Pancreatic small cell cancer

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Clinics and Research in Hepatology and Gastroenterology (2015) xxx, xxx—xxx

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Pancreatic small cell cancer Elie El Rassy a,∗, Samer Tabchi a, Hampig Raphael Kourie b, Tarek Assi a, Ralph Chebib a, Fadi Farhat a, Joseph Kattan a a

Department of Oncology, Hotel Dieu de France University Hospital, Faculty of Medicine, Saint Joseph University, Lebanon, Lebanon b Department of Oncology, Jules Bordet Institute, Free University of Brussels (ULB), 1, Héger-Bordet Street, Brussels, Belgium

Summary Small cell carcinoma (SCC) is most commonly associated with lung cancer. Extrapulmonary SCC can originate in virtually any organ system, with the gastrointestinal tract being the most common site of involvement. We review the clinical presentation, pathogenesis, histology, imaging modalities and optimal therapeutic management of PSCC in light of available evidence. © 2015 Elsevier Masson SAS. All rights reserved.

Introduction and overview Generally, small cell carcinoma (SCC) is known to affect the lungs, but extra-pulmonary SCC can originate in virtually any organ system, particularly the gastrointestinal and the genitourinary tracts [1,2]. In pancreatic cancer, in particular, the presence of tumoral disease usually underlines pancreatic adenocarcinoma (PA) because, until 1951, it was the only histologic subtype of pancreatic cancer identified. Miller et al. reported the presence of other subtypes, including squamous cell carcinoma, acinar cell carcinoma, mucinous cystadenocarcinoma and SCC [3]. Of particular interest to this paper is the neuroendocrine variant of pancreatic cancer because of its poor prognosis. Although rarely reported in the literature, different interchangeable terms describe

this entity as follows: small cell carcinoma, oat cell carcinoma, high-grade neuroendocrine carcinoma and poorly differentiated neuroendocrine carcinoma [3]. There have been very few publications regarding pancreatic SCC (PSCC) in the past 20 years. Most data indicate that PSCC accounts for approximately 1% of all pancreatic cancers [4]. Despite having names similar to those of welldifferentiated neuroendocrine tumors, PSCC and pulmonary SCC differ significantly from these tumors in terms of their proliferative rates, aggressivity, therapeutic approaches and paraendocrine/paraneoplastic secretions. It is also uncertain whether these poorly differentiated cancerous cells arise de novo or derive from well-differentiated neuroendocrine cells or normal ductal precursor cells [5].

Clinical presentation and diagnosis ∗

Corresponding author. E-mail address: [email protected] (E. El Rassy).

The first case series relating to PSCC described weight loss, jaundice, cachexia, hepatomegaly, abdominal pain,

http://dx.doi.org/10.1016/j.clinre.2015.09.010 2210-7401/© 2015 Elsevier Masson SAS. All rights reserved.

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ascites, and disorientation at presentation. In this series, two patients presented with liver metastasis, and one patient presented with lymph node metastasis. Ectopic hormone production was not described in this paper [6]. To date, analyzed data from PSCC publications have presented the tumor in a single pancreatic location in 85% of cases, including 56% in the head, 20% in the tail, and 10% in the body, and in multiple pancreatic locations in 15% of cases [5,7—11]. Clinically, the initial presentation of PSCC is dictated by the location of the disease. Tumors of the head of the pancreas often present with painless jaundice (33%) and weight loss (52%). Other common frequent symptoms encountered at diagnosis are abdominal pain (62%), weight loss (52%), loss of appetite (14%), slight fever (14%), peripheral adenopathy (14%), hepatomegaly (10%), and ascites (10%) [7]. Acute pancreatitis is uncommon [9]. Other possible presentations for PSCC are paraneoplastic syndromes. Unlike pulmonary SCC, in which paraneoplastic syndromes are frequent at presentation, reports of extrapulmonary associated paraendocrine syndromes are sparse. Only two published papers have reported elevated hormone levels in these tumors. The first paper presented a case of increased adrenocorticotrophic hormone (ACTH) secretion, and the second paper presented a case of paraneoplastic hypercalcemia [12,13]. To date, 89% of patients with PSCC have extensive disease at the time of their initial diagnosis, which is attributed to the high proliferative rate of PSCC. In a review by Vos et al. (2008), metastasis predominantly occurred in peripancreatic lymph nodes (62%), the liver (38%), the lungs (14%), the bone marrow (14%), the bone (10%), the colon (10%), and the adrenal glands (10%) [7]. Other reported metastatic sites included the spleen, gallbladder, kidney, skin, brain, and soft tissue [7,11]. Clinically, extrapulmonary SCC and metastatic primary pulmonary SCC are not always distinguishable through histology. Consequently, exclusion of pulmonary SCC is a prerequisite for the diagnosis of extrapulmonary SCC [8].

Histology In most reports, biopsy specimens show sheets of small or oat-like cells that are spindle-shaped with scant cytoplasm and hyperchromatic nuclei. PSCC are immunoreactive for epithelial membrane antigen and keratin, which is a reflection of their epithelial origin. In all reported cases, positive immunoreactivity to chromogranin A or synaptophysin, in addition to CD56 expression, confirms the diagnosis. Neuron-specific enolase (NSE) is another valuable marker of neuroendocrine differentiation showing positive immunoreactivity in biopsy specimens. Biopsy specimens should be tested for CD99 receptor status, which is positive in primitive neuroectodermal tumors of the pancreas [14,15]. Just as immunohistochemistry identifies the neuroendocrine origins of tumors, it may also help localize sites of origin. Thyroid transcription factor-1 is expressed in most poorly differentiated neuroendocrine carcinomas and some well-differentiated NETs of pulmonary origin [16]. In reference to the accepted definition of PSCC, these tumors are usually high grade and poorly differentiated.

Consequently, PSCC are defined by a mitotic index of more than 20 mitoses per high power field and a Ki67 labeling index of more than 20% [17]. In one series of 107 pancreatic resections initially diagnosed as poorly differentiated neuroendocrine carcinoma, fifty-eight percent were reclassified as well differentiated neuroendocrine carcinoma or acinar cell carcinoma. The amplitude of misdiagnosis illustrated by this series demonstrates the importance of following strict criteria to ensure an adequate diagnosis [5]. Alterations in the cellular checkpoints Rb/p16 and p53 abrogate cell cycle control and promote, among other activities, the emergence of pancreatic malignancies. The loss of these proteins is an essential genetic anomaly of poorly differentiated NET. These inactivations are much less common in well-differentiated tumors and PA. Bcl-2 protein, a central apoptotic inhibitor, also plays an essential role in the pathogenesis of PSCC. Bcl-2 appears to be ubiquitously overexpressed in PSCC, which contrasts with its expression in well-differentiated NET and PA. Its overexpression accounts for the high proliferative rate and aggressive malignant phenotype of PSCC [18].

Biomarkers NSE is a biomarker found in neuroendocrine cells and is known for its close correlations with the extent of the disease and response to therapy [4,8,14,19]. With the exception of one published case, all other patients demonstrated increases in serum NSE levels in SCC of the pancreas. Gastrin related peptide (GRP) and Pro-GRP are also possible markers that have been shown to be more sensitive and specific than NSE for extrapulmonary SCC [20]. Pro-GRP is more sensitive than GRP and is a possible marker for the diagnosis of and the assessment of responsiveness to therapy in PSCC [4]. Serum carcinoembryonic antigen (CEA) is another possible marker that may be used for the assessment of treatment response despite its lower specificity [14]. Similar to PA, Ca19-9 is almost constantly elevated in patients with PSSC but is not reported as a valuable marker for follow-up in these patients [8—11].

Imaging features Initial imaging studies should include cross-sectional studies of chest, abdomen, pelvis, and brain (if symptomatic) using computed tomography or magnetic resonance imaging (MRI). Unlike well-differentiated NET, somatostatin receptor scintigraphy holds no value in the workup of PSCC. On the other hand, fluorodeoxyglucose (FDG)-PET scanning is very sensitive in this context due to the high metabolic rate of PSCC [21]. Patients presenting with localized PSCC will not have their disease readily distinguished from PA by imaging studies alone. The distinction of pancreatic islet cell tumors from localized PSCC is challenging because the imaging features displayed by this tumor subtype are almost indistinguishable from those of PSCC [22]. However, some imaging features may be useful in diagnosing PSCC. In several reports, computed tomography and MRI have demonstrated hypervascularized homogenous mass patterns different from the characteristic hypovascular lesions encountered in adenocarcinomas [23]. However, it is

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Pancreatic small cell cancer very challenging to establish the diagnosis of PSCC through imagery, as 20% of PA presents with this hypervascular pattern. Based on the results of this radiologic evaluation, PSCC is classified as a limited disease if confined to the pancreas or peripancreatic lymph nodes, whereas all other types are considered extensive disease. Encountering a metastatic disease at diagnosis does not warrant an extensive workup to identify the primary cause of the tumor as systemic therapy will not vary as a result [24].

Treatment Treatment rational Due to its rarity, there is no consensus regarding the optimal management of PSCC. However, non-randomized studies have shown that median overall survival is significantly inferior in patients undergoing symptomatic management compared with systemic or localized therapy [7]. Surgery is the only curative modality, but, as in patients with localized pulmonary SCC, surgery alone has failed to show a survival benefit over its combination with chemotherapy [7]. One exception was reported by Kinoshita et al. in which complete remission was obtained with surgery alone [23,25,26]. However, as 89% of patients have extensive disease at presentation, extrapulmonary SCC is essentially treated with chemotherapy alone and does not benefit from localized treatments [27]. PSCC in the curative setting In the setting of localized disease, the role of chemoradiation therapy is limited because it does not appear to offer a survival advantage over chemotherapy, but data are limited in this context [28,29]. However, one case report described the treatment of localized PSCC with surgery plus chemotherapy (cisplatin 100 mg/m2 IV on day 1 and etoposide 60 mg/m2 IV on days 1—3 of a four-week schedule, for six cycles) and showed a survival duration of 36 months [8]. Winter et al. reported a six-patient case series of potentially resectable PSSC cases treated with surgery followed by a combination of etoposide and cisplatin with 50 Gy of external beam radiation therapy. In this series, a median overall survival of 20 months was reported, with one patient demonstrating the longest reported survival for PSCC of 173 months. This study showed that surgery may be of benefit when combined with adjuvant therapy [30]. First-line chemotherapy in advanced PSCC An optimal chemotherapy regimen has not yet been established in extensive disease. In 1989, Morant et al. failed to induce remission in advanced PSCC using a combination of streptozocin, doxorubicin, cyclophosphamide, 5-fluorouracil, methotrexate and lomustine (MACC) but reported a complete remission of 50 months with etoposide (150 mg/m2 IV on days 1 to 3) and cisplatin (100 mg/m2 IV on day 2) in 28-day cycles [31]. The largest retrospective study that analyzed the effect of this regimen included 53 patients with neuroendocrine tumors, 13 of whom had PSCC. The objective response rate was 41.5%, with a median duration of response of 9.2 months, a median overall survival (OS) of 15 months and a median progression free survival (PFS) of

3 8.9 months. The most common grade 3 and 4 toxicities were hematological (60%) and digestive (40%) [32]. A decrease in the dosages of the regimen for etoposide (100 mg/m2 IV on days 1 to 3) and cisplatin (80 mg/m2 IV on day 2) resulted in a median OS of 5.8 months and a PFS of 1.8 months without decreasing the risk of toxicity [33]. Another successful regimen using cyclophosphamide (1000 mg/m2 on day 1), doxorubicin (45 mg/m2 IV on day 1) and etoposide (100 mg/m2 IV on days 1, 3, and 5) every three weeks for five cycles allowed for a median of 13.5 months of overall survival [27]. Other regimens of cyclophosphamide, doxorubicin and vincristine (VAC) or gemcitabine with somatostatin analogs failed to show significant benefits [31,34]. In a subgroup of 279 patients diagnosed with malignant pancreatic tumors, four patients had PSCC and were treated with a combination of carboplatin and etoposide. Two patients had complete remission, one patient had partial remission, and one patient had stable disease [35]. In line with small cell lung cancer, irinotecan has been incorporated in chemotherapy regimens for extrapulmonary small cell lung cancers. Forty-four patients with poorly differentiated neuroendocrine cancer, 20 of whom had digestive primary cancer, received a combination of irinotecan-cisplatin (irinotecan 60 mg/m2 on days 1, 8, and 15 and cisplatin 60 mg/m2 on day 1 of a four-week cycle). The response rate was 50%, and PFS reached 4.8 months, with 45—66% of patients presenting with grade 3 or 4 toxicity [36]. Therefore, the combinations of carboplatin-etoposide and cisplatin-etoposide used in the treatment of pulmonary SCC seem to be the most effective and most commonly used regimens in extrapulmonary SCC [1,37].

Chemotherapy regimens for PSCC after first-line treatment In view of the short responses obtained with first-line treatments, the roles of second-line treatments have yet to be determined. In a retrospective analysis, the combination of 5-FU, leucovorin, and irinotecan (FOLFIRI) (irinotecan 180 mg/m2 on day 1, followed by 400 mg/m2 folinic acid in a 2-h infusion, a 10-min bolus of 400 mg/m2 5-FU, and 1200 mg/m2 5-FU in a 44-h infusion [days 1 and 2] every 14 days) in second-line treatment after an etoposide-cisplatin regimen allowed a median OS and PFS of 18 and 4 months, respectively. Only 31% of the patients had grades 3 and 4 toxicity [38]. Another second-line chemotherapy regimen was extrapolated from well-differentiated pancreatic neuroendocrine carcinoma and included temozolomide as a single agent (150—200 mg/m2 for 5 days every fourth week) or in combination with capecitabine and bevacizumab (capecitabine 750—1000 mg twice a day on days 1—14, temozolomide 150 mg/m2 days 10—14, and bevacizumab 5 mg/kg on days 14 and 28 in 28-day cycles). Adding capecitabine and bevacizumab did not show any significant benefit; however, the overall objective response rate was 33%, with a median OS and PFS of 22 and 6 months, respectively, with only one patient having grade 3 toxicity. The improved findings associated with this protocol compared with FOLFIRI were attributed to selection bias in the temozolomide study [39]. In one case series with patients intolerant of FOLFIRI and

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temozolomide, gemcitabine (1000 mg/m2 gemcitabine on days 1, 8 and 15 every four weeks) resulted in a clinical benefit and manageable toxicity. Therefore, salvage therapy with gemcitabine is reasonable in patients with poor performance status [40]. Cranial irradiation In most patients with poorly differentiated NET, prophylactic cranial irradiation has not shown any survival benefit. These recommendations can be extrapolated to PSCC [41].

Conclusion PSCC is highly aggressive neoplasm with a very poor prognosis. This entity is distinct from well-differentiated NET in terms of its proliferative rate, management and overall prognosis. PSCC may benefit from novel therapeutic approaches broadly similar to those used for SCC arising in the lung. However, the best chance of obtaining a durable response would involve early detection at a localized stage followed by surgical-based therapy. More data are necessary in order to better define future guidelines.

Disclosure of interest The authors declare that they have no competing interest.

Acknowledgments None.

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