Pulmonary large-cell neuroendocrine carcinoma causing Cushing s syndrome

Transcription

1 ESMO Preceptorship Programme Large-cell neuroendocrine lung cancer Lugano April 2018 Ioanna Gazouli MD, MSc Athens General Hospital "Korgialenio-Benakio National Red Cross" Pulmonary large-cell neuroendocrine carcinoma causing Cushing s syndrome

2 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

3 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 + : mEq/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

4 Ectopic Cushing syndrome? 10-20% of ACTH-dependent Cushing ectopic ACTH sources NETs (mainly bronchial carcinoids): % (most frequent source in recent pts series) SCLC: % (most frequent cause in early pts series) thymic carcinoids: 5 42% pancreatic NETs: % Pheochromocytomas: % medullary thyroid carcinomas: 2 8% occult tumors: % (Davi et al., 2017)

5 abdominal CT/MRI: -multiple liver lesions (up to 1.8cm) -bilateral adrenal gland enlargement thoracic CT: - bilateral fibroatelectatic changes in both lungs Work-up -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?

6 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) 111 In-DTPA-octreotide scan 68 Galium-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)

7 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

8 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) 177 Lu-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)

9 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

10 Literature 1. 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 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-e 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 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: , Fisseler-Eckhoff, A. and Demes, M. (2012). Neuroendocrine Tumors of the Lung. Cancers, 4(3), pp 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 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 Gabriel, M., Decristoforo, C., Kendler, D., Dobrozemsky, G., Heute, D., Uprimny, C., Kovacs, P., Von Guggenberg, E., Bale, R. and Virgolini, I. (2007). 68Ga-DOTA- Tyr3-Octreotide PET in Neuroendocrine Tumors: Comparison with Somatostatin Receptor Scintigraphy and CT. Journal of Nuclear Medicine, 48(4), pp 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 Deppen, S., Blume, J., Bobbey, A., Shah, C., Graham, M., Lee, P., Delbeke, D. and Walker, R. (2016). 68Ga-DOTATATE Compared with 111In-DTPA-Octreotide and Conventional Imaging for Pulmonary and Gastroenteropancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis. Journal of Nuclear Medicine, 57(6), pp Oberg, K., Hellman, P., Ferolla, P. and Papotti, M. (2012). Neuroendocrine bronchial and thymic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 23(suppl 7), pp.vii120-vii 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 Hiroshima K, Mino-Kenudson M. Update on large cell neuroendocrine carcinoma. Translational Lung Cancer Research. 2017;6(5): 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 Bernick PE, Klimstra DS, Shia J, et al. Neuroendocrine carcinomas of the colon and rectum. Dis Colon Rectum. 2004;47: Rodrigues Â, Castro-Poças F, Pedroto I. Neuroendocrine Rectal Tumors: Main Features and Management. GE Portuguese Journal of Gastroenterology. 2015;22(5): doi: /j.jpge

11 ESMO Preceptorship Programme Thank you for your attention!