Appendiceal mucinous neoplasms: controversial issues.
Abstract: * Low grade appendiceal mucinous neoplasms can spread to the peritoneum as pseudomyxoma peritonei even though they are not obviously invasive in the appendix. During the past several decades, several problematic issues surrounding this enigmatic tumor have been debated in the literature, including appropriate nomenclature for the appendiceal tumors and their peritoneal metastases. In this article, the most contentious issues in the area of appendiceal mucinous tumors are examined. First, the classification systems that have been proposed for these tumors are compared in the context of whether the appendiceal mucinous tumors are ruptured adenomas or invasive carcinomas. The controversy about the nature of pseudomyxoma peritonei and its classification systems is discussed in the following section. A brief discussion follows that examines the issue of localized pseudomyxoma peritonei and its clinical significance. Next reviewed is the largely resolved controversy about whether ovarian mucinous tumors in this setting are separate primaries or are metastases from the appendiceal tumor. Finally, the controversy about the most effective treatment of patients with pseudomyxoma peritonei is discussed.

(Arch Pathol Lab Med. 2010;134:864-870)
Article Type: Disease/Disorder overview
Subject: Digestive system cancer (Risk factors)
Digestive system cancer (Diagnosis)
Digestive system cancer (Care and treatment)
Digestive system cancer (Prognosis)
Author: Misdraji, Joseph
Pub Date: 06/01/2010
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 College of American Pathologists ISSN: 1543-2165
Issue: Date: June, 2010 Source Volume: 134 Source Issue: 6
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230151177
Full Text: Appendiceal mucinous tumors can spread to the peritoneum resulting in the distinctive syndrome called pseudomyxoma peritonei (PP). The appendiceal and peritoneal mucinous tumors have peculiar features that leave the exact nature of this process in doubt. The appendiceal tumors, for instance, frequently lack classic, infiltrative invasion of the appendiceal wall yet manage to seed the peritoneum. In the peritoneum, the mucinous epithelial cells embedded in the abundant mucin are often bland, yet PP is progressive and frequently fatal.

During the past several decades, various controversies in the field of appendiceal mucinous neoplasia have been debated in the literature; some of which are now resolved, but others remain contentious. Some of the controversies surrounding appendiceal mucinous tumors are as follows:

* The classification of appendiceal mucinous tumors.

* The nature and classification of pseudomyxoma peritonei.

* The clinical significance of localized pseudomyxoma peritonei.

* Whether, in women with concomitant ovarian and appendiceal tumors, the ovarian tumors are primary tumors or metastases from the appendix.

* The treatment of patients with pseudomyxoma peritonei.

THE CLASSIFICATION OF APPENDICEAL MUCINOUS TUMORS

In 1940, Woodruff and McDonald1 classified cystic mucinous tumors of the appendix into benign mucoceles and, when they showed "papillary arrangement of the mucous membrane" with hyperchromatic, elongate nuclei, into cystadenocarcinoma, grade 1. In the 1960s and 1970s, doubts began to surface about the malignant nature of these seemingly noninvasive tumors, and they were reclassified as mucinous cystadenomas or villous adenomas of the appendix, in keeping with the nomenclature for colorectal adenomatous polyps. (2-4) However, this engendered the controversy regarding the appropriate classification of those same tumors when they have seeded the peritoneal cavity with neoplastic mucinous epithelium that results in the death of more than 50% of these patients from bowel obstruction. The debate continues today and pits those pathologists who accept the concept of a ruptured appendiceal adenoma seeding the peritoneum with "adenomatous" epithelium (5,6) against those who insist that the presence of epithelium proliferating outside the appendix is unequivocally peritoneal adenocarcinoma and, reasoning backwards, that the appendiceal primary tumors are invasive adenocarcinomas. (7,8) In between are pathologists who have introduced intermediate terms, such as borderline tumor of the appendix, (9) mucinous tumors of low malignant potential, (10) and low-grade appendiceal mucinous neoplasm11 to reconcile the benign appearance of the appendiceal tumor and, often, the peritoneal mucinous epithelium with the relentless and often fatal biologic behavior of PP.

The question of whether these tumors are ruptured adenomas or invasive carcinomas is not easily answered. Common to all these tumors is replacement of the normal appendiceal mucosa with a villiform, undulating, or flat mucinous epithelial proliferation (Figure 1). Frequently, the wall of the appendix becomes increasingly fibrotic and hyalinized (Figure 2), and the appendix may become transformed into a fibrotic cyst lined by attenuated neoplastic mucinous epithelium. Not uncommonly, the neo plastic epithelium directly abuts the hyalinized cyst wall. Dissection of the neoplastic epithelium into the fibrotic wall (Figure 3), diverticula of the tumor, marked alteration of the appendiceal architecture, and eventually, rupture of the fibrotic appendix (Figure 4) can be difficult to distinguish from invasive cancer. Although some pathologists require destructive invasion of the appendix with infiltrating glands to make the diagnosis of adenocarcinoma, others argue that mucinous tumors in the appendix invade along a broad front characterized by neoplastic epithelium directly abutting the hyalinized cyst wall with obliteration of the muscularis mucosae (Figure 5). (12) If the concept of broad-front invasion is accurate, then many appendiceal mucinous tumors that are confined to the appendix and cured by appendectomy and that most pathologists would classify as appendiceal cystadenomas are actually invasive adenocarcinoma. Several decades ago, Higa et al (3) classified appendiceal mucinous tumors as cystadenocarcinomas if they were associated with PP and as cystadenomas if they were not. They acknowledged that this method of distinguishing between cystadenoma and cystadenocarcinoma was arbitrary in that some of the tumors they called cystadenomas were probably cystadenocarcinomas that had been excised before they had a chance to spread to the peritoneum. The lack of consensus on the existence of broad-front invasion is one of the difficulties in arriving at a single classification of these tumors (Table 1).

In 1995, Carr and colleagues8 at the Armed Forces Institute of Pathology proposed a classification of appendiceal mucinous tumors based on their review of 184 tumors:

* Adenoma. Dysplastic tumors that have intact muscularis mucosae. Mucin dissecting in the wall is acceptable provided that the muscularis mucosae is intact.

* Mucinous tumors of uncertain malignant potential. Dysplastic tumors that are difficult to classify as clearly benign or clearly malignant. This category includes tumors with well-differentiated mucinous epithelium pushing deeply into the underlying tissue without clear-cut invasion or tumors with mucin present in the wall or outside the appendix, provided there is a loss of muscularis mucosae.

* Adenocarcinoma. Tumors that demonstrate invasive neoplastic cells present beyond the muscularis mucosae. Also, "evidence of growth of viable cells outside the appendix" is used as a "firm criterion of malignancy."

This classification introduced the term appendiceal mucinous tumor of uncertain malignant potential for tumors that were difficult to classify as benign or malignant, reflecting the possibility that well-differentiated carcinomas may be invading in a "pushing" manner and the poorly defined criteria for this type of invasion. Similar to Higa et at, (3) the category of adenocarcinoma includes any appendiceal mucinous tumor associated with PP, even if that tumor would be classified as an appendiceal cystadenoma had it been confined to the appendix. This latter point means, of course, that classifying mucinous tumors in this manner requires knowledge of the presence or absence of mucinous epithelial cells in the peritoneum, which, in turn, depends on sampling by the surgeon and the pathologist, a practice that some pathologists find objectionable and contrary to the usual methods of tumor classification.

In 2003, me and my colleagues reported our experience with 107 low-grade appendiceal mucinous tumors, ranging from tumors confined to the appendix to those with bulky peritoneal tumors. (11) We felt that because appendiceal tumors that are confined to the appendix (ergo, mucinous cystadenoma or villous adenoma) are indistinguishable from those that have spread to the peritoneum, a single term should be used to encompass low-grade appendiceal mucinous tumors, regardless of their stage. This approach conforms to the manner in which other tumors are classified and staged. Given the resistance to the terminology of ruptured adenoma, we proposed the term low-grade appendiceal mucinous neoplasm (LAMN) for all low-grade mucinous tumors of the appendix that lack destructive invasion of the appendiceal wall, either confined to the appendix or that have spread to the peritoneum. Adenocarcinoma is reserved for tumors with either high-grade cytology or destructive invasion. This approach simplifies the diagnosis for appendiceal mucinous tumors by removing the stage as a criterion for classification.

Recently, Pai and Longacre10 proposed a classification of appendiceal mucinous tumors similar to the classification of Carr and Sobin (8):

* Adenoma. Simple or focally stratified columnar epithelium with goblet cells; mild to moderate atypia; mitoses but no atypical mitoses; no stromal invasion; no extra-appendiceal epithelium. Strictly used to refer to a neoplastic process that "once completely excised, is benign and does not recur." Perforation with acellular mucinous ascites is acceptable.

* Mucinous tumor of uncertain malignant potential. Same as adenoma, but

** The proximal margin is involved,

** Mucin with epithelium is present within the wall but not clearly invasive, and

** Any uncertainty exists about whether there is epithelium within extra-appendiceal mucin.

* Mucinous tumor of low malignant potential. Same as adenoma, but neoplastic cells are present in peritoneal implants.

* Adenocarcinoma. An invasive mucinous tumor.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

This classification introduces the term appendiceal mucinous tumor of low malignant potential for mucinous tumors that have spread to the peritoneum but are not clearly "invasive," a seemingly minor modification from the Armed Forces Institute of Pathology classification but one that carries major philosophic implications. As with our classification, the classification of Pai and Longacre10 uses less-than-malignant terminology to describe these low-grade mucinous tumors associated with PP. However, it retains the dependency on tumor stage for classification and the use of the highly subjective uncertain malignant potential category.

THE NATURE AND CLASSIFICATION OF PSEUDOMYXOMA PERITONEI

Certainly, all pathologists agree that PP is a low-grade neoplastic process that is progressive and frequently fatal. The controversy surrounding PP centers on whether the epithelium is adenomatous or carcinomatous (ie, derived from a ruptured adenoma or an invasive carcinoma). The hypothesis that PP represents growth of adenomatous epithelium within the peritoneal cavity is based on several features of classic PP that differ from the usual peritoneal carcinomatosis:

* The tumor in the appendix lacks obvious invasive carcinoma.

* The mucinous epithelium in the peritoneum lacks overtly malignant cytologic features, and can even have benign cytologic appearance.

* The peritoneal tumor grows along the surface of various organs and, apart from the ovary, rarely invades into the parenchyma of those organs.

* Patients with classic PP have a much better prognosis and a slower tempo of disease progression than patients with usual peritoneal carcinomatosis.

Theoretically, adenomatous epithelium, being in fact neoplastic, might be able to proliferate in the peritoneum yet lacks the ability to invade tissue or metastasize hematogenously. A report of 2 cases of PP developing after colonic segmental resections for adenomas, in which the authors propose that adenomatous epithelium contaminated the peritoneum, suggests that this phenomenon is possible. (13)

Others argue that PP represents low-grade mucinous carcinomatosis, a viewpoint advocated by the World Health Organization. The arguments put forth to support this contention counter each of the points above:

? The tumor in the appendix is, in fact, invasive, but broad-front invasion is not easily recognized.

? Mucinous tumors in other organs, such as the pancreas, can be deceptively bland.

? Parenchymal organ invasion occurs in a significant minority of patients, particularly in the ovary and spleen.

? The disease is relentless and often fatal, indicating its malignant nature. The better prognosis of these patients relative to other patients with peritoneal carcinomatosis is merely a reflection of the low-grade nature of classic PP.

In 1995, Ronnett et al (6) classified 109 cases of PP into a low-grade variety, which they named diffuse peritoneal adenomucinosis (DPAM) and a high-grade variety, which they designated peritoneal mucinous carcinomatosis (PMCA). In their study, they defined adenomucinosis as a peritoneal neoplasm composed largely of mucin associated with fibrosis and containing scant strips of simple to focally proliferative mucinous epithelium with minimal cytologic atypia and rare mitotic figures (Figure 6). The primary appendiceal tumor was an adenoma in all cases. In contrast, they made a diagnosis of peritoneal mucinous carcinoma when the primary tumor was an appendiceal or colonic mucinous adenocarcinoma and the peritoneal tumors were characterized by more abundant, proliferative epithelium, glands, nests, or individual cells, including signet ring cells, and demonstrated marked cytologic atypia. Not surprisingly, they found a significant difference in survival between these groups, with 5-year survival rates of 84% for DPAM and 6.7% for PMCA. In between these 2 extremes were several cases with features mostly reminiscent of DPAM but with focal "well-differentiated adenocarcinoma" (PMCA-intermediate [PMCA-I]) that had intermediate survival. In a follow-up study, Ronnett et al14 reported that the DPAM group had a 10-year survival of nearly 70%, whereas patients with PMCA had a 10-year survival of less than 5%. In this report, the authors clarified that PMCA-I behaved similar to PMCA and should be incorporated into PMCA. These studies illustrate that if one strictly defines PP as low-grade peritoneal mucinous tumors derived from a ruptured LAMN, a homogenous group of patients can be identified that has a better prognosis and more protracted disease course than the typical patient with peritoneal carcinomatosis.

In a recent, large study of pseudomyxoma by Bradley et al, (7) the authors classified peritoneal mucinous tumors as DPAM, PMCA-I, and PMCA based on the Ronnett et al (14) criteria. They confirmed that tumors at the low-grade end of the spectrum had a better prognosis than tumors at the high-grade end. Because they take the view that PP is, by definition, carcinoma, they proposed that all peritoneal mucinous tumors be classified as mucinous carcinoma peritonei, low grade or high grade. However, the authors limited their study to patients with bulky peritoneal disease and suggested that tumors limited to the right lower quadrant be classified using less-than-malignant terminology.

In our study, (11) we focused on low-grade mucinous tumors of the appendix and peritoneum. We found that peri toneal tumors with high-grade cytology, even without complex architectural growth patterns, had a worse prognosis than tumors with low-grade cytology. Therefore, we restrict the term LAMN to only those cases with very bland or low-grade cytology and diagnose peritoneal mucinous adenocarcinoma for tumors with high-grade cytology. Although we made the distinction between classic PP, with its low-grade cytologic and architectural features, and well-differentiated mucinous carcinoma, with high-grade cytology, increased cellularity, and mild architectural complexity, all of the peritoneal mucinous tumors in our study would be classified as mucinous carcinoma peritonei, low grade, using criteria proposed by Bradley et al (7) and as DPAM using criteria proposed by Ronnett et al (14) (Table 2).

In summary, PP is a low-grade neoplastic process, regardless of the terminology one uses to describe it. Within the context of that, higher-grade proliferations behave worse than low-grade ones.

THE CLINICAL SIGNIFICANCE OF LOCALIZED PSEUDOMYXOMA PERITONEI

Most studies that deal with appendiceal neoplasia focus on tumors confined to the appendix or those that have spread widely throughout the abdomen, and large series that focus on tumors with localized PP have not been available. For many years, the prevailing view was that localized pseudomyxoma peritonei is clinically insignificant, in part supported by early studies of appendiceal tumors that included occasional cases with localized PP that had a benign outcome. (15) More recently, this notion has been challenged. In their study of appendiceal tumors, Carr and Sobin (8) reported that 3 ruptured mucoceles and 11 adenomas with acellular periappendiceal mucin were not associated with the development of diffuse PP, but that 1 of 5 (20%) appendiceal mucinous neoplasms with cellular mucin limited to the right lower quadrant recurred.

A recent study specifically addressed the significance of localized PP.16 The authors identified 65 appendiceal mucinous tumors that had ruptured with periappendiceal mucin and at least 6 months of follow-up. Fifty of these tumors (77%) had acellular mucin in the periappendiceal region, and 2 of these 50 (4%) recurred after 56 and 92 months. However, neither of these tumors had been entirely submitted for microscopic examination, raising the question of whether extra-appendiceal epithelial cells had been missed. In contrast, 15 tumors (23%) were associated with 1 to 12 clusters of low-grade epithelial cells in the extra-appendiceal mucin. Of these 15 tumors, 5 (33%) recurred as diffuse PP in 24 to 87 months, and 1 patient died of disease at 60 months. From this study, it can be concluded that rupture of an appendiceal mucinous tumor and extravasation of acellular mucin rarely result in recurrence. However, extra-appendiceal mucin must be completely examined microscopically to confirm the absence of epithelium outside the appendix because the presence of any epithelium outside the appendix indicates an increased risk of recurrence and potential death. Even complete microscopic examination cannot guarantee that epithelium outside the appendix has not been missed, and therefore, in cases of appendiceal rupture and acellular mucin spillage, it is prudent to comment on the risk of recurrence, albeit low.

THE ORIGIN OF PSEUDOMYXOMA PERITONEI IN WOMEN WITH CONCOMITANT OVARIAN AND APPENDICEAL TUMORS

Not so long ago, there was considerable controversy about the origin of the mucin and epithelial cells in cases of PP, particularly in women with concomitant mucinous tumors of the appendix and ovaries. In many series in which the ovary was regarded as the primary, the appendix was not described or examined. (17-19) In some instances, the appendix was not removed because it was felt to be normal by the surgeon,17 although appendices with LAMNs may appear grossly unremarkable. (20) In some reported cases, the appendix was given a benign diagnosis, such as mucocele or mucosal hyperplasia, (19) which may represent LAMNs with either extensive denudation or minimal cytologic atypia, respectively.

Clinicopathologic studies exploring the issue of primary site came to the opposite conclusions. In their study of 22 women with concomitant appendiceal and ovarian mucinous tumors, Young et al (9) concluded that the appendix was the primary site in most cases, and the ovary was secondarily involved. Other authors agreed. (20,21) However, Seidman et al (22) came to the conclusion that the appendiceal and ovarian mucinous tumors, and possibly even the peritoneal tumors, were independent, primary tumors. Other authors have also hypothesized that the peritoneal tumors might be primary at that site. (23,24) Recent immunohistochemical, molecular, and genetic evidence supports an origin in the appendix in most cases, and secondary involvement of the peritoneum and ovaries. (25-30)

TREATMENT OF PATIENTS WITH PSEUDOMYXOMA PERITONEI

The treatment of patients with peritoneal spread from an appendiceal tumor is not standardized. Historically, PP was treated with serial debulking operations, until the development of adhesions precluded additional procedures, and the patient expired from bowel obstruction or other complications of a tumor. Dr Sugarbaker, (31) at the Washington Cancer Institute in Washington, DC, has been a strong advocate of more aggressive treatment for these patients. His method involves 6 peritoneal stripping procedures (called peritonectomies) to be performed at the initial surgery, including (1) greater omentectomy and splenectomy, (2) left upper quadrant peritonectomy, (3) right upper quadrant peritonectomy, (4) lesser omentectomy with cholecystectomy, (5) pelvic peritonectomy with rectosigmoid resection, and (6) antrectomy. Usually, patients do not require all 6 procedures (the reported mean being 3.4 procedures per patient). (32) Peritonectomy is followed by intraoperative hyperthermic chemotherapy to expose the remaining tumor cells to the chemotherapeutic agent before adhesions encase and protect tumor cells. Postoperatively, patients receive additional cycles of combined intraperitoneal and systemic chemotherapy. Using these aggressive techniques, Sugarbaker et al33 report 5-year survival rates of 86% for patients with complete cytoreduction and adenomucinosis (DPAM), 50% survival rates for patients with hybrid or mucinous carcinoma and complete cytoreduction, and 20% survival rates for patients with incomplete cytoreduction.

Whether such aggressive treatment provides sufficient benefit to outweigh the costs is controversial. These protocols are associated with a 35% morbidity and a 5% mortality rate. (32) A favorable outcome is highly correlated with completeness of cytoreduction, (33) yet complete cytoreduction is difficult to achieve, especially in patients with diffuse abdominal disease. (32,34) Sugarbaker emphasizes that patient selection affects the success of this procedure, possibly creating a selection bias in his results. He notes that "noninvasive" histopathology is extremely important in selecting patients who are most likely to benefit from this treatment strategy and that patients with "hybrid" and mucinous adenocarcinoma do not receive as much benefit from these aggressive approaches. (33) In the end, some authors (34,35) have argued that the Sugarbaker et al (33) survival statistics might be no better than those reported by other centers that use more conservative approaches. In 2005, Miner et al (36) reported their experience with surgical debulking in 97 patients with PP at the Memorial Sloan-Kettering Cancer Center (New York, New York). They found that low-grade pathology and ability to achieve complete cytoreduction positively affected outcome. In their experience, absolute cure (defined as prolonged disease-free survival) is uncommon, but among patients with favorable histology, serial debulking resulted in long-term survival results similar to the Sugarbaker et al (33) data.

In summary, the available data suggest that there is a subset of patients with low-grade disease that benefits from aggressive surgical resection of their tumors and that patients with high-grade peritoneal malignancy are not surgical candidates. Beyond that, many of the details, including what constitutes the best surgical approach and the role of chemotherapy, remain the subject of controversy. Importantly, from the perspective of pathologists, the morphologic threshold between low-grade peritoneal mucinous tumors that would benefit from surgery and high-grade tumors that would not is poorly defined and merits additional study.

CONCLUSION: THE SEARCH FOR CONSENSUS

In the end, much of the controversy surrounding appendiceal mucinous tumors is semantic and philosophic. In practice, there is general agreement that there exists a distinct subset of appendiceal mucinous tumors that lacks usual forms of destructive invasion but has a propensity to spread to the peritoneum and ovaries, frequently progresses to the clinical syndrome known as pseudomyxoma peritonei, and often results in the demise of the patient, despite the bland histology of the mucinous epithelium. The inconsistent classification of these tumors hampers our ability to understand these tumors and their biology and to effectively communicate with our clinicians. Therefore, the pathology community should strive to create a consensus classification that can be universally applied, even if it is not universally accepted. This classification must be biologically sound and provide sufficient resolution and consistency for research in this field. Finally, we must work with our clinical colleagues to define the histopathologic parameters that determine which patients will benefit from surgical therapies and which will not.

References

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Joseph Misdraji, MD

Accepted for publication May 5, 2009.

From the Department of Pathology, Massachusetts General Hospital, Boston.

The author has no relevant financial interest in the products or companies described in this article.

Reprints: Joseph Misdraji, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit St, Warren Bldg, 105F, Boston, MA 02114 (e-mail: jmisdraji@partners.org).
Table 1. Comparison of Various Classification Systems for Low-Grade
Appendiceal Mucinous Tumors

                                              Pai and
Characteristics        Carr and Sobin (8)     Longacre (10)

Confined to the        Adenoma                Adenoma
appendix

Various alterations    Uncertain malignant    Uncertain malignant
of the muscu- laris    potential              potential
mucosae or wall

Associated with        Adenocarcinoma         Low malignant
pseudomyxoma                                  potential
peritonei

Destructive            Adenocarcinoma         Invasive
invasion of the                               adenocarcinoma
appendiceal wall

Characteristics        Misdraji et al (11)

Confined to the        LAMN (a)
appendix

Various alterations    LAMN (a)
of the muscu- laris
mucosae or wall

Associated with        LAMN with peritoneal
pseudomyxoma           spreada
peritonei

Destructive            Invasive adenocar
invasion of the
appendiceal wall

Abbreviation: LAMN, low-grade appendiceal mucinous neoplasm.

(a) Used only for tumors with low-grade cytology. Tumors with
high-grade cytology classified as mucinous adenocarcinoma.

Table 2. Comparison of Classification Systems for Peritoneal Mucinous
Neoplasia

Characteristics        Ronnett et al (6)      Bradley et al (7)

Abundant mucin         Diffuse peritoneal     Mucinous carcinoma
containing mucinous    adenomucinosis         peritonei, low grade
epithelium with
mild architectural
complexity and
low-grade cytology

Abundant mucin         Diffuse peritoneal     Mucinous carcinoma
containing mucinous    adenomucinosis         peritonei, low grade
epithelium with
mild architectural
complexity and
high-grade cytology

Cellular               Peritoneal mucinous    Mucinous carcinoma
proliferations with    carcinomatosis         peritonei, high
complex                                       grade
architectural fea-
tures and high-grade
cytology, with
cribriforming
glands, infiltrating
glands, and with or
without single
cells

Characteristics        Misdraji et al11

Abundant mucin         Peritoneal
containing mucinous    involvement by LAMN
epithelium with
mild architectural
complexity and
low-grade cytology

Abundant mucin         Well-differentiated
containing mucinous    mucinous
epithelium with        adenocarcinoma
mild architectural
complexity and
high-grade cytology

Cellular               Moderately or poorly
proliferations with    differentiated
complex                mucinous
architectural fea-     enocarcinoma
tures and high-grade
cytology, with
cribriforming
glands, infiltrating
glands, and with or
without single
cells

Abbreviation: LAMN, low-grade appendiceal mucinous neoplasm.
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