Introduction
Tumors of the ampulla of Vater are pathologically and clinically significant ( Box 41.1 ). Because the distal common bile duct and the main pancreatic duct converge at the level of the ampulla, tumors may obstruct two organs, leading to early onset of symptoms. The potential for early detection has improved the prognosis for neoplasms of the ampulla. However, the newer techniques used for local treatment, such as endoscopic polypectomy and transduodenal ampullectomy, have created challenges in the pathologic analysis of ampullary tumors.
Preinvasive neoplasms
Adenomas of ampullary duodenum
Intraampullary papillary-tubular neoplasm
Invasive carcinoma
Intestinal-type adenocarcinoma
Pancreatobiliary-type adenocarcinoma
Mucinous (colloid) carcinoma
Adenosquamous carcinoma
Poorly cohesive carcinoma (with or without signet ring cells)
Clear cell carcinoma
Micropapillary carcinoma
Poorly differentiated adenocarcinoma, not otherwise specified
Undifferentiated carcinoma
Sarcomatoid carcinoma
Carcinosarcoma
Neuroendocrine neoplasms
Well-differentiated neuroendocrine tumor
Not otherwise specified types of gastrinoma
Ampullary somatostatinoma (glandular psammomatous carcinoid)
Poorly differentiated neuroendocrine carcinoma
Small cell carcinoma
Large cell neuroendocrine carcinoma
Gangliocytic paraganglioma
Mesenchymal neoplasms
Tumor-like lesions
Paraduodenal pancreatitis
Adenomyomatous hyperplasia (“adenomyoma”)
Others
Anatomic and Histologic Considerations
In this chapter, the term ampulla refers to the whole ampullary structure, including all four compartments ( Table 41.1 ). The word papilla refers to the pinnacle (edge) of the ampullary prominence (see Figs. 41.1 and 41.3 ). For lesions that arise from or are localized preferentially at the duodenal surface of the ampulla, the term ampullary duodenum is used. Although the term periampullary duodenum has been used in publications to describe this region, it is not used in this chapter to avoid confusion.
| Term | Synonyms Used in This Chapter | Description |
|---|---|---|
| Ampulla of Vater (see Fig. 41.1 ) | Ampulla major | Protuberance in the second portion of the duodenum composed of: (1) duodenal mucosa; (2) papilla of Vater, lined by specialized epithelium; (3) pancreatobiliary-type ductules in sphincter of Oddi musculature, in the wall; (4) distal ends of the common bile and pancreatic ducts |
| Minor ampulla (see Fig. 41.3 ) | Accessory ampulla | Located 2 cm proximal and anterior to the major ampulla, within the duodenum |
| Papilla of Vater (see Figs. 41.1 and 41.3 ) | None | Refers specifically to the protuberance (edge of the pinnacle) of the ampulla, which is lined by specialized epithelium, and the wall, which is composed of pancreatobiliary-type ductules embedded in sphincter of Oddi musculature |
| Ampullary duodenum (see Fig. 41.5 ) | Duodenal surface of ampulla | Duodenum-facing surface of the ampulla, which is mostly lined by intestinal-type epithelium |
| Ampullary duct (see Figs. 41.2 and 41.6 ) | None | Refers to pancreatobiliary-type ductules and peribiliary mucous glands and tributary ductules, as well as the duct epithelium of the very distal segments of the common bile duct and main pancreatic duct |
The anatomy of the ampulla of Vater can vary considerably between individuals, but in most, the common bile duct and the main pancreatic duct join into a common channel within the wall of the duodenum. Flow of luminal material through the ampulla is regulated by dense fascicles of smooth muscle, called the sphincter of Oddi ( Fig. 41.1, A ). The mucosa forms folds called plicae . Although the length of the common channel varies, it is less than 3 mm long in most persons. In some individuals, the common bile duct and main pancreatic duct are separated by a septum. These anatomic variations are difficult to demonstrate in the routine examination of surgical specimens unless dye injection or specimen radiographs are performed.
The minor ampulla is also subject to anatomic variations. It is typically located 2 cm proximal and anterior to the major ampulla within the duodenum ( Fig. 41.2, A ). It can be mistaken for a polyp endoscopically. The dorsal pancreatic duct drains through the minor ampulla. Although this duct normally regresses with fetal maturation, residual duct elements remain in the submucosa of the duodenum in most individuals. The minor ampulla is patent in 40% of the population. Composition of the minor ampulla varies among individuals.
The epithelium of the major and minor ampullae is the small intestinal type on the duodenal surface ( Fig. 41.3 ; see Fig. 41.1 ). At the edge of the ampullae, where the ducts transition to the duodenal surface (i.e., the papilla), a specialized epithelium with features that resemble gastric-foveolar epithelium with scattered goblet cells is usually seen (see Figs. 41.1, B and 41.3, B ). Because of mucinous epithelium, biopsy specimens from this area can be mistaken as representing peptic injury. Pancreatobiliary-type tributary ductules occur in the wall of the ampulla (see Fig. 41.1, B ). These structures are usually embedded in dense myoid tissue of the sphincter of Oddi or duodenal musculature (see Fig. 41.1, B ). The epithelium of the papilla transitions into ductal epithelium. Pancreatic acinar lobules often reside in the wall of the ampulla (see Fig. 41.3, C ). They may contain islets of Langerhans. Clusters of neuroendocrine cells may also occur in the minor ampulla but only seldom in major ampulla.
Classification of Ampullary Tumors
Various criteria to determine whether a particular tumor originates in the ampulla or in the nonampullary duodenum are offered in the literature. Inconsistent use of the term periampullary has further complicated the issue. In some publications, it refers to the ampullary region proper, whereas in others, it is used to describe the nonampullary segment of the duodenum. In the staging section of the protocol for the examination of ampullary tumor specimens published by the College of American Pathologists (CAP), only tumors that are intraampullary (i.e., developing within the cavity) are regarded as truly ampullary in origin, whereas in the tumor classification section, other anatomic subregions (e.g., periampullary duodenal, papilla of Vater) are also recognized as part of the ampulla.
In a more specific definition of the ampulla, tumors are defined as ampullary if more than 75% of the tumor is localized to or engulfed by the ampulla and the preinvasive component (if any) is localized within one of the four compartments of the ampulla. The four subsets of ampullary tumors (i.e., ampullary-NOS, intraampullary papillary-tubular neoplasm associated, ampullary duct, and ampullary duodenum) are classified according to their primary site of growth ( Table 41.2 ; see Figs. 41.2 and 41.4 through 41.6 ):
- 1.
Ampullary carcinomas not otherwise specified (NOS) correspond to the edge of the ampullary orifice (i.e., the papilla of Vater) ( Fig. 41.7 ; see Figs. 41.1, B and 41.3, B ), which is composed of transitional epithelium with gastric-like features and scattered goblet cells and ductules.
FIGURE 41.7
Early-stage ampullary adenocarcinoma arising in the papilla of Vater (i.e., ampullary carcinoma not otherwise specified). This relatively small carcinoma ( arrow ) invades through the sphincter of Oddi into duodenal submucosa. The American Joint Committee on Cancer tumor-node-metastasis classification regards this as a T2 tumor despite its small size and superficial location.
- 2.
Carcinomas associated with intraampullary papillary-tubular neoplasms (IAPNs) involve the distal ends of the common bile duct and pancreatic duct, which are lined by simple cuboidal to columnar epithelium and contain ductules (i.e., accessory or peribiliary mucous glands) and various amounts of muscle.
- 3.
Carcinomas of the ampullary duct involve the wall of the papilla of Vater, which is composed of pancreatobiliary-type ductules and muscles of the sphincter of Oddi complex, which merges with the duodenal musculature (see Fig. 41.1 ).
- 4.
Carcinomas of ampullary duodenum arise from the duodenal surface of the prominence (see Figs. 41.1, A and 41.5 ).
| Subtype of Ampullary Carcinoma | Luminal Findings | Status of Ampullary Orifice | Cut Section Appearance | Findings in Distal Segments of the Common Bile and Pancreatic Ducts |
|---|---|---|---|---|
| Ampullary-NOS (papilla of Vater) | Ulceration and/or polypoid lesion localized in the ampulla | Centrally located | White, firm lesion involving the papilla of Vater | Nondescript tumor involvement of the distal tips |
| Intraampullary papillary-tubular neoplasm associated | Dilated ampullary orifice with protruding polypoid, granular material | Centrally located; dilated orifice, easy to probe | Preinvasive (polypoid or granular), exophytic lesion within ampullary channel and distal segments of the ducts | Filled with papillary, nodular, or granular material; often significantly dilated |
| Ampullary duct | Minimal changes; button-like mucosal-covered elevation or subtle ulceration or minimal granulation | Centrally located; often relatively difficult to probe | Scirrhous, plaquelike, constrictive, and often subtle lesion on the wall of the papilla of Vater and distal segments of the ducts | Scarlike firmness on the walls, often concentric |
| Ampullary duodenum | Prominent ulcerovegetative nodules on the duodenal surface of the ampulla | Eccentrically located; difficult to probe in some cases, especially if invasive | Granular, nodular tumor on the duodenal surface, pushing into the inner structures | Variable secondary destruction by invasion of the duodenal surface lesion |
Preinvasive Neoplasms
Adenomas of the Ampullary Duodenum
Adenomas of the intestinal type, similar to colorectal adenomas, occur in the ampullary duodenum (i.e., duodenal surface of the ampulla). In the small intestine, the ampulla is a particularly common site of adenoma development, presumably because this is an anatomic site that is prone to chemical or physical injury. Most ampullary adenomas are sporadic, but the ampullary and other parts of the duodenum are the most common sites of extracolonic adenomas in patients with familial adenomatous polyposis (FAP). Between 80% and 90% of patients with FAP develop multiple adenomas in the duodenum, and 25% have them in the ampullary duodenum. Symptomatic adenomas are usually detected within 10 to 15 years of colectomy in these patients. Fortunately, because FAP screening protocols include periodic endoscopic surveillance of the duodenum, adenomas are increasingly detected at an earlier stage of development, while they are asymptomatic.
Adenomas of ampullary duodenum often extend into the papilla and distal common bile duct and may involve the ductules in the wall of the papilla. More than 75% of the lesion should be located on the duodenal surface of the ampulla to be classified as an adenoma of the ampullary duodenum. Those with complete or near-complete intrapapillary growth are classified as intraampullary papillary-tubular neoplasms.
Clinical Features
Patients with sporadic adenomas of the ampullary duodenum are an average of 60 years. In contrast, FAP patients are typically 20 years younger at the time of diagnosis. Sporadic cases have a female predilection, whereas both sexes are affected equally by FAP. Clinical symptoms vary. Larger adenomas may cause bile duct obstruction with jaundice, abdominal pain, and pancreatitis. Smaller adenomas are often asymptomatic. Gastrointestinal hemorrhage is rare and raises concerns regarding the existence of an invasive carcinoma.
Histologically, tubular, villous, and tubulovillous adenomas occur with equal frequency in the sporadic cases, but tubular adenomas are more common in patients with FAP. Villous adenomas tend to be larger than tubular or tubulovillous adenomas. The prevalence of carcinoma in adenomas increases proportionately with the size of the polyp, and villous adenomas are more likely to harbor a carcinoma.
Pathologic Features
Grossly, most tubular adenomas of ampullary duodenum are bosselated in appearance, whereas most villous adenomas have a feathery or papillary appearance ( Fig. 41.8 ). Villous adenomas are usually larger than tubular adenomas. Adenomas of the ampullary duodenum are more likely to harbor an invasive carcinoma than similarly sized colorectal adenomas. A firm texture or surface ulceration raises concern about an invasive component. Invasive carcinomas that arise in adenomas are often hidden in the deep creases of the tumor at the base of the polyp and are difficult to detect in surface biopsies.
Microscopically, adenomas of the ampullary duodenum are similar to those that occur in the large intestine. They have complex glands and villi (papillae) lined by mucin-depleted columnar cells with elongated, hyperchromatic, pencil-shaped nuclei and nuclear pseudostratification. The amount of cytoplasmic mucin varies. Goblet cells may be seen, but they typically are not numerous. The appearance of some FAP-related cases may be subtle and may even show surface maturation.
Adenomas are classified as tubular, tubulovillous, or villous, depending on the amount of glandular and papillary architecture. Tubulovillous adenomas contain more than 25% villi, and villous adenomas contain more than 75% villi. Tubular, villous, and tubulovillous adenomas occur with equal frequency in sporadic cases, but tubular adenomas are more common in patients with FAP.
By definition, all adenomas are dysplastic. Dysplasia is categorized as low or high grade, depending on the degree of cytologic and architectural atypia and complexity of the epithelium. Low-grade dysplasia consists of pseudostratified, relatively monotonous columnar cells with cigar-shaped, elongated nuclei. The nuclei are lined up in the basal aspect of the cell cytoplasm, and there is no or only mild pleomorphism and loss of nuclear polarity. High-grade dysplasia is characterized by marked nuclear pleomorphism, loss of cell polarity, increased nucleus-to-cytoplasm ratio, and increased mitoses combined with architectural complexity, such as cribriforming, back-to-back glands, and micropapillae formation.
Paneth cells and neuroendocrine cells are particularly common in all ampullary adenomas, and in some cases, they can form more than 50% of the neoplastic cell population, particularly in FAP cases. Immunohistochemical staining typically reveals evidence of intestinal differentiation, such as positivity for cytokeratin 20 (CK20), CDX2, and MUC2. CK7 is also commonly positive in these tumors. Paneth cells label for lysozyme, and the endocrine cell component can be detected with chromogranin or synaptophysin.
Differential Diagnosis
Extension of adenomatous epithelium into the ductules in the wall of the papilla can simulate invasive carcinoma ( Fig. 41.9 ), particularly where continuity with the normal surface epithelium is lost, and high-grade dysplasia is found. Because of the complexity of these ductular structures, it can be difficult or impossible to distinguish in situ disease from true invasion (see Fig. 41.9 ). Findings such as paradoxical differentiation (i.e., different cytomorphology in the preinvasive and invasive components), cuboidal epithelium, dispersion in a nonlobular and nonorganoid fashion, marked contour irregularities, formation of complex micropapillary tufts or markedly elongated gland units, and severe cytologic atypia favor invasive carcinoma ( Table 41.3 ). Budding and vascular or perineural invasion are helpful findings. However, invasion can be expansile (i.e., nodular or pushing border), not showing the conventional infiltration patterns.
| Findings | Invasive | Noninvasive |
|---|---|---|
| Dispersion of glands | +++ | − |
| Lobularity | − | +++ |
| Clustering of evenly shaped glands | − | +++ |
| Contour irregularities | ++ | − |
| Different cytomorphology from the surface | ++ | − |
| Loss of cell polarity | ++ | ± |
Another diagnostic dilemma arises when an underlying invasive carcinoma of the pancreas or bile duct involves the ampullary epithelium by colonization (“cancerization”) of the mucosal basement membrane, which simulates in situ disease ( Fig. 41.10 ), in a process called pseudoadenomatous transformation . Because carcinomas usually have pancreatobiliary (rather than intestinal) differentiation, immunohistochemical staining may reveal positivity for only CK7 (rather than CK7 and CK20) and for MUC1 (rather than MUC2 and CDX2). Immunohistochemical stains can help to demonstrate that both components have the same immunophenotype.
Reactive changes associated with inflammatory processes of the ampulla can mimic an adenoma ( Fig. 41.11 ). In addition to having associated inflammation, reactive atypia usually lacks the degree of nuclear elongation and pseudostratification of adenomas. Paradoxically, reactive nuclei occasionally show more atypia than low-grade adenomas in the form of enlargement and macronuclei, but the high degree of architectural complexity characteristic of high-grade dysplasia is not usually seen in reactive epithelium. Reactive changes often have a higher degree of cytoplasmic eosinophilia, presumably because of retaining normal organelles instead of forming abnormal mucins compared with adenomas.
Adenomatous lesions that occur within the papilla and distal common bile duct (i.e., IAPNs) are similar in appearance to primary pancreatic and biliary intraductal neoplasms. They have several distinctive characteristics that distinguish them from adenomas of the ampullary duodenum.
Intraampullary Papillary-Tubular Neoplasms
IAPNs are adenomatous (tumoral, intraepithelial, neoplastic) lesions that occur almost exclusively in the ampulla (see Fig. 41.4 ). They represent the intraampullary counterpart of intraductal neoplasms of the pancreas and biliary tract (see Chapters 38 and 40 ). Included in this category of tumors are noninvasive pancreatobiliary neoplasms and intestinal-type adenomas in the ampulla. Papillary or polypoid tumors can fill the ampullary channel and distal segment of the common bile duct or main pancreatic duct (see Fig. 41.4 ). By definition, involvement of the ampullary duodenum and intramucosal extension into the proximal aspect of the common bile duct and main pancreatic duct is minimal (<25%).
Clinical Features
These tumors account for one third of resections performed for a clinical diagnosis of ampullary tumor. The mean age of affected patients is 64 years (range, 27 to 85 years), and the tumors occur predominantly in men (male-to-female ratio of 2.2). Symptoms (e.g., jaundice, pruritus, light stool, dark urine) are usually related to obstruction of the common bile duct, but patients also may have nonspecific symptoms such as abdominal pain and weight loss.
Pathologic Features
Gross examination of the ampullary duodenum typically reveals a hemispheric elevation of intact mucosa, often with a patulous papilla orifice from which nodules of friable granular material protrude into the duodenal lumen (see Fig. 41.4, A ). A probe inserted into the common bile duct or main pancreatic duct typically extends into the center of the lesion. Ulceration may be evident, but overt mucinous discharge, characteristic of pancreatic intraductal neoplasms, is seldom encountered. On sectioning, the tumors are characterized by a prominent exophytic growth pattern in the dilated distal bile and pancreatic ducts (see Fig. 41.4B ). Obstructive polypoid and light tan, granular nodules, which are often associated with dilation of upstream biliary or pancreatic ducts, may be identified (see Fig. 41.4B ). The mean tumor diameter is 2.9 cm.
Microscopically, IAPNs show various degrees of papillary or tubular growth ( Figs. 41.12 through 41.14 ). Most have a mixture of these patterns. They exhibit a spectrum of dysplasia, and most cases show a mixture of low- and high-grade dysplasia. The criteria used for low- and high-grade dysplasia is the same as that used for adenomas of ampullary duodenum (discussed earlier). However, some cases exhibit gastric differentiation (see Fig. 41.14 ) similar to that of intraductal and intracholecystic tumors of the pancreatobiliary tract and foveolar and pyloric adenomas of the stomach. These cases may lack overt cytologic atypia characteristic of intestinal-type adenomas. In most cases, examination reveals foci of high-grade dysplasia. High-grade dysplasia correlates with a papillary configuration. Unlike adenomas of the ampullary duodenum, approximately 50% of IAPNs show mixed (intestinal, gastric, pancreatobiliary) differentiation.
Approximately 75% of IAPNs are associated with invasive carcinoma at the time of diagnosis, but the invasive component is usually less than 1 cm in diameter. Invasion is mostly tubular and often shows a mixture of intestinal ( Fig. 41.15 ) and pancreatobiliary features ( Fig. 41.16 ). The histologic type of invasive carcinoma parallels that of the preinvasive component in many but not all cases.
The hybrid nature of these lesions is reflected in their immunophenotype. More than 50% of cases coexpress CK7 and CK20. Immunostaining for MUC2 and CDX2 is positive in cases with intestinal differentiation. Results for MUC1, MUC5AC, and MUC6 are positive in cases with gastropancreatobiliary differentiation. However, overlaps are common, and a significant proportion of the cases reveal mixed immunophenotype.
Differential Diagnosis
The most challenging aspect of these lesions is to differentiate invasion from pseudoinvasion. The preinvasive component of these lesions often involves the (tributary) ductules in the wall of the ampulla. The criteria for identifying invasion in adenomas of the ampullary duodenum are applicable in this case (see Table 41.3 ).
Differentiating IAPNs from their pancreatic and biliary counterparts or adenomas of the ampullary duodenum requires knowledge of the location and distribution of the neoplastic lesion. A nonintestinal phenotype is helpful in distinguishing these lesions from adenomas of the ampullary duodenum, because examination of the latter invariably reveals intestinal differentiation.
Natural History and Prognosis
Noninvasive cases have an excellent prognosis. However, cases with extensive high-grade dysplasia without invasion have recurred. Long-term follow-up is warranted, even in noninvasive cases.
Cases with invasive carcinoma are associated with better survival than conventional (invasive) ampullary carcinomas unaccompanied by an IAPN (3-year survival of 69% versus 44%). This survival advantage is likely attributable to early detection of invasion but also reflects differences in tumor biology.
Flat Dysplasia
Some ampullary carcinomas arise from flat dysplasia instead of developing from an adenomatous polyp. In rare cases, dysplastic epithelial cells grow along the ducts at the periphery of an invasive carcinoma. Flat dysplasia of the ampulla in the absence of invasive carcinoma is rarely seen, presumably because these lesions do not obstruct the ampulla and are usually asymptomatic.
Invasive Adenocarcinomas
Because of the proximity of anatomic structures in the ampulla, it is often difficult to grossly and microscopically distinguish tumors that arise in the distal common bile duct from those that arise in the duodenum, pancreatic head, or true ampulla. Published data regarding ampullary neoplasms often contain references to periampullary tumors. In some studies, the term periampullary is used to define all tumors located in pancreatoduodenectomy specimens, whereas in others, the term is used for pure ampullary tumors. In other publications, the term periampullary refers only to nonampullary segments of the duodenum.
Classification
The synoptic reporting document of the CAP recognizes three categories of ampullary tumors: periampullary-duodenal, papilla of Vater, and intraampullary. However, the tumor-node-metastasis (TMN) staging protocol of the American Joint Committee on Cancer (AJCC), which is endorsed by the CAP, considers only intraampullary tumors as ampullary in origin. The three categories of tumors recognized by the CAP were further divided into four groups, and ampullary carcinomas are classified as follows.
- I.
Primary ampullary carcinomas ( Table 41.4 ; see Table 41.1 )
- A.
Ampullary carcinomas not otherwise specified (ampullary-NOS) include tumors that are presumed to arise from the papilla of Vater (i.e., the edge of mucosa where the common bile duct and main pancreatic duct merge into the duodenal mucosa) (see Fig. 41.7 ). Almost 50% of cases that occur in the ampulla fall into this category, presumably because this group of tumors includes those that arise in the papilla of Vater and those that cannot be confidently placed into one of the subsequent categories. With improved gross examination skills and careful evaluation, the percentage of cases in this category is expected to decrease significantly.
- B.
Carcinomas associated with IAPNs are characterized by preinvasive nodules located in the ampullary channel (i.e., distal tip of the common bile duct and main pancreatic duct). Gross examination often reveals light tan, friable nodules (see Fig. 41.4 ). From the duodenal perspective, these tumors show a dilated orifice, from which granular material often protrudes into the lumen of the bowel. Probes placed into the common bile duct and pancreatic duct typically exit into the center of the lesion. Microscopic examination often reveals only a small invasive carcinoma, and the prognosis is relatively good, especially if there is no invasive carcinoma or invasion is limited in amount.
- C.
Carcinomas of ampullary ducts are scirrhous lesions that circumferentially constrict the distal end of the common bile duct and pancreatic duct, with preservation of the papilla of Vater and ampullary duodenal mucosa. From the duodenal perspective, these tumors typically show a button-like elevation of mucosa or a small, ulcerating lesion (see Fig. 41.2 ). Microscopically, they often prove to be pancreatobiliary-type carcinomas. Although these tumors are usually less than 2 cm in diameter, they have an aggressive behavior, the worst among the ampullary carcinoma subtypes but significantly better than pancreatic ductal adenocarcinomas.
- D.
Carcinomas of the ampullary duodenum (i.e., periampullary-duodenal tumors) arise from the ampullary duodenum, usually from an adenoma of the ampullary duodenum, forming bulky lesions in which the ampullary orifice is often eccentrically located (see Fig. 41.5 ). They typically have an intestinal (see Fig. 41.15 ) or mucinous-intestinal phenotype. Although they are usually very large and produce lymph node metastases, their behavior is often better than expected.
Table 41.4
Clinicopathologic Features of Ampullary Carcinomas
Feature
AMP-NOS
Intra-AMP
AMP Duct
AMP Duodenum
Site-specific Percentage (%)
55
25
15
5
Baseline Demographics
Mean age
65
64
69
59
Sex (M/F ratio)
1.5
2.2
0.9
1
Clinical Characteristics
Overall tumor size (cm)
2.5
2.9
1.9
4.7
Invasive tumor size (cm)
1.8
1.5
1.7
3.4
Invasive histology (intestinal/nonintestinal ratio)
0.4
1.2
0.06
3
Lymph node metastasis (%)
42
28
41
50
T stage (T1+T2/T3+T4 ratio)
1.6
5.8
0.6
2
Survival Rates
1 year (%)
80
88
80
80
3 year (%)
54
73
41
69
5 year (%)
39
53
29
55 Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
- A.
