Impact of COVID-19 pandemic on diagnostic pathology in the Netherlands.

BACKGROUND: The COVID-19 pandemic has a huge impact on healthcare provided. The nationwide pathology registry of the Netherlands, PALGA, offers an outstanding opportunity to measure this impact for diseases in which pathology examinations are involved. METHODS: Pathology specimen numbers in 2020 were compared with specimen numbers in 2019 for 5 periods of 4 weeks, representing two lockdowns and the periods in between, taking into account localization, procedure and benign versus malignant diagnosis. RESULTS: The largest decrease was seen during the first lockdown (spring 2020), when numbers of pathology reports declined up to 88% and almost all specimen types were affected. Afterwards each specimen type showed its own dynamics with a decrease during the second lockdown for some, while for others numbers remained relatively low during the whole year. Generally, for most tissue types resections, cytology and malignant diagnoses showed less decrease than biopsies and benign diagnoses. A significant but small catch-up (up to 17%) was seen for benign cervical cytology, benign resections of the lower gastro-intestinal tract, malignant skin resections and gallbladder resections. CONCLUSION: The COVID-19 pandemic has had a significant effect on pathology diagnostics in 2020. This effect was most pronounced during the first lockdown, diverse for different anatomical sites and for cytology compared with histology. The data presented here can help to assess the consequences on (public) health and provide a starting point in the discussion on how to make the best choices in times of scarce healthcare resources, considering the impact of both benign and malignant disease on quality of life.

Velopharyngeal insufficiency in patients without a cleft palate: important considerations for the ENT surgeon.

BACKGROUND: Velopharyngeal insufficiency is the inability to close the velopharyngeal port during speech and swallowing, leading to hypernasal speech and food regurgitation. OBJECTIVE: This study aimed to explore the aetiological factors contributing to the development of velopharyngeal insufficiency in a non-cleft paediatric population, especially following adenoidectomy. METHODS: A retrospective case review was conducted of all children without a known cleft palate, born between 2000 and 2013, who were referred to a tertiary cleft centre with possible velopharyngeal insufficiency. RESULTS: The data for 139 children diagnosed with velopharyngeal insufficiency following referral to the cleft centre were analysed. Thirteen patients developed the condition following adenoidectomy; only 3 of these 13 had a contributing aetiological factor. CONCLUSION: Velopharyngeal insufficiency is a rare but significant complication of adenoidectomy. The majority of patients who developed velopharyngeal insufficiency following adenoidectomy did not have an identifiable predisposing factor. This has important implications for the consent process and when planning adenoidectomy.

C-Reactive Protein Levels and the Risk of Incident Cardiovascular and Cerebrovascular Events in Patients with Obstructive Sleep Apnea.

PURPOSE: Patients with obstructive sleep apnea (OSA) are at increased risk of cardiovascular and cerebrovascular disease (CVD) but it is unclear who are at greatest risk. We determined whether the inflammatory marker, C-reactive protein (CRP), could be a useful prognostic biomarker. METHODS: Adult patients referred for polysomnography (PSG) with OSA were studied. Serum CRP levels were measured using ELISA the morning after PSG. Validated CV events within 4 years of PSG were ascertained by linking to provincial research datasets. RESULTS: 155 patients with OSA (AHI ≥ 5/h) had CRP measured. Median age was 53 and median AHI was 21/h. 10 patients (7.1%) suffered at least one event, but rates varied substantially by CRP (0/35 patients in the lowest quartile, and 7/39 in the highest CRP quartile). In the unadjusted analysis, patients in the highest CRP quartile (≥ 2.38 mg/L) were significantly more likely to suffer an event (odds ratio = 9.72 (95% CI 2.43-38.84), p = 0.001). CRP continued to be a significant predictor after controlling for multiple confounders. OSA severity and desaturation were not significantly associated with prospective events. CONCLUSIONS: In this small preliminary study, OSA patients with an elevated CRP were significantly more likely to suffer a CVD event in the 4 years after PSG. Although these findings need to be confirmed in larger prospective cohorts, CRP may be useful in risk stratifying OSA patients to guide therapy or to identify patients that might be most appropriate for clinical trials of CVD prevention.

Recurrence of Pancreatic Neuroendocrine Tumors and Survival Predicted by Ki67.

BACKGROUND: Despite evidence of different malignant potentials, postoperative follow-up assessment is similar for G1 and G2 pancreatic neuroendocrine tumors (panNETs) and adjuvant treatment currently is not indicated. This study investigated the role of Ki67 with regard to recurrence and survival after curative resection of panNET. METHODS: Patients with resected non-functioning panNET diagnosed between 1992 and 2016 from three institutions were retrospectively analyzed. Patients who had G1 or G2 tumor without distant metastases or hereditary syndromes were included in the study. The patients were re-categorized into Ki67 0-5 and Ki67 6-20%. Cox regression analysis with log-rank testing for recurrence and survival was performed. RESULTS: The study enrolled 241 patients (86%) with Ki67 0-5% and 39 patients (14%) with Ki67 6-20%. Recurrence was seen in 34 patients (14%) with Ki67 0-5% after a median period of 34 months and in 16 patients (41%) with Ki67 6-20% after a median period of 16 months (p < 0.001). The 5-year recurrence-free and 10-year disease-specific survival periods were respectively 90 and 91% for Ki67 0-5% and respectively 55 and 26% for Ki67 6-20% (p < 0.001). The overall survival period after recurrence was 44.9 months, which was comparable between the two groups (p = 0.283). In addition to a Ki67 rate higher than 5%, tumor larger than 4 cm and lymph node metastases were independently associated with recurrence. CONCLUSIONS: Patients at high risk for recurrence after curative resection of G1 or G2 panNET can be identified by a Ki67 rate higher than 5%. These patients should be more closely monitored postoperatively to detect recurrence early and might benefit from adjuvant treatment. A clear postoperative follow-up regimen is proposed.

The reliability of short-term measurement of heart rate variability during spontaneous breathing in people with chronic obstructive pulmonary disease.

BACKGROUND: Reduced heart rate variability (HRV), a marker of autonomic system dysfunction, has been reported in patients with chronic obstructive pulmonary disease (COPD). Yet, limited data exists on the reliability of HRV measurement in this population. Here we investigated the reliability of short-term HRV measurement performed during spontaneous breathing in patients with COPD. METHODS: Thirteen individuals (8 males) with moderate-to-severe COPD (FEV1 46±16% predicted; FEV1/FVC 49±13) underwent standard time and frequency domain HRV measurements derived from 5-minute electrocardiograms collected on two separate days using a SphygmoCor device. Absolute and relative reliability was assessed by a number of coefficients including within-subject random variation, systematic change in the mean, and retest correlations. RESULTS: Within-subject coefficients of variation (CV) ranged from 4.3% to 193.4%. The intraclass correlation coefficients (ICCs) ranged from 0.72 to 0.93 for parameters related to overall HRV, and from 0.57 to 0.59 for those related to parasympathetic tone in both time and frequency domains. Mean heart rate was the only parameter that showed excellent absolute and relative reliability (CV=4.3%, ICC=0.93). CONCLUSION: The HRV measurements showed overall moderate-to-substantial reliability during spontaneous breathing in COPD population. Our findings support the use of HRV parameters for diagnosis and cardiac risk assessment, but only mean heart rate can be used reliably for monitoring changes in autonomic status following rehabilitation intervention in this population.

Feasibility and accuracy of confocal endomicroscopy in comparison with narrow-band imaging and chromoendoscopy for the differentiation of colorectal lesions.

OBJECTIVES: Several advanced imaging techniques have been developed to improve differentiation of colorectal lesions. These techniques need to be assessed for both feasibility and accuracy in order to prove their value in daily clinical practice. The current study assessed the feasibility of probe-based confocal laser endomicroscopy (pCLE) in acquiring videos of sufficient quality. Furthermore, the accuracy of pCLE for the differentiation of colorectal lesions was assessed and compared with narrow-band imaging (NBI) and chromoendoscopy (CE). METHODS: Consecutive patients scheduled for surveillance colonoscopy at our centre were included. All procedures were performed by two expert colonoscopists, who previously participated in studies evaluating pCLE, NBI, and CE. All detected lesions during colonoscopy were differentiated real-time with NBI and CE for Kudo pit pattern. Lesions were also assessed real-time for vascular pattern intensity (VPI) during NBI. Subsequently, pCLE videos of each lesion were acquired and biopsies were taken for histopathology. All pCLE videos were assessed post-hoc for the percentage of time demonstrating sufficient image quality (i.e., depicting at least one crypt or vessel). Finally, pCLE videos were assessed post-hoc for diagnostic accuracy by two experts. RESULTS: A total of 154 lesions detected in 64 patients were included. Accuracy of Kudo pit pattern with NBI for predicting neoplasia (88.7%) was significantly better than accuracy of VPI (77.5%, P = 0.05) but not significantly different from CE (89.3%, P = 0.125). During pCLE, no histology was shown at all on the video in 19 lesions (12%). The mean time to acquire a pCLE video of the remaining 135 lesions was 50 seconds (s.d. 47) per lesion. The median percentage demonstrating sufficient quality per video was 40.5% (interquartile range 21.2-67.0). Accuracy of pCLE for both observers (66.7 and 71.9%) was significantly lower than accuracy of CE (P < 0.001) and NBI (P < 0.001). CONCLUSIONS: Video acquisition with pCLE could not be achieved in a small number of lesions. The majority of pCLE videos demonstrated insufficient quality in more than half of the time recorded. Moreover, post-hoc accuracy of pCLE was significantly lower in comparison with real-time accuracy of CE and NBI. Future research should assess whether further increase in experience could improve pCLE video acquisition and determine the real-time accuracy of pCLE for differentiating colorectal lesions.

The prevalence of dysplasia in the ileoanal pouch following restorative proctocolectomy for ulcerative colitis with associated dysplasia.

AIM: A recent systematic review indicated that dysplasia present before restorative proctocolectomy is a predictor of subsequent dysplasia in the pouch. This prospective study was carried out to assess the prevalence of dysplasia in the ileal pouch in patients having RPC for ulcerative colitis with co-existing dysplasia in the operation specimen. METHOD: Eligible patients were invited for a surveillance endoscopy. The afferent and blind efferent ileal loop, ileoanal pouch and rectal cuff were examined by standard endoscopy using a dye-spray technique with methylene blue. Mucosal abnormalities were biopsied and random biopsies were taken from the afferent and blind ileal loop, pouch and rectal cuff. RESULTS: Fourty-four patients (25 male, mean 49 years) underwent pouch endoscopy at a mean interval from RPC of 8.6 years. Dysplasia was detected in two (4.5%) patients. In one, low-grade dysplasia was found in the rectal cuff and in the other low-grade dysplasia was detected in random biopsies from the pouch and the efferent ileal loop. CONCLUSION: This prospective pouch-endoscopy study detected dysplasia in < 5% of patients over nearly 10 years. The benefit of routine surveillance for dysplasia in the pouch is uncertain, as the significance of low-grade dysplasia in the pouch is not clear.

New classification for probe-based confocal laser endomicroscopy in the colon.

BACKGROUND AND AIMS: Probe-based confocal laser endomicroscopy (pCLE; Cellvizio, Mauna Kea Technologies, Paris, France) enables in vivo histology during colonoscopy and may allow endoscopists to make real-time diagnoses. A collaboration of five experts proposed a new pCLE classification for colonic use. The aim of this study was to assess interobserver agreement and accuracy of the new pCLE classification in the colon. PATIENTS AND METHODS: Eligible patients were prospectively investigated by pCLE. A subset of 13 pCLE video sequences was reviewed post hoc for the establishment of a new classification, which comprised three vessel categories and seven crypt categories. All five blinded observers then scored another set of 102 video sequences, using the new classification. Histopathology was used as a reference standard. RESULTS: The interobserver agreements on vessel and crypt architecture were 'fair' with kappa values of 0.29 and 0.27, respectively. When the classification was reduced to neoplasia vs. non-neoplasia (i.e. vessel or crypt type 3), overall agreement became 'moderate' (κ = 0.56). Overall sensitivity and specificity for predicting neoplasia was 66 % and 83 %, respectively. When all observers agreed (69 % of videos), the corresponding figures became 80 % and 95 %. CONCLUSION: A new classification for pCLE in the colon had a 'moderate' interobserver agreement for differentiating neoplasia from non-neoplastic tissue in the colon. The overall accuracy (81 %) for predicting neoplasia was acceptable and became excellent (94 %) when all five observers agreed. Future research should focus on refinement and validation of the classification.

Increased polyp detection using narrow band imaging compared with high resolution endoscopy in patients with hyperplastic polyposis syndrome.

BACKGROUND AND STUDY AIMS: Hyperplastic polyposis syndrome (HPS) is associated with colorectal cancer and is characterized by multiple hyperplastic polyps, sessile serrated adenomas (SSAs) and adenomas. Narrow band imaging (NBI) may improve the detection of polyps in HPS. We aimed to compare polyp miss rates with NBI with those of high resolution endoscopy (HRE). PATIENTS AND METHODS: In a single center, randomized crossover study consecutive HPS patients underwent tandem colonoscopy with HRE and NBI, in randomized order with removal of all detected polyps. RESULTS: In 22 patients with HPS, 209 polyps were detected, including 27 with normal histology, 116 hyperplastic polyps, 42 SSAs, and 24 adenomas. Among patients assigned to HRE first (n = 11) a total of 78 polyps was detected; subsequent NBI added 44 polyps. In patients examined with NBI first, 78 polyps were detected and subsequent HRE added 9. Polyp miss rates of HRE and NBI were 36% and 10% (OR 0.21; 0.09-0.45). Flat polyp shape was independently associated with increased miss rate. CONCLUSION: NBI significantly reduces polyp miss rates in HPS patients. We recommend using either NBI or chromoendoscopy for colonoscopic surveillance of HPS patients with removal of all detected polyps.

Pilot study of probe-based confocal laser endomicroscopy during colonoscopic surveillance of patients with longstanding ulcerative colitis.

BACKGROUND AND AIMS: Surveillance of patients with ulcerative colitis consists of taking targeted and random biopsies, which is time-consuming and of doubtful efficiency. The use of probe-based confocal laser endomicroscopy (pCLE) may increase efficiency. This prospective pilot study aimed to evaluate the feasibility and diagnostic accuracy of pCLE in ulcerative colitis surveillance. METHODS: In 22 patients with ulcerative colitis, 48 visible lesions and 87 random areas were initially evaluated by real-time narrow-band imaging (NBI) and high-definition endoscopy (HDE). Before taking biopsies, fluorescein-enhanced pCLE was performed. All pCLE videos were scored afterwards by two endoscopists who were blinded to histology and endoscopy. Outcome measures were: (1) the feasibility of pCLE, expressed as pCLE imaging time required, percentage of imaging time with clear pCLE histology, and pCLE video quality as rated by two endoscopists; and (2) the diagnostic accuracy of pCLE. RESULTS: The median pCLE imaging time required was 98 seconds for lesions vs. 66 seconds for random areas ( P = 0.002). The median percentages of imaging time with clear pCLE histology were 61 % vs. 81 % respectively ( P < 0.001). The pCLE video quality was rated as good/excellent in 69 %. Feasibility was significantly poorer for sessile and pedunculated mobile lesions. The sensitivity, specificity, and accuracy of blinded pCLE were 65 %, 82 %, and 81 %, whereas these figures were 100 %, 89 %, and 92 % for real-time endoscopic diagnosis with NBI and HDE. CONCLUSION: This study demonstrates that pCLE for ulcerative colitis surveillance is feasible with reasonable diagnostic accuracy. Future research should show whether increased experience with pCLE improves its ease of use and whether real-time pCLE diagnosis is associated with greater diagnostic accuracy.

Narrow-band imaging versus high-definition endoscopy for the diagnosis of neoplasia in ulcerative colitis.

BACKGROUND AND STUDY AIMS: Controversy exists about which colonoscopic technique is most sensitive for the diagnosis of neoplasia in patients with ulcerative colitis. We compared new-generation narrow-band imaging (NBI) to high-definition endoscopy (HDE) for the detection of neoplasia and evaluated NBI for the differentiation of neoplastic from non-neoplastic mucosa. PATIENTS AND METHODS: Randomized crossover trial in which patients with ulcerative colitis underwent both NBI and HDE colonoscopy in random order with at least 3 weeks between the two procedures, which were performed by different endoscopists. Lesions detected during the first examination were left in situ in order to enable detection during the second examination as well. Main outcome measures were (1) neoplasia detection, and (2) diagnostic accuracy of NBI for differentiating neoplastic from non-neoplastic mucosa by using the Kudo classification and vascular pattern intensity (VPI). RESULTS: Twenty-five patients were randomized to undergo HDE first and 23 to undergo NBI first. Of 16 neoplastic lesions, 11 (69 %) were detected by HDE and 13 (81 %) by NBI ( P = 0.727). Of 11 patients with neoplasia, 9 (82 %) were diagnosed by HDE and 8 (73 %) by NBI ( P = 1.0). The sensitivity, specificity, and accuracy of the Kudo classification were 76 %, 66 % and 67 %. Corresponding figures for VPI were 80 %, 72 %, and 73 %. CONCLUSION: NBI does not improve the detection of neoplasia in patients with ulcerative colitis compared to HDE. In addition, NBI proves unsatisfactory for differentiating neoplastic from non-neoplastic mucosa.

Expression and ligand binding of bombesin receptors in pulmonary and intestinal carcinoids.

INTRODUCTION: Carcinoids are mainly found in the gastrointestinal (65%) and bronchopulmonary tract (25%). These neuroendocrine tumors secrete a wide range of bioactive peptides, including gastrin releasing peptide and neuromedin B, the mammalian analogs of bombesin. The purpose of this study was to investigate the quantity and localization of bombesin receptors in gastrointestinal and pulmonary carcinoids, and to reveal whether bombesin-like peptides (BLP) and their receptors are of any value in distinguishing pulmonary carcinoids from carcinoids of intestinal origin. METHODS: Carcinoid tumors with pulmonary (no.=9) or intestinal (no.=15) localizations were analyzed by immunohistochemistry, autoradiography, and radioimmunoassay, to examine the presence of bombesin receptor subtypes and determine BLP levels in these tumors. RESULTS: All 3 bombesin receptor subtypes (GRPR, NMBR, and BRS-3) were present on pulmonary and intestinal carcinoids by immunohistochemistry. In pulmonary carcinoids, low receptor ligand binding densities together with high and low BLP levels were found. Intestinal carcinoids showed predominantly high receptor ligand binding densities in combination with low BLP levels. CONCLUSIONS: The expression of bombesin receptor subtypes is independent from the carcinoid tumor origin, and is therefore not recommended as a distinction marker, although carcinoids of pulmonary and intestinal origin possess different receptor binding affinities for bombesin and dissimilar BLP levels. The combined presence of bombesin and its receptors might suggest the presence of a paracrine or autocrine growth loop in carcinoids.

[An unusual presentation of a periappendicular infiltrate]. / Een ongebruikelijke manifestatie van een periappendiculair infiltraat.

A 17-year-old boy presented with an atypical manifestation of acute appendicitis. The clinical aspect, radiological investigations and peroperative aspect of the appendix were not conclusive but nevertheless a neuroendocrine tumour (carcinoid tumour) of the appendix was suspected. After ileocaecal resection and resection of pathological lymph nodes, histopathological evaluation revealed the diagnosis: a periappendicular mass without any sign of malignancy. In retrospect, ileocaecal resection was performed for a benign disease. This case illustrates that an unusual presentation of a common disease occurs more frequently than a typical presentation of a rare disease.

[Pain in the throat due to acute suppurative thyroiditis caused by Salmonella]. / Een pijnlijke hals door acute suppuratieve thyreoïditis veroorzaakt door Salmonella.

A 53-year-old woman presented with fever accompanied by chills and an extremely painful swelling of her right thyroid lobe. She was initially diagnosed as having subacute thyroiditis, but after 14 days her disease appeared to be caused by a destructive suppurative thyroiditis due to Salmonella group C. A pre-existing hyperplastic nodule in the right thyroid lobe was the predisposing factor. Antibiotics were given for several weeks and surgical drainage was performed. Finally a hemithyroidectomy was done to eliminate the predisposing factor.

Endoscopic tri-modal imaging for surveillance in ulcerative colitis: randomised comparison of high-resolution endoscopy and autofluorescence imaging for neoplasia detection; and evaluation of narrow-band imaging for classification of lesions.

BACKGROUND: Endoscopic tri-modal imaging (ETMI) incorporates white light endoscopy (WLE), autofluorescence imaging (AFI) and narrow-band imaging (NBI). AIMS: To assess the value of ETMI for the detection and classification of neoplasia in patients with longstanding ulcerative colitis. DESIGN: Randomised comparative trial of tandem colonoscopies. SETTING: Academic Medical Centre Amsterdam, Netherlands. PATIENTS AND METHODS: Fifty patients with ulcerative colitis underwent surveillance colonoscopy with ETMI. Each colonic segment was inspected twice, once with AFI and once with WLE, in random order. All detected lesions were inspected by NBI for Kudo pit pattern analysis and additional random biopsies were taken. MAIN OUTCOME MEASURES: Neoplasia miss-rates of AFI and WLE, and accuracy of the Kudo classification by NBI. RESULTS: Among patients assigned to inspection with AFI first (n = 25), 10 neoplastic lesions were primarily detected. Subsequent WLE detected no additional neoplasia. Among patients examined with WLE first (n = 25), three neoplastic lesions were detected; subsequent inspection with AFI added three neoplastic lesions. Neoplasia miss-rates for AFI and WLE were 0% and 50% (p = 0.036). The Kudo classification by NBI had a sensitivity and specificity of 75% and 81%; however, all neoplasia was coloured purple on AFI (sensitivity 100%). No additional patients with neoplasia were detected by random biopsies. CONCLUSION: Autofluorescence imaging improves the detection of neoplasia in patients with ulcerative colitis and decreases the yield of random biopsies. Pit pattern analysis by NBI has a moderate accuracy for the prediction of histology, whereas AFI colour appears valuable in excluding the presence of neoplasia. TRIAL REGISTRATION NUMBER: ISRCTN05272746.

Wood smoke exposure induces a pulmonary and systemic inflammatory response in firefighters.

Epidemiological studies report an association between exposure to biomass smoke and cardiopulmonary morbidity. The mechanisms for this association are unclear. The aim of the present study was to characterise the acute pulmonary and systemic inflammatory effects of exposure to forest fire smoke. Seasonal forest firefighters (n = 52) were recruited before and/or after a day of fire-fighting. Exposure was assessed by questionnaires and measurement of carbon monoxide levels (used to estimate respirable particulate matter exposure). The pulmonary response was assessed by questionnaires, spirometry and sputum induction. Peripheral blood cell counts and inflammatory cytokines were measured to define the systemic response. Estimated respirable particulate matter exposure was high (peak levels >2 mg x m(-3)) during fire-fighting activities. Respiratory symptoms were reported by 65% of the firefighters. The percentage sputum granulocytes increased significantly from 6.5 to 10.9% following fire-fighting shifts, with concurrent increases in circulating white blood cells (5.55x10(9) to 7.06x10(9) cells x L(-1)) and band cells (0.11x10(9) to 0.16x10(9) cells x L(-1)). Serum interleukin (IL)-6, IL-8 and monocyte chemotactic protein-1 levels significantly increased following fire-fighting. There were no changes in band cells, IL-6, and IL-8 following strenuous physical exertion without fire-fighting. There was a significant association between changes in sputum macrophages containing phagocytosed particles and circulating band cells. In conclusion, acute exposure to air pollution from forest fire smoke elicits inflammation within the lungs, as well as a systemic inflammatory response.

Goblet cell carcinoid of the appendix: a specific type of carcinoma.

AIMS: Goblet cell carcinoid is a poorly understood tumour of the appendix. The aim of this study was to determine whether it should be regarded as a separate entity or as a variant of classical carcinoid. METHODS AND RESULTS: The immunohistochemical expression pattern of 21 markers and the mutation status of KRas codon 12 were determined in 16 goblet cell carcinoids and compared with 14 classical carcinoids, 19 colonic adenocarcinomas and 10 appendiceal mucinous cystadeno (carcino)mas. The results were subjected to a stepwise linear discriminant analysis. Goblet cell carcinoids were significantly different from the control groups. The most important markers for discriminating between the groups were CEA (classical carcinoid versus all others), KRas mutation (present in all mucinous cystadeno (carcino)mas), beta-catenin (goblet cell carcinoid versus left sided colonic adenocarcinoma) and chromogranin (goblet cell carcinoid versus right sided colonic adenocarcinoma). Expression of Math1 and HD5 was similar in goblet cell carcinoid and colonic adenocarcinoma but absent in classical carcinoid. CONCLUSION: The results suggest that goblet cell carcinoids should be regarded as a separate entity. The formerly used term 'crypt cell carcinoma' may be more appropriate because it reflects the more aggressive clinical behaviour of these tumours as well as their greater similarity to adenocarcinomas rather than to carcinoids.