Contemporary Surgical Treatment for Management of Cholangiocarcinoma

Abstract

Cholangiocarcinoma is the second most common cause of liver cancer and is often in advanced stages at the time of diagnosis. The disease is classified and treated by anatomic location - distal, perihilar, and intrahepatic. Diagnosis and staging workup consists of laboratory analysis including liver function, bilirubin, and tumor markers, as well as cross sectional imaging and endoscopic evaluation. Early multidisciplinary management between Hepatology, Oncology, and Surgery teams is necessary to optimize outcomes. Currently, only patients with perihilar cholangiocarcinoma are eligible for wait-list prioritization at liver transplant based on the Mayo Clinic criteria. New evidence may support the extension of eligibility for liver transplant to intrahepatic cholangiocarcinoma. As such, expanded transplant exception criteria have been proposed. Continued advances in medical and radiation therapy along with liver transplant promise to increase the treatment options and survival from patients with cholangiocarcinoma.

1. Introduction

Cholangiocarcinoma (CCA) consists of malignant tumors of biliary epithelial origin that can arise from any point in the biliary tree. These tumors are classified as distal, perihilar, and intrahepatic by their anatomic location. Distal CCA (dCCA) accounts for tumors of the common bile duct from the Ampule of Vater to the insertion of the cystic duct. Perihilar CCA (pCCA) occur from the insertion of the cystic duct through the common hepatic duct and the main right and left hepatic ducts. Finally, intrahepatic CCA (iCCA) encompasses the second-order bile ducts and beyond, to the bile ductules within the liver. The histopathology of CCA also depends on the location along the biliary tree and is notoriously difficult to diagnose. Minimal or vague presenting symptoms are also typical, which decreased the frequency of early stage diagnosis. Due to this, most CCAs are diagnosed in late or advanced stages once obstructive symptoms occur, which often limits treatment options and decreases survival. Surgical resection remains the gold standard of treatment for CCA with anatomically favorable tumors in the absence of underlying liver disease; however, liver transplant can be considered for select patients with otherwise unresectable disease. In this chapter, we will discuss the histopathology, epidemiology, risk factors, diagnosis, and staging of CCA. We will focus on the surgical treatment options for CCA, especially the existing and upcoming evidence on the use of liver transplant to treat CCA.

1.1 Histopathology

Histological diagnosis has increased in complexity in recent years and now acknowledges differences in histology based on anatomic location. Overall, CCAs are adenocarcinomas arising from cholangiocytes along the epithelial lining of the biliary tract [1]. Most pCCAs and dCCAs are pure mucin producing adenocarcinoma, while most iCCAs fall into two main groups: pure mucin producing adenocarcinoma or a mixed subtype. Mixed subtype iCCA can arise from hepatocytes or cholangiocytes within the surface epithelium of the bile ducts [1]. iCCA is further classified by tumor growth pattern as mass forming, periductal-infiltrating, and intraductal growing [1, 2]. Mass forming iCCAs often display the mixed type histology and are more likely to be associated with chronic liver disease; whereas, pure mucin producing iCCA can demonstrate any growth pattern and are more commonly associated with primary sclerosing cholangitis (PSC) [1, 2]. More specific classification systems that further breakdown types of CCA do exist; however, they are not yet recognized by national and international staging systems.

1.2 Epidemiology and risk factors

Liver cancer is the third most common cause of death from cancer worldwide [3]. Of liver cancers, CCA is the second most common cause of liver cancer related mortality behind hepatocellular carcinoma, accounting for 15% of deaths [3]. Although CCA is classified as a rare cancer, the incidence is increasing worldwide, especially in East Asia [4]. In the United States, pCCA is the most common type of CCA followed by dCCA and then iCCA [2]. Worldwide, the mortality rate from iCCA has increased to 1–6/100,000 people per year, while mortality for extrahepatic CCA has decreased to less than 1/100,000 people per year [4]. The rising incidence and mortality has prompted an increase in research and development that focus on CCA treatment options, however 5-year survival from CCA remains below 20% [1].

Many of the risk factors associated with CCA are not particularly specific to the disease but more so reflect risk factors of chronic liver and biliary tract inflammation. General risk factors include alcohol use, smoking, obesity, cirrhosis, and viral hepatitis. Conditions associated with biliary stasis promote biliary inflammation, resulting in increased risk. These include choledochal cysts, cholelithiasis, choledocholithiasis, Caroli disease, and primary sclerosing cholangitis (PSC). Infection with liver flukes, predominantly found in Southeast Asia, are also considered to be a major risk factor in pathogenesis. In a recent systematic review, choledochal cysts, cholelithiasis, cirrhosis, hepatitis B, and hepatitis C were found to be the strongest risk factors for CCA worldwide [5]. By subtype, choledocholithiasis and PSC were stronger risk factors for extrahepatic CCA, while choledochal cysts, cirrhosis, and hepatitis B had greatest association with iCCA [5].

2. Diagnosis and staging

2.1 Clinical diagnosis

The presentation of patients with CCA is usually non-specific, and most patients with early-stage disease are asymptomatic. In later stages, patients usually present with vague symptoms such as weight loss, failure to thrive, malaise, and generalized abdominal pain. Large, advanced tumors can result in hepatomegaly or right upper quadrant pain due to stretch of the hepatic capsule. Biliary obstruction and jaundice can also occur and is more common in patients with perihilar and distal CCA, resulting in acholic stool, dark or “coke-colored” urine, early satiety, puritis, and cholangitis. Due to vague early symptoms, patients with CCA are usually diagnosed at later stages or as an incidental finding on workup for other illnesses; however, surveillance imaging in patients with underlying liver disease or PSC may result in earlier diagnosis.

Further investigation with a laboratory workup usually includes a complete blood count, complete metabolic panel with liver function tests and fractionated bilirubin analysis. In patients with CCA, these commonly return with a non-specific profile unless biliary obstruction is present. Based on the degree of weight loss and malaise, electrolytes and albumin abnormalities may be present. Liver function tests in the setting of concomitant liver disease or biliary obstruction may result in elevation of liver enzymes and bilirubin. Tumor markers such as carbohydrate antigen 19–9 (CA 19–9) and carcinoembryonic antigen (CEA) can be elevated in CCA, but show limitations in diagnostic sensitivity; as, CA19–9 becomes elevated in the setting of biliary obstruction. Elevated CA 19–9 at time of diagnosis of CCA has been shown to be a marker of poor prognosis and unresectability [6]. In the setting of biliary obstruction, IgG4 analysis should also be performed to rule out possible IgG4-related cholangiopathy, which can mimic CCA. In many cases, nonspecific symptoms and laboratory findings will prompt further workup with diagnostic imaging. With clinical suspicion for CCA, we recommend early referral to a center offering multidisciplinary hepatobiliary care, including a hepatobiliary surgeon and liver transplant surgeon to optimize opportunity for surgical treatment.

2.2 Diagnostic imaging and staging

Standard diagnostic imaging for CCA includes abdominal ultrasonography (US), Computed Tomography (CT), and Magnetic Resonance Imaging (MRI) including magnetic resonance cholangiopancreatography (MRCP). US is a common initial evaluation of patients with abdominal pain, especially those with biliary symptoms and jaundice. US may aid in diagnosis through evaluation of the liver, gallbladder, and pancreas. Abdominal US can detect bile duct dilation and the degree and site of obstruction with sensitivities of 89% and 94% respectively [6]. In dCCA, dilated intra and extrahepatic ducts with possible duct thickening or a discrete mass can be visible on US [7]. US findings for pCCA may include nonunion of the right and left hepatic ducts and segmental dilation [7]. In iCCA, an intrahepatic mass with irregular margins and abnormal liver echotexture is common [7]. US can also aid in staging through identification of vascular involvement [6].

Abnormal findings on US or laboratory values generally prompts cross-sectional imaging prior to specialist referral. If there is clinical suspicion for cholangiocarcinoma, we recommend contrast-enhanced CT as the next step in diagnosis and surgical planning. Triple phase CT with arterial phase (20–30 second delay post-injection), portal venous phase (60 second delay post-injection) and delayed (>3 minutes post-injection) with thin cuts through the liver, pancreas, and biliary system. A non-contrast phase is often included and can be helpful in identification of obstructing intrabiliary stones. Contrast-enhanced CT is helpful in identifying tumor anatomic location for potential resectability, tumor vascular involvement, biliary obstruction, underlying liver disease, and volumes for a potential future liver remnant (FLR) after surgical resection. On CT, iCCA is seen as a discrete liver lesion or lesions with peripheral rim enhancement on both phases, as well as contrast uptake on arterial phase and washout on venous phase [6]. Findings suggestive of pCCA on CT include left and right intrahepatic biliary ductal dilation with separation, while dCCA is associated with both intra- and extrahepatic ductular dilation, gallbladder, and common bile duct dilation [6]. Although discrete masses may not be present in pCCA or dCCA, bile duct thickening and the level of ductal dilation are suggestive of the anatomic location. Inclusion of the pelvis on CT imaging allows for the identification of peritoneal disease and drop metastases, and for this reason, we recommend inclusion of the pelvis for CT evaluation. For staging purposes, a non-contrast CT Chest is also necessary for patients with CCA. Positron emission tomography with fluorodeoxyglucose (FDG-PET) can also be used for staging purposes in patients with CCA; however, specific assessment standards are not defined. In the absence of PET avidity of the primary lesion, identification of metastatic disease with PET is limited [6].

While CT is useful in evaluation and diagnosis of CCA, MRI-MRCP offers greatest sensitivity in the identification of ductular involvement and tumor spread. We recommend combined imaging with multi-phase contrast enhanced MRI (including arterial, portal venous, and delayed phases), conventional T1 and T2 weighted sequences (including in- and out- of phase sequences), diffusion weighted imaging, and MRCP with 3D reconstructions. With this, detection of intra and extrahepatic lesions reaches almost 100% sensitivity in the assessment of bile duct obstruction [6]. MRCP is especially valuable in staging as it can precisely assess the extent of bile duct involvement, and contrast enhancement discerns vascular involvement and optimized operative planning [6]. A recent prospective study found MRI/MRCP to have a 96% diagnostic accuracy for CCA as opposed to 70% for triple phase CT [8]. Imaging characteristics of CCA on MRCP include bile duct dilation with visible stenosis and irregular thickening of the bile duct with enhancement on T2 weighted images [8].

Endoscopic retrograde cholangiopancreatography (ERCP) is commonly used to further delineate anatomy and pathology through cholangiography as well as collect specimens for tissue diagnosis. Tissue diagnosis can be made using brush cytology, direct cholangioscopic (SpyGlass) biopsy, and endoscopic ultrasound guided fine needle aspiration (FNA). In addition to brushings, FISH analysis should also be obtained to increase diagnostic sensitivity. A recent systematic review of these modalities showed the diagnostic sensitivity of FNA to be the highest at 74% [9]. ERCP can also intervene and place stents if warranted for biliary decompression. Endoscopic Ultrasound (EUS) is also widely used to evaluate lymph node status, local extent of the tumor, and vascular involvement. EUS with FNA can be used to obtain tissue samples from bile ducts and tumors along with suspicious lymph nodes. EUS with FNA is more sensitive in diagnosing pCCA and dCCA than iCCA [6].

For pCCA, it is critical that transperitoneal biopsy be avoided in any patients that might be considered a candidate for liver transplant; as, it is considered an absolute contraindication to transplant due to the risk of peritoneal seeding. This include EUS guided biopsy of the lesion or mass. EUS evaluation and FNA of any enlarged perihilar lymph nodes, on the other hand, is often required in pre-operative and pre-transplant assessment. Lymph node involvement is an absolute contraindication to liver transplant and a relative contraindication to liver resection (depending on location of the node).

Transductular biopsy of the mass with ERCP/EUS is recommended for pCCA and dCCA if possible. For iCCA, tissue biopsy is not needed to confirm diagnosis if imaging and laboratory results are characteristic [1]; however, biopsy and pathologic assessment are useful in prognostic assessment. In all cases, tumor tissue should be sent for next generation sequencing. Genetic mutation burden for CCA is high, and identification of tumor genetic mutations can assist in guiding therapy as targeted agents becomes increasingly available. At our center, we also obtain a liquid tumor biopsy for both mutation identification from circulating tumor DNA and surveillance of tumor response. A staging laparoscopy is also recommended prior to surgical intervention (either resection or transplant).

3. Current and future treatment

As previously discussed, most patients with CCA present with locally advanced or metastatic disease. Surgical resection remains the only treatment for CCA with possible cure. However, less than one third of patients are deemed resectable at time of diagnosis [10]. Even after resection, five-year survival rates remain dismal at 27–37% for dCCA, 11–41% for pCCA, and 22–44% for iCCA [10]. A multidisciplinary approach involving hepatology, medical oncology, radiation oncology, interventional gastroenterology, medical, anesthesiology, surgical oncology, and liver transplant surgery teams is necessary for every patient with CCA, and ideally treatment decisions should be guided by a multidisciplinary tumor board. In addition to resectability status, the team must ensure each patient is not only a candidate for major surgery and potentially chemotherapy but also fully optimized from a medical and nutritional stand-point.

The goal of surgery for all types of CCA is complete R0 microscopically negative resection with negative margins. Each type of CCA has different definitions of resectability and requires a unique surgical approach for resection based on anatomic locations. The decision tree for surgical options in CCA is shown in Figure 1. The following sections will further explore current and evolving treatment based on anatomic location.

Figure 1.

Decision tree for surgical options in the treatment of cholangiocarcinoma. Abbreviations: CHA – Common Hepatic Artery; Chemo – Chemotherapy; Mets – Metastases; PV – Portal Vein; SMA – Superior Mesenteric Artery.

3.1 Distal cholangiocarcinoma

Distal cholangiocarcinoma is the least common of all CCA. Resectability in dCCA is determined by local vascular involvement as well as distant metastasis. Tumor invading into the common hepatic artery, celiac axis, or superior mesenteric artery would qualify as tumor grade 4 and at least Stage 3B. Any distant metastatic disease would place it in Stage 4 and would make the disease unresectable [11]. According to the National Comprehensive Cancer Network (NCCN) guidelines, treatment would then include biliary drainage if obstruction is present, systemic chemotherapy with or without radiation, surgery, clinical trials, and palliative supportive care [12]. For unresectable disease, first line chemotherapy usually includes Durvalumab or Pembrolizumab with gemcitabine and cisplatin [12]. For resectable dCCA, upfront surgical resection with pancreaticoduodenectomy is recommended [2, 12], and neoadjuvant chemotherapy is generally reserved for patients with borderline resectable disease at presentation. After surgery, adjuvant therapy is guided by the pathologic findings. For example, if RO resection and negative lymph nodes are found then close observation is warranted [12]. If there are positive margins, aggressive pathologic characteristics, or positive lymph nodes, then adjuvant chemotherapy with Capecitabine is recommended [2, 12, 13]. Liver transplantation is not an option for patients with dCCA.

3.2 Perihilar cholangiocarcinoma

One third of patients with pCCA are resectable at presentation, however only 50% of those patients will actually be candidates for resection after staging laparoscopy due to identification of peritoneal implants [10]. Unresectability in pCCA includes tumor invasion of the main portal vein, common hepatic artery or their respective right and left branches bilaterally [11]. It also includes invasion of the second order bile ducts with involvement of the opposite side portal vein or hepatic artery [11]. Surgical resection involves the resection of the involved hepatic lobe with cholecystectomy, bile duct reconstruction, and porta hepatis lymphadenectomy [4]. Pancreaticoduodenectomy may be necessary depending on the extent of common bile duct involvement. For a resection candidate, an R0 resection is the goal, but major hepatectomy with biliary reconstruction is necessary due to the location of the tumor in the hilum. Tumor may also infiltrate microscopically beyond the visible extent of disease. In addition, the FLR must be adequate so as to not cause hepatic insufficiency after resection, which precludes patients with underlying liver disease from consideration. If the FLR is small, portal vein embolization can be done to increase the remnant size and function prior to surgery [4]. Use of neoadjuvant therapy prior to resection varies by center protocols and may be limited to patients with borderline resectability. Adjuvant chemotherapy with Capecitabine is recommended [2, 12].

Due to the potential for unresectability based on local extent or underlying liver disease, liver transplant has been explored as a surgical alternative given the increased likelihood of achieving wide negative margins. Patient selection is key, as early outcomes in patients with extensive disease were poor. The Mayo Protocol, first published in 2000, showed favorable disease-free survival and overall survival in transplant patients with small, early unresectable pCCA after neoadjuvant chemoradiation [14]. Selection for transplant requires diagnosis via positive brush cytology or intraductular biopsy for CCA, a CA 19–9 level over 100 U/mL with radiological diagnosis of malignant bile duct stricture in the absence of cholangitis, tumor extent above the cystic duct, and/or unresectability based on underlying liver disease, such as PSC [14]. In these patients, the protocol included upfront external beam radiation combined with brachytherapy and 5-fluorouracil (5-FU), with capecitabine maintenance until liver transplant [14]. Tumors less than 3 cm in radial diameter without intrahepatic, lymph node, or distant metastatic disease were considered. In this initial study, a 92% disease free survival rate at 12 months with acceptable tolerance of the chemoradiation regimen was reported [14]. Multicenter follow-up demonstrated an 82% five-year survival, and recurrence free and overall survival that exceeds that of liver resection [15, 16]. These outcomes ultimately resulted in approval of a Model of End-Stage Liver Disease (MELD) exception policy for patients with unresectable pCCA after neoadjuvant therapy by United Network of Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) [17]. Currently, patients with unresectable pCCA who remain within selection criteria following completion of neoadjuvant chemoradiation qualify for liver transplantation listing with MELD exception [17]. Each transplant center’s selection criteria must be approved by UNOS for a center to consider these patients, protocol requirements include:

1. Unresectable tumor based on location or presence of underlying liver disease.

2. Diagnosis of pCCA with malignant appearing stricture on cholangiography, positive biopsy or brush cytology, CA 19–9 greater than 100 U/mL (two of three criteria required).

3. If a mass is present then it must be less than 3 cm in radial diameter.

4. No intra or extrahepatic metastatic disease.

5. No regional lymphadenopathy or peritoneal metastasis on staging laparoscopy/laparotomy after neoadjuvant completion.

6. No history of transperitoneal aspiration or biopsy of primary tumor due to elevated risk of tumor seeding.

Since this time, NCCN guidelines and treatment protocols consider liver transplant with neoadjuvant chemoradiation as a standard treatment for select patients with unresectable pCCA in the United States [12]. Despite adoption of these guidelines as practice standards in the United States, international acceptance of similar protocols has been limited. In 2022, a multicenter international benchmark study further investigated the outcomes between patients with pCCA qualifying for transplant compared with those who underwent resection [18]. They confirmed that among 17 international high-volume centers, patients with pCCA undergoing liver transplant had five-year overall survival of 56.3% compared with 39.9% in matched resection recipients (p = 0.07). Five-year recurrence-free survival was 50.2% following transplant, which was significantly better than 17.4% following resection. The overall benefit of transplant persisted in patients without underlying PSC [18]. Based on this, the authors encouraged international adaptation of liver transplant protocols for pCCA.

For patients with larger, unresectable pCCA or with regional or distant metastasis, liver transplant is not an option due to high risk of recurrent disease. Only chemoradiation, clinical trials, and supportive care are recommended [12]. Unfortunately for these patients, short term survival remains dismal even with treatment, although outcomes with medical management have improved with the advent of immunotherapy and targeted treatments. At present, down-staging is not considered in transplant protocols for patient with pCCA; however, the increased tumor response rate have been observed with recent medical therapeutic advances. In the future, reassessment of outcomes for patients with an excellent response to treatment may be warranted.

3.3 Intrahepatic cholangiocarcinoma

The incidence of iCCA has increased significantly worldwide [4]. Hepatic resection with regional lymphadenectomy to achieve negative margins is the goal of curative surgery for iCCA [12, 19]; however, less than 40% of patients with iCCA are resectable at diagnosis and five-year overall survival after resection remains low at 42% [20]. Unresectable disease includes multifocality, lymph node metastasis beyond the porta hepatis, and distant metastasis [11]. Standard treatment for locally unresectable disease includes systemic chemotherapy and/or radiation, clinical trials, and local therapy including ablation and arterially directed therapy [12].

Historically, iCCA has been considered a relative contraindication of liver transplantation due to a high instance of recurrence. Given the success of liver transplant for unresectable pCCA, increasing investigations have re-evaluated the use of transplant for unresectable iCCA. In 2004, a large retrospective study from Spain found an overall survival rate of 42% at five years for patients with unresectable iCCA after liver transplant [21]. Most included patients were only appropriately diagnosed with iCCA after explant analysis. Subsequently, a large multicenter study was conducted in Spain to further analyze outcomes of incidental or misdiagnosed tumors in patients transplanted for cirrhosis. While overall five-year survival was only 45% in these patients [22], subgroup analysis demonstrated that patients with “very early” iCCA (≤ 2 cm) had superior five-year survival of 71% after liver transplant. To build on these findings, the same group conducted a larger retrospective international multicenter cohort study on patients with incidental or misdiagnosed iCCA found on the explants following transplant for HCC or cirrhosis [23]. The cohort was similarly divided into very early iCCA (≤ 2 cm) and advanced iCCA (>2 cm or multifocal). Risk of recurrence at five years was 18% in the very early group compared to 61% in the advanced group. Five-year overall survival was similarly improved at 65% in the very early group versus 45% in the advanced group.

While outcomes for liver transplant with small, solitary iCCA in a background of cirrhosis showed promise, the strict inclusion criteria severely limits patients who might benefit from implementation of such a protocol. A multi-center cohort of French Transplant centers subsequently performed retrospective analysis of patients with incidentally diagnosed iCCA or mixed iCCA/HCC after liver transplant for patients with a cumulative tumor diameter of 2–5 cm compared to liver resection [24]. Liver transplant recipients with tumors >2 cm but ≤5 cm had 5-year recurrence of 21% compared with 48% for liver resection, and 5-year recurrence free survival was 75% for liver transplant compared with 36% for liver resection. Furthermore, on multivariate assessment, liver transplant was protective against recurrence (HR 0.23, 95% CI 0.07–0.82, p = 0.02), while independent predictors of recurrence included diameter of the largest nodule (HR 1.10, 95% CI 1.02–1.73, p = 0.007) and differentiation (HR 4.16, 95% CI 1.37–12.66, p = 0.01). Overall survival for liver transplant recipients with tumors 2-5 cm was 65% at 5 years. While this series only included 49 patients undergoing liver transplant, acceptable survival outcomes may be achieved with expansion of size restrictions beyond 2 cm. These results also supported the need for prospective trials to better assess the candidacy of patients with early iCCA and cirrhosis for transplantation. Support for consideration for transplant candidacy in patients with small iCCA on a background of cirrhosis has subsequently grown, and MELD exception for patients with iCCA ≤3 cm in the setting of underlying cirrhosis has recently been proposed by UNOS/OPTN [25].

While support for transplant for early iCCA in the setting of cirrhosis has increased, limited data was available regarding the efficacy of liver transplant for larger, unresectable, liver-limited iCCA in the absence of underlying liver disease. In 2018, a small prospective case series was conducted by Houston Methodist Hospital and MD Anderson Cancer Center on liver transplant for locally advanced, unresectable iCCA after gemcitabine based neoadjuvant chemotherapy [26]. Under this protocol, six months disease stability or response to therapy rather than tumor size were used as patient selection criteria for transplant. Although only six patients received transplantation, the overall survival was 83.3% with 50% recurrence free survival at five years. Continuing this protocol, this group subsequently reported a follow-up series of 18 patients receiving liver transplant [27]. Overall survival was 57% at five-years survival with 38% disease recurrence, with multifocality increasing the risk of recurrent disease. In intent to treat analysis, qualifying patients that did not receive transplant had 100% mortality at two years. Although these protocols provide insight and possible favorable outcomes of liver transplant for patients with iCCA, additional prospective data is needed to support this indication. At this time, liver transplant for larger iCCA remains restricted to research protocols, but consideration for referral to a transplant center evaluating such protocols should be considered.

4. Conclusion

CCA remains a rare and deadly disease. However, the incidence of liver disease and liver cancer including CCA are increasing worldwide. Managing risk factors and comorbidities is an important step to decrease the disease presence but once CCA is diagnosed survival is poor. Medical and surgical advances are attempting to combat this deadly disease with improved early diagnosis as well as more effective chemotherapy, chemoradiation, localized therapies, and surgical intervention. Although surgical resection remains the gold standard in treatment for all types of CCA, liver transplantation offers a promising avenue for select patient with either pCCA or iCCA. Additional developments in neoadjuvant chemoradiation may beneficially impact future surgical outcomes in resection and transplantation.

Conflict of interest

The authors declare no conflict of interest.

Notes/thanks/other declarations

“The views and information presented are those of the authors and do not represent the official position of the U.S. Army Medical Center of Excellence, the U.S. Army Training and Doctrine Command, or the Departments of Army, Department of Defense, or U.S. Government.”