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Pulmonary large-cell neuroendocrine carcinoma

causing Cushing’s syndrome

Ioanna Gazouli MD, MSc

Athens General Hospital "Korgialenio-Benakio National Red Cross"

Large-cell neuroendocrine lung cancer– Lugano– April 2018

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DISCLOSURE OF INTEREST

None

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Case presentation 56 yo Caucasian female, ex-smoker

Medical history:

colon adenocarcinoma (pT3,pN0,M0) moderately differentiated (2 yrs before presentation)

-treated by partial colectomy plus dissection of 24 unaffected lymph nodes plus adjuvant chemotherapy and radiotherapy

-no evidence of recurrent disease up to presentation

2 small rectal polyps, both endoscopically dissected during follow up colonoscopy

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Clinical presentation

-fatigue, weakness,

depression

-moon face

-obesity, truncal fat

deposition

-arterial hypertension

(SBP~150mmHg)

-decreased limb muscle

strength (4/5)

-limb edema

Laboratory findings

-hypokaliemia (K+:2.2-2.5mEq/lt) refractory to PO/IV potassium administration

-blood sugar>200mg/dl (HbA1C 5.8)

-CA 19-9:74,468 u/ml

(a-FP 5.6 ng/ml, CEA 16ng/ml)

-24h urine free cortisol: >1,953μg

-evening salivary cortisol: 37μg/dl

Morning values

dexamethasone suppression test

ACTH 501 pg/ml 674 pg/ml

Cortisol 89 mcg/dl 105 mcg/dl

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Ectopic Cushing syndrome?

10-20% of ACTH-dependent Cushing

ectopic ACTH sources

NETs (mainly bronchial carcinoids): 3–54.8% (most frequent source in recent pts series)

SCLC: 3.3–50% (most frequent cause in early pts series)

thymic carcinoids: 5–42%

pancreatic NETs: 7.5–25%

Pheochromocytomas: 2.5–25%

medullary thyroid carcinomas: 2–8%

occult tumors: 12–36.5%

(Davi’ et al., 2017)

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Work-up

abdominal CT/MRI:

-multiple liver lesions

(up to 1.8cm)

-bilateral adrenal gland

enlargement

thoracic CT:

- bilateral fibroatelectatic

changes in both lungs

-enlarged hilar lymph nodes

(up to 2 cm)

Liver lesions biopsy:

-Morphology

pulmonary large-cell

neuroendocrine carcinoma

with necrosis and

marked mitotic activity

Ki67~40%

-Immunohistochemistry

EMA+, TTF-1+, CEA+, CDX2-

NEN markers: Chromogranin+,

Synaptophysin+, CD56+

ACTH staining…?

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Possibly enlightening tests

o 80-90% of NETs

express somatostatin

receptors (Fisseler-Eckhoff and Demes, 2012)

o Pulmonary LNECs

have been shown

in vivo to express

somatostatin receptors

by radionuclide

scintigraphy* (Nocuń et al., 2011, Filosso et al., 2005)

111In-DTPA-octreotide scan

68Galium-dotatate-PET/CT

-Sensitivity and specificity>90%

-more sensitive than CT &

octreoscan

-possible therapeutic implications(Gabriel et al., 2007, Srirajaskanthan et al., 2010,

Deppen et al., 2016)

FDG-PET/CT

-may reveal poorly differentiated

tumours (Oberg et al., 2012)

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Treatment and follow up

Patient was started on metyrapone and

spironolactone PO

=>potassium values restored to normal range

Patient was referred to medical oncologist

Anti-neoplastic treatment considered to be of no

benefit

Patient succumbed to her disease ~3mo after

initial presentation

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Treatment opportunities…

somatostatin analogs: octreotide iv or lanreotide sc

everolimus: prolonged median PFS (11 vs 3.9mo)

in RADIANT-4, compared to placebo (Yao et al., 2016)

177Lu-DOTATATE: safely administered in pts with

advanced/metastatic pulmonary NET=> objective response in

12/19 pts, symptomatic response in 15/19 pts

1yr OS: 95%, 4yr OS 39% (Parghane et al., 2017)

platinum/cisplatin: (similarly to SCLC) ORR 73% and

OS 16.5mo, superior to NSCLC regimens

- nonetheless LCNEC ≠ SCLC

-LCNEC’s chemosensitivity is not well established (Hiroshima and Mino-Kenudson, 2017)

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Remarkable points

Liver metastatic lesions with pulmonary large cell carcinoma features, in the absence of prominent lung primary

➢ NETs account for 1% of tumours of occult primary

➢ No primary is identified in 13% of NETs

CA19-9 elevation with no evidence of GI malignant disease, recurrent or new primary

➢ Could it be a rectal NET? 29% of all GEP-NETs (Rodrigues et al.,2015)

➢ Could it be a colonic LCNEC? reported incidence 0.2% (Bernick et al.,2004)

2 distinct malignancies in the same patient

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Literature1. Davi’, M., Cosaro, E., Piacentini, S., Reimondo, G., et al. (2017). Prognostic factors in ectopic Cushing’s syndrome due to neuroendocrine tumors: a multicenter

study. European Journal of Endocrinology, 176(4), pp.451-459.

2. Sehgal, R., Mchayleh, W., Reider, J., Cheema, A. and Ramanathan, R. (2010). Adenocarcinoma of Colon Presenting As Cushing's Syndrome. Journal of Clinical

Oncology, 28(8), pp.e126-e127.

3. Baldvinsdottir, B., Jonasson, J., Agnarsson, U. and Sigurjonsdottir, H. (2014). Ectopic Cushing Syndrome Due to Colon Cancer With Dual Morphology. Journal of

Endocrinology and Metabolism, 4(5-6), pp.153-154.

4. Onishi R, Sano T, Nakamura Y, et al: Ectopic adrenocorticotropin syndrome associated with undifferentiated carcinoma of the colon showing multidirectional

neuroendocrine, exocrine, and squamous differentiation. Virchows Arch 427:537-541,1996

5. Fisseler-Eckhoff, A. and Demes, M. (2012). Neuroendocrine Tumors of the Lung. Cancers, 4(3), pp.777-798.

6. Nocuń, A., Chrapko, B., Gołębiewska, R., Stefaniak, B. and Czekajska-Chehab, E. (2011). Evaluation of somatostatin receptors in large cell pulmonary

neuroendocrine carcinoma with 99mTc-EDDA/HYNIC-TOC scintigraphy. Nuclear Medicine Communications, 32(6), pp.522-529.

7. Filosso, P., Ruffini, E., Oliaro, A., Rena, O., Casadio, C., Mancuso, M., Turello, D., Cristofori, R. and Maggi, G. (2005). Large-cell neuroendocrine carcinoma of the

lung: A clinicopathologic study of eighteen cases and the efficacy of adjuvant treatment with octreotide. The Journal of Thoracic and Cardiovascular Surgery, 129(4),

pp.819-824.

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Tyr3-Octreotide PET in Neuroendocrine Tumors: Comparison with Somatostatin Receptor Scintigraphy and CT. Journal of Nuclear Medicine, 48(4), pp.508-518.

9. Srirajaskanthan, R., Kayani, I., Quigley, A., Soh, J., Caplin, M. and Bomanji, J. (2010). The Role of 68Ga-DOTATATE PET in Patients with Neuroendocrine Tumors

and Negative or Equivocal Findings on 111In-DTPA-Octreotide Scintigraphy. Journal of Nuclear Medicine, 51(6), pp.875-882.

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and follow-up. Annals of Oncology, 23(suppl 7), pp.vii120-vii123.

12. Yao, J., Fazio, N., Singh, S., Buzzoni, R., Carnaghi, C., Wolin, E., Tomasek, J., Raderer, M., Lahner, H., Voi, M., Pacaud, L., Rouyrre, N., Sachs, C., Valle, J., Fave,

G., Van Cutsem, E., Tesselaar, M., Shimada, Y., Oh, D., Strosberg, J., Kulke, M. and Pavel, M. (2016). Everolimus for the treatment of advanced, non-functional

neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. The Lancet, 387(10022), pp.968-977.

13. Hiroshima K, Mino-Kenudson M. Update on large cell neuroendocrine carcinoma. Translational Lung Cancer Research. 2017;6(5):530-539.

14. Parghane, R., Talole, S., Prabhash, K. and Basu, S. (2017). Clinical Response Profile of Metastatic/Advanced Pulmonary Neuroendocrine Tumors to Peptide

Receptor Radionuclide Therapy with 177Lu-DOTATATE. Clinical Nuclear Medicine, 42(6), pp.428-435.

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2015;22(5):213-220. doi:10.1016/j.jpge.2015.04.008.

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Thank you for your attention!