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The neoplastic appendix: a practical approach
MINI-SYMPOSIUM: COLORECTAL PATHOLOGY
The neoplastic appendix: a practical approach
Mucoceles (used to describe cystically dilated appendices containing mucin) are uncommon in patients with colon-type neoplasms. The term “mucocele” does not describe a histologic entity, but rather a macroscopic finding and should be reserved for clinicians, radiologists, and gross descriptions.
Dora Lam-Himlin Elizabeth A Montgomery
Microscopic findings Appendiceal tubular adenomas, traditional serrated adenomas and sessile serrated adenomas may all be encountered (Figure 1). The histologic criteria for these lesions are identical to those of their colonic counterparts. Finding adenomatous change should prompt submission of the entire appendix to exclude a higher-grade lesion (i.e. high-grade dysplasia or invasive carcinoma). The descriptive term “cystadenoma” is sometimes used when these adenomatous lesions cause cystic dilation of the appendix (mucocele) with the simultaneous histologic finding of a low-grade dysplastic epithelial lining. As the appendix dilates, the epithelial lining may become attenuated, causing difficulty in determining whether dysplasia is present (Figure 2). As discussed in the next section on mucinous neoplasms, the term adenoma is reserved for lesions that are completely confined to the appendix and therefore without risk for intra-abdominal or peritoneal spread (pseudomyxoma peritonei); essentially, obtaining a negative margin on an “adenoma” is curative. As such, uncertainty regarding the presence or absence of dysplasia in difficult cases does not impact the patient’s prognosis. Colonic-type (non-mucinous) appendiceal adenocarcinomas are defined as malignant tumours in which less than 50% of the lesion is composed of mucin. These lesions are rare, consisting of infiltrating glands resembling those of colorectal adenocarcinomas. There are high-grade nuclear alterations with full-thickness nuclear stratification, vesicular nuclei, irregular membranes, prominent nucleoli, and frequent mitoses with destructive invasion of the appendiceal wall.
Abstract Neoplastic processes in the appendix are histologically similar to their colonic counterparts, and recognition of these neoplasms is relatively straightforward. However, reporting and tumour staging of the neoplastic appendix can be complex, given numerous proposed classification systems, the uncertainty surrounding extra-appendiceal spread, and the frequently low-grade histology. Prognostication and clinical decisions regarding treatment rely heavily upon the completeness of the pathology report. This review discusses the clinicopathologic features of the epithelial neoplasms of the appendix, including colonic-type (non-mucinous) adenomas and adenocarcinomas, mucinous neoplasms, classical carcinoid tumours (well-differentiated neuroendocrine tumours), and goblet cell carcinoids with a focus on prognosis, terminology and pertinent points to include in the pathology report.
Keywords adenocarcinoma ex goblet cell carcinoid; appendiceal neoplasms; appendix; carcinoid; cystadenoma; goblet cell carcinoid; pseudomyxoma peritonei
Colonic-type (non-mucinous) epithelial neoplasms of the appendix: adenomas and adenocarcinomas Colonic-type adenomas and adenocarcinomas of the appendix are non-mucinous neoplasms histologically equivalent to those found in the colon.
Immunohistochemistry Like colorectal examples, appendiceal colonic-type neoplasms express CK20 and CDX-2. They are almost universally CK-7 negative.
Clinical features The non-mucinous adenomas and adenocarcinomas characteristic of colorectal neoplasia rarely occur in the appendix. The frequency of colonic-type neoplasms in the appendix is about 2% and 7% of all adenomas and adenocarcinomas, respectively; the remainder is mucinous neoplasms.1 Most lesions manifest with appendicitis from luminal obstruction. Gross findings Colonic-type neoplasms frequently reside at the appendiceal orifice, whereas mucinous lesions and carcinoids typically arise in the appendiceal tip. Polypoid luminal masses are rare, but gross examination may show features similar to those found in colon neoplasia, including a mass lesion and transmural thickening. Secondary appendicitis may cause a suppurative exudate.
Dora Lam-Himlin MD is at the Mayo Clinic Arizona, Scottsdale, AZ, USA. Conflicts of interest: none declared. Figure 1 Neoplasms found in the colon may also be seen in the appendix. This is a sessile serrated adenoma involving the appendix. Note the widened crypt bases.
Elizabeth A Montgomery MD is at Johns Hopkins Medical Institutions, Baltimore, MD, USA. Conflicts of interest: none declared.
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potential aggressive biologic behaviour. Numerous perplexing terms and competing classification schemes have characterized these lesions, including “mucinous cystadenoma,” “low-grade appendiceal mucinous neoplasm (LAMN),” “mucinous borderline tumour of the appendix,” “mucinous tumour of uncertain malignant potential,” “low-grade mucinous carcinoma,” “pseudomyxoma peritonei,” and “disseminated peritoneal adenomucinosis”.1,6e11 As a result, there is ongoing confusion regarding proper nomenclature, reporting, and prognostication. Clinical features Mucinous neoplasms are detected in only 0.3% of surgically removed appendices, but account for nearly one-third of appendiceal epithelial tumours.12 Patients present with acute appendicitis, obstruction, or a palpable mass. Intussusception into the colon is a rare complication of appendiceal “mucoceles”. Some patients present with pseudomyxoma peritonei, a term that describes the clinical syndrome in which patients experience slowly increasing abdominal girth caused by mucinous ascites resulting from prior mucocele rupture or transmural extension; the abdominal cavity relentlessly fills with mucin produced by the neoplastic cells.
Figure 2 It may be difficult to determine whether dysplasia is present or absent in cases with attenuated epithelium.
Differential diagnosis Since they can progress to carcinomas, sessile serrated adenomas of the appendix should be separated from hyperplastic changes. Like colonic examples, these lesions show widened crypt bases and lateral branching crypts. Some are difficult to confidently diagnose. The entirely submitted appendix should show at least focal areas of widened crypt bases characteristic of sessile serrated adenomas. Adenomas that produce mucoceles must be distinguished from non-neoplastic retention cysts. Retention cysts dilate the appendix, producing a “mucocele” grossly and radiologically. However, the epithelial lining of a retention cyst is often attenuated but nondysplastic. Simple retention cysts are rarely larger than 2 cm. Mucoceles larger than 2 cm that have been diagnosed as benign retention cysts are likely to be insufficiently sampled neoplasms. Submission of the entire “mucocele” for histologic evaluation is recommended to exclude dysplastic epithelium.
Gross findings On gross examination, the appendix is often distended with tenacious luminal mucin (Figure 3). The wall is thick and sclerotic, or calcified (“porcelain appendix”). The term mucocele describes the gross and clinical appearance of a dilated, mucin-filled appendix, but does not indicate whether the histologic appearance is benign or malignant. When a mucocele is encountered, it is critical to determine whether the appendiceal wall is intact; an assessment of this at both the time of surgery and at gross examination is essential. Proper surgical management of the mucocele is critical as rupture of a neoplastic mucocele by traumatic appendectomy could be an iatrogenic catastrophe for the patient. Mucinous neoplasms confined to the appendix behave in a benign fashion, whereas the same tumours can behave in a malignant fashion if their contents have access to the peritoneal cavity.
Prognosis and reporting Like their colonic counterparts, appendiceal adenocarcinomas of colonic (non-mucinous) type develop from adenomatous precursors (tubular, villous, tubulovillous or sessile serrated adenomas). They are comparable to colorectal adenocarcinoma, with a metastatic potential greater than that of appendiceal carcinoid and less than that of colonic carcinoma.1,2 Reporting is analogous to that for colonic adenocarcinomas; the tumour T staging depends on depth of invasion.3,4 Prognostic factors included in the pathology report are essentially identical to those for colonic adenocarcinomas (stage, margins).1,2
Terminology and microscopic findings The terminology of appendiceal mucinous neoplasms has been confounded by multiple classifications over the years. Some
Treatment Adenomatous lesions and early colonic-type adenocarcinoma of the appendix, although uncommon, may be treated with appendectomy alone although right hemicolectomy is often suggested. Adjuvant therapy mirrors that for colonic adenocarcinomas.
Appendiceal mucinous neoplasm Appendiceal mucinous neoplasm is an epithelial neoplasm that generally lacks overtly malignant features and is associated with extra-appendiceal spread; hence the term “neoplasm” is preferred over “adenoma”.5 The bland cytology can be discordant with the
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Figure 3 “Mucocele” is a clinical term used to describe a dilated appendix filled with mucin. Histologic examination of the epithelial component is necessary for classification of the lesion.
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authors propose the phrase “mucinous adenoma” to underscore frequently low-grade histology and indolent behaviour, while others argue that peritoneal spread leads to biologic behaviour similar to that of adenocarcinoma, and support use of that term. However, many appendiceal neoplasms lack frankly invasive histology characteristic of usual adenocarcinomas. In view of this, the nomenclature “low-grade appendiceal mucinous neoplasm (LAMN)” or “mucinous neoplasm of low malignant potential” has found favour. These terms do not carry the same implications as the terms “adenoma” or “carcinoma”. Non-invasive appendiceal mucinous neoplasms can be classified as low-grade (LAMN) or high-grade. LAMNs have a villous or flat proliferation of mucinous epithelium with mild to moderate cytologic atypia (Figure 4). There is mild nuclear enlargement, pseudostratification and hyperchromasia in the absence of complex architectural features. High-grade tumours have severe cytologic abnormalities, including loss of nuclear polarity, mucin depletion, round or ovoid nuclei with conspicuous nucleoli, and cribriform or micropapillary architectural growth patterns. Invasive lesions show high-grade cytologic features in association with desmoplasia (Figure 5). As the lesion grows, the appendiceal lumen may dilate with mucin and produce a “cystadenoma”. The term “cystadenoma” is not a specific pathologic diagnosis, but rather describes a cystically dilated appendix with an adenomatous lining, which can be either colonic-type or mucinous. Appendiceal dilation weakens the muscular wall with prolapse of the epithelium or dissection of mucin through the muscularis. Care should be taken not to interpret these diverticular-like changes as invasive carcinoma. As with diverticula in other parts of the gastrointestinal tract, the presence of an investing lamina propria around the epithelium helps identify the process as benign. Rupture leading to extra-appendiceal spread of mucin may be localized to the periappendiceal area. The mucin may be acellular (Figure 6) or cellular, harbouring strips or clusters of neoplastic epithelium (Figure 7). As patients with acellular extra-appendiceal mucin have an excellent prognosis, accurate assessment for the presence or absence of epithelial elements is critical. Microscopic
Figure 5 This appendiceal mucinous neoplasm shows areas of invasive adenocarcinoma with desmoplasia.
examination of the entire appendix is necessary, as the epithelial elements may be sparse. Lesions with extra-appendiceal tumour cells are more likely to progress to disseminated disease, even if the mucin is paucicellular and confined to the periappendiceal region.8,10,13 Extension beyond the appendix and into the peritoneum The term “pseudomyxoma peritonei” should be reserved for the clinical finding of mucinous ascites; it is not strictly a histologic diagnosis although the World Health Organization (WHO) offers it as a term for reporting findings since our clinical colleagues understand it.5 The histologic findings include neoplastic mucinous epithelial cells present in the peritoneal cavity with independent growth, which can either be low-grade or high-grade.5 Histologically, the neoplastic cells may be extremely scant within abundant mucinous material and extensive sampling may be required to demonstrate them. If extensive sampling has been performed and epithelial cells cannot be demonstrated, this implies a better prognosis.
Figure 6 Acellular mucin has dissected through the layers of the appendiceal wall, but stops short of extending beyond the appendiceal serosa (inked in blue). Histologic examination of the entire specimen showed that the mucin was confined to the appendix without extra-appendiceal spread. Following complete excision with negative margins, the patient is essentially cured.
Figure 4 Low-grade appendiceal mucinous neoplasm. The neoplasm may demonstrate villiform structures or epithelium thrown up into folds. There is abundant cytoplasmic mucin in the low-grade neoplastic epithelium. Chronic inflammation and submucosal fibrosis may accompany the lesion.
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The corresponding peritoneal disease stains in an identical manner, as expected. Differential diagnosis The distinction between low-grade mucinous neoplasm of the appendix and adenoma (colonic-type tubular adenoma, sessile serrated adenoma, etc) with attenuated epithelium as a result of cystic dilatation can occasionally be unfeasible. Features that can be helpful include frank invasion or periappendiceal mucin characteristic of a mucinous neoplasm. The term “mucinous tumour of uncertain malignant potential” has been used when it is impossible to determine whether the appendiceal tumour is an adenoma or a mucinous neoplasm. Prognosis and reporting The single most important prognostic indicator is the specimen integrity. The prudent surgical approach is to regard every mucocele of the appendix as potentially malignant. This means special care is required during resection of an appendiceal mucocele to avoid trauma and possible rupture of the appendix during the operation. This may mean conversion of a laparoscopic appendectomy to an open laparotomy. Appendiceal mucinous neoplasms confined to the mucosa behave in a benign fashion and excision is curative. Mucinous neoplasms with disseminated peritoneal mucin deposits often follow an indolent, but malignant, course. Not infrequently, extraappendiceal mucin is localized to the periappendiceal region without diffuse peritoneal involvement. Mucin deposits in these cases may be acellular or contain neoplastic epithelium (cellular mucin). Patients with localized acellular periappendiceal mucin are unlikely to develop recurrent disease and only 4% develop diffuse peritoneal disease.13 In contrast, 33% of patients with cellular periappendiceal mucin develop mucinous ascites.13 Microscopic examination of the entire resection specimen is necessary to determine the presence or absence of cells in pools of extraappendiceal mucin. In reporting, choosing a terminology can be a daunting task. It may help to include alternative nomenclature in a comment field or parenthetically; however, this may also confuse clinical colleagues who may be less familiar with the convoluted nomenclature. Uniformity throughout a department and/or institution will help alleviate some of this frustration, but regardless of terminology used, it is necessary for the pathologist to report the key prognostic factors: (1) Specimen integrity: grossly intact or ruptured. (2) Classification of the epithelial component: low-grade, highgrade, or invasive. (3) Presence or absence of mucin outside the appendix. (4) Whether any extra-appendiceal mucin is acellular or cellular. (5) Margin status.
Figure 7 This low-grade appendiceal neoplasm shows a focus of abundant mucin with strips of epithelium and rare clusters of epithelial cells floating in mucin pools. The neoplasm also showed extensive extra-appendiceal spread of mucin. Rare epithelial cells were found floating in pools of mucin outside the appendix; the presence of any extra-appendiceal epithelium signifies a more aggressive clinical course than acellular mucin.
As with its parent neoplasm from the appendix, the classification of pseudomyxoma peritonei is plagued with a number of competing nomenclatures. In one system “disseminated peritoneal adenomucinosis,” a term discouraged by the WHO,5 refers to histologically bland adenomatous mucinous epithelium associated with abundant extracellular mucin and fibrosis14 and “peritoneal mucinous carcinomatosis” is used for high-grade lesions. Lesions with histologic features of both low and high-grade features were identified as “peritoneal mucinous carcinomatosis with intermediate or discordant features”. Using this classification, high-grade lesions had a much more aggressive clinical course as compared to low-grade ones (14% versus 75% 5-year survival, respectively).14 For this reason, it is important to note in the pathology report whether the epithelial component is low-grade or high-grade. This critical information should not be lost in the confusion of choosing nomenclature for reporting e a task that may be seem bewildering, but has little true significance aside from semantics. As the controversy over nomenclature has continued, others argue that the term “adenomucinosis” implies a benign “adenoma”like lesion, which can be misleading to patients and clinicians because this low-grade lesion can ultimately result in mortality. These observers prefer the terms “low-grade mucinous adenocarcinoma” and “high-grade mucinous adenocarcinoma” to indicate malignancy in these lesions.6 Still others have used the terms “nonaggressive histology” and “aggressive histology” after identifying the neoplasm as “appendiceal mucinous neoplasm with extraappendiceal spread”.10,11,15 Note that for each classification scheme, there is a method of conveying whether the lesional cells have low-grade (non-aggressive) or high-grade (aggressive) histology. As such, it is not necessary to place undue stress upon which system to use, so long as the pathologist conveys this important prognostic information to the clinician.
Treatment The above factors will help to guide treatment. Right hemicolectomy is not always the treatment of choice in patients with a mucinous neoplasm of the appendix.16 Some observers recommend a sentinel lymph node approach; if intraoperative frozen sections of appendiceal lymph nodes are negative for tumour, a right hemicolectomy is not indicated.17 Additionally, a cecectomy may be adequate treatment for a positive appendiceal margin.
Immunohistochemistry Mucinous neoplasms of the appendix, like those in the colon, express cytokeratin (CK) 20, CDX-2, carcinoembryonic antigen (CEA), and MUC2. Many neoplasms also co-express CK-7.
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Aggressive surgical debulking for mucinous type tumours improves survival rate and reduces recurrence rates in patients with generalized pseudomyxoma peritonei compared with simple appendectomy. Intraperitoneal hyperthermic chemotherapy following cytoreduction of tumour bulk is the current standard of treatment for peritoneal spread.
Classic carcinoid tumour of the appendix Carcinoid tumours are also known as well-differentiated neuroendocrine tumours (NETs) and arise from cells of the diffuse endocrine system. Appendiceal NETs arise from enterochromaffin cells and enteroglucagon cells found in the lamina propria and submucosa. Clinical features Carcinoid tumours arise throughout the gastrointestinal tract; the appendix is the third commonest site (24%) after small intestine (41.8%) and rectum (27.4%).18,19 Carcinoid tumours comprise 75% of neoplasms found in the appendix.20 While appendiceal NETs occur at any age, patients tend to be much younger than those diagnosed with other appendiceal neoplasms and approximately 20 years younger than those with neuroendocrine neoplasms at other sites. Women predominate, with a male-to-female ratio of 1:2.18,19,21e25 Appendiceal NETs are the most common paediatric GI neoplasm. The most common presentation is that of an incidental nodule detected during appendectomy for presumed appendicitis. Others are found incidentally during laparotomy for other reasons. Still others are found at autopsy. Rarely, patients present with an abdominal mass, pain, or the carcinoid syndrome.
Figure 8 Classic carcinoid tumours in the appendix are histologically identical to their colonic and small intestinal counterparts. Cohesive clusters of exquisitely uniform epithelioid cells may form nests (as in this example), trabeculae, tubules, or acinar structures.
(neuron specific enolase and protein gene product 9.5). Historically, silver impregnation techniques were used to differentiate enterochromaffin (EC) and enteroglucagon (L) cells, as they appear morphologically identical. Argentaffin marks the serotonincontaining granules of EC cells, and argyrophil is positive in all endocrine cells. EC cells are reactive for specific peptide hormone markers serotonin, substance P, somatostatin; L cells are reactive for glucagon, glucagon-like peptides, pancreatic polypeptide, and peptide YY. Use of these ancillary studies to differentiate EC and L cell carcinoids may be useful in confirming the diagnosis but are not necessary as the tumours have the same prognosis.
Gross findings Most appendiceal NETs are localized to the appendix at the time of diagnosis. Eighty percent are smaller than 1 cm.20,26,27 Tumours are round or oval and sometimes palpable. The cut surface is grey to yellow and 70% of appendiceal NETs are found at the distal tip of the appendix.28
Differential diagnosis Most examples are not a diagnostic problem. Some examples of acinar pattern NET may mimic an adenocarcinoma, but strong, diffuse staining with neuroendocrine markers such as chromogranin or synaptophysin confirms a NET. Goblet cell carcinoid remains in the differential diagnosis because of its appendiceal origin and reactivity to synaptophysin and chromogranin. However, goblet cell carcinoids have well defined goblet cells with
Microscopic findings Carcinoids of the appendix are morphologically similar to their small intestinal and rectal counterparts (Figure 8). They are characterized by an exquisitely monotonous proliferation of small, bland polygonal cells with a moderate amount of eosinophilic to amphophilic cytoplasm. Nuclei are round with inconspicuous nucleoli and finely stippled chromatin with a “salt and pepper” quality. Pleomorphism and mitoses are rare. Morphologic features of the cells do not differ by cell of origin (immunohistochemistry is required for this distinction). Carcinoids demonstrate variable architectural growth patterns including nested (insular), trabecular, acinar, and tubular. These patterns lack prognostic significance and often overlap, with multiple patterns seen within any single tumour. The stroma can range from delicate and vascular to dense and fibrous. Immunohistochemistry The vast majority of NETs are diffusely immuno-reactive for chromogranin and synaptophysin, as well as CD56 (Figure 9). Some tumours express synaptophysin without expression of chromogranin. Other generic neuroendocrine markers may also be reactive
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Figure 9 A chromogranin immunohistochemical stain shows strong and diffuse reactivity in carcinoid tumours.
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“adenocarcinoid” is no longer used by the WHO. Distinguishing GCC from these other entities is important because the clinical characteristics and prognoses are distinct. In the past, GCC has also been proposed as crypt cell carcinoma, mucinous carcinoid, microglandular carcinoid or amphicrine carcinoma to distinguish the entity from classical carcinoid tumour of the appendix.
eccentric nuclei that are displaced and compressed by cytoplasmic mucin, which are absent in classic carcinoid tumours. Prognosis and reporting The prognosis for patients with conventional appendiceal NETs is better than that for all other anatomic sites, with a 5-year survival rate greater than 95%. Metastasis to regional lymph nodes occurs in approximately 4% of all appendiceal NETs, and this is usually in tumours larger than 2 cm. Distant metastasis occurs in about 1% of cases, once again usually only in tumours larger than 2 cm. In these rare cases, the carcinoid syndrome has been reported.20,22,26,28,29 As evidenced by these data, size is the most important prognostic indicator in appendiceal NETs. Appendiceal NETs are staged according to size by both the American Joint Commission on Cancer (AJCC) Cancer Staging Manual, 7th edition and the International Union against Cancer (UICC) TNM classification 7th edition.3,4 Like other appendiceal lesions, NETs can also be classified several ways. Most are lowgrade, essentially amitotic, without necrosis, and have traditionally been classified as “carcinoids”, a term falling from favour. The term “carcinoid tumour” remains in widespread use, but may cause confusion for clinicians, who might view a carcinoid tumour as a serotonin-producing tumour associated with the functional manifestations of carcinoid syndrome. The WHO has harmonized grading for such tumours across gastrointestinal anatomic sites, a system largely in accordance with both the TNM and AJCC.3e5 They can be graded by assessing the mitotic activity or by performing Ki-67 immunolabeling such that grade 1 tumours (carcinoids) display <2 mitoses/10 high power fields or <2% Ki-67 index and grade 2 tumours (“atypical carcinoids”) have mitotic counts of 2e20/10 high power fields or 3e20% Ki-67 index. So long as prognostic information is included in the report, the classification scheme is not as important. Inclusion of a synoptic report or checklist is recommended.
Clinical features Goblet cell carcinoids occur in adults (mean age, 50 years). There is a female predominance with a male-to-female ratio of about 1:2. The usual clinical presentation is abdominal pain and a palpable mass (50%). Other patients present with symptoms related to acute appendicitis and only 3% of tumours are diagnosed as incidental findings. Patients with advanced disease most frequently present with abdominal masses. In female patients with stage IV disease, 83% present with ovarian masses and a presumptive diagnosis of a primary ovarian neoplasm. Overall, less than 1% of patients have a preoperative diagnosis of a primary appendiceal tumour. Gross findings At gross examination, GCC tumours rarely form a discrete nodule or mass, and may present as a grossly normal appendix. Due to their infiltrative nature, they most commonly grow in a circumferential pattern with longitudinal extension along the length of the appendix. Most tumours are greater than 2 cm (representing length of tumour extension rather than diameter) and infiltrate the appendiceal wall. Microscopic findings Goblet cell carcinoids arise without a recognizable precursor lesion. They infiltrate in a concentric manner with small clusters, linear rows or single cells that often defy detection at low magnification. They display a wide range of histologic patterns. Fundamental morphologic features common to all GCCs include: (1) The presence, at least focally, of mucin containing gobletshaped or signet-ring epithelial cells arranged in round or oval clusters at the primary site. (2) At least focal immunoreactivity for neuroendocrine markers (chromogranin or synaptophysin). Tang et al have proposed a classification for this family of tumours based on the morphology of the tumour at the primary site.31 The schema divides the tumours into three groups (groups A, B, and C) which show distinct morphologic and prognostic characteristics.
Treatment Appendectomy is usually curative, particularly for tumours smaller than 1 cm. For cases with lymph node metastasis, size larger than 2 cm, high mitotic count, mesoappendiceal invasion, peritoneal studding, or angioinvasion, a right hemicolectomy is advised. Cases lacking these features, but involving the proximal margin, are treated by limited re-excision. In tumours of uncertain malignancy (between 1 and 2 cm), the presence of deep serosal and mesoappendiceal spread and a significant mitotic rate may predict more aggressive behaviour.20,26e28
Goblet cell carcinoid and adenocarcinoma ex goblet cell carcinoid
Typical goblet cell carcinoids (group A) demonstrate well defined goblet cells arranged in tight clusters or a cohesive linear pattern with minimal cytologic atypia and no desmoplasia. There is minimal architectural distortion of the appendiceal wall and continued cohesiveness of tumour cells despite invasion. As tumour cells infiltrate through the muscularis, the clusters often exhibit a compressed linear configuration aligned along the axis of the muscle fibres. This compression of groups can give rise to a single-file pattern, reminiscent of a poorly differentiated signetring carcinoma, but the cells exhibit minimal atypia and remain cohesive (Figure 10a). Extracellular mucin may be seen as a result of degenerative changes.
Appendiceal goblet cell carcinoid (GCC) tumour was first recognized as a distinct entity in 1969 and remains a rare appendiceal neoplasm with uncertain histogenesis. These infiltrative tumours have a mixed phenotype, with partial neuroendocrine differentiation and intestinal-type goblet cell morphology.30 As such, they have been classified in the past with other neoplasms that show both neuroendocrine and glandular differentiation as “adenocarcinoid tumours,” a term that encompasses biologically diverse neoplasms such as tubular pattern carcinoid tumour and a collision tumour of typical carcinoid with a de novo adenocarcinoma.1 It is best to avoid using this term to avoid confusion; the term
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of the appendiceal wall. However, despite the complete near loss of the goblet cell clustered architecture, there is at least a focal component with histologic features of typical GCC. Adenocarcinoma ex goblet cell carcinoid, poorly differentiated carcinoma type (group C) is the least common subtype, comprising about 10% of GCCs. It has at least focal evidence of goblet cell morphology and a component of poorly differentiated adenocarcinoma defined as: >1 low power field (or 1 mm2) of tumour cells which are not otherwise distinguishable from a poorly differentiated adenocarcinoma. The tumour cells may appear as either gland forming, confluent sheets of signet-ring cells, malignant epithelial cells with or without signet-ring features, or simply an undifferentiated carcinoma. Immunohistochemistry Nearly all goblet cell carcinoids express cytokeratin (CK) 20 and up to 70% co-express CK-7. The goblet cells express carcinoembryonic antigen (CEA) and the endocrine cells react at least focally with endocrine markers chromogranin and synaptophysin (Figure 10b). Intracytoplasmic mucin can be demonstrated with mucicarmine, a useful diagnostic tool (Figure 10c). Differential diagnosis Diagnosis of goblet cell carcinoid tumours can be perplexing as a result of unfortunate taxonomy and it is further complicated by shared histologic features with other tumours. Classic carcinoid tumours with glandular differentiation (tubular pattern) were previously regarded as “adenocarcinoid” tumours. Tubular carcinoids are distinguished from GCCs by their formation of glandular structures, lack of goblet or signetring cells, strong diffuse staining with endocrine markers, and lack of mucin. Goblet cell carcinoids have patchy or focal staining with endocrine markers. Tubular carcinoids behave indolently like classic carcinoids and should not be confused with the more aggressive GCC.30 Other entities previously regarded as “adenocarcinoid” include tumours with mixed carcinoid-adenocarcinoma histology, which may represent a true collision tumour of adenocarcinoma and a separate de novo carcinoid. Alternatively, tumours with mixed morphology may be carcinoid tumours with entrapped nonneoplastic epithelium. Differentiating these tumours from goblet cell carcinoids can be aided by the infiltrative and concentric pattern of growth that is typical of goblet cell carcinoid. Figure 10 (a) Goblet cell carcinoids infiltrate in a concentric fashion, often in small clusters, linear rows, or single cells e a feature that makes them difficult to detect at low power. (b) A chromogranin immunohistochemical stain is reactive in the goblet cells, although it may be weak or patchy. The intensity of staining in this goblet cell carcinoid is characteristically weaker in comparison to that of the classic carcinoid tumour (Figure 9). (c) A mucicarmine stain highlights the intracytoplasmic mucin in the neoplastic goblet cells.
Prognosis and reporting Compared to classic carcinoid tumours of the appendix, GCCs behave aggressively with the exception of “group A” neoplasms. Most patients (97%) have transmural extension of the tumour at the time of diagnosis and more than half present with metastatic (stage IV-type) disease if all types are included, but stage is related to the histologic grade of the primary tumour. Thus 33% of group A, 88% of group B and 100% of group C tumours are metastatic at presentation. The ovary is the most common site of metastasis in women (88%), usually presenting as Krukenberg tumours. Lymph node metastases are detected in more than onethird of patients, dependent on the histologic subtype. Of patients with group A tumours, 20% have lymph node metastases, compared to 75% of group B and 100% of group C patients.
Adenocarcinoma ex goblet cell carcinoid, signet-ring type (group B) is comprised of goblet cells or signet-ring cells arranged in irregular, large, disorganized clusters that have lost cohesion. There is significant cytologic atypia (hyperchromatic and irregular nuclei) and a discohesive single-file or single cell infiltrating pattern may be present along with desmoplasia and associated destruction
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11 Pai RK, Longacre TA. Appendiceal mucinous tumors and pseudomyxoma peritonei: histologic features, diagnostic problems, and proposed classification. Adv Anat Pathol 2005; 12: 291e311. 12 Smeenk RM, van Velthuysen ML, Verwaal VJ, et al. Appendiceal neoplasms and pseudomyxoma peritonei: a population based study. Eur J Surg Oncol 2008; 34: 196e201. 13 Yantiss RK, Shia J, Klimstra DS, et al. Prognostic significance of localized extra-appendiceal mucin deposition in appendiceal mucinous neoplasms. Am J Surg Pathol 2009; 33: 248e55. 14 Ronnett BM, Zahn CM, Kurman RJ, et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19: 1390e408. 15 Pai RK, Beck AH, Norton JA, et al. Appendiceal mucinous neoplasms: clinicopathologic study of 116 cases with analysis of factors predicting recurrence. Am J Surg Pathol 2009; 33: 1425e39. 16 Gonzalez-Moreno S, Sugarbaker PH. Right hemicolectomy does not confer a survival advantage in patients with mucinous carcinoma of the appendix and peritoneal seeding. Br J Surg 2004; 91: 304e11. 17 Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol 2001; 27: 239e43. 18 Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97: 934e59. 19 Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997; 79: 813e29. 20 Plockinger U, Couvelard A, Falconi M, et al. Consensus guidelines for the management of patients with digestive neuroendocrine tumours: well-differentiated tumour/carcinoma of the appendix and goblet cell carcinoma. Neuroendocrinology 2008; 87: 20e30. 21 Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. Cancer 2001; 92: 2204e10. 22 Godwin 2nd JD. Carcinoid tumors. An analysis of 2,837 cases. Cancer 1975; 36: 560e9. 23 Caplin ME, Buscombe JR, Hilson AJ, et al. Carcinoid tumour. Lancet 1998; 352: 799e805. 24 Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999; 340: 858e68. 25 Maggard MA, O’Connell JB, Ko CY. Updated population-based review of carcinoid tumors. Ann Surg 2004; 240: 117e22. 26 O’Donnell ME, Carson J, Garstin WI. Surgical treatment of malignant carcinoid tumours of the appendix. Int J Clin Pract 2007; 61: 431e7. 27 Stinner B, Rothmund M. Neuroendocrine tumours (carcinoids) of the appendix. Best Pract Res Clin Gastroenterol 2005; 19: 729e38. 28 Deans GT, Spence RA. Neoplastic lesions of the appendix. Br J Surg 1995; 82: 299e306. 29 Gustafsson BI, Siddique L, Chan A, et al. Uncommon cancers of the small intestine, appendix and colon: an analysis of SEER 1973e2004, and current diagnosis and therapy. Int J Oncol 2008; 33: 1121e31. 30 Burke AP, Sobin LH, Federspiel BH, et al. Goblet cell carcinoids and related tumors of the vermiform appendix. Am J Clin Pathol 1990; 94: 27e35. 31 Tang LH, Shia J, Soslow RA, et al. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol 2008; 32: 1429e43.
As GCCs behave more aggressively than classic carcinoids, it is important to note that GCCs are staged and reported similarly to adenocarcinomas according to the AJCC, TNM and WHO;3e5 thus GCCs are T staged according to depth and extent of invasion by all staging systems. Pertinent elements to include in reporting are essentially the same as for adenocarcinomas (extent of invasion, lymph nodes, margin status, histologic grade, etc.). As mentioned previously, the term “goblet cell carcinoid” is preferred, as older terms such as “adenocarcinoid” may cause confusion. Inclusion of histologic grade is the critical element for prognosis, but specific reference to the Tang grading system is not necessary. Treatment Surgical management with right hemicolectomy is recommended after appendectomy for most cases, particularly those with an adenocarcinoma component (groups B and C). Additional debulking procedures and chemotherapy may be needed. Chemotherapy regimens are similar to those used for colonic adenocarcinomas. Intraperitoneal spread may warrant oophorectomy and intraperitoneal chemotherapy. The disease specific 5-year survival for group A tumours is 100%, while that for groups B and C are 36% and 0% respectively.31 A
REFERENCES 1 Carr NJ, Sobin LH. Epithelial noncarcinoid tumors and tumor-like lesions of the appendix. Cancer 1995; 76: 2383e4. 2 Carr NJ, Emory TS, Sobin LH. Epithelial neoplasms of the appendix and colorectum: an analysis of cell proliferation, apoptosis, and expression of p53, CD44, bcl-2. Arch Pathol Lab Med 2002; 126: 837e41. 3 Edge S, Byrd D, Compton C, et al., eds. AJCC Cancer Staging Manual. New York: Springer, 2010. 4 Sobin L, Gospodarowicz M, Wittekind C, eds. International Union against Cancer TNM Classification of Malignant Tumours. Lyon: Wiley-Blackwell, 2009. 5 Bosman F, Carneiro F, Hruban R, et al., eds. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010. 6 Bradley RF, Stewart JHT, Russell GB, et al. Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review. Am J Surg Pathol 2006; 30: 551e9. 7 Gibbs NM. Mucinous cystadenoma and cystadenocarcinoma of the vermiform appendix with particular reference to mucocele and pseudomyxoma peritonei. J Clin Pathol 1973; 26: 413e21. 8 Higa E, Rosai J, Pizzimbono CA, et al. Mucosal hyperplasia, mucinous cystadenoma, and mucinous cystadenocarcinoma of the appendix. A re-evaluation of appendiceal “mucocele”. Cancer 1973; 32: 1525e41. 9 Melcher DH, Rayan AS. Columnar-cell (non-carcinoid) tumours of the appendix. Br J Surg 1968; 55: 693e6. 10 Misdraji J, Yantiss RK, Graeme-Cook FM, et al. Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases. Am J Surg Pathol 2003; 27: 1089e103.
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C
Practice points
Appendiceal well-differentiated neuroendocrine tumour (classic carcinoid) C Staged by size, not extent of invasion. C Right hemicolectomy is suggested for tumours >2 cm, presence of regional lymph node metastasis, high mitotic count, mesoappendiceal invasion, and angioinvasion. C If only the proximal resection margin is involved, conservative local re-excision may be considered.
All neoplasms C Gross examination for specimen integrity is essential. C When dealing with a simple appendectomy, submission of the entire specimen for histologic evaluation is prudent all cases. Colonic-type (non-mucinous) epithelial neoplasms C Mucocele formation is rarely found. C Classification, morphology, reporting/staging, and adjuvant are essentially identical to colonic counterparts.
Goblet cell carcinoid C Avoid older terminology such as “adenocarcinoid” or “mucinous carcinoid”. C T staged as per adenocarcinoma by the extent of invasion in contrast to classic carcinoids. C Prognosis is related to tumour stage at presentation and histologic grade. C 5-year survival based on Tang’s histologic groups: C Group A (well-differentiated): 100%. C Group B (adenocarcinoma ex GCC with signet-ring cells): 36%. C Group C (adenocarcinoma ex GCC, poorly differentiated): 0%.
Appendiceal mucinous neoplasms C Mucinous neoplasms are much more frequent than colonictype (non-mucinous) neoplasms, and frequently result in a mucin-filled, dilated appendix. C Complete excision of a neoplasm confined to the appendix is curative. C Patients with extra-appendiceal spread of either cellular or acellular mucin are at risk for development of pseudomyxoma peritonei (mucinous ascites). C While the majority of these neoplasms are low-grade, the report should identify the epithelial component as low-grade, high-grade, or invasive for prognostication. C The presence or absence of extra-appendiceal spread of mucin should be included in the report; if present, also state whether epithelial elements are present or absent. C So long as these prognostic factors are included in the report, one should not agonize over which nomenclature to use.
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Following peritoneal spread, aggressive surgical debulking and hyperthermic chemotherapy are treatments of choice.
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Advanced disease and peritoneal spread may require additional debulking, oophorectomy and intraperitoneal chemotherapy.
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The neoplastic appendix: a practical approach
Mucoceles (used to describe cystically dilated appendices containing mucin) are uncommon in patients with colon-type neoplasms. The term “mucocele” does not describe a histologic entity, but rather a macroscopic finding and should be reserved for clinicians, radiologists, and gross descriptions.
Dora Lam-Himlin Elizabeth A Montgomery
Microscopic findings Appendiceal tubular adenomas, traditional serrated adenomas and sessile serrated adenomas may all be encountered (Figure 1). The histologic criteria for these lesions are identical to those of their colonic counterparts. Finding adenomatous change should prompt submission of the entire appendix to exclude a higher-grade lesion (i.e. high-grade dysplasia or invasive carcinoma). The descriptive term “cystadenoma” is sometimes used when these adenomatous lesions cause cystic dilation of the appendix (mucocele) with the simultaneous histologic finding of a low-grade dysplastic epithelial lining. As the appendix dilates, the epithelial lining may become attenuated, causing difficulty in determining whether dysplasia is present (Figure 2). As discussed in the next section on mucinous neoplasms, the term adenoma is reserved for lesions that are completely confined to the appendix and therefore without risk for intra-abdominal or peritoneal spread (pseudomyxoma peritonei); essentially, obtaining a negative margin on an “adenoma” is curative. As such, uncertainty regarding the presence or absence of dysplasia in difficult cases does not impact the patient’s prognosis. Colonic-type (non-mucinous) appendiceal adenocarcinomas are defined as malignant tumours in which less than 50% of the lesion is composed of mucin. These lesions are rare, consisting of infiltrating glands resembling those of colorectal adenocarcinomas. There are high-grade nuclear alterations with full-thickness nuclear stratification, vesicular nuclei, irregular membranes, prominent nucleoli, and frequent mitoses with destructive invasion of the appendiceal wall.
Abstract Neoplastic processes in the appendix are histologically similar to their colonic counterparts, and recognition of these neoplasms is relatively straightforward. However, reporting and tumour staging of the neoplastic appendix can be complex, given numerous proposed classification systems, the uncertainty surrounding extra-appendiceal spread, and the frequently low-grade histology. Prognostication and clinical decisions regarding treatment rely heavily upon the completeness of the pathology report. This review discusses the clinicopathologic features of the epithelial neoplasms of the appendix, including colonic-type (non-mucinous) adenomas and adenocarcinomas, mucinous neoplasms, classical carcinoid tumours (well-differentiated neuroendocrine tumours), and goblet cell carcinoids with a focus on prognosis, terminology and pertinent points to include in the pathology report.
Keywords adenocarcinoma ex goblet cell carcinoid; appendiceal neoplasms; appendix; carcinoid; cystadenoma; goblet cell carcinoid; pseudomyxoma peritonei
Colonic-type (non-mucinous) epithelial neoplasms of the appendix: adenomas and adenocarcinomas Colonic-type adenomas and adenocarcinomas of the appendix are non-mucinous neoplasms histologically equivalent to those found in the colon.
Immunohistochemistry Like colorectal examples, appendiceal colonic-type neoplasms express CK20 and CDX-2. They are almost universally CK-7 negative.
Clinical features The non-mucinous adenomas and adenocarcinomas characteristic of colorectal neoplasia rarely occur in the appendix. The frequency of colonic-type neoplasms in the appendix is about 2% and 7% of all adenomas and adenocarcinomas, respectively; the remainder is mucinous neoplasms.1 Most lesions manifest with appendicitis from luminal obstruction. Gross findings Colonic-type neoplasms frequently reside at the appendiceal orifice, whereas mucinous lesions and carcinoids typically arise in the appendiceal tip. Polypoid luminal masses are rare, but gross examination may show features similar to those found in colon neoplasia, including a mass lesion and transmural thickening. Secondary appendicitis may cause a suppurative exudate.
Dora Lam-Himlin MD is at the Mayo Clinic Arizona, Scottsdale, AZ, USA. Conflicts of interest: none declared. Figure 1 Neoplasms found in the colon may also be seen in the appendix. This is a sessile serrated adenoma involving the appendix. Note the widened crypt bases.
Elizabeth A Montgomery MD is at Johns Hopkins Medical Institutions, Baltimore, MD, USA. Conflicts of interest: none declared.
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potential aggressive biologic behaviour. Numerous perplexing terms and competing classification schemes have characterized these lesions, including “mucinous cystadenoma,” “low-grade appendiceal mucinous neoplasm (LAMN),” “mucinous borderline tumour of the appendix,” “mucinous tumour of uncertain malignant potential,” “low-grade mucinous carcinoma,” “pseudomyxoma peritonei,” and “disseminated peritoneal adenomucinosis”.1,6e11 As a result, there is ongoing confusion regarding proper nomenclature, reporting, and prognostication. Clinical features Mucinous neoplasms are detected in only 0.3% of surgically removed appendices, but account for nearly one-third of appendiceal epithelial tumours.12 Patients present with acute appendicitis, obstruction, or a palpable mass. Intussusception into the colon is a rare complication of appendiceal “mucoceles”. Some patients present with pseudomyxoma peritonei, a term that describes the clinical syndrome in which patients experience slowly increasing abdominal girth caused by mucinous ascites resulting from prior mucocele rupture or transmural extension; the abdominal cavity relentlessly fills with mucin produced by the neoplastic cells.
Figure 2 It may be difficult to determine whether dysplasia is present or absent in cases with attenuated epithelium.
Differential diagnosis Since they can progress to carcinomas, sessile serrated adenomas of the appendix should be separated from hyperplastic changes. Like colonic examples, these lesions show widened crypt bases and lateral branching crypts. Some are difficult to confidently diagnose. The entirely submitted appendix should show at least focal areas of widened crypt bases characteristic of sessile serrated adenomas. Adenomas that produce mucoceles must be distinguished from non-neoplastic retention cysts. Retention cysts dilate the appendix, producing a “mucocele” grossly and radiologically. However, the epithelial lining of a retention cyst is often attenuated but nondysplastic. Simple retention cysts are rarely larger than 2 cm. Mucoceles larger than 2 cm that have been diagnosed as benign retention cysts are likely to be insufficiently sampled neoplasms. Submission of the entire “mucocele” for histologic evaluation is recommended to exclude dysplastic epithelium.
Gross findings On gross examination, the appendix is often distended with tenacious luminal mucin (Figure 3). The wall is thick and sclerotic, or calcified (“porcelain appendix”). The term mucocele describes the gross and clinical appearance of a dilated, mucin-filled appendix, but does not indicate whether the histologic appearance is benign or malignant. When a mucocele is encountered, it is critical to determine whether the appendiceal wall is intact; an assessment of this at both the time of surgery and at gross examination is essential. Proper surgical management of the mucocele is critical as rupture of a neoplastic mucocele by traumatic appendectomy could be an iatrogenic catastrophe for the patient. Mucinous neoplasms confined to the appendix behave in a benign fashion, whereas the same tumours can behave in a malignant fashion if their contents have access to the peritoneal cavity.
Prognosis and reporting Like their colonic counterparts, appendiceal adenocarcinomas of colonic (non-mucinous) type develop from adenomatous precursors (tubular, villous, tubulovillous or sessile serrated adenomas). They are comparable to colorectal adenocarcinoma, with a metastatic potential greater than that of appendiceal carcinoid and less than that of colonic carcinoma.1,2 Reporting is analogous to that for colonic adenocarcinomas; the tumour T staging depends on depth of invasion.3,4 Prognostic factors included in the pathology report are essentially identical to those for colonic adenocarcinomas (stage, margins).1,2
Terminology and microscopic findings The terminology of appendiceal mucinous neoplasms has been confounded by multiple classifications over the years. Some
Treatment Adenomatous lesions and early colonic-type adenocarcinoma of the appendix, although uncommon, may be treated with appendectomy alone although right hemicolectomy is often suggested. Adjuvant therapy mirrors that for colonic adenocarcinomas.
Appendiceal mucinous neoplasm Appendiceal mucinous neoplasm is an epithelial neoplasm that generally lacks overtly malignant features and is associated with extra-appendiceal spread; hence the term “neoplasm” is preferred over “adenoma”.5 The bland cytology can be discordant with the
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Figure 3 “Mucocele” is a clinical term used to describe a dilated appendix filled with mucin. Histologic examination of the epithelial component is necessary for classification of the lesion.
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authors propose the phrase “mucinous adenoma” to underscore frequently low-grade histology and indolent behaviour, while others argue that peritoneal spread leads to biologic behaviour similar to that of adenocarcinoma, and support use of that term. However, many appendiceal neoplasms lack frankly invasive histology characteristic of usual adenocarcinomas. In view of this, the nomenclature “low-grade appendiceal mucinous neoplasm (LAMN)” or “mucinous neoplasm of low malignant potential” has found favour. These terms do not carry the same implications as the terms “adenoma” or “carcinoma”. Non-invasive appendiceal mucinous neoplasms can be classified as low-grade (LAMN) or high-grade. LAMNs have a villous or flat proliferation of mucinous epithelium with mild to moderate cytologic atypia (Figure 4). There is mild nuclear enlargement, pseudostratification and hyperchromasia in the absence of complex architectural features. High-grade tumours have severe cytologic abnormalities, including loss of nuclear polarity, mucin depletion, round or ovoid nuclei with conspicuous nucleoli, and cribriform or micropapillary architectural growth patterns. Invasive lesions show high-grade cytologic features in association with desmoplasia (Figure 5). As the lesion grows, the appendiceal lumen may dilate with mucin and produce a “cystadenoma”. The term “cystadenoma” is not a specific pathologic diagnosis, but rather describes a cystically dilated appendix with an adenomatous lining, which can be either colonic-type or mucinous. Appendiceal dilation weakens the muscular wall with prolapse of the epithelium or dissection of mucin through the muscularis. Care should be taken not to interpret these diverticular-like changes as invasive carcinoma. As with diverticula in other parts of the gastrointestinal tract, the presence of an investing lamina propria around the epithelium helps identify the process as benign. Rupture leading to extra-appendiceal spread of mucin may be localized to the periappendiceal area. The mucin may be acellular (Figure 6) or cellular, harbouring strips or clusters of neoplastic epithelium (Figure 7). As patients with acellular extra-appendiceal mucin have an excellent prognosis, accurate assessment for the presence or absence of epithelial elements is critical. Microscopic
Figure 5 This appendiceal mucinous neoplasm shows areas of invasive adenocarcinoma with desmoplasia.
examination of the entire appendix is necessary, as the epithelial elements may be sparse. Lesions with extra-appendiceal tumour cells are more likely to progress to disseminated disease, even if the mucin is paucicellular and confined to the periappendiceal region.8,10,13 Extension beyond the appendix and into the peritoneum The term “pseudomyxoma peritonei” should be reserved for the clinical finding of mucinous ascites; it is not strictly a histologic diagnosis although the World Health Organization (WHO) offers it as a term for reporting findings since our clinical colleagues understand it.5 The histologic findings include neoplastic mucinous epithelial cells present in the peritoneal cavity with independent growth, which can either be low-grade or high-grade.5 Histologically, the neoplastic cells may be extremely scant within abundant mucinous material and extensive sampling may be required to demonstrate them. If extensive sampling has been performed and epithelial cells cannot be demonstrated, this implies a better prognosis.
Figure 6 Acellular mucin has dissected through the layers of the appendiceal wall, but stops short of extending beyond the appendiceal serosa (inked in blue). Histologic examination of the entire specimen showed that the mucin was confined to the appendix without extra-appendiceal spread. Following complete excision with negative margins, the patient is essentially cured.
Figure 4 Low-grade appendiceal mucinous neoplasm. The neoplasm may demonstrate villiform structures or epithelium thrown up into folds. There is abundant cytoplasmic mucin in the low-grade neoplastic epithelium. Chronic inflammation and submucosal fibrosis may accompany the lesion.
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The corresponding peritoneal disease stains in an identical manner, as expected. Differential diagnosis The distinction between low-grade mucinous neoplasm of the appendix and adenoma (colonic-type tubular adenoma, sessile serrated adenoma, etc) with attenuated epithelium as a result of cystic dilatation can occasionally be unfeasible. Features that can be helpful include frank invasion or periappendiceal mucin characteristic of a mucinous neoplasm. The term “mucinous tumour of uncertain malignant potential” has been used when it is impossible to determine whether the appendiceal tumour is an adenoma or a mucinous neoplasm. Prognosis and reporting The single most important prognostic indicator is the specimen integrity. The prudent surgical approach is to regard every mucocele of the appendix as potentially malignant. This means special care is required during resection of an appendiceal mucocele to avoid trauma and possible rupture of the appendix during the operation. This may mean conversion of a laparoscopic appendectomy to an open laparotomy. Appendiceal mucinous neoplasms confined to the mucosa behave in a benign fashion and excision is curative. Mucinous neoplasms with disseminated peritoneal mucin deposits often follow an indolent, but malignant, course. Not infrequently, extraappendiceal mucin is localized to the periappendiceal region without diffuse peritoneal involvement. Mucin deposits in these cases may be acellular or contain neoplastic epithelium (cellular mucin). Patients with localized acellular periappendiceal mucin are unlikely to develop recurrent disease and only 4% develop diffuse peritoneal disease.13 In contrast, 33% of patients with cellular periappendiceal mucin develop mucinous ascites.13 Microscopic examination of the entire resection specimen is necessary to determine the presence or absence of cells in pools of extraappendiceal mucin. In reporting, choosing a terminology can be a daunting task. It may help to include alternative nomenclature in a comment field or parenthetically; however, this may also confuse clinical colleagues who may be less familiar with the convoluted nomenclature. Uniformity throughout a department and/or institution will help alleviate some of this frustration, but regardless of terminology used, it is necessary for the pathologist to report the key prognostic factors: (1) Specimen integrity: grossly intact or ruptured. (2) Classification of the epithelial component: low-grade, highgrade, or invasive. (3) Presence or absence of mucin outside the appendix. (4) Whether any extra-appendiceal mucin is acellular or cellular. (5) Margin status.
Figure 7 This low-grade appendiceal neoplasm shows a focus of abundant mucin with strips of epithelium and rare clusters of epithelial cells floating in mucin pools. The neoplasm also showed extensive extra-appendiceal spread of mucin. Rare epithelial cells were found floating in pools of mucin outside the appendix; the presence of any extra-appendiceal epithelium signifies a more aggressive clinical course than acellular mucin.
As with its parent neoplasm from the appendix, the classification of pseudomyxoma peritonei is plagued with a number of competing nomenclatures. In one system “disseminated peritoneal adenomucinosis,” a term discouraged by the WHO,5 refers to histologically bland adenomatous mucinous epithelium associated with abundant extracellular mucin and fibrosis14 and “peritoneal mucinous carcinomatosis” is used for high-grade lesions. Lesions with histologic features of both low and high-grade features were identified as “peritoneal mucinous carcinomatosis with intermediate or discordant features”. Using this classification, high-grade lesions had a much more aggressive clinical course as compared to low-grade ones (14% versus 75% 5-year survival, respectively).14 For this reason, it is important to note in the pathology report whether the epithelial component is low-grade or high-grade. This critical information should not be lost in the confusion of choosing nomenclature for reporting e a task that may be seem bewildering, but has little true significance aside from semantics. As the controversy over nomenclature has continued, others argue that the term “adenomucinosis” implies a benign “adenoma”like lesion, which can be misleading to patients and clinicians because this low-grade lesion can ultimately result in mortality. These observers prefer the terms “low-grade mucinous adenocarcinoma” and “high-grade mucinous adenocarcinoma” to indicate malignancy in these lesions.6 Still others have used the terms “nonaggressive histology” and “aggressive histology” after identifying the neoplasm as “appendiceal mucinous neoplasm with extraappendiceal spread”.10,11,15 Note that for each classification scheme, there is a method of conveying whether the lesional cells have low-grade (non-aggressive) or high-grade (aggressive) histology. As such, it is not necessary to place undue stress upon which system to use, so long as the pathologist conveys this important prognostic information to the clinician.
Treatment The above factors will help to guide treatment. Right hemicolectomy is not always the treatment of choice in patients with a mucinous neoplasm of the appendix.16 Some observers recommend a sentinel lymph node approach; if intraoperative frozen sections of appendiceal lymph nodes are negative for tumour, a right hemicolectomy is not indicated.17 Additionally, a cecectomy may be adequate treatment for a positive appendiceal margin.
Immunohistochemistry Mucinous neoplasms of the appendix, like those in the colon, express cytokeratin (CK) 20, CDX-2, carcinoembryonic antigen (CEA), and MUC2. Many neoplasms also co-express CK-7.
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Aggressive surgical debulking for mucinous type tumours improves survival rate and reduces recurrence rates in patients with generalized pseudomyxoma peritonei compared with simple appendectomy. Intraperitoneal hyperthermic chemotherapy following cytoreduction of tumour bulk is the current standard of treatment for peritoneal spread.
Classic carcinoid tumour of the appendix Carcinoid tumours are also known as well-differentiated neuroendocrine tumours (NETs) and arise from cells of the diffuse endocrine system. Appendiceal NETs arise from enterochromaffin cells and enteroglucagon cells found in the lamina propria and submucosa. Clinical features Carcinoid tumours arise throughout the gastrointestinal tract; the appendix is the third commonest site (24%) after small intestine (41.8%) and rectum (27.4%).18,19 Carcinoid tumours comprise 75% of neoplasms found in the appendix.20 While appendiceal NETs occur at any age, patients tend to be much younger than those diagnosed with other appendiceal neoplasms and approximately 20 years younger than those with neuroendocrine neoplasms at other sites. Women predominate, with a male-to-female ratio of 1:2.18,19,21e25 Appendiceal NETs are the most common paediatric GI neoplasm. The most common presentation is that of an incidental nodule detected during appendectomy for presumed appendicitis. Others are found incidentally during laparotomy for other reasons. Still others are found at autopsy. Rarely, patients present with an abdominal mass, pain, or the carcinoid syndrome.
Figure 8 Classic carcinoid tumours in the appendix are histologically identical to their colonic and small intestinal counterparts. Cohesive clusters of exquisitely uniform epithelioid cells may form nests (as in this example), trabeculae, tubules, or acinar structures.
(neuron specific enolase and protein gene product 9.5). Historically, silver impregnation techniques were used to differentiate enterochromaffin (EC) and enteroglucagon (L) cells, as they appear morphologically identical. Argentaffin marks the serotonincontaining granules of EC cells, and argyrophil is positive in all endocrine cells. EC cells are reactive for specific peptide hormone markers serotonin, substance P, somatostatin; L cells are reactive for glucagon, glucagon-like peptides, pancreatic polypeptide, and peptide YY. Use of these ancillary studies to differentiate EC and L cell carcinoids may be useful in confirming the diagnosis but are not necessary as the tumours have the same prognosis.
Gross findings Most appendiceal NETs are localized to the appendix at the time of diagnosis. Eighty percent are smaller than 1 cm.20,26,27 Tumours are round or oval and sometimes palpable. The cut surface is grey to yellow and 70% of appendiceal NETs are found at the distal tip of the appendix.28
Differential diagnosis Most examples are not a diagnostic problem. Some examples of acinar pattern NET may mimic an adenocarcinoma, but strong, diffuse staining with neuroendocrine markers such as chromogranin or synaptophysin confirms a NET. Goblet cell carcinoid remains in the differential diagnosis because of its appendiceal origin and reactivity to synaptophysin and chromogranin. However, goblet cell carcinoids have well defined goblet cells with
Microscopic findings Carcinoids of the appendix are morphologically similar to their small intestinal and rectal counterparts (Figure 8). They are characterized by an exquisitely monotonous proliferation of small, bland polygonal cells with a moderate amount of eosinophilic to amphophilic cytoplasm. Nuclei are round with inconspicuous nucleoli and finely stippled chromatin with a “salt and pepper” quality. Pleomorphism and mitoses are rare. Morphologic features of the cells do not differ by cell of origin (immunohistochemistry is required for this distinction). Carcinoids demonstrate variable architectural growth patterns including nested (insular), trabecular, acinar, and tubular. These patterns lack prognostic significance and often overlap, with multiple patterns seen within any single tumour. The stroma can range from delicate and vascular to dense and fibrous. Immunohistochemistry The vast majority of NETs are diffusely immuno-reactive for chromogranin and synaptophysin, as well as CD56 (Figure 9). Some tumours express synaptophysin without expression of chromogranin. Other generic neuroendocrine markers may also be reactive
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Figure 9 A chromogranin immunohistochemical stain shows strong and diffuse reactivity in carcinoid tumours.
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“adenocarcinoid” is no longer used by the WHO. Distinguishing GCC from these other entities is important because the clinical characteristics and prognoses are distinct. In the past, GCC has also been proposed as crypt cell carcinoma, mucinous carcinoid, microglandular carcinoid or amphicrine carcinoma to distinguish the entity from classical carcinoid tumour of the appendix.
eccentric nuclei that are displaced and compressed by cytoplasmic mucin, which are absent in classic carcinoid tumours. Prognosis and reporting The prognosis for patients with conventional appendiceal NETs is better than that for all other anatomic sites, with a 5-year survival rate greater than 95%. Metastasis to regional lymph nodes occurs in approximately 4% of all appendiceal NETs, and this is usually in tumours larger than 2 cm. Distant metastasis occurs in about 1% of cases, once again usually only in tumours larger than 2 cm. In these rare cases, the carcinoid syndrome has been reported.20,22,26,28,29 As evidenced by these data, size is the most important prognostic indicator in appendiceal NETs. Appendiceal NETs are staged according to size by both the American Joint Commission on Cancer (AJCC) Cancer Staging Manual, 7th edition and the International Union against Cancer (UICC) TNM classification 7th edition.3,4 Like other appendiceal lesions, NETs can also be classified several ways. Most are lowgrade, essentially amitotic, without necrosis, and have traditionally been classified as “carcinoids”, a term falling from favour. The term “carcinoid tumour” remains in widespread use, but may cause confusion for clinicians, who might view a carcinoid tumour as a serotonin-producing tumour associated with the functional manifestations of carcinoid syndrome. The WHO has harmonized grading for such tumours across gastrointestinal anatomic sites, a system largely in accordance with both the TNM and AJCC.3e5 They can be graded by assessing the mitotic activity or by performing Ki-67 immunolabeling such that grade 1 tumours (carcinoids) display <2 mitoses/10 high power fields or <2% Ki-67 index and grade 2 tumours (“atypical carcinoids”) have mitotic counts of 2e20/10 high power fields or 3e20% Ki-67 index. So long as prognostic information is included in the report, the classification scheme is not as important. Inclusion of a synoptic report or checklist is recommended.
Clinical features Goblet cell carcinoids occur in adults (mean age, 50 years). There is a female predominance with a male-to-female ratio of about 1:2. The usual clinical presentation is abdominal pain and a palpable mass (50%). Other patients present with symptoms related to acute appendicitis and only 3% of tumours are diagnosed as incidental findings. Patients with advanced disease most frequently present with abdominal masses. In female patients with stage IV disease, 83% present with ovarian masses and a presumptive diagnosis of a primary ovarian neoplasm. Overall, less than 1% of patients have a preoperative diagnosis of a primary appendiceal tumour. Gross findings At gross examination, GCC tumours rarely form a discrete nodule or mass, and may present as a grossly normal appendix. Due to their infiltrative nature, they most commonly grow in a circumferential pattern with longitudinal extension along the length of the appendix. Most tumours are greater than 2 cm (representing length of tumour extension rather than diameter) and infiltrate the appendiceal wall. Microscopic findings Goblet cell carcinoids arise without a recognizable precursor lesion. They infiltrate in a concentric manner with small clusters, linear rows or single cells that often defy detection at low magnification. They display a wide range of histologic patterns. Fundamental morphologic features common to all GCCs include: (1) The presence, at least focally, of mucin containing gobletshaped or signet-ring epithelial cells arranged in round or oval clusters at the primary site. (2) At least focal immunoreactivity for neuroendocrine markers (chromogranin or synaptophysin). Tang et al have proposed a classification for this family of tumours based on the morphology of the tumour at the primary site.31 The schema divides the tumours into three groups (groups A, B, and C) which show distinct morphologic and prognostic characteristics.
Treatment Appendectomy is usually curative, particularly for tumours smaller than 1 cm. For cases with lymph node metastasis, size larger than 2 cm, high mitotic count, mesoappendiceal invasion, peritoneal studding, or angioinvasion, a right hemicolectomy is advised. Cases lacking these features, but involving the proximal margin, are treated by limited re-excision. In tumours of uncertain malignancy (between 1 and 2 cm), the presence of deep serosal and mesoappendiceal spread and a significant mitotic rate may predict more aggressive behaviour.20,26e28
Goblet cell carcinoid and adenocarcinoma ex goblet cell carcinoid
Typical goblet cell carcinoids (group A) demonstrate well defined goblet cells arranged in tight clusters or a cohesive linear pattern with minimal cytologic atypia and no desmoplasia. There is minimal architectural distortion of the appendiceal wall and continued cohesiveness of tumour cells despite invasion. As tumour cells infiltrate through the muscularis, the clusters often exhibit a compressed linear configuration aligned along the axis of the muscle fibres. This compression of groups can give rise to a single-file pattern, reminiscent of a poorly differentiated signetring carcinoma, but the cells exhibit minimal atypia and remain cohesive (Figure 10a). Extracellular mucin may be seen as a result of degenerative changes.
Appendiceal goblet cell carcinoid (GCC) tumour was first recognized as a distinct entity in 1969 and remains a rare appendiceal neoplasm with uncertain histogenesis. These infiltrative tumours have a mixed phenotype, with partial neuroendocrine differentiation and intestinal-type goblet cell morphology.30 As such, they have been classified in the past with other neoplasms that show both neuroendocrine and glandular differentiation as “adenocarcinoid tumours,” a term that encompasses biologically diverse neoplasms such as tubular pattern carcinoid tumour and a collision tumour of typical carcinoid with a de novo adenocarcinoma.1 It is best to avoid using this term to avoid confusion; the term
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of the appendiceal wall. However, despite the complete near loss of the goblet cell clustered architecture, there is at least a focal component with histologic features of typical GCC. Adenocarcinoma ex goblet cell carcinoid, poorly differentiated carcinoma type (group C) is the least common subtype, comprising about 10% of GCCs. It has at least focal evidence of goblet cell morphology and a component of poorly differentiated adenocarcinoma defined as: >1 low power field (or 1 mm2) of tumour cells which are not otherwise distinguishable from a poorly differentiated adenocarcinoma. The tumour cells may appear as either gland forming, confluent sheets of signet-ring cells, malignant epithelial cells with or without signet-ring features, or simply an undifferentiated carcinoma. Immunohistochemistry Nearly all goblet cell carcinoids express cytokeratin (CK) 20 and up to 70% co-express CK-7. The goblet cells express carcinoembryonic antigen (CEA) and the endocrine cells react at least focally with endocrine markers chromogranin and synaptophysin (Figure 10b). Intracytoplasmic mucin can be demonstrated with mucicarmine, a useful diagnostic tool (Figure 10c). Differential diagnosis Diagnosis of goblet cell carcinoid tumours can be perplexing as a result of unfortunate taxonomy and it is further complicated by shared histologic features with other tumours. Classic carcinoid tumours with glandular differentiation (tubular pattern) were previously regarded as “adenocarcinoid” tumours. Tubular carcinoids are distinguished from GCCs by their formation of glandular structures, lack of goblet or signetring cells, strong diffuse staining with endocrine markers, and lack of mucin. Goblet cell carcinoids have patchy or focal staining with endocrine markers. Tubular carcinoids behave indolently like classic carcinoids and should not be confused with the more aggressive GCC.30 Other entities previously regarded as “adenocarcinoid” include tumours with mixed carcinoid-adenocarcinoma histology, which may represent a true collision tumour of adenocarcinoma and a separate de novo carcinoid. Alternatively, tumours with mixed morphology may be carcinoid tumours with entrapped nonneoplastic epithelium. Differentiating these tumours from goblet cell carcinoids can be aided by the infiltrative and concentric pattern of growth that is typical of goblet cell carcinoid. Figure 10 (a) Goblet cell carcinoids infiltrate in a concentric fashion, often in small clusters, linear rows, or single cells e a feature that makes them difficult to detect at low power. (b) A chromogranin immunohistochemical stain is reactive in the goblet cells, although it may be weak or patchy. The intensity of staining in this goblet cell carcinoid is characteristically weaker in comparison to that of the classic carcinoid tumour (Figure 9). (c) A mucicarmine stain highlights the intracytoplasmic mucin in the neoplastic goblet cells.
Prognosis and reporting Compared to classic carcinoid tumours of the appendix, GCCs behave aggressively with the exception of “group A” neoplasms. Most patients (97%) have transmural extension of the tumour at the time of diagnosis and more than half present with metastatic (stage IV-type) disease if all types are included, but stage is related to the histologic grade of the primary tumour. Thus 33% of group A, 88% of group B and 100% of group C tumours are metastatic at presentation. The ovary is the most common site of metastasis in women (88%), usually presenting as Krukenberg tumours. Lymph node metastases are detected in more than onethird of patients, dependent on the histologic subtype. Of patients with group A tumours, 20% have lymph node metastases, compared to 75% of group B and 100% of group C patients.
Adenocarcinoma ex goblet cell carcinoid, signet-ring type (group B) is comprised of goblet cells or signet-ring cells arranged in irregular, large, disorganized clusters that have lost cohesion. There is significant cytologic atypia (hyperchromatic and irregular nuclei) and a discohesive single-file or single cell infiltrating pattern may be present along with desmoplasia and associated destruction
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11 Pai RK, Longacre TA. Appendiceal mucinous tumors and pseudomyxoma peritonei: histologic features, diagnostic problems, and proposed classification. Adv Anat Pathol 2005; 12: 291e311. 12 Smeenk RM, van Velthuysen ML, Verwaal VJ, et al. Appendiceal neoplasms and pseudomyxoma peritonei: a population based study. Eur J Surg Oncol 2008; 34: 196e201. 13 Yantiss RK, Shia J, Klimstra DS, et al. Prognostic significance of localized extra-appendiceal mucin deposition in appendiceal mucinous neoplasms. Am J Surg Pathol 2009; 33: 248e55. 14 Ronnett BM, Zahn CM, Kurman RJ, et al. Disseminated peritoneal adenomucinosis and peritoneal mucinous carcinomatosis. A clinicopathologic analysis of 109 cases with emphasis on distinguishing pathologic features, site of origin, prognosis, and relationship to “pseudomyxoma peritonei”. Am J Surg Pathol 1995; 19: 1390e408. 15 Pai RK, Beck AH, Norton JA, et al. Appendiceal mucinous neoplasms: clinicopathologic study of 116 cases with analysis of factors predicting recurrence. Am J Surg Pathol 2009; 33: 1425e39. 16 Gonzalez-Moreno S, Sugarbaker PH. Right hemicolectomy does not confer a survival advantage in patients with mucinous carcinoma of the appendix and peritoneal seeding. Br J Surg 2004; 91: 304e11. 17 Sugarbaker PH. Cytoreductive surgery and peri-operative intraperitoneal chemotherapy as a curative approach to pseudomyxoma peritonei syndrome. Eur J Surg Oncol 2001; 27: 239e43. 18 Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tumors. Cancer 2003; 97: 934e59. 19 Modlin IM, Sandor A. An analysis of 8305 cases of carcinoid tumors. Cancer 1997; 79: 813e29. 20 Plockinger U, Couvelard A, Falconi M, et al. Consensus guidelines for the management of patients with digestive neuroendocrine tumours: well-differentiated tumour/carcinoma of the appendix and goblet cell carcinoma. Neuroendocrinology 2008; 87: 20e30. 21 Hemminki K, Li X. Incidence trends and risk factors of carcinoid tumors: a nationwide epidemiologic study from Sweden. Cancer 2001; 92: 2204e10. 22 Godwin 2nd JD. Carcinoid tumors. An analysis of 2,837 cases. Cancer 1975; 36: 560e9. 23 Caplin ME, Buscombe JR, Hilson AJ, et al. Carcinoid tumour. Lancet 1998; 352: 799e805. 24 Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999; 340: 858e68. 25 Maggard MA, O’Connell JB, Ko CY. Updated population-based review of carcinoid tumors. Ann Surg 2004; 240: 117e22. 26 O’Donnell ME, Carson J, Garstin WI. Surgical treatment of malignant carcinoid tumours of the appendix. Int J Clin Pract 2007; 61: 431e7. 27 Stinner B, Rothmund M. Neuroendocrine tumours (carcinoids) of the appendix. Best Pract Res Clin Gastroenterol 2005; 19: 729e38. 28 Deans GT, Spence RA. Neoplastic lesions of the appendix. Br J Surg 1995; 82: 299e306. 29 Gustafsson BI, Siddique L, Chan A, et al. Uncommon cancers of the small intestine, appendix and colon: an analysis of SEER 1973e2004, and current diagnosis and therapy. Int J Oncol 2008; 33: 1121e31. 30 Burke AP, Sobin LH, Federspiel BH, et al. Goblet cell carcinoids and related tumors of the vermiform appendix. Am J Clin Pathol 1990; 94: 27e35. 31 Tang LH, Shia J, Soslow RA, et al. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol 2008; 32: 1429e43.
As GCCs behave more aggressively than classic carcinoids, it is important to note that GCCs are staged and reported similarly to adenocarcinomas according to the AJCC, TNM and WHO;3e5 thus GCCs are T staged according to depth and extent of invasion by all staging systems. Pertinent elements to include in reporting are essentially the same as for adenocarcinomas (extent of invasion, lymph nodes, margin status, histologic grade, etc.). As mentioned previously, the term “goblet cell carcinoid” is preferred, as older terms such as “adenocarcinoid” may cause confusion. Inclusion of histologic grade is the critical element for prognosis, but specific reference to the Tang grading system is not necessary. Treatment Surgical management with right hemicolectomy is recommended after appendectomy for most cases, particularly those with an adenocarcinoma component (groups B and C). Additional debulking procedures and chemotherapy may be needed. Chemotherapy regimens are similar to those used for colonic adenocarcinomas. Intraperitoneal spread may warrant oophorectomy and intraperitoneal chemotherapy. The disease specific 5-year survival for group A tumours is 100%, while that for groups B and C are 36% and 0% respectively.31 A
REFERENCES 1 Carr NJ, Sobin LH. Epithelial noncarcinoid tumors and tumor-like lesions of the appendix. Cancer 1995; 76: 2383e4. 2 Carr NJ, Emory TS, Sobin LH. Epithelial neoplasms of the appendix and colorectum: an analysis of cell proliferation, apoptosis, and expression of p53, CD44, bcl-2. Arch Pathol Lab Med 2002; 126: 837e41. 3 Edge S, Byrd D, Compton C, et al., eds. AJCC Cancer Staging Manual. New York: Springer, 2010. 4 Sobin L, Gospodarowicz M, Wittekind C, eds. International Union against Cancer TNM Classification of Malignant Tumours. Lyon: Wiley-Blackwell, 2009. 5 Bosman F, Carneiro F, Hruban R, et al., eds. WHO Classification of Tumours of the Digestive System. Lyon: IARC, 2010. 6 Bradley RF, Stewart JHT, Russell GB, et al. Pseudomyxoma peritonei of appendiceal origin: a clinicopathologic analysis of 101 patients uniformly treated at a single institution, with literature review. Am J Surg Pathol 2006; 30: 551e9. 7 Gibbs NM. Mucinous cystadenoma and cystadenocarcinoma of the vermiform appendix with particular reference to mucocele and pseudomyxoma peritonei. J Clin Pathol 1973; 26: 413e21. 8 Higa E, Rosai J, Pizzimbono CA, et al. Mucosal hyperplasia, mucinous cystadenoma, and mucinous cystadenocarcinoma of the appendix. A re-evaluation of appendiceal “mucocele”. Cancer 1973; 32: 1525e41. 9 Melcher DH, Rayan AS. Columnar-cell (non-carcinoid) tumours of the appendix. Br J Surg 1968; 55: 693e6. 10 Misdraji J, Yantiss RK, Graeme-Cook FM, et al. Appendiceal mucinous neoplasms: a clinicopathologic analysis of 107 cases. Am J Surg Pathol 2003; 27: 1089e103.
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C
Practice points
Appendiceal well-differentiated neuroendocrine tumour (classic carcinoid) C Staged by size, not extent of invasion. C Right hemicolectomy is suggested for tumours >2 cm, presence of regional lymph node metastasis, high mitotic count, mesoappendiceal invasion, and angioinvasion. C If only the proximal resection margin is involved, conservative local re-excision may be considered.
All neoplasms C Gross examination for specimen integrity is essential. C When dealing with a simple appendectomy, submission of the entire specimen for histologic evaluation is prudent all cases. Colonic-type (non-mucinous) epithelial neoplasms C Mucocele formation is rarely found. C Classification, morphology, reporting/staging, and adjuvant are essentially identical to colonic counterparts.
Goblet cell carcinoid C Avoid older terminology such as “adenocarcinoid” or “mucinous carcinoid”. C T staged as per adenocarcinoma by the extent of invasion in contrast to classic carcinoids. C Prognosis is related to tumour stage at presentation and histologic grade. C 5-year survival based on Tang’s histologic groups: C Group A (well-differentiated): 100%. C Group B (adenocarcinoma ex GCC with signet-ring cells): 36%. C Group C (adenocarcinoma ex GCC, poorly differentiated): 0%.
Appendiceal mucinous neoplasms C Mucinous neoplasms are much more frequent than colonictype (non-mucinous) neoplasms, and frequently result in a mucin-filled, dilated appendix. C Complete excision of a neoplasm confined to the appendix is curative. C Patients with extra-appendiceal spread of either cellular or acellular mucin are at risk for development of pseudomyxoma peritonei (mucinous ascites). C While the majority of these neoplasms are low-grade, the report should identify the epithelial component as low-grade, high-grade, or invasive for prognostication. C The presence or absence of extra-appendiceal spread of mucin should be included in the report; if present, also state whether epithelial elements are present or absent. C So long as these prognostic factors are included in the report, one should not agonize over which nomenclature to use.
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Following peritoneal spread, aggressive surgical debulking and hyperthermic chemotherapy are treatments of choice.
C
403
Advanced disease and peritoneal spread may require additional debulking, oophorectomy and intraperitoneal chemotherapy.
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