Page 64 – Practical Gastro

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Screening for colorectal cancer is one of the most effective public health interventions. First- generation stool DNA tests demonstrated better sensitivity for colorectal cancer than fecal occult blood tests. Improvements to stool DNA tests have made them more sensitive and less complex. The newer marker panels can detect the vast majority of colorectal cancers and a large proportion of advanced adenomas, regardless of location in the colon. This review summarizes the development and advances to stool DNA testing for colorectal cancer.

Steven H. Itzkowitz, MD, FACP, FACG, AGAF Professor of Medicine and Oncological Sciences, The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, NY Disclosures: Dr. Itzkowitz receives research support and is on the Scientific Advisory Board of Exact Sciences Corporation.

INTRODUCTION

Screening for colorectal cancer (CRC) is highly effective in preventing CRC, which is why it has been endorsed by all major medical societies, receiving a Grade A recommendation from the United States Preventive Services Task Force (USPSTF).^1,2 Many screening tests have been recommended by guideline committees. In practice, colonoscopy and fecal occult blood tests, especially fecal immunochemical tests (FIT), are the predominant methods used, particularly colonoscopy in most settings.

An ideal cancer screening test should be non- invasive, easy to perform, convenient, safe, highly accurate, operator-independent, and inexpensive. Furthermore, since most cancer screening tests need to be repeated over time, patients should be willing to adhere to periodic testing. FIT testing has most of these advantages. It is non-invasive, performed at home on a single stool sample, safe, inexpensive, and operator-independent. However, FIT is known to miss up to 30% of cancers and 70-80% of the most precancerous polyps because bleeding rates may be low. For this reason, FIT is recommended as an annual test, something that most patients (and their physicians) find hard to do, or keep track of. Even when this is done, the nature of bleeding by colon cancers and polyps is such that those located in the distal colon are detected better than those in the proximal colon. Sessile serrated polyps, important new precursor lesions that do not bleed, are also unlikely to be detected by FIT. Moreover, false-positives occur if there is blood in the stool for a reason other than a cancer/polyp.

Given the limitations of FIT in terms of sensitivity, lower detection of proximal cancers and polyps, and poor adherence with annual testing, efforts have been made in the last two decades to develop a more sensitive stool-based test. A new multi-target stool DNA test (MT-sDNA; Cologuard®; Exact Sciences Corporation) goes beyond detecting occult blood in the stool because it also incorporates an analysis of abnormal DNA. This review will discuss the principle behind stool DNA testing, and summarize the recent findings of studies using the MT-sDNA test.

Rationale for Stool DNA Testing

Until about 20 years ago, the notion that specific human gene mutations could be detected in stool among the enormous amount of bacterial DNA seemed an insurmountable hurdle. After all, human DNA represents only 0.01% of total stool DNA, the other 99.99% coming from non-human sources such as the microflora and diet.³ Thanks to technological advances, analyzing DNA alterations in stool has become a reality.

There are several reasons why DNA is a promising analyte in stool. First, because so much is known about the molecular pathogenesis of colorectal neoplasia, highly discriminant markers can be chosen which represent the molecular pathways used by neoplastic, but not by normal, colonocytes. Second, unlike proteins for example, DNA is stable and can be amplified. Indeed, the use of sensitive PCR techniques with PCR inhibitors, and modern approaches for capturing DNA, has greatly facilitated the detection of even tiny amounts of mutated human DNA from stool. Third, DNA is exfoliated continuously from the surface of polyps and cancers, whereas bleeding from lesions is intermittent. Studies indicate that when normal colonocytes mature and eventually die, they undergo programmed cell death (anoikis) whereby their DNA is digested and phagocytosed by lamina propria macrophages and not much is shed into the lumen. However, since neoplastic colonocytes have impaired anoikis, proportionately more mutated DNA is shed into the lumen from these lesions. Fourth, the epithelial layer of an adenoma is much larger than the size of the polyp might suggest due to the extensive network of infolded, complex tubules. If one were to unravel the epithelial layer of a tubular adenoma, the surface area is approximately 250-fold larger than the polyp appears. As such, an adenoma measuring 2 cm in diameter has a surface area of approximately 800-1600 cm².⁴

Clinical Validation Studies

Numerous early studies used single and multiple DNA markers to demonstrate proof of concept that stool DNA testing was a viable approach (reviewed in 5). Some of these studies compared stool DNA tests to fecal occult blood tests and demonstrated superior sensitivity for CRC using the sDNA test.^6,7 However, these earlier molecular panels were cumbersome, expensive and still had suboptimal sensitivity for CRC and adenomas. They did, however, set the stage for the current version of the MT-sDNA test. The current test analyzes two highly discriminant methylated genes (BMP3 and NDRG4), the seven most informative point mutations of the k-ras oncogene, a marker for total human DNA (beta-actin) and fecal hemoglobin.

Two large multicenter case-control studies were conducted with the MT-sDNA test before it was subjected to a pivotal validation study. One study used a non-optimized prototype of the MT-sDNA test and identified 87% of patients with CRC stages I-III, 54% of advanced adenomas, with 90% specificity.⁸ Importantly, adenoma detection increased with larger adenoma size, and detection rates for CRC as well as adenomas was similar between the proximal and distal colon. The second case-control study used an optimized and automated MT-sDNA test.⁹ Here, the sensitivity for CRC was 98% overall. Again, detection was not affected by tumor stage or location in the colon, and the specificity was 90%. The sensitivity for advanced precancerous lesions (which included advanced adenomas as well as sessile serrated polyps) was 57%, 73% and 83% for lesions ≥1 cm, >2 cm, and >3 cm, respectively.

Given the ability of the optimized, automated MT- sDNA test to detect the vast majority of cancers, a significant proportion of advanced precancerous lesions, a large, prospective pivotal validation study, called Deep-C, was performed.¹⁰ This study enrolled over 10,000 asymptomatic, average-risk men and women across 90 North American sites. All subjects submitted a stool sample for MT-sDNA, as well as a commercial FIT test, and then underwent their screening colonoscopy. An independent clinical research organization oversaw the study, and the laboratory was blinded to the clinical findings. The age, gender, and ethnic distribution of the study population was nearly identical to that of the general U.S. population. The sensitivity of MT- sDNA versus commercial FIT was 92% vs. 74% for CRC overall, 93% vs. 73% for CRC stages I-III, and 94% vs. 70% for CRC stages I-II (all statistically significant). Advanced adenomas in this study was defined as adenomas or sessile serrated polyps >1 cm or any size adenoma containing villous features or HGD. Sensitivity of MT-sDNA for advanced adenomas was 42%, compared to 24% with FIT (P<0.001). Sensitivity for MT-sDNA was 66% for adenomas ≥2 cm, 42% for sessile serrated polyps ≥1 cm, and 69% for adenomas with HGD, compared to 43%, 5%, and 46%, respectively with FIT (all statistically significant). MT- sDNA detected advanced adenomas and sessile serrated polyps in proportion to size, and was better than FIT for detecting lesions in the proximal colon. Specificity of FIT was higher than MT-sDNA. If patients with non- advanced findings at colonoscopy were included (for example, polyps < 1cm of any number), the specificity of MT-sDNA was 87% compared to 95% with FIT (P<0.001). However, if specificity was calculated using only patients with normal colonoscopies, the respective specificities were 90% and 96% with MT-sDNA and FIT (P<0.001).

Based on the Deep-C study (and the supporting data leading up to it), on August 11, 2014, the US Food and Drug Administration (FDA) approved the MT-sDNA test for use in general CRC screening. On the same date, the Center for Medicare and Medicaid Services (CMS) ruled that the test would be covered by Medicare at a frequency of every 3 years (based on mathematical modeling studies). Since the publication of the Deep-C study, very similar findings comparing MT-sDNA to FIT were observed in a screening trial of Alaska Natives.¹¹ In that study, the sensitivity of MT-sDNA vs. FIT for CRC (n=10) – 100% vs. 80% (P=0.48); for adenomas >2 cm – 62% vs. 29% (P=0.05); for sessile serrated polyps >1 cm – 67% vs. 11% (P=0.07), with specificity 93% vs. 96% (P<0.03).

Practical Clinical Questions

Based on the results of the Deep-C pivotal study, and the availability of Cologuard® in clinical practice, a variety of clinical questions arise which are on the minds of many healthcare providers, policy makers, payors and patients. I will offer my own position on these matters in this section.

• Is the sensitivity of MT-sDNA high enough to be an effective screening test?

With a 93% sensitivity for stage I-III CRC, MT-sDNA is similar to that of colonoscopy, and significantly higher than the point sensitivity of 70% for FIT.¹⁰ Thus, MT- sDNA misses about 7% of CRC, whereas FIT misses 30%. In the Deep-C study, of the 65 cancers, 13 were detected by MT-sDNA and missed by FIT, whereas only one was detected by FIT and missed by MT-sDNA. Because the compliance over time for CRC screening can be uncertain for an individual patient, in my opinion you want to make sure that the test will at least detect cancer at that single point in time, in case the patient does not return for regular surveillance. Also important for an effective screening test is its ability to detect those precursor lesions that are most likely to develop into cancer. In this regard, adenomas larger than 2 cm and those with HGD are among the most likely lesions to progress, and MT-sDNA outperformed FIT for detecting these lesions. Likewise, the sensitivity of MT-sDNA for detecting sessile serrated polyps ≥1 cm was 9-times greater than FIT, a finding that is readily understandable knowing that these subtle, often invisible lesions, do not bleed. It is worth considering that if an adenoma is missed by MT-sDNA, and the patient is compliant with follow-up testing, the programmatic sensitivity of the test will increase to a rather respectable level. Mathematical models suggest that assuming a screening frequency of every 3-years, and a polyp growth doubling time of 6 years, the point-sensitivity of 69% for HGD would yield programmatic sensitivities of 93% and 99% by the second and third screening rounds, respectively.¹²

• Will patients accept this test?

Because the MT-sDNA is a new test in clinical practice, there are limited data on patient acceptance. A prospective survey of 4,042 (84%) subjects participating in an earlier generation sDNA test revealed that sDNA testing received the same or higher mean ratings than guaiac based FOBT for most prep- and test-related features, and except for perceived accuracy, also received higher ratings than colonoscopy.¹³ Post- marketing data may help answer this important question with respect to the new MT-sDNA test.

• How often should MT-sDNA be performed?

Again because the MT-sDNA test is new, there has not been enough time to do a study, which would offer guidance regarding screening interval. CMS has recommended a 3-year interval based on modeling studies. Other recent modeling studies support the 3-year interval and show that MT-sDNA every 3 years lies within the 98% of the efficiency frontier and provides greater than 90% of the Life Years Gained (LYG) with screening colonoscopy.¹⁴

• With a higher false positive rate, won’t this subject more patients to colonoscopy than FIT?

It is true that more positive tests will generate more colonoscopies. However, at present, all individuals older than age 50 are recommended to have screening colonoscopy, so they would be referred for a test that is already recommended.

• How do I interpret a positive MT-sDNA when the colonoscopy is normal?

This does pose a clinical dilemma but several things should be considered. First, one would want to make sure that the colonoscopy is of good enough quality to reasonably exclude any neoplasia. Second, for decades clinicians have been faced with the finding of a normal colonoscopy after a positive fecal occult blood test, and most tend to reassure the patient or repeat the stool test at some interval. Since the MT-sDNA test detects occult blood, it is possible that the false-positive result is from the hemoglobin component. Since the test results are reported as either positive or negative (the individual markers are not reported), there is no way to know if this is the case. Third, false-positive tests may be a function of age. Many genes become hypermethylated with age and we know from the Deep-C study that individuals over 65 years old had a higher false positive rate than those between ages 50-65 years. Fourth, there is concern that this situation might mean that a cancer higher up in the GI tract (or even the lungs) might be contributing abnormal DNA in the stool. However, as currently configured, the MT-sDNA has been optimized to detect colorectal, rather than upper GI neoplasia. Previous studies using an earlier generation sDNA test found no neoplastic pathology above the colon when upper endoscopy and CT scanning was performed on 60 consecutive patients with a positive sDNA and negative colonoscopy.¹²

• Isn’t this test too expensive?

At present, the MT-sDNA list price is $649 (Medicare cost $509). However, this price includes a national 24 hour, 7 days a week, patient navigation and compliance service. Also, if the test is done every 3 years, the cost can be amortized to approximately $216 per year. Compared to not screening, the cost effectiveness ratio of $11,313 per quality-adjusted life year is within the acceptable range.¹⁴

• Can I use this test in high-risk patients?

No. The currently available MT-sDNA test was designed for, and tested only in, average risk, asymptomatic individuals. High-risk individuals with inflammatory bowel disease should not perform this test since they may have blood in the stool producing too many false positives. Studies are ongoing to develop an IBD- specific MT-sDNA test.¹⁵ Also, the markers in this the panel have not been tested in patients with genetic susceptibility due to familial polyposis and Lynch Syndrome.

CONCLUSION

Currently, in the U.S., approximately one-third of screen eligible individuals have not undergone screening. The reasons for this are multifactorial, and include barriers at the system, physician and patient level. There is currently a national campaign to increase CRC screening rates to 80% by 2018.¹⁶ While efforts are ongoing to maximize the use of screening colonoscopy and FIT testing across the country, the performance characteristics and results from clinical studies using MT-sDNA offers a very reasonable and important contribution to our fight against one of the most preventable cancers.

Frontiers In Endoscopy, Series #27

Endoscopic Approaches to Diagnose Cholangiocarcinoma in Patients with Primary Sclerosing Cholangitis

July 2016 • Volume XL, Issue 7

Jeffrey S. Bank

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Patients with PSC have a lifetime risk of developing CCA of 10-15%. The ability to distinguish between benign strictures and CCA can be challenging as they may have similar appearances on imaging ERCP and MRCP. Here, we will review the different endoscopic techniquies to diagnose CCA in patients with PSC, as well as their success rates, risks and benefits.

Jeffrey S. Bank MD and Douglas G. Adler MD, FACG, AGAF, FASGE, University of Utah School of Medicine, Gastroenterology and Hepatology, Huntsman Cancer Center, Salt Lake City, UT

INTRODUCTION

Patients with PSC have a lifetime risk of developing cholangiocarcinoma (CCA) of 10-15%.¹ The ability to distinguish between benign strictures and CCA can be challenging as they may have similar appearances on imaging with endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography. Visualization and definitive sampling of a dominant mass lesion is diagnostic, but mass lesions often are not always seen in patients with early CCA.² In addition, up to 37% of patients with PSC and elevated CA 19-9 do not have CCA.3 Brush cytology, fluorescence in situ hybridization (FISH), cholangioscopy, probe-based confocal laser endomicroscopy (pCLE), and endoscopic ultrasound with fine needle aspiration (EUS FNA) can be used to obtain a more definitive diagnosis. This manuscript will review the different endoscopic techniques to diagnose CCA in patients with PSC, as well as their success rates, risks and benefits.

Brush Cytology

Brush cytology is the most common method for tissue acquisition during ERCP as some lesions are too proximal in the biliary tree (or are in ducts too small) to biopsy. Brush cytology has a high specificity (97-100%) to detect biliary malignancy, but has traditionally had a low sensitivity.^4,5 In a recent meta-analysis that included 11 studies and 747 patients with PSC, the sensitivity of brush cytology was 43% and the specificity was 97%.⁶

The inherent benefit of brush cytology lies in its high specificity when positive for malignancy. However, due to its low sensitivity, the primary drawback of cytology is the frequent inability to rule out malignancy.⁷ The chronic inflammation inherent with PSC can also lead to reactive atypia, which can lead to malignancy, making the diagnosis of cholangiocarcinoma challenging.^8,9

Biliary brushing results are classified into one of three cellular categories: benign, malignant, or “atypical.” In a cohort study of 86 patients with atypical biliary brushings (many of whom, but not all, had PSC), Witt et al. sought to identify factors predictive of malignancy. Sixty of these patients were ultimately found to have confirmed cancer of pancreatobiliary origin. In the setting of an atypical biliary brushing result, the risk of malignancy was significantly correlated with age ≥ 60, suspicious/malignant endoscopic impression, the presence of a pancreatic mass, indications for ERCP including jaundice and/or dilated bile ducts, stricture within common bile duct, PSC, and CA 19-9 greater than 300 U/ml. For patients with a CBD stricture, 45/59 (76%) were diagnosed with malignancy. The authors created a scoring model to predict malignancy called the Atypical Biliary Brushing Score (ABBS), made up of the above factors predictive of malignancy. (Table 1) A score ≥ 4 suggests patients are at high risk for malignancy. The PSC subgroup had a 29% rate of malignancy.¹⁰

In a review of 107 biliary brushings from 51 patients with PSC, sensitivity and specificity were 62.5% and 100%, respectively. With a CA 19-9 cutoff of 186 IU/ ml for CCA, sensitivity and specificity were 100% and 94%, respectively.¹¹

In a large population of patients referred for their first ERCP due to suspicion for PSC, PSC was diagnosed by brush cytology in 261 patients, 211 (80.8%) of whom were asymptomatic at the time of diagnosis. The ERCP findings were categorized by a modified version of the Amsterdam endoscopic retrograde cholangiography (mERC) score defined by Ponsioen et al.⁶ Symptoms of PSC included jaundice, pruritis, fatigue, weight loss, fever, or cholangitis. The authors found 42.9% of patients with PSC had advanced disease and 6.9% had suspicious or malignant brush cytology at first ERCP. Patients with advanced PSC (mERC score > 3) were not significantly more symptomatic (p = 0.303) than patients with early PSC (mERC 2-3). CA 19-9 levels did not correlate with brush cytology results (p = 0.751).¹²

A meta-analysis of 747 patients found that the pooled sensitivity and specificity of bile duct brushings for diagnosis of CCA in patients with PSC were 43% and 97%, respectively. Pooled diagnostic odds ratio was 20.23, meaning that if a bile duct brushing in a PSC stricture shows CCA, the patient has a 20 times higher likelihood of a final, positive pathological diagnosis. Pooled positive likelihood ratio was 8.87 and the pooled negative likelihood ratio was 0.56. This again demonstrates bile duct brushing is reliable in the diagnosis of CCA as well as in the exclusion of benign strictures.¹³

Although ERCP is generally very safe when performed by experienced endoscopists, it is not without risks and complications. In a multicenter study of 83 patients who underwent a total of 106 ERCPs for suspected PSC, complications occurred in 10 cases (9%). Complications include pancreatitis (n = 3), cholangitis (n = 2), increase of cholestasis (n = 2), postsphincterotomy bleeding (n = 1), cystic duct perforation (n = 1), and venous thrombosis (n = 1). All of these resolved quickly with medical therapy. Complications occurred in 16% of ERCPs with biliary intervention (ex: sphincterotomy or stent placement) compared to 4% in ERCPs without interventions (RR 4.5, 95% CI 0.94-30, p = 0.04).¹⁴

A retrospective cohort study of 185 ERCPs performed on 75 patients with PSC examined 30- day post-ERCP adverse event rates and found that the endoscopist with the highest ERCP volume had the lowest lower complication rate, arguing for PSC ERCPs to be done at high volume centers or by those experienced with PSC cases. Multivariate analysis also revealed statistically significant associations with biliary dilation, sphincterotomy, presence of cirrhosis, Crohn’s disease and autoimmune hepatitis. They did not find an increased adverse event rate when looking at gender, the placement of a stent during the procedure, the presence of a dominant stricture, or cholangitis.¹⁵

FISH

Routine cytology, despite its ease of use and low cost, has limited sensitivity, which is problematic in the diagnosis of cholangiocarcinoma (CCA). Many patients with CCA are not diagnosed by routine cytology alone. Fluorescent in situ hybridization (FISH) probes are used to target the centromeric regions of chromosomes 3, 7, and 17 and the 9p21 band (p16) to examine for evidence of aneuploidy and aid in the diagnosis of CCA. (Figure 1) FISH testing has been available commercially in the United States for over a decade, but many endoscopists still have limited knowledge of and experience with its role in diagnosing biliary malignancies.

In a study of 235 patients with PSC, 120 (51%) had evidence of aneupoidy by FISH, but only one third of these positive patients had CCA. Sensitivity and specificity for FISH polysomy were 46% and 88%, respectively; for trisomy/tetrasomy, they were 25% and 67%, respectively. Survival analysis of 120 patients with PSC with FISH polysomy had outcomes similar to patients with CCA. If patients had evidence of a dominant stricture as well as FISH polysomy, the specificity was 88%. The authors proposed the following set of guidelines: 1) FISH testing should not be used as a screening modality in unselected PSC patients undergoing ERCP. However, in patients with clinical or laboratory suspicion of CCA, such as weight loss, abdominal pain, dominant stricture, or elevated CA 19-9, FISH can be extremely helpful given the limitations of routine cytology. In patients with clinical or laboratory suspicion of CCA, such as weight loss, abdominal pain, dominant stricture, or elevated CA 19- 9, FISH can be helpful.¹⁶

A dysplasia-carcinoma sequence has been proposed in the pathophysiology of PSC. Patients with history of or current CCA were more likely to have polysomy in dysplasia results by FISH than patients without CCA (70% versus 14%; p = 0.05). Patients with biliary dysplasia and CCA have evidence of polysomy and homozygous 9p21 loss. Cytogenetic abnormalities demonstrated in CCA are also seen in precursor lesions. High-grade dysplasia is found disproportionately in PSC patients with CCA. Overall, these findings could help delineate the grading of biliary dysplasia in this group of patients.¹⁷

In a study of 102 patients with PSC, 30 (29%) with an equivocal cytology developed carcinoma within 2 years. Serum CA 19-9 ≥ 129 U/ml (HR 3.19, P = .001) and polysomy (HR 8.70; P < 0.001) were each found to be predictive of future malignancy by univariate analysis. Polysomy FISH was the only significant predictor of malignancy in a multivariable analysis (HR 6.96). In a subgroup analysis of ten patients with both an elevated CA 19-9 and polysomy, all developed cancer (nine within two years). In this subgroup analysis, the combined finding of CA 19-9 ≥ 129 U/ml and polysomy by FISH was found to put patients at high risk of malignancy (HR 10.92; P < 0.001). The investigators suggested that regular lab monitoring with alkaline phosphatase, total bilirubin, and serum CA 19-9 levels does not adequately predict malignancy in patients with PSC. Based on their findings, they found polysomy by FISH is able to identify patients at risk for malignancy without evidence of mass lesion on imaging and with equivocal cytology.¹⁸ Regarding bilirubin specifically in PSC, Haseeb et al. performed a retrospective cohort study of 81 patients with PSC and found that an initial bilirubin more than two times the upper limit of normal was significantly associated with the development of CCA, subsequent liver transplantation, and death (p < 0.017). In addition, hyperbilirubinemia correlated with increased severity of biliary ductal disease (p < 0.0001).¹⁹

In a retrospective review of 30 patients with PSC who had polysomy FISH result and no radiological or pathological evidence of malignancy at the time of first polysomy, Barr Fritcher et al. demonstrated that 9 of 13 patients (69%) with serial polysomy FISH results were diagnosed with CCA compared with 3 of 17 patients (18%) with subsequent non-polysomy FISH results (PPV 69% vs 18%, p = 0.008). Furthermore, patients with serial polysomy developed CCA in a shorter period of time than those patients with serial non-polysomy results. Interestingly, 47% of patients with PSC with a polysomy FISH result did not have evidence of malignancy by ERCP at the time FISH was obtained.

In a retrospective review of 371 patients with PSC, multifocal polysomy (MFP) was found to be the strongest predictor of CCA compared to patients with unifocal polysomy (UFP)

Compared to patients with UFP, patients with MFP had an increased likelihood of weight loss (32% vs 9%), suspicious cytology (45% vs 13%), and develop serial polysomy (91% vs 35%). MFP was strongly correlated with CCA (HR 82.42). However, patients with UFP and suspicious cytology are still at an increased risk of CCA.²⁰

Overall, FISH has limited sensitivity but high specificity. A meta-analysis with 8 studies and 828 patients demonstrated pooled sensitivity and specificity of FISH for diagnosis of CCA in patients with PSC were 68% and 70%, respectively. Pooled likelihood ratio was 2.69 and negative likelihood ratio was 0.47. Pooled odds ratio was 7.24. Pooled sensitivity and specificity for FISH polysomy (6 studies with 690 patients) were 51% and 93%, respectively. The authors recommend that FISH be employed if clinical suspicion of malignancy remains high despite an inconclusive brushing cytology result.²¹

Cholangioscopy

Diagnosing malignancy in patients with PSC with dominant bile duct strictures has historically been challenging. Cholangiocarcinomas tend to be fibrotic, hypocellular, and often display significant desmoplasia, all of which complicate adequate tissue acquisition. Cholangioscopy, performed in the context of ERCP, can aid in tissue diagnosis in patients with (and without) PSC. (Figure 2) In 53 patients with PSC with dominant bile duct strictures, when compared with brush cytology, cholangioscopy had increased sensitivity (92% vs 66%; p = 0.25), specificity (93% vs 51%; p < 0.001), accuracy (93% vs 55%; p < 0.001), PPV (79% vs 29%, p < 0.001) and NPV (97% vs 84%; p < 0.001). In 75% of the PSC patients with CCA, an intraductal mass was visualized on cholangioscopy, which allowed these patients to be differentiated from those with benign strictures. The authors recommend cholangioscopy with repeat tissue sampling in patients with suspected malignancy but benign tissue biopsies.²²

Cholangioscopy assists in localizing sites for tissue acquisition in patients with PSC with biliary strictures suspicious for malignancy. (Figure 3) In a retrospective study of 18 patients with PSC who underwent cholangioscopy for suspected CCA, the overall operating characteristics were a sensitivity of 75%, specificity of 55%, PPV of 23%, and a NPV of 92%. Results of cholangioscopy-directed biopsies correlated well with brush cytology and FISH brush cytology. Cholangioscopy increased visualization of fine intra-ductal details allowing for improved tissue acquisition with brushings, FISH studies, and cholangioscopy-directed biopsies. Due to its high sensitivity, cholangiosocopy could be used to screen for malignancy in patients with and without PSC suspected of having CCA. Advantages of cholangioscopy included improved visualization of bile duct tissue when compared to cholangiogram and highly targeted biopsies and brushings in all patients, allowing specific locations within strictures to be marked for tissue acquisition. Disadvantages of cholangioscopy included increased cost and procedure time, with an average of 20 minutes for cholangioscopy time.²³

In another study of 62 patients with indeterminate strictures who underwent 72 cholangioscopies (16 for stricture in setting of PSC), Shah et al. demonstrated that cholangioscopy with and without biopsy had a high accuracy in diagnosing and excluding CCA. Overall, sensitivity was 89%, specificity 96%, PPV 89%, and NPV 96%.²⁴

In a prospective cohort of 41 patients with PSC who underwent 60 cholangioscopy procedures, Awadallah et al. noted an increased rate of biliary stone detection with cholangioscopy compared to cholaniogram; 30% of stones had been missed by cholaniogram. Cholangioscopy-directed biopsies were able to exclude CCA in the majority of patients; biopsies were positive for malignancy in one patient and excluded malignancy in 31 patients at a median follow up of 17 months (range 1-56 months). However, the investigators had difficulty accessing 25% of desired strictures in patients with PSC using cholangioscopy.²⁵

In 47 patients with PSC, single-operator peroral cholangioscopy (SOC) was performed to evaluate 64 biliary strictures and technical success occurred in 96% (45/47) patients. Sample quality was adequate in 98% (62/63) of the cytology brushings and in 95% (21/22) of the mini-forceps biopsies. When evaluating for malignancy, sensitivity, specificity, accuracy, and NPV were 33%, 100%, 96%, and 95%, respectively. A key advantage of SOC in PSC is the ability to visually direct guidewire placement in patients with complex anatomy in whom a specific duct needs to be accessed. In four patients (9%), reaching the target lesion would not have been possible without SOC. Complications occurred in 15% (7/47) of patients; these included pancreatitis (n = 4), cholangitis (n = 2), extravasal contrast leakage (n = 1), stent due to suspected bile duct perforation (n = 1). The vast majority of complications (71%, 5/7) occurred in the first 15 patients included in the study.²⁶

In another study, SpyGlass imaging and brush cytology with directed biopsies were performed in 29 of 31 (93.%) patients, 19 of whom had known PSC, and 10 with non-PSC strictures. SpyGlass directed biopsies demonstrated an increased diagnostic yield when compared to brush cytology as the SpyGlass biospies showed more inflammatory characteristics and also obtained more tissue material.²⁷

From a limitations point of view, Sethi et al. examined interobserver agreement (IOA) with single operator choledochoscopy among 7 interventional endoscopists who examined 38 SpyGlass choledochoscopy video clips and found that it was slight to fair. They felt that SOC could not replace tissue diagnosis currently due to the low level of IOA; they suggested that a standardized scoring system should be developed.²⁸

Sethi et al. performed a second follow up study looking at IOA for single operator cholangioscopy. Specifically, they found that IOA was “slight” for scoring of surface strictures as well as for characterization of blood vessels and lesions. In addition, IOA was only “slight” for describing cholangioscopy findings and for providing a final diagnosis. They found that the diagnostic accuracy by visual impression was less than 50%. The authors concluded that high IOA agreement and reproducibility are necessary to establish a valid imaging-based diagnostic sytem for cholangioscopy. Currently, the fair to poor agreement on the above criteria is an impediment for establishing definitive cholangioscopic criteria for accurate diagnosis.²⁹

The SpyGlass single-operator cholangioscope has been shown to aid tissue diagnosis in patients with PSC, but it is not without limitations. SpyGlass was performed in 11 consecutive patients to monitor progression of PSC in a single tertiary center. SpyGlass directed biopsies were adequate for cytological and histological diagnosis in 9 (82%) and 10 patients (91%), respectively. Two cases of post-ERCP pancreatitis were observed.³⁰

Probe Based Confocal Laser Endomicroscopy (pCLE)

Probe-based confocal laser endomicroscopy (pCLE) enables endoscopists to view the biliary tree using live microscopic imaging. pCLE requires the injection of contrast, typically fluorescein, which stains the extracellular matrix of the surface epithelium and allows the endoscopist to view the architecture of the surface mucosa and examine for neoplastic changes.³¹ In addition, the smaller diameter of the pCLE probe compared to the cholangioscopy probe (3F vs. 10F), allows it to be advanced more easily into strictures without pre-dilation.³²

In a single center chart review of 15 patients with PSC with 21 dominant strictures evaluated by pCLE, Heif et al. successfully visualized strictures in 95% of the procedures. Sensitivity was 100% (95% CI 19.3-100%), specificity was 61.1% (95% CI 35.8-82.6%), PPV was 22% (95% CI 3.5-59.9%), and NPV was 100% (95% CI 71.3-100%) for detection of malignancy. The low specificity was likely due to ductal inflammation in setting of PSC. However, the high NPV of pCLE may be able to rule out malignancy. Given the limited number of patients, the authors concluded that pCLE could be used to risk stratify dominant strictures in patients with PSC if validated on a larger scale.³³

In a single center retrospective review of 35 patients (13 with PSC, 22 without PSC) with histologically proven inflammatory strictures (IS), Karia et al. examined pCLE images for each of the Paris Classification (PC) criteria for descriptive criteria of IS:

1. vascular congestion
2. dark granular pattern
3. increased inter-glandular space
4. thickened reticular structures (TRS)

Each of the PC criteria was found more often in patients without PSC. TRS was found in 95% of patients without PSC versus 62% of patients with PSC (p = 0.01). Presence of TRS has a 13-fold increase in predicting non-PSC etiology as the cause of IS.³⁴

A consensus report by 16 physicians, some of whom are on the Mauna Kea Technologies advisory board, on the use of pCLE in biliary strictures determined the following six statements:

1. CLE can be used to evaluate biliary strictures and the probe can be delivered via a biliary catheter or a cholangioscope
2. CLE is more accurate than ERCP with brush cytology and/or forceps biopsy in determing malignant or benign strictures, using established criteria
3. The NPV of CLE is very high
4. The use of CLE can assist clinical decision- making such as excluding malignancy
5. CLE should be cited in official guidelines as a valuable tool for an increased diagnostic yield
6. The ‘black bands’ that can be seen in pCLE images have been shown to be collagen fibrils that predictably increase in pathologic tissue³⁵

The limitations of pCLE are:

1. Costs of pCLE devices is high
2. Limited number of clinical uses
3. Low number of centers specialized for pCLE procedures
4. Generalizability of increased diagnostic needs to be validated by more studies and endoscopists
5. Incremental diagnostic yield should be cost effective³⁶
6. The interreader reliability of pCLE is not well defined.

EUS FNA

EUS FNA is another method to attempt to diagnose malignancy in patients with PSC. DeWitt et al. performed EUS-FNA on 24 patients with PSC who had ERCP brush cytology studies that were either negative/ non-diagnostic or unable to be performed. They were able to visualize a mass with EUS in 23 (96%) patients, including 13 in whom prior imaging did not demonstrate a lesion. EUS-FNA was positive for malignancy in 17 (71%) patients. Sensitivity was 77%, specificity was 100%, PPV was 100%, NPV was 29%, and overall accuracy of EUS-FNA was 79%. The authors concluded that the sub-optimal NPV does not allow for exclusion of malignancy after a negative biopsy result.³⁷ Of note, FNA of suspected cholangiocarcinoma is discouraged given the risk of tumor seeding at some centers.

EUS is not the first line imaging choice for identification of CCA when compared to other imaging and sampling techniques. It can be technically difficult as early CCA, in patients with and without PSC, can be laterally spreading along the duct with minimal to no demonstration of a mass or wall thickening. FNA of a thin-walled mass is typically not diagnostic. Intraductal ultrasonography during ERCP may provide additional information in the evaluation of suspected CCA, but accuracy in differentiation between benign and malignant strictures appears poor.³⁷ Intraductal ultrasound, while once more popular, is now rarely used in clinical practice.

CONCLUSION

Although the diagnosis of CCA remains clinically challenging, brush cytology, FISH, cholangioscopy, pCLE, and EUS FNA can add to our armamentarium. Brush cytology has been the mainstay for tissue diagnosis of CCA due to its high specificity and ability to exclude malignancy, but its low sensitivity is problematic. When clinical suspicion for CCA remains high, FISH allows for detection of aneuploidy to aid in diagnosis. It has been shown to have increased sensitivity compared to brush cytology while retaining a high specificity. Cholangioscopy allows for specific locations within strictures to be accessed for tissue acquisition, but its high cost and procedure time remain limiting factors. pCLE enables endoscopists to analyze surface mucosa for evidence of neoplasia in real-time, but it seems likely that the interreader reliability needs to be improved before it disseminates into widespread practice. EUS is limited by its sub-optimal NPV as well as the risk of tumor seeding of suspected CCA with FNA.

A Case Report

All-Purpose Palliative Endoscopy in Pancreatic Cancer

July 2016 • Volume XL, Issue 7

Patrick Hickey,Hiral Shah,Shashin Shah

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Patrick Hickey, DO¹ Hiral Shah MD² Shashin Shah MD² ¹Lehigh Valley Health Network, ²Lehigh Valley Health Network, Eastern Pennsylvania Gastroenterology and Liver Specialists

INTRODUCTION

Pancreatic cancer is a devastating diagnosis with rapid progression and poor prognosis. It is the fourth leading cause of cancer death in the United States while having the least survival improvement over the last three decades.¹ Less than 20% of diagnosed pancreatic cancers present as localized and potentially curable tumors at time of diagnosis.² Because of often advanced disease, availability of palliative treatments is increasingly important. Biliary obstruction, duodenal obstruction and pain are commonly associated complications amendable to endoscopic therapies. Historically, the diagnosis and palliative treatment of pancreatic cancer required percutaneous and surgical interventions. Advances in endoscopic modalities have begun to change the approach to unresectable pancreatic cancer. We review a case of newly diagnosed advanced pancreatic cancer that obliged endoscopic diagnostics and palliative therapy. The endoscopic procedures performed in this case are described in detail with supporting literature review.

CASE PRESENTATION

A 59 year-old Caucasian female with a history of peptic ulcer disease presented to her family physician with six weeks of worsening epigastric abdominal pain, intractable nausea and vomiting, and 50 pound weight loss over several months. A computed tomography (CT) of the abdomen and pelvis revealed a large pancreatic mass in the uncinate process encasing the superior mesenteric vein and artery concerning for pancreatic cancer with extensive local invasion and adjacent adenopathy (Figure 1). The mass was found to be compressing the duodenum distal to the papilla. There was mild pancreatic and biliary ductal dilatation, several subcentimeter liver lesions concerning for metastatic disease and basilar lung nodules.

Upon her referral to our gastroenterology department, linear endoscopic ultrasound (EUS) was performed for diagnostic and therapeutic purposes. A large mass measuring 4.5 x 3.2 cm was noted as the linear ultrasound endoscope was advanced to the gastroesophageal junction. There was also difficulty passing into the third portion of the duodenum because of significant luminal narrowing. The mass involved the superior mesenteric artery and vein, there was regional adenopathy and a lesion in the left lobe of the liver were noted. Fine needle aspiration (EUS-FNA) of the mass was performed using a 25-gauge needle and the specimen was sent for cytology.

The patient’s chronic abdominal pain was managed by celiac plexus neurolysis (CPN) utilizing 0.25% bupivacaine and 98% dehydrated ethanol. The patient was admitted for serial blood pressure monitoring and further palliative endoscopic interventions. Lab abnormalities included alanine aminotransferase (ALT) 151 U/L, aspartate aminotransferase (AST) 74 U/L and a total bilirubin of 2.1 mg/dL. Whole body imaging showed multiple minuscule bilateral pulmonary metastases without osseous metastasis.

On the second day of hospitalization, the EUS- FNA cytology confirmed pancreatic adenocarcinoma. The patient’s abdominal pain had significantly improved following CPN. She decided to proceed with duodenal stenting for obstruction and endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and biliary stenting to alleviate her obstructive jaundice. A duodenoscope was advanced to the major papilla and cannulated with difficulty owing to distorted anatomy from the duodenal obstruction. Cholangiography showed dilatation of intrahepatic, proximal and mid bile ducts with a 2 cm stricture in the distal bile duct. A sphincterotomy was performed and an 8 mm diameter x 6 cm length uncovered self-expanding metal stent was deployed across the stricture resulting in good bile flow. A pediatric upper endoscope could not traverse the duodenal stricture. A sphincterotome was used to pass a guidewire into the distal duodenum until contrast injection showed dilatated duodenal lumen and a 3 cm stricture. External marking identified the distal deployment site. Fluoroscopic and endoscopic guidance was used to deploy a 9 cm length x 22 mm diameter uncovered duodenal stent. Post-deployment contrast showed improved small bowel filling and endoscopic suction was rapid suggesting correct placement. The procedure was well tolerated and abdominal x-ray confirmed favorable position of the stents (Figure 3).

The patient was hospitalized for seven days with rapid diet advancement aided by pancreatic enzyme supplementation. She had significantly reduced nausea, vomiting and abdominal pain, however she developed diarrhea, possibly secondary to CPN. Labs at the time of discharge were improved with ALT 67 U/L, AST 54 U/L, total bilirubin 0.6 mg/dL and CA 19-9 28,344 U/ mL. Palliative chemotherapy was discussed and family discussions helped orient the patient and family through her diagnosis. She was discharged home with oncology and gastroenterology follow-up.

CASE DISCUSSION

In this case a patient with newly diagnosed pancreatic cancer underwent multiple palliative endoscopic therapies in a two day span. This presented the opportunity to review endoscopic therapy modalities and the evidence supporting their use in pancreatic cancer. Interventions focused on diagnostic evaluation (including anatomy and tissue sampling) as well as relief of biliary obstruction, duodenal obstruction and pain. We review the current literature supporting the use of these procedures.

Endoscopic ultrasound and EUS-FNA for pancreatic tumors have both been identified as an accurate way to diagnose pancreatic cancer.³ EUS provides the endoscopist the ability to capture high resolution ultrasound images of the pancreas. Compared to CT, EUS is more sensitive in local tumor staging and equally sensitive in detecting lymph node involvement and tumor resectability. FNA is the preferred method for obtaining tissue from pancreatic tumors.³

Most pancreatic cancers occur in the pancreatic head and commonly cause obstructive jaundice. Biliary stenting is the treatment of choice for unresectable pancreatic cancer in patients with obstructive jaundice.⁴ Endoscopic biliary stenting allows obstruction relief via minimally invasive approach. Endoscopic advantages over surgical decompression include fewer complications, lower-procedure related mortality, cost- effectiveness and improved quality of life.⁴ Historically, biliary stent occlusion was a significant limitation to stenting, but advancements in stent technology have improved stent patency. In unresectable cancers, uncovered biliary stents are commonly placed due to their tendency to migrate less and their equivalent patency to covered stents.

Pain is a large detractor from quality of life in pancreatic cancer. Treatment with opiate analgesics is often required and may be complicated by side-effects. Neuropathic pain can be difficult to control, but can be alleviated by CPN. The procedure involves injecting alcohol and local anesthetic into the celiac plexus to temporarily degrade nerve fibers. EUS-CPN allows direct access and better visualization of the celiac plexus than transcutaneous approaches (Figure 2). The pain alleviation rate after EUS-CPN is estimated to be 80%,⁵ with effects lasting 4-5 weeks. Procedural complications include postural hypotension, diarrhea, transient pain exacerbation or abscess.

Duodenal obstruction commonly complicates pancreatic cancer with resultant anorexia, nausea and vomiting. An estimated 38% of patients with unresectable pancreatic adenocarcinoma develop duodenal outlet obstruction within one year of cancer diagnosis.⁶ Surgical procedures like gastrojejunostomy were historically used to treat malignant gastric outlet obstruction. Endoscopic enteral stenting in malignant gastric outlet obstruction is a promising alternative to surgical intervention. A recent meta-analysis compared gastrojejunostomy to endoscopic bowel stenting showing self-expandable metal stents had significantly less complications and shorter time to oral intake.⁷

CONCLUSION

Advances in endoscopic techniques confer gastroenterologists the ability to provide effective palliative treatment to patients with unresectable pancreatic cancer. These procedures are less invasive, have fewer complications, decrease hospital length-of- stay, reduce pain and improve quality of life. It is vital that palliative treatment of advanced pancreatic cancer focuses on quick, safe and effective interventions that improve patient quality of life. Clinicians should be aware of and offer these treatments to patients in need, and understand the management of patients before and after procedures.

Gastrointestinal Motility And Functional Bowel Disorders, Series #17

Intestinal Angioedema An Often Misdiagnosed Entity

Obiajulu Kanu,

Marco Bustamante-Bernal,

Marynna Popp,

Richard W. McCallum

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In this article, we aim to heighten the awareness of intestinal angioedema among gastroenterologists as well as help differentiate it from other more common similar gastrointestinal conditions. We review the pertinent literature and provide guidelines which could assist in the timely diagnosis and treatment of this condition.

Most clinicians are familiar with angioedema involving the face and the upper respiratory airways. Bradykinin mediated angioedema may sometimes present with gastrointestinal symptoms alone. Such uncommon presentations are easily misdiagnosed, bearing serious consequences for the patient and the hospital system through unnecessary extensive workups. We include a typical example of the situation where a 60 year old woman presented multiple times to the hospital with gastrointestinal (GI) symptoms due to ACE inhibitor associated angioedema superimposed on hereditary angioedema. Her unusual presentation was initially treated symptomatically and this led to a late diagnosis and intervention consequently prolonging her hospital stay. In addition, we review the pertinent literature and provide guidelines for gastroenterologists encountering this challenging entity which could assist in the timely diagnosis and treatment of this condition.

Obiajulu Kanu, MD¹ Marco Bustamante- Bernal, MD¹ Marynna Popp, MD¹ Richard W. McCallum, MD² ¹Department of Internal Medicine, ²Division of Gastroenterology, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, TX

CASE REPORT

A60 year old Hispanic female presented with generalized crampy abdominal pain of 24 hours duration. Pain was acute in onset and associated with nausea, nonbilious emesis, and several bouts of watery, nonbloody diarrhea. She denied fever, chills, dysuria or sick contacts. Medical history was significant for multiple admissions in the past for similar episodes as well as hypertension, diabetes mellitus type 2, chronic deep venous thrombosis and dyslipidemia. Family history is positive for hereditary angioedema in four family members. Social history was negative for alcohol, tobacco or illicit drug use and she had no known allergies. Home medications included warfarin, metformin, Lisinopril, Lantus, and simvastatin.

On physical examination, she was lethargic. Vital signs were BP 68/39mmHg; heart rate 130beats/min; Respiratory rate 16/min; temperature 36.4 o C; Mean arterial pressure 49mmHg. Oxygen saturation was 93% at room air. Other pertinent findings included dry skin and mucous membranes, generalized abdominal tenderness with voluntary guarding but without rebound tenderness. Bowel sounds were hyperactive. Rectal examination was unremarkable and a stool guaiac done was negative.

Laboratory investigations showed: increased White Blood Cell (WBC) count of 15060/mcl and bands of 7%; potassium 3.1mEq/l; chloride 107mEq/l; bicarbonate 17mEq/l with an anion gap of 17; lactate 7.5mEq/l; BUN 17mg/dl and creatinine 1.4mg/dl; plasma glucose 256mg/dl. Her hemoglobin of 15.4 and hematocrit of 46.6 was explained by her severe dehydration and hemoconcentration which also explained the low potassium and borderline changes in renal function.

CT scan of the abdomen and pelvis without contrast showed a small amount of ascites with a ventral wall hernia containing small bowel without any evidence of obstruction or strangulation. The wall of the bowel could not be commented on as contrast was not used due to concerns about the renal function.

Resuscitative management was instituted upon presentation including central line placement, several boluses of intravenous normal saline and norepinephrine drip to address her severe hypotensive state. While being managed as a case of recurrent gastroenteritis, she underwent an extensive work up including antibodies for celiac disease, clostridium difficile stool studies, adrenal insufficiency, and hyperthyroidism which all came out negative. Eventually, C1 inhibitor, functional level was done which showed a low level. This new finding together with her strong family history of angioedema and her recurrent episodes while on Lisinopril led to the diagnosis of ACE inhibitor associated angioedema superimposed on hereditary angioedema.

The patient was properly educated about her condition, including medications to avoid. Her symptoms resolved after four days of symptomatic therapy for nausea, vomiting, abdominal pain and dehydration and she was discharged home in stable condition after her Lisinopril was permanently discontinued and a safer antihypertensive agent of a different class prescribed.

INTRODUCTION

There are two main categories of angioedema: the mast-cell mediated and the bradykinin mediated angioedema.¹ Bradykinin mediated angioedema, unlike the mast-cell mediated angioedema is usually without symptoms of pruritus and urticaria and includes 3 major categories. The hereditary form is known as hereditary angioedema (HAE) which is an autosomal dominant condition typically presenting as recurrent attacks of angioedema with a variable age of onset.^2,3 Another category is termed acquired C1 inhibitor (C1 INH) deficiency which is a rare syndrome of recurrent episodes of angioedema, without urticaria and is associated with B cell lymphoproliferative disorders in some patients.⁴ A third presentation is the drug induced angioedema of which the most commonly recognized medication has been Angiotensin Converting Enzyme inhibitor (ACEi). Angioedema has also been reported as a rare event with Angiotensin Receptor Blockers (ARBs), fibrinolytic agents, estrogens, antihypertensive drugs other than ACE inhibitors, psychotropic drugs and nonsteroidal anti-inflammatory drugs.⁵ Angioedema from ACEi accounts for approximately 30% of all cases of angioedema; however, only 0.1% to 0.5% of patients taking ACEi develop angioedema.^6,7 Considering that 35 to 40 million patients are treated worldwide with ACE inhibitors, this drug class could theoretically account for several hundred deaths per year from laryngeal oedema.5 However, ACEi induced angioedema of the gastrointestinal tract is very rare and its incidence is not well described.^7-9

C1 esterase inhibitor is a serine protease inhibitor that works directly on complement and contact plasma cascades to reduce bradykinin release, which is the primary pathologic mechanism in HAE and acquired C1 inhibitor (see Figure 1). Hereditary angioedema (HAE) involves quantitative deficiency (type 1) or qualitative dysfunction (type 2) of C1 esterase inhibitor protein (HAE). A third type of familial angioedema is characterized by normal C1INH levels and is called HAE with normal C1INH. The drug-induced angioedema (mostly ACE inhibitors) is as a result of enhanced activity of bradykinin, a potent vasodilating peptide due to inhibition of ACE, an enzyme responsible for its breakdown (see Figure 1 below). Pharmacological inhibition of ACE leads to increased plasma levels of bradykinin and high levels have been demonstrated in plasma during an acute episode of angioedema.^10,11 Notably, although degradation of bradykinin is blocked in all patients treated with ACE inhibitors, angioedema only occurs in a small percentage of such patients. Therefore it is likely that factors, other than impaired bradykinin degradation, are involved in the development of angioedema.⁵ In our patient, the background biochemical profile for HAE could be considered as a predisposing factor when an ACE inhibitor is introduced.

Classically, bradykinin mediated angioedema is located in the pharynx, extremities, or face. However, the bowel wall may be involved concomitantly in up to 75% of cases.¹² Rarely, as we present in this case, angioedema of the bowel mucosa may be the only site of angioedema.^13,14 The initial clinical presentation in patients with isolated gastrointestinal involvement may include colicky abdominal pain accompanied by nausea and vomiting that may easily be mistaken for other etiologies.¹³ About a day into an acute attack, the patient may experience watery diarrhea secondary to extravasation of fluid into the intraluminal space.¹³

Discussion

Abdominal pain is one of the most common conditions in clinical practice and yet a challenging complaint to accurately diagnose due to the vast number of possible etiologies.¹⁵ Intestinal angioedema is an uncommon but well described cause of abdominal pain and diarrhea easily misdiagnosed, leading to unnecessary surgical procedures and the possibility of a mortality rate.¹ In a series of 235 patients with HAE up to a third of these patients had undergone exploratory laparotomies, appendectomies, or both, during their abdominal attacks.¹⁶

Considering the infrequent occurrence of intestinal angioedema, a high index of suspicion with a detailed history and physical examination are paramount for a diagnosis to be made. A detailed history should include the following: appropriate characterization of the attack; history of previous attacks; age at first attack; intervals between attacks; presence or absence of inciting factors or medications; complete medication history; presence or absence of respiratory system involvement, and whether there is a family history of similar attacks.¹⁷ Physical examination is most relevant during an acute attack and it will include a proper examination of the skin as well as the face and eyelids and upper airways, the commonly involved areas. For episodes with acute abdominal involvement, the abdominal examination findings are very nonspecific. Palpation of the abdomen may reveal diffuse abdominal tenderness with or without rebound.¹⁷ Usually there is no distension to suggest an obstructive picture. Bowel sounds may be hypoactive or hyperactive and the patient may have signs of dehydration from diarrhea depending on the presentation.

Radiologic tests may help confirm a diagnosis of intestinal angioedema. In severe cases, plain abdominal radiographs may show dilated loops of bowel along with “thumbprinting,” which describes an area of mucosal edema (see Figure 2).¹ Ultrasonography often reveals mucosal thickening and free peritoneal fluid in dependent areas of the abdomen.¹⁸

There may also be a detectable compressible but edematous bowel wall with increased intraluminal fluid and decreased motility.¹⁹ The most sensitive diagnostic imaging study is a contrast-enhanced CT scan of the abdomen. CT is more useful for identifying milder degrees of intestinal edema, dilated loops of small or large bowel, and ascites than ultrasound and plain radiographs.²⁰ CT findings typically include massive edema of the small bowel or colon, prominent mesenteric vessels, thickened omentum, moderate ascites, and a normal appearance of the pericolic fat. Normal appearance of pericolic fat is useful for ruling out inflammatory changes seen in other diseases, such as appendicitis or diverticulitis.^21,22 If imaging is delayed until after recovery, then radiologic imaging may only show normal results.¹ As in the patient described, subtle or mild intestinal edema of any cause may be overlooked by interpreting radiologists even in symptomatic patients.¹⁷

Worsening abdominal pain severity after an earlier negative CT scan should not necessarily preclude consideration of intestinal angioedema diagnosis or a repeat imaging study.¹⁷ Sometimes these CT findings involving the bowel lead to a Gastroenterology consultation and if colonoscopy is performed, massive edema of the the bowel wall can be documented (Figure 3).

Laboratory tests are necessary to confirm a diagnosis of angioedema.¹ However there may be no need to do a further laboratory test in a patient with drug (ACE inhibitor) induced angioedema whose diagnosis can easily be made from history and confirmed with radiologic studies. If HAE is suspected, 4 laboratory tests should be obtained: C1 INH level, C1 INH activity, serum C4 level, and serum C1q, which is a byproduct of C1 INH degradation.^15,23,24 Low C4 is always present in HAE. In addition to low C4, a low C1 INH level and activity along with a normal C1q level is consistent with type I HAE. A normal C1 INH level with low functional activity and a normal C1q are consistent with type II HAE.¹

Management

Acute management will involve airway protection, hemodynamic stability and symptomatic therapy (antinausea and pain medications) depending on presentation and initial assessment. There are currently three FDA-approved intravenous pharmacologic agents available in the United States for the targeted acute treatment of HAE: plasma-derived C1 INH replacement protein (C1 INHRP), icatibant, and ecallantide (see Figure 4 below).¹⁷ Plasma-derived C1 INHRP obtained from pooled human plasma is the best studied first- line therapy for an acute HAE attack and it acts by repleting plasma C1 INH to exert inhibitory effects on the angioedema-causing pathways.^25,26 Icatibant, marketed as Firazyr, is a synthetic B2 receptor antagonist that blocks the effects of bradykinin during an acute angioedema attack by competitively binding to B2 receptors resulting in resolution of swelling and pain. Note that bradykinin, generated during HAE attacks, interacts with bradykinin-1 and B2 receptors to cause angioedema.^25,27 Ecallantide is a novel plasma kallikrein inhibitor (thereby blocking the production of bradykinin) approved in the United States in Decemeber 2009 for the treatment of acute attacks of HAE. Data from 2 randomized double-blind, placebo-controlled phase 3 trials of ecallantide in 143 patients with HAE to examine the speed of efficacy of ecallantide vs placebo showed that its beneficial effect was demonstrated earliest for abdominal attacks, followed by laryngeal and peripheral attacks.²⁸ Most patients given any of the first line therapies take 15 minutes to 2 hours before experiencing onset of relief, and major swelling may take up to 24 hours to completely resolve after drug therapy. A second line agent Fresh frozen plasma may be used when the first line agents are not available or have not shown efficacy.

Following acute management, adequate patient education as well as prophylactic therapy is usually given as patients are prone to having recurrence of attacks. Prophylaxis may be administered short term in anticipation of a procedure or period of stress, or long term for the reduction of attack rates.29 Two agents are currently FDA approved for both long term and short term prophylaxis in the United States: oral attenuated androgens (mainly, danazol) and Cinryze, a nanofiltered C1 INH concentrate.³⁰ Antifibrinolytics (eg, tranexamic acid) currently being used in Europe is not recommended in the United States due to concerns about its prothrombotic side effects. In addition to prophylactic therapy referral to an allergist and/or a geneticist and permanent discontinuation of unsafe medications may be indicated.

Clinical Pearls for Gastroenterologists

Recurrent admissions for presentations of abdominal pain with no unifying diagnosis being made but sometimes accompanied by surgical intervention should prompt consideration of the diagnosis of intestinal angioedema. Even without involvement of any other part of the body like the eyes or the upper airways, this should not be ruled out when there is a high index of suspicion based on the history, physical exam or radiological findings.

Intestinal angioedema can be well managed if diagnosed early. Due to the debilitating nature of this condition, and the risk of complications from misdiagnosis (such as surgery) there is need for a high index of suspicion among clinicians. Clinicians should be cognizant of medications that can induce this condition particularly ACEi in order to immediately discontinue its use. The treatment guideline we have provided will also facilitate management decisions.

This case report and literature review serve to heighten the awareness of intestinal angioedema among gastroenterologists as well as help differentiate the condition from other more common gastrointestinal conditions. Intestinal angioedema should feature in the differential diagnosis when CT and other imaging modalities or colonoscopy identify bowel wall edema.

A Case Report

Fixing A Rare Complication-Broncho-Esophageal Fistula from Squamous Cell Carcinoma

Scott Harrison,Neil R. Sharma

Scott Harrison, BS, Indiana University School of Medicine-Fort Wayne, IN, Neil R. Sharma, MD, Parkview Health, Volunteer Assistant Professor of Medicine at Indiana University School of Medicine

INTRODUCTION

The development of an airway-esophageal fistula (AEF) in advanced esophageal or lung cancers, though rare, is a dangerously debilitating condition. Patients undergoing radiation or chemotherapy treatment may also secondarily develop AEF. These fistula may lead to poor nutrition, deterioration of the airway and pulmonary sepsis, threatening patient survival and inevitably diminishing quality of life.¹ The mean survival in patients with supportive management alone has been reported to be one to six weeks, demonstrating the need for a viable treatment.²

Repair of the AEF is difficult, however, stent placement in the airway via bronchoscopy, esophageal stent placement using endoscopy guided by fluoroscopy, or both have been effective in restoring the patency of the upper GI tract. The use of self-expanding metallic stents (SEMS) has improved patient outcomes and self- reported quality of life when compared to the formerly used plastic and silicone stents.³ It is unclear whether combined stent placement provides better outcomes than the single esophageal or airway stent; however, current limited data suggests no advantage for one approach over the other. This report will discuss the case of a patient who had developed an AEF after tumor dehiscence, and the following treatment with combined SEMS placement.

Case Report

A 57-year-old male patient presented with a six- month history of esophagitis and dysphagia, which initially was only to solids. The patient had recently developed coughing and unintentional weight loss of approximately 25 pounds. The medical history of the patient included hypertension and a long history of tobacco and alcohol abuse.

Initial chest computed tomography (CT) preformed in October revealed a mass in the subcarinal region protruding to the left, occluding the bronchus and extending two cm into the left lower lobe. Subsequent bronchoscopy showed near complete occlusion of the left lower lobe bronchus and biopsy was consistent with non-keratinizing squamous cell carcinoma. Upper gastrointestinal (GI) fluoroscopy study exhibited dilation of the proximal esophagus with an apple-core lesion identified at the level of the carina. Esophagogastroduodenoscopy (EGD) with biopsy of the esophageal lesion was consistent with squamous cell carcinoma – upper GI primary. Endoscopic ultrasound was performed for staging and helped to define the anatomy. Subsequent self-expanding metal stents were placed in the esophagus and left bronchi, permitting closure of the esophago-pulmonary fistula. The patient went on to receive chemotherapy and radiation. He is alive more than a year-and-a-half since the diagnosis.

Discussion

The first effective treatment for AEF was surgical bypass using either the stomach or colon to substitute for the esophagus.⁴ Despite relative success, few patients were eligible to undergo such a major surgery and the procedure often incurred severe complications. Hence, esophageal intubation developed as a less invasive option. Prior to the advent of endoscopy, intubation involved manual insertion of the prosthesis, however, serious complications such as perforation of the esophagus and hemorrhaging limited its use.⁵

Modern advanced interventional endoscopy has enabled the precise placement of esophageal and bronchial stents, while reducing complications in the treatment of AEF.2 After stent insertion, there is immediate relief of dysphagia and odynophagia and termination of airway-ablating aspiration. Although plastic or silicone stents have been used in years past, self-expanding metallic stents (SEMS) have become the gold standard as they provide a better seal for large defects, experience a lower rate of migration and demonstrate a greater increase in post-operative quality of life.⁶

Depending on the individual case, stent placement may be in the esophagus, airway or both. The location of stenosis is an important consideration when placing a stent, such that the stent will not only seal the AEF, but also relieve stricture-associated symptoms.⁶ Deployment of an esophageal stent may be at a location that compromises the adjacent trachea, obstructing ventilation. Thus, an initial stent should be placed in the trachea so as to resist compression from the esophageal stent.⁷ Combined stenting is invariably indicated when fistula closure with the single stent proves unsuccessful, however, recent evidence has suggested the potential for combined stenting as the gold standard in all AEF cases.³

Whether the placement of the SEMS in the airway, esophagus or both is advantageous is currently unresolved. Several studies have found the placement of a single stent to encounter higher incidences of initial failure to seal the defect, as well as more frequent reopening of the fistula.⁴ The drawbacks of the single stent have led to the implementation of combined airway-esophageal stenting. Although combined stenting has curbed the rates of initial failure and subsequent reopening, more stent-related complications have been reported, such as vascular erosion.⁸

In conclusion, we report a case of esophageal carcinoma with subsequent development of an airway- esophageal fistula. Self-expanding metal stents were placed in the esophagus and left bronchus, relieving the patient of his dysphagia and effectively sealing the fistulization.

Colorectal Cancer: Real Progress In Diagnosis And Treatment, Series #4

Integrative Genomic Approaches for Evolving Personalized Colorectal Cancer Therapy

Eric E. Schadt

Increasingly the molecular characterization of tumors is playing a crucial role in the diagnosis and treatment of Colorectal Cancer (CRC). The focus of this review is on the state of the art clinical genomic testing of CRCs and the implications of this type of testing for developing individualized treatment strategies.

Increasingly the molecular characterization of tumors is playing a crucial role in the diagnosis and treatment of CRC. The genomic landscape of a tumor can define its tissue of origin, the key driver genes leading to the onset and progression of the tumor, the cancer pathways that are activated or suppressed, and the prognosis for individual patients. The cost of generating the DNA and RNA sequencing data that enable this detailed portrait of a tumor, has decreased at a super Moore’s law rate, providing for the possibility of generating this information routinely for all cancer patients. Whole genome and transcriptome sequencing casts a wide net over the landscape of genomic alterations that cause cancer and that define the broad spectrum of tumor expressivity leading to a diversity of outcomes. In this review, I will focus on the state of the art clinical genomic testing of CRCs and the implications of this type of testing for developing individualized treatment strategies.

Eric E. Schadt, Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY

INTRODUCTION

Colorectal (CRC) and other types of cancer represent diseases of the genome, where small nucleotide variations, larger insertions and deletions, large structural variations, and epigenetic changes accumulate in ways that activate and/or suppress critical molecular pathways that in turn alter cellular function, ultimately resulting in unconstrained cellular proliferation. Every cancer patient harbors a unique constellation of germline and somatic DNA variants and changes in their epigenome that at least partially define their risk of developing cancer, the severity and rate of progression of their tumor(s), and ultimate the ability of their tumor and system more generally to respond to specific therapies. Given the unique constellation of mutations underlying any individual tumor and the array of molecular pathways that can be affected as a result, personalizing cancer therapy has not only become a well-established concept, it continues to make its way into the standard of care for a great diversity of cancer types.¹

Today we are at the beginning stages of developing personalized therapy strategies that aim to ensure an optimal outcome for individual cancer patients, developments that are enabled by the rapid progress in basic cancer research at the molecular level, the rapid advancement of cost effective technologies that make it possible to comprehensively characterize tumors at the molecular level, and an expanding repertoire of targeted cancer therapeutics. An increasing number of FDA-approved targeted cancer drugs are associated with companion biomarkers that are predictive for drug response in certain types of cancers, in addition to germline variants that are associated with drug metabolism that may also impact treatment response.² In cases where a patient tests positive for a specific biomarker that indicates an FDA-approved therapy for the given tumor type, developing a personalized therapeutic strategy is straightforward. For example, vemurafenib is indicated as a treatment for metastatic melanoma tumors harboring the BRAF p.V600E mutation. However, for the vast majority of tumor types and available therapeutics, a biomarker-therapeutic link is not so straightforward. In this review, I will focus on the state of the art clinical genomic testing of CRCs and the implications of this type of testing for developing individualized treatment strategies.

A Revolution in Genomics Transforms the Molecular Characterization Of Tumors

Nucleic acid sequencing technologies have evolved at an astonishing pace, one of the few, if only, technologies to move at a super Moore’s Law rate with respect to sequencing a human genome.³ The current generation of DNA sequencers, commonly referred to as next- generation sequencing (NGS) technologies, deliver a high-throughput, low-cost way of generating whole-genome (WGS), whole-exome (WES) sequence, and whole transcriptome RNA sequence data. These technologies are enabling a new paradigm in precision medicine for oncology, driven by large-scale NGS studies carried out over the last several years, which have uncovered novel oncogenic drivers and started to depict genetic landscapes across a number of cancer types.^4-6 This research has not only advanced our understanding of the underlying genetics of cancer, but it has accelerated us towards personalized cancer therapy.⁷ Retrospective analyses of archived tumor samples using targeted gene panels or WES have been recently reported.^8-11 Across these different studies, mutations that had the potential to impact clinical decision making (that is, mutations that were actionable) were identified in 80-90% of the tumor samples profiled. A number of prospective cancer genetic sequencing studies have also demonstrated this same level of clinical utility.^12-15 These studies are among the first to directly demonstrate that comprehensive genomic characterization of an individual’s tumor can have a direct impact on their treatment choices.

Strategies for Personalizing the Treatment of CRC

We are at the beginning stages of determining the best strategies for genomic characterization of tumors to maximize impact on clinical decision making relating to the treatment of cancer patients. Presently a wide spectrum of alternatives exist to profile tumors at the genomic level in order to understand the pathways that have been activated or suppressed in individual cancer patients, knowledge that can directly impact the choice of therapy. Foundation Medicine offers sequencing of tumor DNA using a targeted panel of a few hundred genes that cover the most commonly mutated genes across a diversity of cancer types. While such targeted panels may inform on a majority of cases, they fall short in a number of ways. First, targeted panels sequenced only on tumor DNA do not capture variants in the germline that may aid in the interpretation of somatic variants. Second, they do not capture all genes and regulatory regions that may harbor mutations that impact key driver genes. Third, sequencing of targeted panels does not involve RNAseq data generated on RNA derived from a patient’s tumor, and thus such strategies will miss potentially important functional information on the tumor that may directly indicate the activation or suppression status of cancer pathways, even in the absence of key driver mutations in those pathways. Finally, targeted panel strategies do not capture the thousands of other genes that may be relevant to therapy choices, such as genes involved in metabolizing drugs.

At the other end of the cancer molecular profiling spectrum are companies like NantOmics that generate orders of magnitude more data and more diverse data than strategies based on DNA sequencing of targeted gene panels. NantOmics’ full suite of assays include WGS carried out on tumor and germline DNA, RNA sequencing of tumor-derived RNA, and metabolomics and proteomics assays derived from the tumor to comprehensively functionally characterize individual tumors. Such comprehensive molecular profiles generated on cancer patients are the most extensive to date, although the cost for generating such extensive data is prohibitive for most, and whether the cost of such data is justified given the actionability of the findings that are specific to those data, remain to be shown. For example, whether WGS offers significant advantages over WES in personalizing cancer therapy for patients remains to be proven. Beyond the direct characterization of tumor samples are sequence-based assays run on circulating tumor cells and cell-free DNA, technologies that promise to facilitate early detection of cancer, comprehensive characterization of the heterogeneity of tumors in a given individual, and enable long-term monitoring of cancer progression and remission.^16,17 The oncology field more generally is actively engaged in building up different lines of evidence to support what these different technologies bring to the table in terms of diagnosing and treating cancer patients. Reimbursement for the application of these different tests is also not at all routine, with health insurers and health management systems waiting for the evidence to accumulate that generating this type of information can have a meaningful impact on outcomes. However, given waves of new therapies targeting specific cancer pathways are making their way through clinical trials, understanding the state of these pathways that can be targeted in individual cancer patients will largely come to determine treatment choices in the near future.

To provide more insight into the type of testing that can be carried out today to impact personalized CRC therapy choices, consider the workflow we employ to provide for comprehensive molecular characterization of tumors (Figure 1). Our workflow is representative of a current state of the art process that provides for multi-lab, multi-assay molecular profiling of tumor specimens, generation of genomic findings and interpretations relevant to clinical decisions, and their subsequent delivery to cancer patients and their treating physicians. The first step of this workflow is the isolation of normal DNA from peripheral blood or uninvolved normal tissue, tumor DNA isolated from FFPE or fresh frozen tumor samples, and total RNA isolated from fresh frozen tumor and adjacent normal tissue when available. The DNA and RNA are then interrogated with a variety of genomic technologies. The choice of assays to run on any given case can depend on the quantity and quality of the available material, the purity of the available tumor specimen, the heterogeneity of the tumor type, and cost.

The primary goal of generating and processing these data is to take an integrative approach that utilizes multi-platform genomic profiling data to generate, at the cellular level, molecular portraits of the oncogenic signaling networks underlying individual cancer cases. Recommendations of appropriate targeted therapeutics can then follow through the execution of manual or automated review processes performed in a case- by-case manner. DNA alterations that have clinical implications are identified as actionable alterations, while clinical trial connections, inclusion/exclusion criteria, trial location and open/close date information can be assembled from ClinicalTrials.gov and used to direct patients to the most appropriate clinical trials.

For CRC in particular, the data generated on any particular case can be interpreted in the context of all that is known in the available literature, genomic repositories, and clinical reports to make actionable recommendations given the molecular make up of a tumor (Figure 2). The most straightforward utility of genomic CRC data is for predicting insensitivity to anti- EGFR antibodies.¹⁸ Additionally, selective targeting of the ERK pathway through inhibition of either BRAF or MEK can be well informed by the genomic data. More generally, the data can be interpreted in the context of common cancer pathways; the state of one pathway may be inferred given the state of another. For example, we may infer PI3K activation given the absence of ERK pathway activation, even though activating mutations are not directly observed in PIK3CA (one of the primary ways in which PI3K is activated). This inference would allow for the consideration of additional targeted strategies utilizing AKT/mTOR inhibition. Of course, observing driver mutations in well-established CRC- associated genes such as TP53, KRAS, NRAS, BRAF, and PIK3CA mutations provides a primary framework from which a tumors can be classified,¹⁹ including assessing the risk of developing metastatic disease (or having metastatic disease), given genes such as TP53 are known to promote metastasis in multiple cancer types.²⁰

Beyond small nucleotide variants in cancer driver genes, somatic copy number alterations (CNAs) affect a greater portion of cancer genomes than SNVs and play a critical role in activating oncogenes or inactivating tumor suppressors.²¹ A major challenge in CNA analysis is to differentiate driver CNAs that contribute to oncogenesis and cancer progression from those passenger CNAs that are acquired during cancer development but do not have functional consequences. Common criteria for driver CNA predictions include amplicon size and association of gene expression with copy number alterations. In order to determine potential oncogenic driver CNA events with high confidence, the relationship between CNAs and gene expression based on RNAseq data must be examined. Gene fusions represent another key oncogenic event in many cancer types.²² Becoming standard in most cancer pipelines today are comprehensive computational components that incorporate multiple programs for detecting gene fusions from RNAseq data, given the driver role gene fusions can play in many types of cancer. Finally, in cases where a tumor identified in a patient has an unknown origin, the genomic sequence data can well complement pathologic assessments to deliver a more accurate diagnosis, given certain types of mutations or other genomic alterations are known to be specific to certain types of cancer.

Once the processed genomic data, patient medical history and available pathology reports are in hand, today they are manually reviewed by a team of bioinformaticians, cancer molecular biologists, a medical oncologist, and a genetic counselor, to produce an electronic document that summarizes clinically- relevant findings. The results of this testing will include a list of relevant somatic mutations/alterations, drugs whose benefit may be altered given the patient’s somatic or germline variant makeup, a prognostic biomarker summary, clinical trial recommendations (with an emphasis on those where enrollment criteria include variants detected in the patient), and a cancer pathway perturbation summary (similar to what is depicted in Figure 2). The information in these reports can then be considered by the patient and his/her treating physician in determining treatment strategies going forward. The genomic reports are just one of many dimensions of information regarding a patient’s condition that can be considered by the treating physician in treating the patient.

Moving Towards the Future of Genomic Cancer Testing

Despite the rapid advancement of cancer genomic testing, a number of obstacles remain in order to make this testing routine. The cost of WES and RNAseq remain an issue given their substantially higher price compared to targeted panels and the fact that today there is not a clear reimbursement mechanism for generating such data. Sample availability and quality also pose a barrier to perform genome-wide profiling, where obtaining high purity tumor samples from FFPE specimens is still challenging. The tumor purity of the specimen delivered for profiling has a dramatic impact on the ability to identify somatic alterations with confidence. The extent to which targeting of sub-clonal alterations can achieve clinical benefit is also still under investigation, so that balancing the costs and benefits for these different personalized genomics strategies is an evolving process.

Beyond these issues, however, lies perhaps the most important issue to address in order to maximize the informativeness and accuracy of cancer genomic testing: how to better leverage the digital universe of information to construct predictive models of cancer to more accurately diagnose and treat cancer. Most cancer genomic tests today focus more naively on individual somatic variants and their known impact on cancer driver genes. Advanced cognitive systems such as IBM’s Watson attempt to leverage the published literature and existing databases to automate the annotation of somatic alterations in ways that inform on treatment choices. However, such approaches still fail to recognize cancer as a complex disease, with genetic and environmental forces impacting highly interconnected molecular networks that in turn alter cellular behavior, tissue and organ functioning, and ultimately system-wide behavior, whether it is a tumor metastasizing from one organ to another, or the tumor evading the immune system to grow and metastasize in unconstrained ways.

In order to achieve an understanding of the changes we observe in the vast sea of genomic information we generate today in disease contexts, including cancer, we must employ advanced computational frameworks capable of simultaneously organizing and modeling these big data, in order to learn from the data how to accurately classify individuals along wellness and cancer disease spectra, to accurately identify the most appropriate interventions to change their trajectories in order to treat or provide protection against disease. The focus today in cancer genomic testing on identification of obvious mutations in protein coding sequence that activate oncogenes or inactivate tumor suppressor genes, leaves unexplored the variations in DNA in the germline and somatic genomes that affect the regulation of genes with respect to their role in cancer. But even with knowledge of such variations we would not necessarily understand the genes that are impacted, the pathways those genes operate in, the larger networks in which the pathways operate, whether you activate or suppress such genes and pathways for treatment, and so on.

Changes in DNA do not directly lead to changes in disease related phenotypes, but instead lead to changes in molecular phenotypes that in turn affect molecular and cellular processes that in turn lead to higher order changes in tissues, organs and entire systems that ultimately lead to changes in physiological states.^23-26 While DNA information on its own may not reflect the dynamic, fluid nature of biological systems that are able to reconfigure themselves as conditions demand, integrating this information with transcriptional, metabolite, protein, and methylation data under different contexts can elucidate the regulatory networks that define cancer risk, onset, progression and response to treatments (Figure 3). Networks provide a convenient graphical framework for organizing vast amounts of data and representing the relationships among features in them. Modeling biological systems as a network provides a more holistic model of the system under study, providing for a far richer context within which to understand single genes and pathways, thereby well complementing reductionist methodologies by providing a more integrated, holistic view. Once constructed and validated, system-wide network models can be systematically mined to identify key drivers of cancer, interpret the molecular impact of cancer-causing perturbagens (whether genetic or environmental), and identify the best targets for therapeutic intervention. However, unlike traditional biological research where modifications to genes are engineered experimentally to make such identifications, with a predictive computational model we can carry out such explorations on super computers in seconds.

Ultimately, our ability to construct the most predictive models of diseases such as CRC will equate with our ability to master the extremely large-scale, high- dimensional information being collected on systems relevant to disease. Without sophisticated mathematical algorithms capable of appropriately integrating the large-scale data, achieving a true understanding of cancer and the most accurate ways to diagnose and treat it will be difficult to achieve. Mature quantitative disciplines such as high energy physics, climatology, and quantitative finance have all evolved to depend on mathematical models as repositories of knowledge and understanding. The complexity of common human diseases such as CRC demand that we employ this same model-based approach as a matter of necessity, if we hope to realize the vision of precision medicine that ensures the right drug is delivered to the right person at the right time.

Nutrition Issues In Gastroenterology, Series #152

Hyperinsulinemic Hypoglycemia After Gastric Bypass Surgery

Kelly O’Donnell

Hypoglycemia after Roux-en-Y gastric bypass (RGBP) is a rare, yet challenging condition. The optimal treatment of these patients has not been well studied and the underlying etiology requires further research. The goal of this paper is to provide a practical approach to the evaluation and management of the patient who presents with hypoglycemia after RGBP.

Hypoglycemia after Roux-en-Y gastric bypass is a rare, yet challenging condition. Patients typically present with post-prandial hypoglycemia 1-5 years after their surgery, often after weight stabilization. Most concerning are the subset of patients who present with symptoms of neuroglycopenia. Hypoglycemia in these patients is felt to be due to an altered GLP-1 response in the post-prandial period. Treatment options include dietary interventions such as limitation of carbohydrate intake, pharmacotherapy aimed at reducing post-prandial glucose excursion and in more recalcitrant cases, surgical reversion of the bypass. However, the optimal treatment of these patients has not been well studied and the underlying etiology requires further research.

Jennifer L. Kirby, MD-PhD¹ Kelly O’Donnell, MS, RD, CNSC² ¹Division of Endocrinology and Metabolism, Department of Medicine, ²Surgery Nutrition Support, University of Virginia Health System, Charlottesville, VA

REPRESENTATIVE CASE

A 42 year old female presents with one year of flushing, shaking and diaphoresis. These episodes have been increasing in frequency, occur approximately 1.5-2 hours after meals and improve with food. She has a history of obesity and underwent Roux- en-Y gastric bypass (RGBP) five years earlier. Twenty months after her surgery, she had lost 120 pounds and her weight stabilized. Self-monitoring with capillary blood glucose now reveals values measuring<60 mg/ dL, with the lowest measuring 33 mg/dL, all associated with symptoms. Symptoms resolve with carbohydrate intake. Her episodes have continued to increase in frequency and of late, include a syncopal episode.

INTRODUCTION

Hyperinsulinemic hypoglycemia after RGBP was first described in 2005 by two independent groups.^1,2 In the 10 years since, numerous articles have been written about this entity and although much has been learned, our understanding of the etiology and optimum treatment has not been fully elucidated. Initial reports suggested a role for increased b-cell mass or nesidioblastosis.^1,3 However, these findings were not universally supported.⁴ Subsequent studies have shown that in RGBP patients, the rapid passage of nutrients directly into the intestine results in a rapid rise of serum glucose with higher peak values and lower nadirs compared to controls.⁵ Additionally, RGBP patients have increased post-meal insulin and GLP- 1 responses. Studies involving patients with hypoglycemia suggest that this response is exaggerated and provide evidence for a prominent role of GLP-1.⁶ Some authors have proposed that hyperinsulinemic hypoglycemia after RGBP is due to dumping syndrome, which occurs due to rapid passage of nutrients from the stomach remnant into the proximal small intestine.⁷ Regardless of mechanism, a small subset of these patients develop severe neuroglycopenic symptoms (see Table 1) that can result in seizure, syncope and trauma such as a motor vehicle collision.^2,3 Often these patients are refractory to conservative therapies with dietary changes and pharmacotherapy. Many have undergone more invasive therapies, such as gastrostomy tube placement, partial/ full pancreatectomy or reversal of the bypass. The goal of this paper is to provide a practical approach to the evaluation and management of the patient who presents with hypoglycemia after RGBP.

DIAGNOSIS

Most patients with hyperinsulinemic hypoglycemia after RGBP present within 1-5 years after surgery, but it has been observed in patients within months post- operatively and as long as 20+ years later. The typical patient develops hypoglycemia 1-3 hours after ingestion of a carbohydrate-containing meal and hypoglycemia is absent in the fasting state. Per Endocrine Society guidelines,⁸ evaluation should proceed only after Whipple’s triad has been satisfied (development of symptoms typical of hypoglycemia, low serum glucose at the time of symptoms and relief of symptoms with the administration of glucose).

The symptoms of hypoglycemia can be divided into autonomic and neuroglycopenic symptoms (see Table 1). A detailed history of the symptoms of hypoglycemia should be obtained to identify patients who have neuroglycopenic symptoms as these are the most concerning given the potential risk for harm. A reasonable approach to establish the diagnosis of hyperinsulinemic hypoglycemia would be to obtain serum glucose, insulin, and C-peptide levels in addition to a sulfonylurea screen at the time of hypoglycemia. The utility of other studies in the assessment of the patient with post-RGBP hypoglycemia is not clear. Oral glucose tolerance tests are not recommended to diagnose hypoglycemia in any setting.⁸ Mixed meal testing has been used in research studies, but not all patients with a history of hypoglycemia after RGBP will develop hypoglycemia in this setting.^6,9-11 More recently, continuous glucose monitoring (CGM) has shown promise not only for diagnosis, but also for monitoring response to treatment. Notably, results should be viewed with caution as the accuracy of CGM in the hypoglycemic range is poor.^12,13 The clinical history, time course with regard to onset after surgery, and symptoms should steer the clinician towards a diagnosis of post-gastric bypass hypoglycemia. It is unclear what role more detailed studies, such as 72- hour fast, radiologic imaging or selective arterial calcium stimulation play in evaluation. However, atypical symptoms in these patients (such as fasting or overnight hypoglycemia) should be fully explained with a thorough evaluation.⁸ Rarely, hypoglycemia after RGBP has been due to insulinoma.¹ See Table 2 for suggested guidelines for the initial evaluation.

INTERVENTION
Dietary Modification

Dietary intervention is recommended as the first treatment option for patients diagnosed with hypoglycemia after RGBP. Several different strategies have been published, but all target reducing carbohydrate intake to avoid an insulin surge (summarized in Table 3). Kellogg et al.⁵ treated 12 patients with symptoms suggestive of hyperinsulinemic hypoglycemia with a high carbohydrate (79%) meal on day 1 of the study followed by a low (2%) carbohydrate meal on day 2. The meals contained the same amount of calories. After the high carbohydrate meal, serum insulin levels peaked at 30- 90 minutes, while the mean glucose nadir (44 mg/dL) occurred at 90-120 minutes. After the low carbohydrate meal, there was only a modest rise in plasma insulin with very little change in glucose levels. After one month of a low carbohydrate diet, 25% of patients reported complete resolution of symptoms while another 25% had improvement in major symptoms, 33% had improvement in minor symptoms and 17% experienced no improvement at all. Botros et al.¹⁴ found that when patients with hyperinsulinemic hypoglycemia consumed a meal containing 30 grams of carbohydrate, none of them experienced hypoglycemia. Based on these results, the authors suggested consuming three meals per day containing 30 grams carbohydrate plus three snacks per day, each containing 15-30 grams carbohydrate while avoiding simple sugars. Because this study occurred in a supervised clinical setting, results and compliance may be altered in real world practice. Also, only 30-gram carbohydrate meals were tested and it may be possible that some patients can tolerate a more liberal carbohydrate allowance. Five of six gastric bypass patients had improvement in symptoms of hyperinsulinemic hypoglycemia with diet modification consisting of three small meals plus 2-3 small snacks with 60 grams of protein daily.¹⁶ High carbohydrate, high fat foods were eliminated as well as sugar-containing fluids.

Pharmacotherapy

When dietary modification fails, pharmacotherapy is often employed for treatment. Several agents including acarbose, calcium-channel blockers, diazoxide, octreotide and GLP-1 receptor agonists have been effective in case reports and case series either alone or in combination (see Table 3). To date, these medications have not been rigorously studied for treatment of hyperinsulinemic hypoglycemia after RGBP and are not FDA-approved for this reason. However, patients may clearly benefit from a trial of therapy, particularly when having severe and debilitating symptoms associated with neuroglycopenia. A reasonable approach would be to try each agent and assess effectiveness, leaving in place those agents that prove beneficial and discontinuing those with either intolerable side effects or lack of efficacy. Combinations of agents that target different mechanisms have also shown benefit (e.g., acarbose with calcium-channel blocker).¹⁹

Partial or Full Pancreatectomy

Initial reports of nesidioblastosis as a cause of hyperinsulinemic hypoglycemia after RGBP led to many patients being treated with partial or full pancreatectomy. Recently, pancreatectomy has fallen out of favor, likely due to studies providing an alternative mechanism to nesidioblastosis as the underlying cause as well as the significant associated morbidity. A recent review of the literature noted that 34 out of 51 patients (67%) had resolution of symptoms after pancreatic resection.²⁷ However, follow-up in these studies was short; longer-term follow-up has shown that some patients have a return of symptoms farther out from surgery.²⁸ In addition, the risk of developing diabetes and pancreatic exocrine dysfunction increased with more aggressive resection.²⁹

Gastrostomy Tube Placement

In 2010, McLaughlin et al. incidentally noted improvement in neuroglycopenic hypoglycemic symptoms after placement of a gastrostomy tube (G tube) into the remnant stomach of a patient with a small bowel obstruction.⁷ To formally assess the reason for the improvement, the patient was readmitted to the hospital and given a can of liquid formula by mouth followed by overnight fasting and administration of the same liquid formula through the G tube. Feeding by mouth versus G tube caused symptomatic hypoglycemia at 90-120 minutes (60 mg/dL vs 80 mg/dL) and insulin concentrations that were eight times higher, respectively. The authors concluded that the results were inconsistent with b-cell hyperplasia or increased b-cell activity as a cause of the hypoglycemia. Rather, hyperinsulinemia was a result of nutrients delivered through the bypassed GI tract, but not through the remnant stomach, perhaps due to altered incretin responses. In another study, a G tube was placed in the gastric remnant of 5 patients who were refractory to medical and diet management of their hyperinsulinemic hypoglycemia.¹⁵ The patients received 3 bolus feedings per day of a standard formula providing a total of 450 calories and experienced no symptoms of hypoglycemia. All 5 patients had remission of hypoglycemia after placement of the G tube. However, successful resolution of hypoglycemia with G tube placement is not universal.¹⁷

Gastric Bypass Reversal

Several groups have now shown successful remission of hypoglycemia with reversal of gastric bypass with or without modified sleeve gastrectomy. In the review by Mala, 13 out of 17 patients (76%) had resolution of symptoms and weight regain was a common outcome.²⁷ In patients with reversal without modified sleeve gastrectomy, weight regain can be an issue.

TREATMENT APPROACH

When approaching a patient with symptoms suggestive of hypoglycemia after gastric bypass, it is important to document evidence of Whipple’s triad. In particular, the provider should assess for symptoms of neuroglycopenia, which place the patient at risk for severe adverse events, such as seizure and death. In patients with documented hypoglycemia, it is reasonable to obtain serum glucose, insulin, and c-peptide levels with a sulfonylurea screen. Provocative testing, such as a mixed meal tolerance test, can be used as a method to confirm the diagnosis. In cases where the history is inconsistent with typical hyperinsulinemic hypoglycemia after RGBP (e.g., fasting or overnight hypoglycemia), further diagnostic testing and imaging are warranted as indicated.⁸

Initial therapy should be directed at dietary modification to reduce the content of total carbohydrate in the patient’s diet, ideally targeting for 4-6 small meals per day containing 30 grams or less per meal. Elimination of simple sugars is critical. A journal that includes dietary information, blood glucose values and symptoms can be helpful to elucidate particular triggers to guide dietary interventions. If dietary changes are unsuccessful at reducing/eliminating hypoglycemic episodes, pharmacologic agents (listed in Table 4) can be used either alone or in combination. Given that there are no trials comparing these medications, a trial of each agent to assess for benefit may be attempted prior to proceeding with more invasive therapies. Certainly cost and tolerability will play a role in the ability of patients to try these agents. Although it is unclear what utility continuous glucose monitoring (CGM) has in the diagnosis of hyperinsulinemic hypoglycemia, CGM can be useful for patients who have neuroglycopenic symptoms for monitoring to prevent severe episodes and to assess responses to therapy. Again, cost may be a barrier as this is not a traditional use for CGM and may not be covered by many insurance plans.

Surgical procedures such as placement of a gastrostomy tube into the gastric remnant and reversal of the gastric bypass with or without gastrectomy should be used only if more conservative therapies have been tried and failed. In addition, involvement of providers with experience treating these patients should be sought, including dietitians, endocrinologists and bariatric surgeons.

CONCLUSION

Hyperinsulinemic hypoglycemia after gastric bypass, particularly with neuroglycopenia, is a rare and difficult entity to treat. Although our understanding of the pathophysiology underlying this entity has advanced in the 10 years since it was initially described, there are no evidenced-based guidelines for the diagnosis and treatment at this time. Further research regarding the underlying mechanism driving hyperinsulinemia in these patients is needed and will hopefully provide better therapeutic options. Early identification of patients with neuroglycopenia is warranted. These patients may benefit from systematic intervention from dietary changes on up to surgical revision of the bypass in some.

Gastrointestinal Motility And Functional Bowel Disorders, Series #17

Intestinal Angioedema An Often Misdiagnosed Entity

May 2016 • Volume XL, Issue 5

Obiajulu Kanu,

Marco Bustamante-Bernal,

Marynna Popp,

Richard W. McCallum

CASE REPORT

INTRODUCTION

Discussion

Management

Clinical Pearls for Gastroenterologists

A Case Report

A Case Report Of Spontaneous Pneumoperitoneum Related to Scleroderma without Evidence of Pneumatosis Cystoides Intestinalis

May 2016 • Volume XL, Issue 5

Ross Heil,Jason Schairer,Brad Warren

We report a case of a 72-year-old male with a history of scleroderma who presented to the emergency room with an asymptomatic pneumoperitonum after undergoing a CT thorax for evaluation of intersitial lung disease. Abdominal imaging was performed with oral contrast and did not reveal extravasation of the contrast into the peritoneum suggesting there was no perforated viscus. The patient was managed conservatively with serial abdominal exams, bowel rest, empiric antibiotics, supplemental oxygen, and total parenteral nutrition. The patient was subsequently diagnosed with a spontaneous pneumoperitoneum related to scleroderma without evidence of pneumatosis cystoides intestinalis. Over a course of 3 months the pneumoperitoneum resolved and the patient remained well.

Ross Heil, D.O., Providence Hospital and Medical Center Jason Schairer, M.D., Henry Ford Health System Brad Warren D.O. Providence Hospital and Medical Center

INTRODUCTION

In 1915, Hugo Popper first described the technique of utilizing radiographic methods to detect pneumoperitoneum.² Radiological techniques that are available for the diagnosis include ultrasound, plain X-ray and computed tomography (CT). Pneumoperitoneum appears as a radiolucency below the diaphragms on chest radiography or in a superiorly dependent location on an abdominal radiograph. Miller and Nelson described a process that can detect as little as one cubic centimeter of gas in the abdominal cavity.⁸ This includes placing the patient in the left lateral decubitus position for 10 to 20 minutes then exposing a left lateral decubitus film. The patient is then moved into an erect position where an anteroposterior chest film is taken as well as an erect abdominal film. The patient is next tilted to a horizontal position where a supine abdominal film is taken.8 If there is concern that the pneumoperitoneum is from an area above the diaphragm then abdominal x-rays should demonstrate air in the paraspinal area of the retroperitoneum.¹⁰ Computed tomography is more sensitive for detecting intraperitoneal air than upright chest radiographs.⁶ Visceral perforation may not always be detected by contrast examination with computed tomography.¹⁰ The causes of most pneumoperitoneum have been linked to intra-abdominal disease. Approximately 90% of the cases of pneumoperitoneum are due to visceral perforation, usually associated with a gastric or duodenal ulcer.² Pneumoperitoneum due to perforation is a surgical emergency. Generally these patients will present with fever, leukocytosis and peritoneal signs. There are, however, cases of an occult leakage due to visceral perforation where the patient may only demonstrate mild abdominal pain without fever, leukocytosis, or peritoneal signs. These occult leakages may be due to sigmoid diverticulitis, fecal impaction, or peptic ulcer perforations.² It has been noted that patients with peptic ulcer perforations may present less symptomatic than other sites of perforation or even asymptomatic with subsequent healing without intervention.²

The remaining 10% of cases of pneumoperitoneum not associated with visceral perforation fall into the classification of spontaneous pneumoperitoneum.² The term spontaneous pneumoperitoneum has been used synonymously with aseptic spontaneous, idiopathic, spontaneous asymptomatic and nonsurgical pneumoperitoneum.^² Causes of spontaneous pneumoperitoneum can be divided into abdominal, thoracic, gynecologic, pseudopneumoperitoneum, miscellaneous and idiopathic etiologies.⁶

Abdominal causes of spontaneous pneumoperitoneum are the most common.⁸ The etiologies include abdominal surgery, peritoneal dialysis, and most endoscopic gastrointestinal procedures.⁶ By far the most common abdominal cause is due to open abdominal surgery. It generally resolves within 2 days in two thirds of the cases and within 5 days in 97% cases when followed by abdominal radiographs.⁶ If followed by CT, which is more sensitive, intraperitoneal air at 3 days will be detected in 85% of the cases and 50% of cases at day six.⁶ Older, leaner adults more commonly retain a greater volume of free air over a longer period of time.⁸

Pneumatosis cystoides intestinalis, also known as cystic lymphomatosis or enteromesenteric emphysema, is the most common abdominal cause of nonsurgical pneumoperitoneum.⁶ It was first described in 1730 by DuVernoi during a cadaver dissection.¹⁰ The development of pneumatosis cystoides intestinalis has been associated with idiopathic development, scleroderma, bone marrow transplant, AIDS, diverticular disease, small bowel resection, intestinal pseudo obstruction, dermatomyositis, nontropical sprue, jejunal-ileal bypass, gastric outlet obstruction, sclerotherapy, and heart transplantation.⁶ It is characterized by intramural gas filled cysts in any portion of the gastrointestinal tract; however, it is most commonly found in the terminal ileum.⁶ Even though the small bowel is the most common site for these cysts, they can be found anywhere in the gastrointestinal tract including the stomach (gastric pneumatosis cystoides) and the colon (pneumatosis coli).⁸ It is the rupture of these cysts that lead to pneumoperitoneum.⁷ The cysts are constantly filling, rupturing, sealing, and then filling again providing a constant spontaneous pneumoperitoneum. This condition generally resolves spontaneously, but has been known to reoccur. There have been five possible explanations for the development of these cysts. The first two theories suggest that an increase in acidic byproducts result in increased levels of lactic acid leading to a decrease in carbon dioxide and oxygen resorption leading to the cyst formation.⁸ The mechanical theory states that gas is forced into the bowel by obstructions, anastomotic sites, the pulmonary system, trauma, mucosal breaks, increased pressure, or increased peristalsis. The bacterial theory suggests that bacteria gain entrance to the bowel wall and produce the cysts.¹⁰ The last theory is mentioned due to historical interest, which is a neoplastic theory described by Bangs.⁸

Outside of the abdomen, other locations that may cause pneumoperitoneum include thoracic, gynecolic, and other locations. Thoracic causes include mechanical ventilation, cardiopulmonary resuscitation, and pneumothorax. Thoracic causes are the second most common cause of spontaneous pneumoperitoneum and barotraumas represents the most frequent of the intrathoracic causes.⁸ Gynecologic etiologies are rare compared to the other locations. These generally occur due to air traveling through the genital tract into the peritoneum via the uterus and fallopian tubes.¹⁰ Examples include vaginal insufflation by orogenital sex, vaginal douching, postpartum knee-chest exercises, use of bulb aspiration in pelvic exam, tubal insufflation in hysterosalpingogram, pelvic inflammatory disease, and coitus.¹⁰ In the differential of pneumoperitoneum is pseudopneumoperitoneum. This was first described in the 1930s and represents a simulated appearance of free intraperitoneal air.⁶ This is frequently due to adventitial air shadows, over distension of hollow viscera, the basal lung appearing to lie in the diaphragm, gas trapped in wounds, basal pulmonary atelectasis resembling subphrenic air, subdiaphragmatic extraperitoneal fat, and positioning of colonic hepatic flexure between the right lobe of the liver and diaphragm, also known as Chilaiditi sign.⁶ Failure of the air to shift during different positioning or to localize to the most superior aspect of the radiographic imaging should lead to the suspicion of pseudopneumoperitoneum.⁶ Other causes of pneumoperitoneum include scleroderma without pneumatosis cystoides intestinalis, idiopathic, cocaine use, diving and decompression, and dental extraction.

There are many reports of pneumoperitoneum in patients who have mild abdominal pain but no leukocytosis, fever, or peritoneal signs that were treated successfully with conservative management.² When spontaneous pneumoperitoneum is suspected, emergency surgery is not required. A difficult situation arises when the physical examination is unreliable such as in an unresponsive patient on a ventilator or a patient with a depressed immune system causing a delay in the signs and symptoms of peritonitis. In these cases, a diagnostic peritoneal lavage may aid in the decision where to perform surgery or to treat conservatively.⁸ Methylene blue may be instilled via a nasogastric tube to help increase the accuracy of detecting an upper gastrointestinal perforation.⁸ If the lavage is negative and the patient is unremarkable, then continued observation is warranted. Also aiding in the decision for surgery would be to instill water-soluble contrast through a nasogastric tube with a subsequent abdominal film.⁸

CASE REPORT

Here we report a 72 year-old white male who was having thoracic CT surveillance without contrast for evaluation of interstitial lung disease due to his history of scleroderma. Thoracic CT incidentally revealed free air in his abdomen and he was subsequently instructed to seek further evaluation in the emergency department. The patient’s past medical history included rheumatoid arthritis, scleroderma and a previous gastrointestinal bleed with an unclear etiology five years prior to admission. The patient did not have any surgeries or procedures in the last six months.

Upon admission to the emergency department, his blood pressure was 153/76 mm Hg, heart rate 78 bpm, temperature 97.7 oF and an oxygen saturation of 99% on room air. The patient’s physical exam was benign. The initial complete blood count (CBC) and complete metabolic panel (CMP) were within normal limits. While in emergency department, the patient had a chest X-ray demonstrating free air within the abdomen. A CT of the abdomen without contrast confirmed a pneumoperitoneum (Figure 1). The patient was evaluated by both gastroenterology and surgery. Conservative measures of bowel rest along with serial abdominal and x-ray examinations were undertaken which remained stable throughout the admission. Abdominal imaging did not show evidence of pneumatosis cystoides intestinalis. An upper gastrointestinal series was completed and did not demonstrate extravasation of contrast, shown in Figure 2. The patient’s diet was advanced over six ,days; he tolerated this well and was discharged.

Approximately six weeks later, the patient had a follow up abdominal CT with oral contrast. It demonstrated a mild increase in the pneumoperitoneum along with right pleural calcification, which was noted on a previous thoracic CT. He was again instructed to return to the emergency department. Upon arrival to the emergency department his physical exam, vital signs, CBC and CMP were all normal. The patient remained asymptomatic. Another upper gastrointestinal series was done, again demonstrating no obvious extravasation of contrast. He was treated with bowel rest, supplemental oxygen and placed on total parenteral nutrition for several weeks. Cefazolin and metronidazole were started as empiric treatment for a bacterial source of the gas and antibiotics were continued for one week. An abdominal x-ray one week later demonstrated a resolving pneumoperitoneum. A follow up abdominal CT scan two months after being discharged from his second hospital admission demonstrated no free air in the abdomen.

DISCUSSION

Pneumoperitoneum generally occurs in the presence of a visceral perforation with peritoneal signs; however, in some cases where the patient is asymptomatic, the physician should consider causes of spontaneous pneumoperitoneum. In the case above, we reported a spontaneous pneumoperitoneum thought to be due to scleroderma without relation to pneumatosis cystoides intestinalis. After a thorough search of the medical literature only five published case reports are available for review, making this an extremely rare entity.

Once our patient was in the emergency department, a CT of the abdomen was completed which did not demonstrate any evidence of pneumatosis cystoides intestinalis. When attempting to identify pneumatosis intestinalis with computed tomography, it is best to view the bowel wall in the lung window for evidence of air within the gut wall.³ However, there was always a chance that the pneumatosis cystoides intestinalis was below the resolution of the computed tomography in our patient, although this is unlikely.7 It is also possible that there was a microperforation in the stomach that had subsequently healed. As noted above, patients can be minimally symptomatic, if not asymptomatic, with a microperforation of the stomach. It is interesting to note that the patient had a gastrointestinal bleed in the preceding five years with an unclear etiology. The patient had a colonoscopy in the past, but was never evaluated with an esophagogastroduodenoscopy, leaving room for gastric pathology. The patient did have two upper gastrointestinal series and a CT with oral contrast that did not demonstrate extravasation of contrast. However, that does not rule out a perforation but does make it less likely. Since our patient had a history of scleroderma and demonstrated no obvious source of visceral perforation, was asymptomatic and radiographic imagining did not show evidence of pneumatosis cystoides intestinalis, this led us to believe that the pneumoperitoneum was related to scleroderma.

As stated by Rowe et al., determining which patient with a pneumoperitoneum needs to undergo exploratory laparotomy versus those that can be managed conservatively can be challenging. However, Rowe et al. suggests that the laparotomy rate can be decreased to near zero if a thorough history and physical examination is performed and does not suggest perforation. Since our patient was stable a conservative approach was taken with antibiotics, increased fractional inspired oxygen content to 27% and total parenteral nutrition and he responded well. In the other five known cases, one case report performed a laparotomy, another case report performed a peritoneal lavage, and in the remaining case reports, conservative treatment without invasive intervention was the preferred approach. The conservative approach, rather than an unnecessary exploratory laparotomy, saved our patient significant morbidity and he responded well.

Our patient’s pneumoperitoneum resolved in three months. The other cases reported resolution ranging from six months to two years. This is in drastic contrast to those patients who undergo abdominal surgery or have endoscopic procedures, which generally have resolution of the pneumoperitoneum in five days in approximately 97% of cases followed by abdominal radiographs.

In patients with scleroderma associated with spontaneous pneumoperitoneum without evidence of pneumatosis cystoides intestinalis, the pathophysiology of the pneumoperitoneum is still unclear. It could be that pneumatosis cystoides intestinalis in many of these cases are at an undetectable level from radiographic imaging and could be causing a pneumoperitoneum. The cysts have been postulated to form in scleroderma due to gut hypomotility with subsequent bacterial overgrowth. It was for that reason that empiric antibiotics were used in the conservative approach in our patient to reduced bacterial overgrowth and possible cyst formation. It has also been postulated that there are recurrent microperforations in colonic diverticula causing a pneumoperitoneum in scleroderma without evidence to pneumatosis cystoides intestinalis.⁷ The microperforations may arise due to intestinal ischemia due to the vasculitic nature of scleroderm.⁹ It may also be related to the atrophy of the muscularis propria and collagen tissue replacing it, which occurs throughout the gastrointestinal tract in patients with systemic sclerosis.⁴

CONCLUSION

Spontaneous pneumoperitoneum associated with scleroderma without evidence of pneumatosis intestinalis cystoides is an extremely rare presentation. Surgical intervention is not generally needed unless the history and physical suggests perforation. Patents can be treated conservatively with bowel rest and total parenteral nutrition. Patients should also be educated about the prolonged time of resolution of the pneumoperitoneum as well as the likelihood of the recurrence.