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Hindawi Case Reports in Oncological Medicine Volume 2021, Article ID 8896254, 8 pages https://doi.org/10.1155/2021/8896254 Case Report A Patient with an Ileocecal MiNEN and a Synchronous Squamous Non-Small-Cell Lung Cancer: Case Report and Review of the Literature 1 2 1 Santiago Teran , Maria Camara Jurado, and Juan Antonio Nuñez Sobrino Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain Pathology Department, Hospital Universitario 12 de Octubre, Madrid, Spain Correspondence should be addressed to Santiago Teran; email@example.com Received 26 August 2020; Revised 17 February 2021; Accepted 23 March 2021; Published 31 March 2021 Academic Editor: Mauro Cives Copyright © 2021 Santiago Teran et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are rare tumors composed of two diﬀerent histological components, one of which is of a neuroendocrine origin. Given its suggested underdiagnosis and consequent low prevalence, no clear diagnostic and treatment guidelines are available, and treatment usually follows regimens similar to that of the most aggressive component. On the other hand, multiple primary tumors (MPTs) are also rare neoplastic entities that usually confer a challenge regarding treatment options, for a regimen that comprises both the primary and the synchronous/metachronous malignancy should be used. Here, we discuss the challenging diagnostic and therapeutic management of a patient with an ileocecal MiNEN that presented along with a synchronous squamous non-small-cell lung cancer (SQ-NSCLC). The patient presented with intestinal obstruction symptoms for which he underwent an emergency resection of the ileocecal MiNEN. An initial CT scan showed an additional lung mass later identiﬁed as an SQ-NSCLC after bronchoscopy biopsy analysis. Given the rapid hepatic metastatic progression, palliative platinum-based chemotherapy was initiated, with an adequate response of the local and metastatic lesions of the MiNEN, but suggested platinum resistance and progression of the pulmonary neoplasm. Second-line treatment with pembrolizumab directed for the SQ-NSCLC was initiated; however, it was stopped after immune- mediated toxicities developed. A third-line chemotherapy scheme with carboplatin/gemcitabine was initiated, but central nervous system (CNS) progression developed, with the patient dying 11 months after initial diagnosis. 1. Introduction the parameter that often dictates the grade of malignancy, prognosis, and management to be followed [5–7]. MiNENs Previously called mixed adenoneuroendocrine carcinomas are extremely rare tumors with very limited scientiﬁc biblio- (MANECs), these tumors have been subjected to a new classi- graphic data available, showing an incidence as low as ﬁcation by the World Health Organization (WHO) classiﬁca- 0.01/100,000 cases per year . tion of tumors of endocrine and digestive organs of 2017 and We report the case of a patient with an ileocecal MiNEN 2019, respectively, changing their nomenclature to mixed neu- that presented along with a secondary synchronous squa- roendocrine non-neuroendocrine neoplasms (MiNENs) [1, mous non-small-cell lung cancer. 2]. This change was based mainly on the fact that the MANEC terminology restricted the non-neuroendocrine component to 2. Case Presentation adenocarcinoma histology, and although such conﬁguration is the most commonly found , it leaves aside other possible A 71-year-old heavy smoker male patient (116PY), with past conﬁgurations both at the histopathological subtype of the medical history relevant for stage 1 COPD, presented to the non-neuroendocrine component and the degree of diﬀerenti- emergency room with complaints of a 2-week diﬀuse abdom- ation of the neuroendocrine component [4, 5], the latter being inal pain, with no nausea, vomiting, GI transit disturbances, 2 Case Reports in Oncological Medicine noma. Molecular data of the patient MiNEN showed an or changes in stool appearance associated. He additionally described a 13 kg weight loss over the past year, as well MSI stable marker, TMB: 11.5, as well as a PD‐L1 > 5%. as a chronic nonproductive cough, which he endorsed to The patient was referred to medical oncology consults and began urgent palliative chemotherapy (ChT) treatment his smoking habit and had not worsened recently. He denied other respiratory symptoms. Physical examination under a carboplatin+etoposide regimen, directed to the was only remarkable for hypophonesis in the left upper NEC component of the MiNEN given the evidence of pulmonary quadrant and acropachy in the upper extremi- suggested rapid progression at the hepatic level. Radiologic ties. A complete blood count and serum chemistry showed control after 2 cycles showed resolution of the hepatic lesions (Figure 1(d)) and no recurrence at the colonic level; however, no abnormalities. A chest X-ray was performed, which showed a paramediastinal mass in the left upper lobe with it showed tumor progression at the pulmonary mass. To homogeneous density and regular edges that did not seem optimize the treatment for the SQ-NSCLC, without neglect- to deviate the upper airway or compromise the great ing that of the digestive MiNEN, the ChT regimen was vessels in the mediastinum. The patient was admitted for switched to carboplatin+paclitaxel, showing stability of the SQ-NSCLC after 3 cycles, but later progression with increas- further evaluation. On the following days, the patient presented worsening ing size and metabolic activity at the lung mass (Figure 1(e)). abdominal pain, bloating, vomiting, GI transit disturbances Second-line monotherapy treatment with pembrolizumab with ultimately complete GI transit stoppage, and important directed to the SQ-NSCLC was initiated (PD-L1 greater or abdominal distention. Physical examination showed a dis- equal to 1%) with immune-mediated toxicities (e.g., G3 thy- roiditis and cytopenias) developing, forcing to completely tended, hyperresonant abdomen, with no rebound tender- ness or peritoneal irritation signs associated. A nasogastric stop the immunotherapy treatment after only one cycle and tube was placed and an emergency abdominal CT scan was progress to a third-line chemotherapy scheme with carbopla- performed, which showed a 7 cm lesion located in the poste- tin+gemcitabine. Once again, tumor progression at the CNS rior apical segment of the left upper lobe in a paramediastinal level developed, for which he received palliative holocraneal radiotherapy treatment, along with the chemotherapy situation, in close contact with the superior margin of the oblique ﬁssure, main left pulmonary artery, and left margin scheme proposed. The patient died 11 months after the of the aortic arch (3 cm). At the abdominal level, it showed primary diagnosis was made. a hypervascular lesion of neoplastic appearance of approximately 7 cm in the ileocecal junction, along with ade- 3. Discussion nopathies in the ileocolic, subcarinal, mediastinal, and pul- monary hilum territories (Figure 1(a)). An emergency right Each component of a MiNEN tumor must constitute at least hemicolectomy was performed with intraoperative ﬁndings 30% of the entire neoplasm. This threshold has been arbi- of an ileocecal mass strongly adhered to the right parietocolic trarily deﬁned based on the assumption that lower compo- gutter, as well as several adenopathies along the ileocolonic nent percentages are not decisive for clinical prognosis . axis, free abdominal ﬂuid, and proximal distension of the However, it has been shown that nonpredominant compo- small bowel. nents (those <30%) can be determinant given the fact that After adequate postsurgical evolution, a diagnostic bron- they often show aggressive histologies (e.g., neuroendocrine choscopy with biopsy sampling and a body PET scan were carcinoma and its pathological similarity with that of the performed. The latter showed an abnormal FDG-avid activ- small cell lung cancer (SCLC)) . The most commonly ity of the left parahilar mass (6cm × 6cm × 4cm) with soft found non-NE components of MiNEN are adenocarcinoma, tissue density, well-deﬁned margins, and in stretch contact followed by adenoma and squamous cell carcinoma . On with the aortic arch (SUV max 24.18); newly evidenced cen- the other hand, diﬀerent conformations of both components timetric lesions in hepatic segments IV, V, and VI (with have been described at the histological level, giving us some SUVs of 6.06, 8.15, and 4.66, respectively) (Figures 1(b) and insight into their origin. Thus, collision subtype MiNEN 1(c)); and para-aortic mediastinal lymphadenopathies with (two diﬀerent cell types that collide and merge, but do not an SUV max of up to 16.8 for the largest one. Histopatholog- fuse) suggests a synchronic/metachronic origin from two dif- ical results of the resected colonic mass were compatible with ferent cell lineages [3, 6]. Composite and amphicrine subtype a mixed neuroendocrine non-neuroendocrine neoplasm MiNENs (one cell type that displays phenotypic characteris- (MiNEN): moderately diﬀerentiated colorectal adenocarci- tics of others) suggest a common origin from a pluripotent noma+poorly diﬀerentiated small cell neuroendocrine stem cell that accumulates diﬀerent molecular aberrations carcinoma (NEC) (the neuroendocrine component (NE) in genes such as Tp53, KRAS, BRAF, and MSI among the comprised 30-35% of the total, with high-grade characteris- most relevant [3, 6, 7]. It has been suggested that the NEC tics and intense positivity for synaptophysin, CD56, and component of the MiNEN originates from the adenocarci- chromogranin A) at the ileocolic level (Figures 2(a)–2(d)), noma one, due to the “more malignant” characteristics of which inﬁltrated the muscular layer and perivisceral fat the latter , following the adenoma-adenocarcinoma multi- focally, also extending to the muscular layer of the appendix step sequence hypothesis [6, 9]. Nevertheless, this would and its mucosa but with no serosa perforation. Lymphovas- contrast the fact that these tumors normally develop in neu- cular invasion in 3/28 lymph nodes corresponded to NEC. roendocrine cell-rich organs, which would implicate neuro- Histopathology of the lung mass after bronchoscopy biopsies endocrine cells as those responsible for initiating the described a lesion corresponding with squamous cell carci- carcinogenic process given their stem cell potential, presence Case Reports in Oncological Medicine 3 (a) (b) (c) (d) 39.8mm 19.6mm 42.9mm 54.5mm 69.7mm 70.4mm (e) Figure 1: (a) Initial diagnostic CT scan shows an ileocecal mass of approx. 7 cm of diameter, with no clear radiologic signs of bowel distention or obstruction. (b) Initial PET/CT scan shows a 7 cm FDG-avid paramediastinal lesion in stretch contact with the aortic arch. (c) Initial PET/CT scan shows a metastatic lesion at the hepatic segment V. (d) Control PET/CT scan after 2 cycles of carboplatin/etoposide shows complete resolution of the hepatic lesions. (e) Control CT scan after 2 cycles of carboplatin/etoposide and 3 cycles of carboplatin/paclitaxel shows tumor progression (left image) of the paramediastinal mass, further compromising the aortic arch. 4 Case Reports in Oncological Medicine (a) (b) (c) (d) Figure 2: (a) Ileocolic high-grade MiNEN showing both the adenocarcinoma (mucinous glands at the bottom left) and neuroendocrine carcinoma (numerous solid irregular cords and nests, without lumen or mucin production) components. (b) High-power ﬁeld of the neuroendocrine carcinoma: irregular nuclei with hyperchromasia, high nuclear/cytoplasmic ratio, no prominent nucleoli, and abundant mitotic ﬁgures. (c) Ki-67 immunostain shows a very high proliferating index (about 80%) in a NEC metastatic lymph node. (d) Strong and diﬀuse synaptophysin positivity in a lymph node sample, correspondent with NEC. of molecular aberrations, and other physiological peculiari- >20, respectively) [4, 6], with Ki-67 being the marker with ties, such as the lack of E-cadherin and serotonin production, the highest validity in case of discordant proliferative criteria characteristics that explain their metastatic and vasculogenic  and the grade of histological diﬀerentiation being the most relevant parameter for discerning between NET and properties, as well as their aggressiveness and malignant potential [7, 8]. NEC (well-diﬀerentiated + any grade of proliferation vs. MiNEN tumors can develop at any level of the digestive poorly diﬀerentiated + grade 3 of proliferation) [4, 6]. Finally, tract , with the colon, pancreas, and biliary tract being there are still controversy and diﬃculties to diﬀerentiate a the most commonly aﬀected sites. The liver, on the other NET G3 from a NEC according to the latest WHO classiﬁca- hand, is the most common place for metastatic involvement tion, for which molecular determinations such as the [3, 10]. The diagnosis of MiNEN involves imaging tech- expression of Rb1 and p53 have been ultimately useful to niques (CT scan, MRI, US, and upper and lower endoscopy), diﬀerentiate them . specimen biopsy, and immunohistochemical (iHQ) markers. In addition to the aforementioned, the fact that on a his- In the case of the latter, these are useful to deﬁne the topathological level the NE and non-NE components are histopathological characteristics of the tumor as well as ther- often found in variable conﬁgurations and proportions apeutic strategies; however, they have shown little clinical within the tumor sample commonly leads to unrepresenta- prognostic correlation . Synaptophysin and chromogra- tive sample analysis and consequent underdiagnosis [3, 4, nin A stains are recognized as the most reliable iHQ markers 10], somehow explaining their low prevalence described in for NE lineage, with the former being the one that shows diﬀerent series. In line with this, within the tumor database greater immunoreactivity in the case of NEC . On the of our center and taking into account a cohort from January other hand, substances produced by NE cells, such as seroto- 2001 to December 2019, a total of 16128 digestive system nin (5-HIAA), are of little or no use in recognizing NECs, tumors were recorded (anywhere within the digestive tract). Out of these, 460 (2.85%) were classiﬁed as neuroendocrine since these are generally nonsecretory unlike NETs . Once the NE nature of the tumor has been identiﬁed, it is neoplasms, of which 296 (64.3%) were neuroendocrine important to deﬁne the grade of histopathological diﬀerenti- tumors (NETs), 158 (34.4%) neuroendocrine carcinomas ation (well vs. poorly diﬀerentiated), as well as the grade of (NECs), and 6 (1.3% out of NEN and 0.04% of all digestive proliferative criteria (G1, G2, and G3, corresponding to Ki- neoplasms) were cataloged as MiNEN/MANEC. No recorded data regarding clinical outcomes of such cases was 67: <3, Mi: <2; Ki-67: 3-20, Mi: 2-20; and Ki-67: >20, Mi: Case Reports in Oncological Medicine 5 tion of treatment was curative with surgery in addition to available. This data correlates to that of scientiﬁc reports showing a prevalence of 0.048% for NEN in the USA and perioperative ChT (60.4% surgery alone, 33.3% surgery recently increasing incidences ranging from 2.5-5/100,000 +ChT) following in most cases regimens based on clinical guidelines for early-stage adenocarcinomas (66.7% non- to 8.4/100,000 (in the USA and Europe, respectively), mostly thanks to earlier detection and increased use of endoscopy NE-like regimens, versus 22.2% NEC-like regimens). On and other diagnostic techniques over time [11, 13]. MiNENs, the other hand, in the advanced setting, palliative strategies on the other hand, are even rarest entities, representing 1- followed treatment regimens for both adenocarcinoma and 1.5% of all gastroenteropancreatic neoplasms , data that NEC, in similar proportions (53.3% non-NE-like regimens versus 46.7% NEC-like regimens) . Other strategies such however highly surpasses that of ours. Interestingly, none of the 6 MiNEN/MANEC cases in our center was recorded as targeting tumors with mTOR or KRAS mutations with before 2018. In this matter, it is important to remember that components such as everolimus and anti-EGFRs have been it was not until the 2010 WHO classiﬁcation of neuroendo- proposed as possible therapeutic options, although they have crine neoplasms that MANEC was ﬁrst described as a single not yet been implemented in a systematic manner [6, 20, 22]. Finally, despite being tumors of a NE nature, somatostatin entity , which together with the underdiagnosis mislead- ing factors mentioned before could explain our center’s low analogs have not shown to be useful in NECs, since these lack MiNEN prevalence. serotonin receptor expression (SSTR-2), unlike their coun- Despite similarities with small cell lung cancer (SCLC), terpart NETs 1 and 2 (low grade) which, given their potential NECs are less associated with smoking , have lower to secrete serotonin metabolism products, have shown response to such treatments [6, 20]. Our case was particularly local/regional metastatic potential, and show lesser response to platinum therapies compared to SCLC . On the other challenging given the fact that a treatment regimen that not hand, the patient’s clinical and pathological characteristics, only covered both the most aggressive component of the such as the performance status, LDH levels, tumor site of ori- MiNEN and the squamous cell lung cancer (SQ-NSCLC) gin, and Ki-67% (less response to platinum-based regimens if had to be used. In line with the aforementioned, a regimen based on carboplatin combined with etoposide and later pac- <55%), are all taken into account when deciding about treat- ment regimens, which usually follows those of SCLC . litaxel was chosen. Such regimen showed an adequate Treatment of NEC diﬀers for both the localized versus response at the MiNEN level; however, tumor progression was evidenced for the SQ-NSCLC after 5 cycles and almost advanced (metastatic) staging of the tumor. Regarding the latter, the North American Neuroendocrine Tumor Society 6 months of treatment, and even when platinum resistance could not be certainly assumed [23, 24], second-line mono- (NANETS) consensus suggests carboplatin/cisplatin-based ﬁrst-line ChT regimens combined with etoposide/irinotecan, therapy with pembrolizumab directed to the SQ-NSCLC consistent with those of SCLC, as well as the use of gemcita- was initiated. There are no standard second-line therapy schemes for bine, paclitaxel, and docetaxel, as other drug options with action both in NEC and SCLC . This regimen (cisplatin poorly diﬀerentiated neuroendocrine carcinomas  and as the therapeutic option scenario broadens taking into +etoposide) has shown overall response rates (RR) ranging from 42% to 67% and median overall survival times (mOS) account immunotherapy; predictive molecular/genetic bio- of up to 15-19 months in the ﬁrst-line treatment setting markers have been studied to guide clinical and therapeutic decisions . Among these, MSI (microsatellite instability), . In the case of second-line treatment regimens, oxalipla- tin, irinotecan, and temozolomide have achieved RR of up to which reﬂects a high mutational load and antigenicity with a consequent response to immunotherapy, is higher in NECs 33% and mOS of up to 22 months in the case of the latter [17, 19]. Curiously, these regimens have shown better outcomes than NETs [27–29] and has been described in up to 12.4% in patients with Ki‐67% <55 – 60%, implying the importance of NEC/MANECs [25, 29, 30]. Also, a high tumor mutational burden (TMB) has been described as a positive predictive of a proper pathological characterization of the tumor at the time of diagnosis . biomarker for response to PD-1/PD-L1 inhibition [26, 29, In the case of low, intermediate, and high-grade MiNEN, 31–34]. Several studies of immunotherapy in NEC are cur- surgical excision of the primary tumor and the metastasis rently under investigation, prompted by previous positive should always be taken into account whenever feasible , results found in Merkel cell carcinoma, a tumor that is closely related to NEC ; however, mostly conﬂicting results from given the improvement in survival rates and symptom con- trol described with these interventions . Adjuvant treat- phase 1 and phase 2 trials have been encountered. Among ment is generally directed to that of the most aggressive these, a phase 1b trial (Keynote-028) which included patients component . Thus, in the case of low- and intermediate- with advanced solid tumors in diﬀerent locations treated grade MiNEN, regimens directed to the adenocarcinoma with pembrolizumab as monotherapy described an objective response rate (RR) of 12% for advanced PD-L1-positive component are usually followed (since the NE component in these cases is usually well diﬀerentiated), while for high- carcinoid patients, as well as a 6% RR, 27% 12-month grade MiNEN, regimens similar to those of poorly progression-free survival (PFS), and 87% overall survival diﬀerentiated NEC/SCLC are followed, in consonance with (OS) for pancreatic NEC patients [26, 29, 35, 36]. This result recommendations for NEC treatment from the European correlates to other phase 2 studies showing RRs ranging from 5 to 17.9% [25, 37, 38]. On the contrary, some other phase 1 Neuroendocrine Tumor Society (ENETS) . One of the largest and most recent systematic reviews on the subject by studies describing results of monotherapy with pembrolizu- Frizziero et al.  found that for localized tumors, the inten- mab have concluded that this was not eﬀective in biomarker 6 Case Reports in Oncological Medicine unselected populations of patients with poorly diﬀerentiated Ethical Approval extrapulmonary NECs, like the one by Mulvey et al., describ- This case report is compliant with all relevant laws, institu- ing a median PFS of 58 days, with almost half of the study tional guidelines, and industry standards. Other guidelines population (n =14) presenting early progression (PD) before for reporting clinical trials such as the CONSORT statements the ﬁrst checkup [25, 39, 40]. Another phase 2 study of are not relevant for the present case report publication. Ethics pembrolizumab as monotherapy (Keynote-158) in well- codes, with regard to human and animal subject experimen- diﬀerentiated NETs concluded that the PD-1 inhibitor tation, such as the Declaration of Helsinki, the U.S. Public was ineﬀective, with only 3% of the entire population stud- Health Service Policy on Human Care and Use of Laboratory ied (n = 107) presenting an objective partial radiographic Animals, and the EU Directive 2010/63/EU on the protection response [41, 42]. Finally, similarly, other anti-PD-L1 mol- of animals used for scientiﬁc purposes, are not relevant to ecules such as spartalizumab have been studied in phase 2 this case report. trials, showing once again little response (OR < 10%)in GEP NETs [26, 37, 43]. Given that our patient only Consent received 1 cycle of pembrolizumab, it is diﬃcult to deter- mine any possible response to it, although the molecular Informed consent approval from the patient was received proﬁle of the MiNEN tumor with only minimally elevated before publication. TMB and MSI stable would have predicted little response to such therapy. Conflicts of Interest Regarding multiple primary tumors (MPTs), they have an incidence of 2-17%, being more common in patients with The authors ST, MCJ, and JANS declare that they have no tumors or under treatments that confer long survival periods. known competing ﬁnancial interests or personal relation- In the case of colon and lung cancer, the incidence of second ships that could have appeared to inﬂuence the work primaries accounts for 19.7% and 21%, respectively . reported in this paper. MPTs are classiﬁed as synchronous or metachronous whether the diagnosis interval between the ﬁrst and second Authors’ Contributions tumors is less or greater than 6 months, respectively . Among the epidemiological factors related to the develop- ST, MCJ, and JANS contributed to patient care. ST wrote and ment of MPTs, tobacco exposure has been described as one edited the manuscript. MCJ and JANS reviewed and edited of the most determining and commonly shared risk factors the manuscript. in several studies [44, 45]. Patients with MPTs have the worst prognosis compared to those with a single neoplasm, and References among these, synchronous neoplasms present a statistically signiﬁcant decrease in mOS when compared with the meta-  S. la Rosa, S. Uccella, F. 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Case Reports in Oncological Medicine – Hindawi Publishing Corporation
Published: Mar 31, 2021
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