An Update on the Diagnosis, Grading, and Staging of Appendiceal Mucinous Neoplasms.

REVIEW ARTICLE

An Update on the Diagnosis, Grading, and Staging of Appendiceal Mucinous Neoplasms Mark A. Valasek, MD, PhD* and Reetesh K. Pai, MD†

Abstract: Despite advances in our understanding of appendiceal mucinous neoplasms and their relationship to the pseudomyxoma peritonei syndrome, the classification of mucinous tumors of the appendix is still confusing. This review will provide an update on the various classification systems that have been recently proposed for appendiceal mucinous neoplasia, with a particular emphasis on how to handle and report the histologic findings for these tumors using the newly published Peritoneal Surface Oncology Group International (PSOGI) and American Joint Committee on Cancer (AJCC) eighth edition guidelines. A simplified approach to diagnostic reporting of appendiceal mucinous neoplasms based on the 3-tier AJCC grading scheme is detailed and specific criteria for assessing grade in appendiceal mucinous neoplasia will be outlined. In addition, histologic mimics of appendiceal mucinous neoplasia and how to distinguish these mimics from mucinous neoplasia will be discussed. Finally, despite improvements in diagnostic terminology, significant challenges in classifying appendiceal mucinous neoplasia persist and diagnostic strategies will be detailed to assist practicing pathologists in these challenging scenarios. Key Words: appendix, mucinous neoplasm, mucinous adenocarcinoma, pseudomyxoma peritonei, low-grade appendiceal mucinous neoplasm, LAMN, signet ring cell carcinoma, mucinous carcinoma peritonei

(Adv Anat Pathol 2017;00:000–000)

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espite advances in our understanding of appendiceal mucinous neoplasms and their relationship to the pseudomyxoma peritonei syndrome, the classification of mucinous tumors of the appendix is still confusing. Most cases of classic pseudomyxoma peritonei, a clinical entity characterized by grossly evident, diffuse, intra-abdominal mucinous ascites involving the peritoneal surfaces, develop as a result of a mucinous neoplasm arising in the appendix.1–5 Several studies have demonstrated that appendiceal mucinous neoplasms exhibit a wide spectrum of clinical behavior, ranging from neoplasms which are relatively slow-growing but with considerable risk for recurrence and eventual death and those neoplasms that are highly aggressive with increased likelihood of early death.6–11 In an attempt to simplify the diagnostic terminology of appendiceal mucinous neoplasms, the fourth edition of the World Health Organization (WHO) Classification of Tumors of the Digestive System differentiated low-grade from high-grade disease. The WHO identifies morphologic

characteristics (architecture, cytology, presence of signet ring cells, and mitotic activity) that can be used to classify low-grade and high-grade tumors.12 Despite the simplified WHO classification, the Peritoneal Surface Oncology Group International (PSOGI) recognized a persistent lack of uniform diagnostic terminology in appendiceal mucinous neoplasia. An international working group of surgical pathologists, surgical oncologists, and medical oncologists convened by PSOGI adopted a consensus on diagnostic terminology for appendiceal mucinous neoplasia that expands on current WHO diagnostic terminology.13 Finally, the eighth edition of the American Joint Committee on Cancer (AJCC) Staging Manual now uses a 3-tiered approach (low-grade tumors are classified as grade G1, but high-grade tumors are classified as grade G2 or grade G3).14 The AJCC system also uses the descriptive terminology well-differentiated, moderately, and poorly differentiated in parallel with the alphanumeric grades (G1, G2, G3, respectively). These descriptive terms are widely used to grade other gastrointestinal cancers but can be particularly confusing and difficult to apply directly to mucinous tumors of the appendix. In addition, the AJCC eighth edition initiated significant changes to the staging of appendiceal mucinous neoplasia, particularly for low-grade tumors. This review will attempt to provide pathologists with up-to-date knowledge of the various classification systems that have been recently proposed for appendiceal mucinous neoplasia, with a particular emphasis on how to handle and report the histologic findings for these tumors using the newly published PSOGI and AJCC eighth edition guidelines. A simplified approach to diagnostic reporting of appendiceal mucinous neoplasms is detailed and specific criteria for assessing grade in appendiceal mucinous neoplasia will be outlined. In addition, histologic mimics of appendiceal mucinous neoplasia and how to distinguish these mimics from appendiceal mucinous neoplasia will be discussed. Finally, despite improvements in diagnostic terminology, significant challenges in classifying appendiceal mucinous neoplasia persist and diagnostic strategies will be detailed to assist practicing pathologists in these challenging scenarios.

LOW-GRADE APPENDICEAL MUCINOUS NEOPLASM Diagnostic Criteria

From the *Department of Pathology, University of California, San Diego, CA; and †Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA. The authors have no funding or conflicts of interest to disclose. Reprints: Reetesh K. Pai, MD, Department of Pathology, Presbyterian Hospital, University of Pittsburgh, 200 Lothrop Street, Room A-610, Pittsburgh, PA 15213 (e-mail: [email protected]). All figures can be viewed online in color at www.anatomicpathology.com. Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved.

In 2012, the PSOGI recognized a persistent lack of uniform terminology used by practicing pathologists throughout the world for appendiceal mucinous neoplasms. This persistent lack of uniform terminology hinders the development of a unified and coherent approach to the diagnosis and clinical management of mucinous neoplasms of the appendix. Led by Dr Norman Carr, a working group of 71 participants including surgical pathologists, surgical

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TABLE 1. Diagnostic Terminology for Appendiceal Mucinous Neoplasia Based on the PSOGI Consensus and AJCC Eighth Edition

Diagnostic Terminology

Histologic Criteria

Serrated polyp with or without dysplasia

Serrated crypt profiles confined to the mucosa with intact muscularis mucosae. When present, dysplasia can be classified as low grade or high grade LAMN Mucinous neoplasm with low-grade cytology and any of the following Loss of the lamina propria and muscularis mucosae Fibrosis of the submucosa “Pushing” diverticulum-like growth into the wall Dissection of acellular mucin in the wall Mucin and/or neoplastic cells outside of the appendix HAMN Mucinous neoplasm with high-grade cytology present (at least focally) and lacking infiltrative invasion Mucinous Mucinous neoplasm with infiltrative adenocarcinoma invasion. Patterns of infiltrative invasion include (1) Infiltrative glands, incomplete glands, or single infiltrative tumor cells associated with extracellular mucin and desmoplastic stroma (2) “Small cellular mucin pool” pattern characterized by small dissecting pools of mucin containing floating nests, glands, or single neoplastic cells Grade assessment is based on AJCC criteria (Table 2) Mucinous adenocarcinoma Mucinous neoplasm with a signet ring with signet ring cells cell component accounting for ≤ 50% of the tumor cells Mucinous signet ring cell Mucinous neoplasm with a signet ring carcinoma cell component accounting for > 50% of the tumor cells AJCC indicates American Joint Committee on Cancer; HAMN, highgrade appendiceal mucinous neoplasm; LAMN, low-grade appendiceal mucinous neoplasm; PSOGI, Peritoneal Surface Oncology Group International.

oncologists, and medical oncologists was convened to develop consensus diagnostic terminology for appendiceal mucinous neoplasia and the findings were published in 2016.13 The PSOGI diagnostic terminology and criteria represents an improvement on the classification of primary appendiceal neoplasia outlined in the WHO classification of tumors of the gastrointestinal tract by Carr and Sobin,12 and the PSOGI diagnostic terminology for primary mucinous neoplasms should be used in diagnostic pathology reporting. The PSOGI defined low-grade appendiceal mucinous neoplasms (LAMN) as a mucinous neoplasm with lowgrade cytology and any of the following: loss of the lamina propria and muscularis mucosae, fibrosis of the submucosa, a “pushing” pattern of growth into the wall imparting an expansile or diverticulum-like growth, dissection of acellular mucin into the wall, or mucin and/or neoplastic mucinous epithelium outside the wall of the appendix (Table 1).


The neoplastic epithelium typically exhibits circumferential involvement of the mucosa by a mucin-rich epithelium in at least 1 segment of the appendix or may be diffusely present throughout the appendix (Fig. 1). By definition, the neoplastic epithelium is low grade; the cells typically have abundant cytoplasmic mucin and basally oriented small, uniform and “pencillate” nuclei that maintain nuclear polarity and have inconspicuous nucleoli (Fig. 2). Occasional mitoses can be seen but prominent mitotic activity is not typical. The neoplastic mucinous epithelium may be arranged in uniform slender villi or demonstrate an undulating appearance (Fig. 2). Some neoplasms have a dilated, patent appendiceal lumen with a flat mucinous epithelial lining (Fig. 2). Full-thickness nuclear stratification and complex cribriform or papillary architecture is not seen. The AJCC eighth edition indicates that LAMN should be assigned to the well-differentiated (G1) grade category (Table 2). Importantly, use of the term mucinous adenoma or mucinous cystadenoma was not supported by the PSOGI participants. The reason for this is that the term mucinous adenoma implies no potential for peritoneal dissemination which is not true of LAMN. Instead, the use of the term adenoma should only be reserved for lesions that resemble conventional colorectal adenomas (described below). Similarly, a diagnosis of mucocele is discouraged as this term is a gross or macroscopic description referring to a dilated and mucin-filled appendix and not a histopathologic diagnosis. In almost all cases of LAMN, there is loss of the normal mucosal architecture of the appendix, at least focally, with loss of the lamina and muscularis mucosa with lymphoid follicle atrophy associated with fibrosis of the submucosa (Figs. 1, 2). In some cases, the muscularis propria can also exhibit extensive fibrosis. Dystrophic calcifications or ossification may also be seen within the wall. Intramural glandular epithelium protruding into the muscular wall and exhibiting a rounded, “pushing” border is commonly seen and imparts a diverticulum-like growth (Fig. 3). This “pushing” pattern of growth does not represent true invasion and should not be considered as evidence of mucinous adenocarcinoma. LAMNs lack infiltrative invasion that characterize mucinous adenocarcinoma. Diverticula may be associated with extruded acellular mucin within the appendiceal wall or on the visceral peritoneal surface (Fig. 3). However, numerous cellular dissecting mucin pools within the appendiceal wall are not allowed in LAMNs and should prompt consideration for a diagnosis of mucinous adenocarcinoma. A subset of LAMNs demonstrates mucinous deposits on the visceral peritoneal surface and assessment for the presence of mucinous deposits on the visceral peritoneal surface is necessary for assessment of risk of recurrent disease (Fig. 4). On gross evaluation, most appendices involved by a mucinous neoplasm demonstrate dilatation of the appendiceal lumen as a result of abnormal accumulation of mucin within the lumen. The gross and macroscopic examination of these neoplasms should include the location of the tumor within the appendix (tip vs. body vs. base), the distance of tumor from proximal resection margin, the presence or absence of grossly identifiable mucin deposits on the serosal surface or in the wall of the appendix, the presence or absence of perforation, and the presence of any solid areas. The entire appendix should be submitted for histologic examination with the margin of resection separately designated.

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Update on Appendiceal Mucinous Neoplasms

FIGURE 1. A, Low-grade appendiceal mucinous neoplasm (LAMN) demonstrate circumferential involvement of the appendix by a mucin-rich epithelium (×10). B, LAMNs characteristically are associated with loss of the lamina propria and muscularis mucosae and fibrosis of the submucosa and muscularis propria. In this case, the neoplastic mucinous epithelium sits directly on the fibrotic appendiceal wall without intervening lamina propria, muscularis mucosa, or submucosa (×40). C, LAMNs frequently demonstrate a “pushing” pattern of growth into the fibrotic wall. This should not be considered as evidence of infiltrative invasion (×100).

Histologic Mimics of Low-grade Appendiceal Mucinous Neoplasm Serrated Polyp Appendiceal serrated polyps morphologically resemble their colorectal counterparts. However, serrated polyps of the appendix that resemble hyperplastic polyps and sessile serrated adenomas often harbor KRAS mutations and infrequently display BRAF mutations indicating the serrated pathway in the appendix is likely different from the serrated pathway in the colon/rectum.15 Given the differences in molecular alterations, the PSOGI recommended the use of a “neutral” descriptive diagnosis of serrated polyp with a comment on the presence or absence of dysplasia13 (Table 1). Serrated polyps of the appendix can be distinguished from LAMN by the preservation of the mucosal architecture (Table 1). In contrast to LAMN which results in loss of lamina propria and muscularis mucosae as well as mural fibrosis, serrated polyps retain the normal architecture of the appendix and have an intact muscularis mucosae and lamina propria (Fig. 5). Dissection of mucin into the wall of the appendix and intramural glandular epithelium protruding into the muscular wall is usually not

seen in serrated polyps and, if present, should prompt consideration for LAMN. Serrated polyps without cytologic dysplasia may be either a discrete area (∼30% of cases) or circumferentially involve the appendiceal mucosa (∼70% of cases).15 Serrated luminal architecture similar to that seen in hyperplastic polyps and sessile serrated adenomas of the colon is identified. These polyps are incidentally identified in appendectomy specimens or in right hemicolectomy specimens performed for other clinical reasons. Once removed by appendectomy, serrated polyps without cytologic dysplasia have no risk of progression to invasive adenocarcinoma or disseminated peritoneal disease.15 Serrated polyps with cytologic dysplasia often result in gross dilatation of the appendix and circumferentially involve the appendiceal mucosa. Serrated luminal architecture similar to that seen in sessile serrated adenomas or traditional serrated adenomas of the colon is identified.15,16 These polyps may be associated with invasive adenocarcinoma which can exhibit a nonmucinous histology.16 If a serrated polyp with cytologic dysplasia is identified, the entire appendix should be submitted for histologic review to evaluate for invasive adenocarcinoma. If invasive adenocarcinoma is excluded and the margin of resection is

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FIGURE 2. Low-grade appendiceal mucinous neoplasm (LAMN) is defined by low-grade neoplastic mucinous epithelium. The cells have abundant cytoplasmic mucin and basally oriented small, uniform, and “pencillate” nuclei that maintain nuclear polarity and have inconspicuous nucleoli. The neoplastic mucinous epithelium may have a villous (A, ×100), undulating (B, ×100), or flattened (C, ×100) architectural arrangement. Please see this image in color online.

uninvolved, then no further therapy is required and there is no risk for disseminated disease.

Adenoma Resembling Conventional Colorectal Adenoma Rarely, an adenoma of the appendix will be nonmucinous and histologically resemble conventional tubular/ TABLE 2. AJCC Eighth Edition Grading of Appendiceal Mucinous Neoplasia

AJCC Eighth Edition Grade

Synonym

G1, welldifferentiated G2, moderately differentiated

Low-grade

G3, poorly differentiated

High-grade with signet ring cells

High-grade

tubulovillous/villous adenomas of the colorectum (Fig. 5). Adenomas resembling conventional colorectal adenomas involving the appendix can be distinguished from LAMN by the lack of abundant cytoplasmic mucinous and the relative preservation of the mucosal architecture. These adenomas may be associated with invasive adenocarcinoma which can exhibit a nonmucinous histology. If a tubular/tubulovillous/ villous adenoma of the appendix is identified, the entire appendix should be submitted for histologic review to evaluate for invasive adenocarcinoma. If invasive adenocarcinoma is excluded and the margin of resection is uninvolved, then no further therapy is required.

Histologic Criteria Low-grade cytology and no infiltrative invasion High-grade cytology without signet ring cells typically with infiltrative invasion High-grade cytology with signet ring cells and infiltrative invasion

AJCC indicates American Joint Committee on Cancer.

Ruptured Appendiceal Diverticula

Appendiceal diverticula can be seen in ∼3% of appendectomies performed for a clinical diagnosis of acute appendicitis.17 Appendiceal diverticula have a high rate of perforation compared with acute appendicitis with 1 study identifying a perforation rate of ∼30%.17 Ruptured appendiceal diverticula are one of the most common mimics of LAMN. Hsu et al18 reported 11 cases of ruptured appendiceal diverticula some of which were initially misdiagnosed as appendiceal mucinous neoplasms. Ruptured diverticula are characterized by herniation of the appendiceal mucosa


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FIGURE 3. A, Low-grade appendiceal mucinous neoplasms (LAMNs) frequently demonstrate a “pushing” pattern of growth into the wall imparting an expansile or diverticulum-like growth (×20). B, This “pushing” pattern of growth can result in rupture and mucinous deposits on the visceral peritoneal surface and place a patient at risk for diffuse peritoneal dissemination (×10). Please see this image in color online.

through the muscularis propria and can be multifocal within the appendix (Fig. 5). Continuity between the diverticula and appendiceal lumen is not always seen on the initial sections of the appendix which can complicate the diagnosis. However, additional level sections and entire submission of the appendix can help in establishing the diagnosis of diverticula. As they can be multiple, background intact diverticula can also be helpful in establishing the diagnosis. Mucin deposits within the subserosa, mesoappendix, and on the visceral peritoneal surface are typically seen in ruptured diverticula and this finding often raises concern for LAMN. Rarely, non-neoplastic appendiceal epithelium can be seen within the mucinous deposits. In addition, Hsu and colleagues also described 2 cases with “eversion” of the diverticular lining onto the serosal surface. In contrast to LAMN, ruptured diverticula contain appendiceal mucosa with predominantly nonmucinous appendiceal epithelium invested by preserved lamina propria (Fig. 5). Lamina propria associated with diverticula can also exhibit a nodular neural-like proliferation which is another characteristic feature of that can help distinguish diverticula from LAMN. None of the 9 patients with available clinical outcome reported by Hsu and colleagues developed evidence of mucinous neoplasia with a mean follow-up of 23 months. Although appendiceal diverticula are an important nonneoplastic mimic of LAMN, it is important to note that diverticulum-like growth is a common feature of LAMN8,9,19 (Fig. 3). When entertaining a diagnosis of ruptured diverticula, it is prudent to entirely submit the appendix to evaluate for the possibility of neoplastic mucinous epithelium indicative of LAMN.

Endometriosis With Mucinous Metaplasia Endometriosis is a common disease and can involve the gastrointestinal tract in between ∼5% to 40% of cases.20 The most frequent location is the sigmoid colon followed by the rectum, ileum, appendix, and cecum.20 Endometriosis involving the appendix is typically not a challenging diagnosis and is easy to recognize. However, in 13% of cases of appendiceal endometriosis, intestinal metaplasia is seen and can mimic a LAMN.21,22 Misdraji et al22 and Vyas et al21 described cases of appendiceal and cecal endometriosis that resulted in obliteration of the appendiceal lumen and were

associated extracellular mucin in the mesoappendix or serosal surface.21,22 Hybrid glands containing intestinal goblet-like mucinous cells admixed endometrial-type glands are seen (Fig. 5). Typically, these glands are invested by endometrial stroma. However, some endometriotic foci with intestinal metaplasia lacked endometrial-type stroma. In all cases, areas of conventional endometriosis were seen. Immunohistochemistry for markers of endometriosis such as estrogen receptor (Fig. 5), progesterone receptor, and CD10 can aid in the diagnosis. CDX2 and cytokeratin 20 will be positive in the areas of intestinal metaplasia (Fig. 5). Although endometriosis with intestinal metaplasia is a non-neoplastic mimic of LAMN, Pai et al8 described the cooccurrence of endometriosis with appendiceal mucinous neoplasia in 5% of cases of LAMN. Thus, the presence of endometriosis does not entirely exclude the possibility of LAMN and careful evaluation for neoplastic mucinous epithelium involving the appendiceal lumen is necessary.

Mucosal Hyperplasia in the Setting of Acute Appendicitis Mucosal hyperplasia can be seen as a reactive process in the setting of acute appendicitis and sometimes in association with diverticular disease (Fig. 5). The hyperplastic mucosa is characterized by serrated crypt profiles and crypt disarray and tends to be more pronounced toward the luminal aspect of the mucosa. Mucosal hyperplasia is present in areas of intense inflammation and not prominent in areas lacking inflammation. In contrast to LAMN, the mucosal architecture is preserved and dissection of mucin into the wall of the appendix and intramural glandular epithelium protruding into the muscular wall is not seen.

Staging of Low-grade Appendiceal Mucinous Neoplasm The AJCC seventh edition staging manual was not entirely clear how to apply staging criteria in LAMN. Given this uncertainty, many pathologists either did not provide a stage for LAMN or attempted to fit LAMN staging using the criteria described for infiltrating carcinoma. However, there are a number of challenges unique to LAMN that do


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FIGURE 4. A, Some low-grade appendiceal mucinous neoplasms (LAMNs) are associated with acellular mucinous deposits on the visceral peritoneal surface without evidence of a “pushing” pattern of growth of the epithelium into the appendiceal wall (×20). B, True mucinous deposits of the appendiceal serosal surface are associated with a granulation tissue-like response and/or neovascularization where numerous small capillaries containing luminal red blood cells are seen coursing through the mucin. Mesothelial hyperplasia is also common and it is important not to mistake mesothelial cells for neoplastic mucinous epithelial cells within the mucinous deposits (×100). C, The presence of neoplastic mucinous epithelium within the mucinous deposits on the visceral peritoneal surface is important to document. The presence of neoplastic mucinous epithelium within the mucinous deposits on the visceral peritoneal surface is associated with significant risk of developing peritoneal recurrence (×100). D, Some LAMNs are associated with dissecting mucin within the wall and appendiceal subserosa or mesoappendix. The risk of peritoneal recurrence for these patients is uncertain but likely very low (×40). Please see this image in color online.

not allow for staging using conventional criteria used elsewhere in the gastrointestinal tract. First, as detailed above, LAMN significantly distorts the architecture of the appendix. In most cases, the neoplasm will efface the normal mucosal architecture and there will not be discernable lamina propria, muscularis mucosae, or submucosa. In this setting, assessing involvement of the lamina propria, muscularis mucosae, and submucosa is not possible, and the pT1 designation cannot be applied to LAMN. Second, LAMN often exhibits a “pushing” diverticulum-like growth into the muscularis propria. However, studies evaluating outcome in LAMN have determined that this “pushing” pattern of extension into the appendiceal wall is not associated with tumor recurrence.8,9,23 Thus, the pT2 designation does not apply to LAMN. Finally, both acellular mucin and neoplastic mucinous epithelium can extend through the muscularis propria to involve the appendiceal subserosa or mesoappendix or be present on the appendiceal visceral peritoneal surface. In contrast to other sites of the luminal

gastrointestinal tract, acellular mucinous deposits present outside of the appendix carries risk for tumor recurrence. Thus, both the extent of mucin and neoplastic mucinous epithelium should be considered when assessing stage in appendiceal mucinous neoplasia. Given these unique issues with appendiceal mucinous neoplasia, the AJCC eighth edition has made significant and necessary changes to the staging of LAMN. The AJCC eighth edition created a new T category specifically for LAMN, termed the Tis(LAMN) (Table 3). Tis(LAMN) refers to an LAMN confined to the muscularis propria. The pT1 and pT2 designations do not apply to LAMN. Mucinous epithelium with a “pushing” pattern of extension imparting a diverticulum-like growth into the muscularis propria would be classified as Tis(LAMN). Acellular mucin extending into the muscularis propria is also classified as Tis (LAMN) as long as it does not extend into the subserosa and mesoappendix or extend to involve visceral peritoneal surface. Dissecting cellular mucinous deposits into the


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FIGURE 5. A, Serrated polyp without dysplasia resembling a colorectal sessile serrated adenoma/polyp can be seen in the appendix and represent a common mimic of low-grade appendiceal mucinous neoplasm (LAMN). Serrated polyps can be distinguished from LAMN by the preservation of the mucosal architecture including intact muscularis mucosae (×40). B, Conventional villous adenoma resembling a colorectal adenoma is rare in the appendix (×20). Conventional adenomas are distinguished from LAMN by the preservation of the mucosal architecture and lack of prominent cytoplasmic mucin as seen in the inset (×200). C, Endometriosis with mucinous metaplasia can involve the appendix and mimic an LAMN (×200). The intestinal glands can have abundant cytoplasmic mucin; however, the presence of endometrial stroma is a clue to the diagnosis. D, Hybrid glands containing intestinal goblet-like mucinous cells admixed endometrial-type glands are seen. CDX2 immunohistochemistry highlights the intestinal epithelium, whereas estrogen receptor immunohistochemistry labels the endometrial glands and stroma (×40). E, Appendiceal diverticula are characterized by herniation of the appendiceal mucosa through the muscularis propria associated with mural acellular mucin (×10). Rupture of diverticula can result mucinous deposits within the appendiceal wall, subserosa, mesoappendix, and on the visceral peritoneal surface. In contrast to LAMN, ruptured diverticula contain appendiceal mucosa with predominantly nonmucinous appendiceal crypt epithelium invested by preserved lamina propria (inset, ×100). F, Mucosal hyperplasia is a reactive process characterized by serrated crypt profiles more pronounced toward the luminal aspect of the mucosa in the setting of acute inflammation (×40). In contrast to LAMN, the mucosal architecture is preserved. Please see this image in color online.


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TABLE 3. AJCC Eighth Edition Staging of LAMN and Associated Prognostic Significance

AJCC Eighth Edition Stage pTis(LAMN)

LAMN pT3

LAMN pT4a due to acellular mucinous deposits LAMN pT4a due to cellular mucinous deposits

Definition

Prognostic Considerations

LAMN confined to the muscularis propria after So defined, patients with pTis(LAMN) have essentially no histologic examination of the entire appendix. risk of recurrence. The Tis(LAMN) designation requires Mucin or mucinous epithelium may extend into the correlation with the intraoperative findings and a diligent muscularis propria evaluation by the surgeon at the time of appendectomy for any evidence of disease outside of the appendix LAMN with acellular mucin or neoplastic mucinous Unknown risk of developing peritoneal recurrence. Longepithelium extending into the subserosa or term clinical follow-up for ∼10 y is suggested until mesoappendix but without involvement of the additional data on recurrence risk becomes available visceral peritoneal surface after histologic examination of the entire appendix LAMN with acellular mucinous deposits on the ∼3% risk of developing peritoneal recurrence. Long-term visceral peritoneal surface after histologic clinical follow-up for ∼10 y with periodic abdominal examination of the entire appendix and pelvic imaging is recommended LAMN with mucinous deposits on the visceral ∼36% risk of developing peritoneal recurrence. Longperitoneal surface containing low-grade neoplastic term clinical follow-up for ∼10 y with periodic mucinous epithelium abdominal and pelvic imaging is recommended. The role for additional surgery or HIPEC is uncertain but is used in some centers

AJCC indicates American Joint Committee on Cancer; HIPEC, hyperthermic intraperitoneal chemoperfusion; LAMN, low-grade appendiceal mucinous neoplasms.

subserosa or muscularis propria are not typical of LAMN, and their presence should prompt consideration for an infiltrating mucinous adenocarcinoma for which the pT1 or pT2 designations do apply. The AJCC eighth edition defines T3 as tumor invading through the muscularis propria into the subserosa or mesoappendix (Table 3). Unfortunately, “tumor” is not explicitly defined in the section on T3 in the AJCC eighth edition; however, elsewhere in the chapter, acellular mucin within the subserosa or mesoappendix is designated as T3. In addition, a pushing, diverticulum-like pattern of growth into the subserosa or mesoappendix should also be designated as pT3. In LAMN, the muscularis propria is often replaced by fibrosis with no residual smooth muscle discernable making assessment for transmural involvement by neoplasm difficult. Practically, a pT3 designation should only be applied in LAMN for either acellular mucin or diverticulum-like growth of neoplastic mucinous epithelium into the periappendiceal adipose tissue. Penetration of the visceral peritoneum by LAMN is associated with risk of peritoneal dissemination. Given the risk for peritoneal recurrence, the T4 designation in the AJCC eighth edition includes assessment for both acellular mucin and neoplastic mucinous epithelium (Table 4). If acellular mucin or neoplastic mucinous epithelium penetrates the visceral peritoneal surface, the tumor is designated T4a. If acellular mucin or neoplastic mucinous epithelium directly invades adjacent organs or structures, the tumor is designated T4b. Importantly, the pT4a designation does not include luminal or mural spread into the adjacent cecum which commonly occurs in LAMN. The inclusion of the assessment of acellular mucin in staging appendiceal mucinous neoplasia represents a significant change from the rest of the luminal gastrointestinal tract where only neoplastic epithelium is staged. In addition, this also introduces significant challenges when assessing appendiceal mucinous neoplasia and could potentially result in overstaging of these tumors. LAMNs are associated with abundant luminal acellular mucin. Frequently, gross tissue

sectioning and/or histologic processing can “carry-over” this luminal acellular mucin onto the visceral peritoneal surface of the appendix (Fig. 6). However, this should not be considered as evidence of a T4a neoplasm. There are a number of histologic features that help to distinguish “carry-over” of luminal mucin from true mucinous deposits on the visceral peritoneal surface. True mucinous deposits of the appendiceal serosal surface are associated with a granulation tissuelike response and/or neovascularization where numerous small capillaries containing luminal red blood cells are seen coursing through the mucin (Fig. 4). The presence of neovascularization is indicative of tissue response to the mucinous deposits and ensures that the mucin deposits are not the result of artifactual “carry-over” contamination from tissue sectioning or processing. Mucinous deposits may also be accompanied by mesothelial hyperplasia and chronic inflammation.8,23 (Fig. 4). When assessing for acellular mucinous deposits on the visceral peritoneal surface, only those deposits with either neovascularization and/or inflammatory and mesothelial reaction or should be considered as true mucinous deposits.

Prognosis and Treatment The Tis(LAMN) diagnosis should be strictly reserved for those LAMNs that are confined to the muscularis propria after histologic examination of the entire appendix. This diagnosis also requires correlating with the intraoperative findings and a diligent search by the surgeon for any evidence of disease outside of the appendix. Patients with Tis(LAMN), so defined, are typically cured by complete resection with no risk for recurrent disease.8,9 There is limited to no literature data regarding the natural history of LAMN associated with acellular mucin or neoplastic mucinous epithelium within the subserosa or mesoappendix (T3) without involvement of the visceral peritoneal surface. Many of the studies that evaluated the recurrence risk for patients with LAMN with localized “extra-appendiceal” mucin and/or neoplastic mucinous epithelium did not specifically assess T3 LAMN.8,9,23


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TABLE 4. Diagnostic Terminology, Treatment and Prognosis in Disseminated Appendiceal Mucinous Neoplasia

Diagnostic Terminology

PSOGI Synonyms

Acellular mucin

Acellular mucin

Low-grade mucinous neoplasm (G1, welldifferentiated)

Low-grade mucinous carcinoma peritonei or DPAM

High-grade High-grade (G2, moderately mucinous differentiated) carcinoma mucinous peritonei or adenocarcinoma PMCA

High-grade High-grade (G3, poorly mucinous differentiated) carcinoma mucinous peritonei with adenocarcinoma signet ring with signet ring cells or cells PMCA-S

Histologic Features

Treatment

Copious mucin without evidence of neoplastic epithelium. Requires extensive sampling to evaluate for epithelium Copious mucinous deposits containing cytologically low-grade mucinous epithelium. Neoplastic mucinous epithelium is scant and accounts for 20% of tumor volume). Must lack a signet ring cell component Presence of a signet ring cell component. Infiltrative invasion into subjacent tissues also present. Neoplastic mucinous epithelium is abundant ( > 20% of tumor volume). Tumor cells with degenerative changes imparting a signet ring–like morphology and accounting for 50% signet ring cells, the PSOGI terminology is mucinous signet ring cell carcinoma (Fig. 9). The PSOGI consensus classification advocates for a 3-tiered grading of primary appendiceal mucinous neoplasia using the descriptive terminology well-differentiated, moderately, and poorly differentiated similar to carcinomas in the remainder of the luminal gastrointestinal tract. However, the PSOGI consensus classification does not provide diagnostic criteria for these descriptive terms with regard to appendiceal mucinous neoplasia. In our experience, the well-differentiated, moderately, and poorly differentiated grading criteria from the remainder of the luminal gastrointestinal tract is difficult to apply directly to appendiceal mucinous neoplasia. Recognizing the difficulty in this descriptive terminology, the AJCC eighth edition proposed diagnostic criteria for a 3-tier grading of appendiceal mucinous neoplasia based on a scheme proposed by Davison et al25 (Table 2). The AJCC eighth edition defines welldifferentiated (G1) neoplasms as demonstrating low-grade cytology and lacking infiltrative invasion. So defined, welldifferentiated (G1) in primary appendiceal mucinous neoplasia essentially refers to LAMN. Given that mucinous adenocarcinoma is defined by infiltrative invasion and almost always exhibits at least focal areas of high-grade cytology, the well-differentiated (G1) grade should not be applied to mucinous adenocarcinoma. Using the AJCC eighth edition criteria for grading, mucinous

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FIGURE 8. A, Moderately differentiated (G2) mucinous adenocarcinoma markedly distorts the appendix with dissecting cellular pools present within the appendiceal wall and subserosa (A, ×10). B, The moderately differentiated (G2) mucinous adenocarcinoma seen in (A) demonstrates complex cribriform architecture and infiltrating glands associated with desmoplastic stroma (×40). The neoplastic mucinous epithelium exhibit high-grade cytology as seen in the inset (×200). C, This moderately differentiated (G2) mucinous adenocarcinoma demonstrates a prominent “small cellular mucin pool” pattern of invasion characterized by small dissecting pools of mucin containing floating nests, glands, or single neoplastic cells without associated stromal desmoplasia (×10). D, The neoplastic mucinous epithelium identified in the moderately differentiated mucinous adenocarcinoma seen in (C) exhibits high-grade cytology (×200). Please see this image in color online.

FIGURE 9. A, This poorly differentiated (G3) mucinous signet ring cell carcinoma of the appendix essentially replaces the entire wall of the appendix with invasion of the mesoappendix by infiltrating cellular mucin pools (×10). B, Neoplastic signet ring cells are seen in clusters floating within the dissecting mucin pools (×200). Please see this image in color online.


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adenocarcinoma can be either moderately differentiated (G2) or poorly differentiated (G3). The AJCC eighth edition defines moderately differentiated (G2) mucinous adenocarcinomas as exhibiting high-grade cytology with most demonstrating infiltrative invasion. The AJCC eighth edition defined poorly differentiated (G3) as demonstrating infiltrative invasion and with most having signet ring cell differentiation. Signet ring cells are characterized by infiltrating tumor cells with prominent intracytoplasmic mucin displacing and indenting the nucleus and may infiltrate singly or in aggregates. Both signet ring cells floating in mucin and signet ring cells infiltrating surrounding tissues should be classified as grade G3. Most G3 tumors are composed almost entirely of signet ring cells while a minority of cases display mixed glandular and signet ring cell morphology. Mucinous adenocarcinoma can arise from a number of precursor lesions within the appendix. Some of the precursor lesions to mucinous adenocarcinoma display complex architecture comprised papillary fronds with confluent, cribriform epithelial growth often filling the appendiceal lumen. However, some cases may lack complex architecture and be composed of a flat or undulating mucinous epithelial lining exhibiting high-grade cytology. Rarely, the precursor lesion to mucinous adenocarcinoma resembles an LAMN. However, cytologic grade within the precursor lesion can be heterogenous with areas of low cytologic grade admixed with areas of unequivocal high cytologic grade. This heterogeneity highlights the need for complete sampling of the appendix for adequate classification.

Prognosis and Treatment Mucinous adenocarcinomas of the appendix are clinically aggressive and frequently metastasize to involve the peritoneum. At the time of presentation, most mucinous adenocarcinomas have infiltrated through the appendiceal wall and are associated with penetration of the visceral peritoneal surface (T4) and many will present with abdominal peritoneal and/or pelvic metastasis.8,9 A diagnosis of mucinous adenocarcinoma in an appendectomy specimen should result in subsequent right hemicolectomy to evaluate for lymph node metastases. An oncologic treatment regimen similar to colorectal carcinoma is often followed. Disseminated peritoneal involvement is common for appendiceal mucinous adenocarcinoma and a discussion on the prognosis and therapy of disseminated appendiceal mucinous neoplasia is detailed below.

CLASSIFYING PERITONEAL DISEASE FROM APPENDICEAL MUCINOUS NEOPLASIA General Considerations Pseudomyxoma peritonei is a clinical condition that has been characterized as a localized or generalized accumulation of thick, gelatinous material in the abdominal and/ or pelvic peritoneal cavity. Most cases of pseudomyxoma peritonei develop as a result of appendiceal mucinous neoplasia. However, other primary sites of origin, including mucinous neoplasms of the pancreas,26–28 urachus of the bladder,29–31 and ovarian teratoma32 rarely give rise to pseudomyxoma peritonei. Given this, pseudomyxoma peritonei is best used as a clinical, radiologic, or even syndromic descriptor and should not be used as a histopathologic diagnosis. In pseudomyxoma peritonei, the mucin-secreting epithelium tends to accumulate in the regions of the liver


and splenic capsule, paracolic gutters, omentum, and pelvis in what is termed the “redistribution” phenomenon. As described by Carr et al,13 the redistribution phenomenon refers to how the “mucin and the neoplastic cells it contains follows the normal flow of peritoneal fluid and are redistributed within the peritoneal cavity to sites of fluid absorption through lymphatic lacunae and lymphoid aggregates.” Extraperitoneal spread of disease through pleural extension is unusual and if present, typically occurs following aggressive cytoreductive surgical therapy. Distant metastasis through lymphatics or hematogenous spread is uncommon but can occur in high-grade disease. Much of the literature has classified pseudomyxoma peritonei into 3 prognostically relevant categories using the terminology and criteria proposed by Ronnett et al10,11: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and peritoneal mucinous carcinomatosis-intermediate category (PMCA-I). However, it is important to realize that Ronnett and colleagues included nonappendiceal primary colonic adenocarcinoma in their analysis. Bradley et al7 failed to find prognostic relevance of the 3-tiered Ronnett classification and proposed a 2-tiered classification of pseudomyxoma peritonei. The histologic criteria for the diagnostic categories proposed by Ronnett and colleagues are not wellcharacterized and this likely led to the conflicting results among these studies. In addition, the terminology used by Ronnett and colleagues is not standard for neoplasms of the luminal gastrointestinal tract, and the reference to an “adenomatous” process in the setting of disseminated peritoneal disease is potentially confusing. Given recent updates on diagnostic terminology for appendiceal mucinous neoplasia described below, the terms DPAM and PMCA should likely not be used as stand-alone diagnoses in pathology reports but can be referred to as a synonyms for the more standardized diagnostic terminology proposed by the PSOGI and the AJCC eighth edition.

Histologic Grading and Diagnostic Terminology of Peritoneal Disease Two large retrospective studies using the Surveillance, Epidemiology, and End Results (SEER)33 and National Cancer Database (NCDB)34 analyzed the effect of histologic grade on patient survival in the setting of stage IV appendiceal mucinous neoplasia. Using the SEER database, Overman et al33 analyzed 1375 patients with appendiceal mucinous neoplasia and found that histologic grade (well, moderately, and poorly differentiated) was the strongest independent predictor of survival in patients with stage IV disease. In their analysis of 5971 patients, Asare et al34 also found that a 3-tiered grading scheme (well, moderately, and poorly differentiated) was a strong independent predictor of overall survival in stage IV appendiceal mucinous neoplasms. Both of these studies used large population databases that did not allow for histologic rereview of the appendiceal tumors and associated peritoneal disease and the criteria for grading were not explicitly discussed. Two retrospective studies of stage IV appendiceal mucinous neoplasia by Davison et al25 and Shetty et al35 both of which performed rereview of histology also determined that a 3-tiered assessment of tumor grade is the single most important predictor of patient survival. The histologic criteria for the 3-tiered grading were similar in both studies. Both the PSOGI and the AJCC eighth edition advocate for a 3-tier grading of appendiceal mucinous neoplasia using a


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modification of the histologic criteria proposed by Davison et al and Shetty et al as detailed below.

Low-grade (G1, Well Differentiated) For stage IV appendiceal mucinous neoplasia, low grade is synonymous with the well-differentiated and grade G1. Low-grade (G1, well-differentiated) peritoneal disease is defined as neoplasms with low-grade cytology and the absence of infiltrative invasion. Low-grade (G1, well-differentiated) peritoneal disease almost always arises from a primary LAMN. Disseminated low-grade (G1, well-differentiated) peritoneal disease is characterized by a predominance of copious mucin pools within the peritoneal cavity (Figs. 10, 11). Typically, neoplastic mucinous epithelium accounts for 20% of the mucinous component of the tumor (Fig. 11). Assessment of overall cellularity is best performed with review of the entire case and is best determined at low-power (×20) magnification. The low-power assessment of cellularity is often the first histologic clue to the diagnosis of a high-grade (G2, moderately differentiated) mucinous adenocarcinoma. In contrast to lowgrade (G1, well-differentiated) tumors, lymph node metastases are seen in ∼20% of high-grade (G2, moderately differentiated) mucinous adenocarcinomas.

High-grade (G3, Poorly Differentiated) Mucinous Adenocarcinoma This group represents a heterogenous group of appendiceal adenocarcinomas and is most often characterized by the presence of a signet ring cell component (Table 4). Most tumors will demonstrate > 95% signet ring cells (Fig. 15). A minority of cases display a mixed glandular and signet ring cell morphology (Fig. 15). Infiltrating, destructive invasion, and high tumor cellularity are seen in almost all cases of high-grade (G3, poorly differentiated) mucinous adenocarcinomas. In contrast to high-grade (G2, moderately differentiated) mucinous adenocarcinoma, lymph node metastases are seen in ∼70% of high-grade (G3, poorly differentiated) mucinous adenocarcinomas and most cases will demonstrate both angiolymphatic and perineural invasion. Rare cases of G3 adenocarcinoma demonstrate a solid, sheet-like growth pattern (Fig. 15).

Assessment of Stage in Peritoneal Disease The AJCC eighth edition has updated the M category for appendiceal mucinous neoplasia. The M1 category has been expanded to include 3 options instead of the 2 options detailed in the seventh edition. The AJCC eighth edition now defines M1a as intraperitoneal acellular mucin without identifiable tumor cells in the disseminated peritoneal mucinous deposits. There is limited literature data on the prognostic significance of acellular intraperitoneal mucinous disease (Table 4). In a study by Young et al,5 5 patients with acellular intraperitoneal disease had long-term clinical follow-up with 1 patient developing recurrence 18 years after presentation. Pai et al8 analyzed 2 patients with acellular intraperitoneal disease with long-term ( > 10 y) clinical follow-up with neither patient developing recurrence. Finally,


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FIGURE 10. A, Low-grade (G1) cytology in intraperitoneal disease can be characterized by long strips of epithelium with basally located small uniform nuclei (×400). B, Nuclear stratification is allowed in low-grade (G1) neoplasms as seen in this case (×400). Note the preservation of nuclear polarity, lack of full-thickness nuclear stratification, and inconspicuous mitotic activity. C, A subset of low-grade (G1) cases can demonstrate an area of focal increased cytologic atypia that raises concern for a component of high-grade disease but that does not satisfy diagnostic criteria for high cytologic grade (×400). D & E, High-grade cytology in intraperitoneal disease is characterized by nuclear enlargement and rounding of the nuclei, nuclear membrane irregularities, irregular chromatin, prominent (full-thickness) nuclear stratification, and loss of nuclear polarity. Cytoplasmic mucin may be lacking (D, ×200) or can be prominent (E, ×400). Papillary tufting can also be seen (D). F, High-grade cytology in intraperitoneal disease can be associated with glandular complexity (cribriform glands, “back-to-back” glands) although this is not required for the diagnosis (×400). Please see this image in color online.

Davison et al25 identified 5 patients with acellular intraperitoneal disease with relatively limited clinical follow-up (median, 32 mo) with no patients developing recurrent disease. The limited

literature data suggest that patients with intraperitoneal acellular mucinous disease have a decreased risk of recurrence compared with patients with cellular disease and support the inclusion of a


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FIGURE 11. A, Peritoneal dissemination of low-grade (G1, well-differentiated) neoplasm is characterized by a predominance of copious mucin pools with low-cellularity (×20). B, The neoplastic epithelium in the low-grade (G1, well-differentiated) neoplasm seen in (A) displays low-grade cytology (×400). C, Peritoneal dissemination of high-grade (G2, moderately differentiated) mucinous adenocarcinoma can demonstrate a “small cellular mucin pool” pattern of invasion characterized by small epithelial clusters with or without tubule formation floating in small pools of mucin invading through the subjacent normal tissues but not necessarily eliciting a prominent stromal desmoplastic response (×20). D, The neoplastic mucinous epithelium in the high-grade (G2, moderately differentiated) mucinous adenocarcinoma seen in (C) demonstrates high-grade cytology. Please see this image in color online.

separate M category for intraperitoneal acellular mucinous disease. However, additional study with more patients with longterm clinical follow-up is necessary. The M1b category is defined as intraperitoneal metastasis only, and the M1c category refers to metastasis to sites other than the peritoneum. Peritoneal implants will often involve underlying tissue. For example, although involvement of the ovary may be limited to surface implants, more commonly the ovarian parenchyma will be replaced by metastatic mucinous neoplasm. Involvement of abdominopelvic organs should still be classified using the M1b category, regardless of whether the implants infiltrate underlying tissue. Thus, most stage IV tumors will be classified as M1b. Metastases to sites other than the peritoneum such as pleuropulmonary involvement are rare and should be classified using the M1c category.

Prognosis and Treatment There are multiple clinical factors that influence survival in patients with disseminated mucinous appendiceal neoplasms, but pathologic grade has repeatedly been shown to be an independent prognostic factor.6–9,11,33–36 Patients with high-grade (G2 or G3) mucinous adenocarcinoma have a

significantly worse overall survival in comparison to patients with disseminated low-grade (G1, well-differentiated) mucinous neoplasms. The overall 5-year overall survival for patients with disseminated low-grade (G1, well-differentiated) mucinous neoplasms ranges from 60% to 90% with an estimated 10-year overall survival of ∼50%.6,7,9–11,33–35 The overall 5-year and 10-year overall survival for patients with high-grade (G2, moderately differentiated) mucinous adenocarcinoma ranges from 30% to 60% and 20% to 30%, respectively.25,34,35 The overall 5-year and 10-year overall survival for patients with high-grade (G3, poorly differentiated) mucinous adenocarcinoma with signet ring cells ranges from 10% to 40% and 10% to 20%, respectively.25,34,35 Patients with stage IV (disseminated) low-grade (G1, well-differentiated) neoplasms are most commonly treated with cytoreductive surgery (CRS) and HIPEC25,37,38 (Table 4). Importantly, systemic chemotherapy is not effective in patients with stage IV low-grade (G1, well-differentiated) mucinous neoplasms34 underscoring the importance of tumor grade assessment in therapeutic management. In contrast, for patients with stage IV G2 or G3 mucinous adenocarcinoma, systemic chemotherapy has been shown to improve overall survival.34 Patients with stage IV high-grade (G2, moderately


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FIGURE 12. A, Peritoneal dissemination of low-grade (G1, well-differentiated) mucinous neoplasm can involve other abdominal organs and display a “pushing” border without infiltrative invasion as seen in this case involving the muscularis propria of the stomach (×20). B, The neoplastic mucinous epithelium within the muscularis propria of the stomach is low-grade (×200). C, In contrast, this high-grade (G2, moderately differentiated) mucinous adenocarcinoma demonstrates destructive infiltrative invasion of small cellular mucin pools into small intestine (×40). Please see this image in color online.

differentiated) mucinous adenocarcinomas are often given systemic chemotherapy in an attempt to reduce tumor volume with the option for CRS-HIPEC after assessment of tumor response to systemic chemotherapy.37,39,40 Patients with stage IV high-grade (G3, poorly differentiated) mucinous adenocarcinoma with signet ring cell differentiation also benefit from systemic chemotherapy followed by CRS-HIPEC if there is evidence of tumor response to chemotherapy and the patient is deemed to have resectable disease.41 Patients with unresectable high-grade (G2 or G3) adenocarcinoma are often treated with systemic chemotherapy alone.42

Challenges in Classifying Peritoneal Disease Distinguishing Low-grade (G1) From High-grade (G2) Disease Cytoarchitectural atypia occurs on a continuum and any attempt to stratify atypia into discrete categories results in diagnostic challenges. Distinguishing low-grade (G1) and high-grade (G2) disease is usually straightforward; however, some cases demonstrate features that straddle between these histologic grades and are difficult to definitively classify. Two common challenging scenarios include: (1) cases of predominantly low-grade neoplasm with a microscopic area

of focal increased cytologic atypia that raises concern for a component of high-grade disease but that does not satisfy diagnostic criteria for high cytologic grade (Fig. 10) and (2) cases of predominantly low-grade neoplasm with a microscopic area of questionable infiltrative infiltration. Davison et al25 identified 12% of low-grade tumors that had either a questionable microscopic area of infiltrative invasion or nuclear atypia beyond that typical for low nuclear grade but insufficient for an unequivocal label of high-nuclear grade accounting for

Appendiceal or cecal endometriosis with intestinal metaplasia: a potential mimic of appendiceal mucinous neoplasms.

Low interobserver agreement in cytology grading of mucinous pancreatic neoplasms.

Appendiceal mucinous neoplasms: an uncertain nosological entity. Report of a case.

Mucinous cystic neoplasms of the pancreas: update on the surgical pathology and molecular genetics.

Appendiceal mucinous cystadenoma.

Does obesity affect outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for disseminated mucinous appendiceal neoplasms?

Significance of proximal margin involvement in low-grade appendiceal mucinous neoplasms.

Low-Grade Appendiceal Mucinous Neoplasm Presenting as an Adnexal Mass.

Pancreatic Cystic Neoplasms: An Update.

Diagnosis and Treatment of Mucinous Appendiceal Neoplasm Presented as Acute Appendicitis.

Mucinous appendiceal tumor presenting as perforated appendicitis.

Mucinous Neoplasms of the Vermiform Appendix.

Noninvasive intraductal papillary mucinous neoplasms and mucinous cystic neoplasms: recurrence rates and postoperative imaging follow-up.

Non-pancreatic retroperitoneal mucinous neoplasms and a discussion of the differential diagnosis.

Pathology of Mucinous Appendiceal Tumors and Pseudomyxoma Peritonei.

Intraductal papillary mucinous neoplasm of the pancreas: an update.

Intraductal papillary mucinous neoplasms of the pancreas.

An update on the diagnosis and treatment of Parkinson disease.

Clinical experience in appendiceal neuroendocrine neoplasms.

The Dieulafoy's Lesion: An Update on Evaluation, Diagnosis, and Management.

An update on the grading of muscle injuries: a narrative review from clinical to comprehensive systems.

Identification of Differentially Expressed miRNAs in Appendiceal Mucinous Cystadenocarcinoma from Mucinous Cystadenoma.

Update on differentiated thyroid cancer staging.

Acupuncture for Neoplasms: An Update from the PubMed Database.