edema, dysgeusia, fatigue, post-prandial nausea/abdominal pain **Aug 2025** Endocrine workup: Very high Cortisol + ACTH. Overnight Dexamethasone suppression test abnormal. **Diagnosis: Ectopic ACTH-dependent Cushing Syndrome** likely from NET recurrence **30th Aug 2025** Hospitalization for severe left abdominal + chest pain + persistent edema. USG Abdomen, CT Chest, MRI Pituitary done *3. Key Current Issues as of Aug 2025* 1. *Recurrent Metastatic NET* - DOTA + FDG avid, rising Chromogranin A despite Sandostatin LAR 2. *Ectopic ACTH Cushing Syndrome* - Confirmed biochemically. Clinical features: weight gain, edema, fatigue, abdominal pain 3. *Thrombotic history* - Prior PE + IVC thrombus + adrenal hemorrhage. Off anticoagulation since July 2023 4. *Endocrine workup pending correlation* - MRI Pituitary to rule out pituitary Cushing vs Ectopic *Clinical Approach & Management for NET with Ectopic Cushing’s Syndrome* This is a complex case requiring a *NET MDT + Endocrinology + Oncology* team. Goals: 1. Control cortisol 2. Control tumor 3. Manage complications *A. Immediate Priorities - Control Hypercortisolism* Ectopic Cushing is life-threatening due to infection, thrombosis, metabolic risk. 1. *Medical Adrenalectomy / Steroidogenesis Inhibitors* - Choose based on liver profile: - *Metyrapone* - Often first line for rapid control. Less hepatotoxic than ketoconazole - *Osilodrostat* - Good for long-term. FDA approved for Cushing disease - *Levoketoconazole* - Alternative if others not available, but monitor LFTs closely given prior hepatic issues - *Etomidate infusion* - If severely unwell/ICU 2. *Glucocorticoid Receptor Blocker*: *Mifepristone* - If surgery not immediate. Also helps with metabolic effects 3. *Monitor*: Electrolytes K+, Glucose, BP, Infection risk. May need steroid replacement once cortisol controlled *B. Tumor Directed Therapy for Recurrent NET* 1. *Confirm somatostatin receptor status* - Already DOTA positive 2. *Continue/Increase SSA*: Sandostatin LAR 30mg monthly. Can consider dose escalation to 40mg or 28-day cycle if tolerated 3. *PRRT*: *Lu-177 DOTATATE* - Strong option for SSTR+ progressive NET with multiple recurrences 4. *Targeted Therapy*: *Everolimus* or *Sunitinib* - If pancreatic origin confirmed, for progressive disease 5. *CAPTEM Chemo*: Capecitabine + Temozolomide - Consider if Ki-67 is G2/G3 or rapid progression. _Caution: Monitor liver closely given Cushing + prior drugs_ 6. *Surgical Debulking*: Assess if lesion is resectable again. Discuss with Dr. Deshpande 7. *Liver-directed therapy* if liver mets predominant *C. Thrombosis & Cardiovascular Risk* 1. *Hypercoagulable state*: Cushing + malignancy + prior PE = very high risk. Consider restarting prophylactic anticoagulation after bleeding risk assessed 2. *BP, Glucose, Bone protection*: Start anti-hypertensives, anti-diabetics, Calcium + Vit D + Bisphosphonate if needed *D. Investigations Still Needed* 1. *Histopathology review* of 2022 + 2024 specimen: Grade, Ki-67, Origin, ACTH IHC 2. *MRI Pituitary correlation* to definitively prove ectopic vs pituitary 3. *Genetic testing* - MEN1, SDH etc if indicated 4. *Baseline LFT, RFT* before starting steroidogenesis inhibitors *4. Key Questions for MDT Discussion* 1. Can the current recurrence be resected or is it diffuse? 2. Is patient candidate for PRRT now vs chemo/targeted therapy? 3. Which steroidogenesis inhibitor is safest given liver + thrombosis history? 4. Should anticoagulation be restarted? 5. Clinical trial eligibility for advanced NET + Ectopic Cushing Shresthvi has already shown remarkable resilience through 2 surgeries and ongoing treatment. The priority now is *urgent cortisol control* followed by definitive tumor control.

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"ectopic ACTH" AND "neuroendocrine tumor" AND treatment

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"Lu-177 DOTATATE" AND "neuroendocrine tumor" AND Cushing

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PMID: 41042443

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PMID: 42126756

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"osilodrostat" OR "metyrapone" AND "ectopic Cushing" treatment

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"PRRT" AND "neuroendocrine tumor" AND "Cushing" hypercortisolism

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PMID: 40104565

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PMID: 41335191

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PMID: 42049172

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PMID: 39980506

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I now have comprehensive data from textbooks and current literature. Let me compose the detailed clinical response.

Clinical Review: Shresthvi Havelia - Recurrent Mediastinal NET with Ectopic ACTH Cushing Syndrome

This is a remarkably complex and rare case - a young woman with a recurrent/metastatic mediastinal (likely thymic) NET now presenting with ectopic ACTH-dependent Cushing Syndrome. What follows is a structured clinical commentary organized by priority.

1. Pathophysiology: What is Happening

The mediastinal NET - resected twice (VATS 2022, sternotomy 2024) and now recurrent on April 2025 DOTA - has acquired or expressed ACTH secretory function, driving bilateral adrenocortical hyperplasia. This is the mechanism behind the ectopic ACTH syndrome (EAS). Per the Tietz Textbook of Laboratory Medicine (7th Ed.), "In about 20% of endogenous ACTH-dependent Cushing syndrome cases, the source of excess ACTH is not the pituitary...EAS is associated with pancreatic and thymic neuroendocrine tumors, gastrinomas, medullary thyroid cancer, and pheochromocytoma."

Key points for this patient:

Thymic NETs are the prototype of mediastinal ectopic Cushing - this almost certainly represents the known recurrent NET expressing ACTH rather than a new pituitary pathology
The MRI Pituitary (done Aug 2025) is the correct move to formally exclude Cushing's disease, but the biochemical picture (high ACTH + non-suppression on overnight dex) in the context of known recurrent DOTA+ mediastinal NET strongly points to ectopic origin
The prior PCOD resolution after first surgery 2022 was likely incidental (ovulatory function restored), but the current cortisol excess will itself drive amenorrhea and metabolic derangement
The distinction from pseudo-Cushing (depression, obesity, alcohol) is not relevant here given the confirmed tumor context

A 2026 case-based review (Peixe et al., Ir J Med Sci 2026) specifically describes cyclical ectopic Cushing from a mediastinal NET - virtually identical to this case - noting disease courses marked by "recurrent peaks of hypercortisolism interspersed with partial remissions" and emphasizing bilateral adrenalectomy as a life-saving option when sustained control fails.

2. Immediate Priority: Control Hypercortisolism

This is the single most urgent intervention. Uncontrolled hypercortisolism in this setting carries very high short-term mortality from infection, thromboembolic events, and metabolic crisis. Harrison's Principles (22E, 2025) is unambiguous: "In some patients with very severe, overt Cushing's...it may be necessary to introduce medical therapy to rapidly control the cortisol excess" and for ectopic ACTH syndrome with unlocated or unresectable tumor, "one must carefully weigh whether drug treatment or bilateral adrenalectomy is the most appropriate choice."

Steroidogenesis Inhibitor Selection

The synopsis correctly lists the options. Here is the evidence-based ranking for this specific patient:

Drug	Mechanism	Starting Dose	Key Consideration for Shresthvi
Osilodrostat	11β-hydroxylase inhibitor	1-2 mg BD (max 60 mg/day)	First choice. 88% complete response rate in real-world ectopic Cushing (multicenter Spanish study, Araujo-Castro et al., J Endocrinol Invest 2026). Median UFC normalization in 4.5 weeks. Oral. Monitor QTc and adrenal insufficiency.
Metyrapone	11β-hydroxylase inhibitor	500 mg TID (max 6 g/day)	Good for rapid bridging. Salt/water retention (worsens edema - a concern here). Causes androgen precursor accumulation - hirsutism. Per Katzung (16th Ed.), available on compassionate basis only in some countries.
Levoketoconazole	Early steroidogenesis (CYP17A1, CYP11B1)	150 mg BD	LFT monitoring mandatory. Less preferred given prior cholecystectomy and concern about hepatic processing.
Mifepristone	Glucocorticoid receptor blocker	300 mg OD	Does NOT lower serum cortisol - cannot monitor response by cortisol levels. Useful adjunct or if inhibitors fail.
Etomidate IV	11β-hydroxylase inhibitor	0.03-0.1 mg/kg/hr infusion	Reserve for ICU/crash cortisol control if hospitalization turns critical. The Aug 30 hospitalization may warrant consideration.

Recommended approach: Start osilodrostat at 2 mg BD and titrate every 1-2 weeks based on UFC/serum cortisol. The 2025 review by Fleseriu et al., J Endocr Soc 2025 emphasizes individualized dosing based on severity, comorbidities, and QTc monitoring.

Critical monitoring after starting steroidogenesis inhibitor:

Daily electrolytes (K+) - correct hypokalemia aggressively (target >3.5)
Fasting glucose and BP control
Watch for adrenal insufficiency (too-rapid cortisol fall) - keep hydrocortisone 10 mg sachets accessible
Repeat UFC at 4 weeks
QTc baseline ECG before osilodrostat - the adrenal hemorrhage history and prior PE do not directly contra-indicate, but QTc prolongation risk needs assessment

3. Thrombosis Risk: Critical and Urgent

This patient currently has three simultaneous pro-thrombotic states:

Active malignancy (NET)
Hypercortisolism (Cushing's - induces hypercoagulability via elevated Factor VIII, von Willebrand factor, PAI-1, and fibrinogen)
Personal history of bilateral PE + IVC thrombus (2022)

She has been off anticoagulation since July 2023 - a significant gap given the current disease state. Restart of therapeutic anticoagulation is strongly indicated and should be discussed with the MDT on an urgent basis at the Aug 30 admission, weighing the prior adrenal hemorrhage (which occurred in 2022 and is now 3+ years past).

Recommendation: LMWH (enoxaparin weight-based) is preferred over direct oral anticoagulants in active cancer per ISTH/ASCO guidelines. Apixaban (as previously used) is acceptable if renal function is normal - it was well tolerated before. Avoid warfarin given its unpredictability with metabolic flux from cortisol changes and any enzyme-altering medications.

4. Tumor-Directed Therapy: Anti-Neoplastic Plan

The tumor is:

DOTA-positive (somatostatin receptor expressing) - confirmed on both 2022 DOTA and June 2024 DOTA, and recurrent April 2025
FDG-avid on April 8 2025 PET - this indicates higher metabolic activity/grade
Rising Chromogranin A despite Sandostatin LAR 30 mg monthly (5 doses)
Has undergone 2 prior surgical resections

The FDG-avidity alongside DOTA-avidity is the critical staging point. FDG-positive NETs indicate more aggressive biology (typically Ki-67 > 5%, G2 or possibly G3). This changes the therapeutic calculus.

Priority Sequence

A. Histopathology Upgrade (Immediate) Request formal re-review of both 2022 and 2024 surgical specimens by an expert NET pathologist:

Ki-67 index (grading: G1 <3%, G2 3-20%, G3 >20%)
ACTH immunohistochemistry (IHC) - this will confirm the tumor is the ACTH source
Ki-67 ≥10% in FDG-avid NET = likely G2-G3, which changes treatment priorities

B. PRRT (Lu-177 DOTATATE) - Strong Candidate Given SSTR positivity and progressive disease through SSA, PRRT is a logical next step. The emerging evidence in ectopic Cushing specifically supports this:

Majumder et al., Endocrinol Diabetes Metab Case Rep 2026: Recurrent thymic NEN with ectopic Cushing - treated with osilodrostat + PRRT → cortisol normalized after 12 months. "PRRT continues to have a role in the setting of functional NENs."
Koizumi et al., Case Rep Oncol 2025: ACTH-producing NET with metastatic hepatic disease - PRRT with 177Lu-DOTATATE produced remarkable tumor reduction with ACTH normalization after 4 cycles. However, ACTH levels initially spiked after PRRT initiation ("hormonal crisis during therapy") - necessitating increased steroidogenesis inhibitor dosing
Tsoli et al., Curr Treat Options Oncol 2025: "Among various anti-tumor systemic treatment options, PRRT seems to be an effective option for the control of hypercortisolism" in ACTH-secreting NENs

Important PRRT caveat for this patient: Given the FDG-avid component, the NETTER-1 trial eligibility criteria and EANM guidelines recommend PRRT primarily for SSTR high-expressors (DOTA SUVmax > liver uptake, typically Krenning score 3-4). If a portion of disease is dedifferentiated (FDG+ but DOTA-), PRRT will not cover that clone. This heterogeneity needs imaging correlation.

C. Systemic Therapy Options (If PRRT not immediately feasible or concurrent)

Everolimus 10 mg/day - approved for progressive NET (RADIANT-3 trial data). Works via mTOR pathway inhibition. Has independent activity on ACTH secretion in some case reports. Monitor glucose closely (causes hyperglycemia - worse in Cushing's state)
CAPTEM (Capecitabine + Temozolomide) - preferred for G2/G3 or Ki-67 >10% NETs, especially thymic origin. Response rates 30-70% in selected patients
Sunitinib - for pancreatic NET specifically; less evidence for thymic origin
SSA dose escalation: Sandostatin LAR 40 mg (monthly) or 30 mg every 3 weeks - can try before/alongside PRRT; antiproliferative role, but less evidence for cortisol control in ectopic Cushing vs. the carcinoid syndrome setting

D. Surgical Debulking Dr. Deshpande has performed two prior resections. A third resection should be discussed at MDT, but the April 2025 DOTA showing recurrent disease (timing is ~8 months post second surgery) suggests an aggressive biological course. If the recurrence is focal/resectable, debulking may enable better hypercortisolism control. If diffuse/multifocal, systemic therapy is the priority.

E. Bilateral Adrenalectomy (Contingency Plan) If medical control of hypercortisolism fails despite maximal steroidogenesis inhibitor dosing (Fischer's Surgery 8th Ed.: "bilateral adrenalectomy may be considered in highly specialized centers as palliation for medically refractory CS mediated by ACTH hypersecretion"), this becomes the definitive cortisol control strategy. It does NOT treat the tumor but rapidly and permanently resolves the Cushing state. Requires lifelong hydrocortisone + fludrocortisone replacement. The 2026 cyclical ectopic Cushing case report (mediastinal NET - Peixe et al.) ultimately required bilateral adrenalectomy for "biochemical remission."

5. Complication Management

Metabolic Complications of Hypercortisolism:

Hypertension: Likely present/worsening. Start or optimize antihypertensive - spironolactone has anti-mineralocorticoid benefits useful here (cortisol cross-reacts with mineralocorticoid receptors in excess), but watch potassium
Diabetes/Glucose Intolerance: High likelihood. HbA1c + fasting glucose. Metformin first (if no renal impairment), insulin if needed
Hypokalemia: Cortisol-driven renal K+ wasting. IV/oral supplementation. Target K+ >3.5 mEq/L before cardiac events
Infection Risk: Hypercortisolism is profoundly immunosuppressive. The Sep 2025 hospitalization for abdominal + chest pain warrants active sepsis screening. Prophylactic PCP coverage (Co-trimoxazole) if cortisol remains uncontrolled
Bone: Start Calcium 1200 mg/day + Vitamin D 800 IU. Consider bisphosphonate if DXA shows T-score < -1.5 or after 3 months of active Cushing's

Edema (Current Symptom): Both Sandostatin LAR and hypercortisolism (fluid retention, hypoalbuminemia) contribute. Once cortisol is controlled, edema should resolve. In the interim, compression stockings + gentle diuresis (aldosterone antagonist preferred).

Nausea/Abdominal Pain Post-prandially: Classic Sandostatin LAR side effect (GI dysmotility, bile acid retention - note: cholecystectomy already done, so gallstone risk from SSA is moot). Consider domperidone/metoclopramide. If abdominal pain is severe (Aug 30 presentation), rule out adrenal crisis, mesenteric ischemia (thrombosis), and cortisol-driven peptic ulceration.

6. Investigations - What is Still Needed

Investigation	Purpose	Timing
MRI Pituitary correlation	Rule out pituitary microadenoma - already done Aug 2025. If normal: confirms ectopic	Awaiting result
24-hr UFC + late-night salivary cortisol	Baseline severity quantification before treatment	Immediate
CRH stimulation test	If MRI equivocal: >35% ACTH rise = pituitary; flat = ectopic	If needed
ACTH IHC on 2022/2024 specimens	Proves tumor is the ACTH source	Within 2 weeks
Ki-67 on specimens	Determines grade (G1/G2/G3) = determines PRRT vs. CAPTEM priority	Within 2 weeks
Baseline LFT, RFT, K+, Mg2+, ECG, HbA1c	Pre-treatment workup before osilodrostat	Same day
Genetic panel (MEN1, CDKN1B, TP53, SDH)	Given young age, bilateral/multifocal recurrence	Referral
Repeat DOTA-PET after steroidogenesis inhibitor	Assess tumor response to PRRT planning	After 2-3 months

7. MDT Structure and Urgent Actions

Team Required:

Endocrinology (Cushing expert)
NET/GEP-NET oncologist
Thoracic surgery (Dr. Deshpande - re-resection discussion)
Nuclear medicine (PRRT eligibility and planning)
Hematology (anticoagulation decision)
Pharmacy/Clinical pharmacology (drug interactions between osilodrostat, SSA, everolimus)

Urgent Actions at Aug 30 Hospitalization:

Electrolytes, ECG, LFT/RFT, fasting glucose, UFC - same day
Start osilodrostat 2 mg BD after baseline bloods (do not delay treatment waiting for MRI pituitary result if ectopic is already strongly suspected)
Restart LMWH prophylaxis (hematology input if therapeutic dose required)
Request urgent pathology re-review (Ki-67, ACTH IHC)
Referral to PRRT center for eligibility assessment

Key Literature Supporting This Plan

Tsoli et al., Curr Treat Options Oncol 2025 - Comprehensive management update for ACTH-secreting GEP and thoracic NENs - PRRT + steroidogenesis inhibitors, bilateral adrenalectomy for refractory cases [PMID: 41042443]
Araujo-Castro et al., J Endocrinol Invest 2026 - Osilodrostat in ectopic Cushing: 88% complete response, median normalization 4.5 weeks [PMID: 41335191]
Fleseriu et al., J Endocr Soc 2025 - Practical guide to osilodrostat dosing for ectopic/adrenal Cushing [PMID: 40104565]
Majumder et al., Endocrinol Diabetes Metab Case Rep 2026 - Thymic NEN + ectopic Cushing: osilodrostat + PRRT → normalization at 12 months [PMID: 42049172]
Koizumi et al., Case Rep Oncol 2025 - ACTH-producing NET: PRRT effective but watch for hormonal crisis [PMID: 39980506]
Peixe et al., Ir J Med Sci 2026 - Cyclical ectopic Cushing from mediastinal NET: closest analog to this case [PMID: 42126756]
Harrison's Principles of Internal Medicine 22E (2025), Chapter 398 - Cushing syndrome treatment algorithm
Katzung Basic and Clinical Pharmacology 16th Ed. - Steroidogenesis inhibitor pharmacology

Summary Framing for MDT

This case represents recurring/refractory mediastinal NET (likely thymic origin, SSTR+/FDG+) with secondary ectopic ACTH Cushing Syndrome - a rare but recognized complication carrying high immediate mortality risk if untreated. The two parallel problems (tumor and cortisol excess) must be addressed simultaneously, not sequentially.

The evidence in 2025-2026 literature converges on:

Osilodrostat as first-line steroidogenesis inhibitor for ectopic Cushing (superseding metyrapone/ketoconazole in recent practice)
PRRT (Lu-177 DOTATATE) as tumor-directed therapy for SSTR+ progressive NET with functional syndrome - with the important caution that ACTH can paradoxically spike during PRRT cycles, requiring intensified steroidogenesis inhibitor dosing
Bilateral adrenalectomy as a definitive backstop for medically refractory hypercortisolism

Shresthvi has a long road ahead, but the therapeutic tools now exist to address each component of this problem.

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