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*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. Give good solutions and similar cases

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ectopic ACTH syndrome neuroendocrine tumor management

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metyrapone osilodrostat ectopic Cushing treatment

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PMID: 41042443

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PMID: 40104565

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PMID: 40071083

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mediastinal thymic neuroendocrine tumor PRRT somatostatin receptor

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PMID: 40563625

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PMID: 37855644

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PMID: 35769081

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anticoagulation thrombosis Cushing syndrome cancer venous thromboembolism

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PMID: 38529392

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PRRT Lu-177 dotatate thoracic neuroendocrine tumor bronchial thymic outcomes

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Lu-177 DOTATATE PRRT thoracic NET bronchopulmonary carcinoid

I now have sufficient information to compose a comprehensive, well-cited clinical response. Let me synthesize everything.

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

This is one of the more unusual presentations in clinical oncology - a young woman with a recurrent anterior mediastinal/thymic NET (most likely thymic carcinoid origin given the anterior mediastinal location) who has now developed ectopic ACTH-dependent Cushing syndrome after two prior resections, with Sandostatin LAR showing inadequate disease control. The 2025 literature on ACTH-secreting thoracic NETs is directly relevant to this case.

How This Presentation Fits the Literature

The 2025 review by Tsoli et al. (PMID 41042443) on ACTH-secreting gastroenteropancreatic and thoracic NENs confirms that this pattern - metastatic/recurrent disease causing ectopic ACTH syndrome with poor response to SSAs alone - represents a distinct high-risk subgroup requiring an individualized, multimodal strategy. Thymic carcinoids specifically account for 5-16% of ectopic ACTH syndrome cases. The 2025 thymic NET case by Zdrojowy-Welna et al. (PMID 40071083) is strikingly parallel to Shresthvi's situation: a young woman with a small thymic NET, repeated surgical recurrences over years, with hypercortisolism treated sequentially by ketoconazole → metyrapone → osilodrostat, with 68Ga-DOTA PET guiding surgery each time. That patient achieved good outcomes with each intervention, underscoring the importance of serial nuclear imaging and willingness to reoperate.

Part 1: Urgent Cortisol Control (Top Priority)

Ectopic Cushing Syndrome carries life-threatening risk: VTE, severe infection, glucose dysregulation, hypokalemia, cardiovascular events. Harrison's 22e confirms: "In some patients with very severe, overt Cushing's... it may be necessary to introduce medical therapy to rapidly control the cortisol excess during the period leading up to surgery, which also can help to alleviate hypercoagulability." - Harrison's Principles of Internal Medicine 22e, p. 3102

Drug Selection Hierarchy for Shresthvi

DrugMechanismKey Consideration for This Patient
Osilodrostat11β-hydroxylase inhibitor (oral)Preferred first-line in 2025 - fastest cortisol reduction, once-daily, approved for ectopic CS. Titrate from 1-2 mg BD up to 60 mg/day max. Monitor QTc carefully given prior PE/cardiovascular history
Metyrapone11β-hydroxylase inhibitorStrong alternative. More established safety profile, less QTc risk. Start 500 mg TID up to 6g/day. Available quickly. May exacerbate hypertension/hypokalemia
CombinationBoth drugs togetherUsed in severe/refractory cases. Detomas et al. 2022 (PMID 35769081) showed osilodrostat achieves faster cortisol reduction (UFC -68% vs -21% at 2 weeks), but metyrapone catches up and has lower QTc risk
IV Etomidate infusion11β-hydroxylase blockReserve for ICU/crash cortisol control. Immediate effect within 24 hours. Requires ICU monitoring - Bailey & Love 28e, p. 915
MifepristoneGR antagonistUseful for metabolic effects (hyperglycemia), but does not lower measured cortisol levels, complicating monitoring. Second-line adjunct
Practical recommendation for Shresthvi:
  • Start osilodrostat 2 mg BD immediately given severity, titrate up every 1-2 weeks guided by 24h UFC and serum cortisol
  • If unavailable within 48 hours or QTc is prolonged at baseline (ECG mandatory before starting), start metyrapone 500 mg TID as bridge
  • Hana et al. 2023 (PMID 37855644) reported a 28-year-old woman with ectopic ACTH from bronchial metastatic NET treated successfully with osilodrostat once-daily, with transient hypocortisolism managed by hydrocortisone - directly comparable scenario to Shresthvi
  • The 2025 Fleseriu et al. review (PMID 40104565) confirms individualized dosing and QT monitoring are the main practical considerations for ectopic CS with osilodrostat
Monitoring targets:
  • 24h UFC: target upper normal range (not overcorrect - risk of adrenal insufficiency)
  • Serum K⁺ (hypokalemia is common in ectopic CS - replace aggressively)
  • Fasting glucose / HbA1c (steroid diabetes likely)
  • ECG for QTc (osilodrostat)
  • LFTs if ketoconazole/levoketoconazole used (not first choice here)
  • Keep hydrocortisone replacement ready for overcorrection episodes

Part 2: Tumor-Directed Therapy

Step 1: Histopathology Review (URGENT, before deciding therapy)

The 2022 and 2024 specimens must be reviewed for:
  • Ki-67 / grade (G1 <3%, G2 3-20%, G3 >20% - determines chemo eligibility)
  • ACTH immunohistochemistry (confirm ectopic production at tumor level)
  • Origin markers (thymic vs mediastinal carcinoid - they have different prognosis)
  • MEN1 / DAXX / ATRX mutations (relevant for prognosis and targeted therapy per 2025 Piorek et al., PMID 40563625)

Step 2: Escalate Somatostatin Analog

Already on Sandostatin LAR 30 mg. She has rising CgA and recurrence despite this, suggesting partial SSA failure. Options:
  • Increase to Sandostatin LAR 40 mg q28 days (off-label dose escalation - evidence in bronchopulmonary NETs)
  • Switch to or add Pasireotide LAR - has broader SSR subtype activity (SSR1, 2, 3, 5 vs octreotide's mainly SSR2), potentially more effective for ACTH-secreting NETs specifically since these often express SSR5

Step 3: PRRT with Lu-177 DOTATATE (Strong Candidate)

Given she is DOTA-avid on 68Ga-DOTA PET, she is eligible for PRRT. This is a particularly important option here because:
  1. PRRT targets the SSTR+ tumor directly - it may control both the tumor AND the ectopic ACTH production simultaneously. The 2025 Tsoli et al. review (PMID 41042443) states: "amongst the various anti-tumor systemic treatment options, peptide receptor radionuclide therapy (PRRT) seems to also be an effective option for the control of hypercortisolism" in ACTH-secreting NENs
  2. NETTER-1 trial data (Lu-177 DOTATATE) showed progression-free survival benefit for midgut NETs and the approach is used off-label for thoracic NETs
  3. Timing caveat: Cushing Syndrome causes immunosuppression and poor wound healing. The hypercortisolism should ideally be controlled medically FIRST before PRRT to reduce infection risk and optimize renal function. Coordinate with nuclear medicine team

Step 4: Targeted Therapy

  • Everolimus (Afinitor) - approved for non-functional lung/GI NETs, well-studied in thoracic carcinoids. The 2025 Piorek thymic carcinoid review (PMID 40563625) lists everolimus as a standard option for advanced thymic NETs. Caution: can worsen hyperglycemia in an already Cushingoid patient
  • Sunitinib - if Ki-67 higher grade

Step 5: CAPTEM Chemotherapy

  • Consider if Ki-67 G2/G3 confirmed or rapid clinical/biochemical progression
  • Capecitabine + Temozolomide - active in well-differentiated NETs, especially G2/G3
  • A note of caution: Cushing Syndrome causes immunosuppression; myelosuppression from chemotherapy would be compounded

Step 6: Surgical Debulking / Reassessment with Dr. Deshpande

  • Given two prior clean resections (2022 VATS, 2024 sternotomy), this team knows the anatomy
  • Current recurrence localization: the April 2025 DOTA PET and FDG PET should guide whether disease is focal (resectable) vs diffuse
  • The parallel thymic NET case (PMID 40071083) achieved remission three times with serial resections, each time guided by DOTA PET
  • If disease is localized and performance status allows, surgical debulking remains a legitimate option even for the third recurrence in this histology

Part 3: Thrombosis - This Is an Emergency-Level Risk

Shresthvi's VTE risk is compounded by four simultaneous major risk factors:
  1. Cushing syndrome (hypercoagulable state - PAI-1 elevated, factor VIII/vWF elevated)
  2. Active malignancy (NET + ectopic ACTH secreting)
  3. Prior VTE (bilateral PE, IVC thrombus 2022)
  4. Current hospitalization (Aug 2025)
The 2024 Bryk-Wiazania et al. review (PMID 38529392) provides an algorithm specifically for CS + VTE and confirms: "ectopic ACTH syndrome" patients require VTE exclusion FIRST (Doppler, CT PE), followed by routine prophylactic anticoagulation. The cancer-related VTE risk independently prompts thromboprophylaxis with LMWH.
Bailey & Love 28e states: "Cushing's syndrome predisposes patients to increased risk of venous thromboembolism... Patients should therefore receive chemical and mechanical thromboprophylaxis." - p. 916
Recommendation:
  • Restart therapeutic or prophylactic LMWH immediately unless bleeding source identified on current CT/MRI. The left abdominal + chest pain at Aug 2025 admission needs bleeding vs clot ruled out urgently
  • Once stable, transition to Apixaban (she has prior experience with this, good tolerability)
  • Do NOT leave her off anticoagulation given this risk profile - the decision to stop in July 2023 should be revisited

Part 4: MRI Pituitary - Confirming Ectopic vs Pituitary Source

The MRI Pituitary is important but the biochemical context already strongly favors ectopic origin:
  • Very high ACTH + cortisol
  • Failed overnight DST
  • No suppression on standard low-dose DST (implied)
  • Known metastatic NET (DOTA-avid)
  • No classical Cushing's disease features (no gradual weight gain, rapid onset)
If MRI pituitary is normal or inconclusive: Inferior petrosal sinus sampling (IPSS) is the gold standard to definitively distinguish pituitary vs ectopic - "Inferior petrosal sinus sampling is used to distinguish eutopic and ectopic sources of ACTH production." - Frameworks for Internal Medicine, p. 112
In this patient with metastatic NET and ectopic features, IPSS may be deferred and clinical/biochemical/imaging correlation may suffice for MDT decision-making.

Part 5: Genetic Testing

Given:
  • Thymic NET + young age + multiple recurrences → MEN1 mutation screen is strongly indicated (MEN1 causes parathyroid, pituitary, and GEP/thoracic NETs)
  • SDH mutations (SDHA/B/C/D) - relevant if pheo/paraganglioma component suspected
  • DAXX/ATRX mutations - prognostic in pancreatic NETs, emerging in thymic NETs per PMID 40563625

Parallel Case Summary

FeatureShresthviReported Parallel Cases
Age/Sex23F28F (PMID 37855644), 34F (PMID 40071083), adolescent (PMID 37908982)
TumorAnterior mediastinal NETThymic NET (PMID 40071083), Bronchial NET (PMID 37855644)
Recurrences2 surgical, now 3rd recurrence3 recurrences over 7 years (PMID 40071083)
Ectopic CS treatmentSandostatin LAR only (pending)Ketoconazole → metyrapone → osilodrostat (PMID 40071083)
OutcomeOngoingSerial remissions with each surgical + medical intervention
The parallel case in PMID 40071083 (thymic NET, 34-year-old woman, 3 recurrences, treated with metyrapone → osilodrostat + serial resections guided by DOTA PET) is essentially a blueprint for Shresthvi's management pathway. That patient remains under active follow-up with good outcomes.

Immediate Action Summary for MDT

This week (Aug 2025 hospitalization):
  1. ECG → start osilodrostat 2 mg BD (or metyrapone 500 mg TID if unavailable/QTc prolonged)
  2. Urgent electrolytes, K⁺ replacement, glucose management
  3. Rule out active bleeding (CT chest/abdomen already in progress) → restart LMWH once cleared
  4. Review 2022/2024 histopathology: Ki-67 grade, ACTH IHC
  5. MRI pituitary review → IPSS if inconclusive
Next 4-8 weeks:
  1. Cortisol control confirmed biochemically (24h UFC in target range)
  2. MDT: thoracic surgery (Dr. Deshpande) + endocrinology + nuclear medicine + oncology
  3. Assess DOTA PET + FDG PET: focal vs diffuse - decide resection vs PRRT first
  4. Refer to PRRT center (Lu-177 DOTATATE) - strong candidate if not operable
  5. Consider Pasireotide LAR switch/addition
  6. MEN1 genetic testing
Longer-term:
  • Everolimus if progressive post-PRRT
  • CAPTEM if grade escalation confirmed
  • Lifelong surveillance (thymic NETs have late recurrences - case above recurred at 5 and 7 years)
Key references used:
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