However, long-term follow-up to determine the efficacy of these treatments is not available. Resection, chemotherapy, and focused radiation have all been used; however, the response has been generally unpredictable. Management of invasive anal squamous cell carcinoma has shifted during the past 3 to 4 decades from surgery ie, abdominoperineal resection to a combined therapy incorporating pelvic radiation and chemotherapy 5-fluorouracil and mitomycin C , with surgery reserved for persistent or recurrent disease.
Distinction of these tumors from lower rectal adenocarcinomas directly extending into the anal canal can be very difficult or impossible. Finally, Paget disease represents a form of intraepithelial adenocarcinoma and will be discussed in this section as well.
As a whole, adenocarcinoma of the anal canal represents a unique challenge both for pathologic diagnosis and for clinical management. Its rarity makes it difficult to perform controlled clinical studies or large retrospective reviews. Little is known about risk factors.
High-risk HPV types may play a role, as their presence has been documented in at least some cases of anal adenocarcinoma. The most significant clinical implication of distinguishing the anal canal origin of these tumors relates to its pattern of local spread, which reflects the dual lymphatic drainage as mentioned under staging of squamous cell carcinomas. Thus, a colorectal type adenocarcinoma occurring within the anal canal carries a higher risk of nodal disease along the inguinal and femoral nodal chains than a rectum-based adenocarcinoma.
Histologic diagnosis rarely poses a significant challenge. However, it is worth mentioning that colorectal type adenocarcinoma of this site as is also true for the distal rectum may have unexpected CK7 expression, although it is usually accompanied by coexpression of CK20 as opposed to anal gland carcinomas that usually do not have CK20 positivity, see below.
Hobbs et al 44 in studied 14 cases of anal canal adenocarcinoma and identified 7 cases that fit a set of criteria that the authors defined for carcinoma of anal gland type: haphazardly dispersed, small glands with scant mucin production that invade the wall of the anorectal area without an intraluminal component; the tumor glands are positive for CK7. Others reported clinically and grossly typical anal gland—type cancers with a histologic appearance inseparable from that of conventional mucinous-type colorectal adenocarcinoma.
Moreover, carcinomas associated with anal fistulae are often mucinous, and it remains to be determined if at least some of such fistula-associated tumors are actually of anal gland or anal duct origin.
Thus, the histologic pattern of anal gland adenocarcinoma remains to be sharply defined. In practice, it would seem reasonable to render this diagnosis when the tumor is primary to the anal canal, centered within the wall of the anorectal area without a preexisting fistula and without surface mucosa dysplasia, irrespective of the extent of mucin production Figure 7. Figure 7. This mucin-producing adenocarcinoma is centered in the wall of the anorectal transition zone, not associated with surface mucosa dysplasia or fistula disease.
Figure 8. Anorectal fistulae may be developmental or acquired. The latter are often secondary to inflammatory conditions such as Crohn disease. Adenocarcinomas arising in anorectal fistulae have been documented and histologic appearance of such tumors is often that of a well-differentiated mucinous adenocarcinoma. The exact cell of origin is difficult to determine.
Some may possibly be related to rectal-type glandular mucosa, while others are related to anal glands or ducts. As mentioned above, distinction of anal gland adenocarcinoma from adenocarcinoma within anorectal fistula can be difficult, as some fistulae may result from dilated anal glands or ducts. Indeed, histochemical studies seem to suggest that at least some fistula-associated adenocarcinomas have mucin characteristics that are similar to those of anal glands.
Clinically, the disease often presents in elderly patients as a pruritic, red or white, crusted patch in anal skin. Primary Paget disease encompasses those cases that originate from the epidermis or squamous epithelium and may or may not evolve into an invasive lesion during its course.
The histogenesis of primary Paget disease remains elusive, with the proposed cells of origin including pluripotent epidermal stem cells, 49 , 50 adnexal stem cells, 51 intraepidermal Toker cells, 52 , 53 or apocrine glands. The visceral malignancy may be synchronous or metachronous. Given that the literature reports are largely limited to case reports or small series, it is difficult to accurately determine the prevalence of primary versus secondary Paget disease.
Sometimes, a distal rectal or anal canal adenocarcinoma may be associated with very limited pagetoid extension of cancer cells in the overlying or immediately adjacent squamous epithelium that does not result in a gross appearance of Paget disease. Strictly speaking, this is a form of secondary Paget disease as well, although its clinical significance in this setting seems trivial. Diagnostic issues arise when a primary anal Paget disease is associated with an invasive component, or when a secondary Paget disease is associated with a metachronous internal malignancy that is not apparent at the time the Paget disease manifests clinically.
Consequently, there have been research efforts that aim at distinguishing primary from secondary conditions by immunohistochemical phenotyping. The rarity of the disease, however, has been a significant limiting factor to such efforts. Thus, although promising patterns have emerged, issues remain. Similar results also have been reported by others in both anal and vulvar Paget disease.
Thus, CK7 appears to be a universal marker of Paget cells, regardless of their site or the presence of an associated internal malignancy. CK20 positivity seems to be a uniform finding in cases that are associated with rectal adenocarcinoma. However, CK20 expression has been observed in occasional cases of primary anal and vulvar Paget disease; thus, its specificity is less than perfect.
The question then is what promotes certain CK7-positive rectal adenocarcinomas to develop secondary Paget disease. Interestingly, anal Paget disease is typically associated with hyperplastic changes in the involved squamous mucosa Figure 8. Awareness of such changes may help point to the diagnosis of Paget disease particularly at the time of frozen section procedure or avoid the misdiagnosis of squamous dysplasia.
Little is known about cancer prevention that is specific for anal adenocarcinoma. Treatment options vary widely from primary surgical resection to definitive chemoradiation or neoadjuvant chemoradiation and surgical resection. Local recurrence is common because of the common presence of multifocal disease, and the difficulty in delineating the lesion grossly. Survival outcome in these patients is often dictated by the presence or absence and stage of an invasive component.
Neuroendocrine neoplasms may occasionally occur in the anal canal. Most such tumors probably originate from neuroendocrine cells residing in colorectal type mucosa, although neuroendocrine cells are known to exist in ATZ mucosa as well. Studies dedicated solely to anal canal neuroendocrine neoplasms are essentially limited to case reports. As a group, well-differentiated neuroendocrine tumors, that is, carcinoid tumors, of the anorectum are believed to have an indolent clinical course.
From a diagnostic point of view, anorectal carcinoid tumors with a tubular pattern a pattern not uncommonly seen in this location may be confused with conventional adenocarcinoma; and high-grade neuroendocrine carcinomas may be confused with poorly differentiated adenocarcinoma, basaloid squamous cell carcinoma, or melanoma.
This may be particularly problematic in biopsy samples. In this scenario, immunohistochemical stains are helpful. Expression of neuroendocrine markers is common but not universal, and labeling may be focal. Small cell carcinomas of the anus may show immunoreactivity for thyroid transcription factor—1 TTF-1 , a phenomenon reported in a variety of other extrapulmonary sites as well.
The histologic features of anal melanoma resemble those of cutaneous melanomas. Most show a junctional component adjacent to the invasive tumor, and this finding is evidence that the lesion is primary. The desmoplastic variant may occasionally occur at this site as well, and diagnosis may be challenging and requires immunohistochemical support.
Management of anal melanoma remains a major challenge. Despite the fact that most patients present with localized and apparently curable primary tumors, the mean survival is only 2 years.
The extent of surgical resection abdominoperineal resection versus local excision does not seem to significantly impact outcome, as patients often die of distant metastases. In a study of 46 patients, 64 perineural invasion was an important prognostic factor. Recent studies 65 have shed light on the pathogenetic molecular pathways in melanoma of various sites. In a study of 20 anal melanomas, Antonescu et al 66 identified 3 KIT mutation-carrying tumors, and by in vitro drug testing, showed that the KIT LP mutant was responsive to specific kinase inhibitors.
An accurate estimation of their relative frequency is difficult because many tumors previously designated as smooth muscle or neural tumors may now be classified as GISTs. Leiomyomas often originate from muscularis mucosae, appear as intraluminal polyps, 69 and are cured by complete removal.
Leiomyosarcomas, on the other hand, are histologically high-grade sarcomas with at least focal pleomorphism and high mitotic activity.
Most leiomyosarcomas also present as intraluminal polypoid tumors, although origin specifically from the muscularis mucosae could not be documented in any of the 8 leiomyosarcomas of the rectum and anus studied by Miettinen et al.
Gastrointestinal stromal tumors only infrequently arise in the large bowel. Within the large bowel, however, the rectum is the most common site. Miettinen et al 70 have shown that in the rectum and anus, GISTs larger than 5 cm or with more than 5 mitoses per 50 HPFs are likely to behave in a malignant fashion, whereas those smaller than 2 cm and with less than 5 mitoses per 50 HPFs only rarely recur or cause death, and those with a size between 2 cm and 5 cm and a mitotic count of less than 5 mitoses per 50 HPFs have a low frequency of malignant behavior, intermediate between the above 2 categories.
Primary lymphoma of the anal canal is rare. However, cases of both Hodgkin disease and non-Hodgkin lymphomas are on record. In contrast, in the non-HIV—infected population, anal lymphomas tend to occur in older patients, are also B-cell type, but are often lower grade.
A variety of lesions may mimic anal neoplasms. For example, ectopic prostatic tissue, endometriosis, inflammatory cloacogenic polyp, and prolapse-related lesions can all form a mass lesion. Essentially all malignant tumor entities occurring in the anal canal may be poorly differentiated, such that the distinction among the various histologic types becomes a challenge.
Commonly, these tumors assume the appearance of a cellular neoplasm with a solid growth pattern Figure 9, A through D. A typical challenging scenario is distinguishing a poorly differentiated squamous cell carcinoma with basaloid features from a small cell neuroendocrine carcinoma.
Also typically challenging is the distinction of a malignant melanoma from literally every other cellular tumor with a solid growth pattern, including GIST. Table 1 provides some key morphologic and immunohistochemical features that are useful in resolving these diagnostic dilemmas. Morphologically, a number of points deserve special attention.
First, small cell carcinoma may have foci of abrupt squamous differentiation, as described above, and as such, can be mistaken for squamous cell carcinoma. In this scenario, the presence of increased mitotic activity and high Ki labeling index favor a diagnosis of high-grade neuroendocrine carcinoma or small cell carcinoma. Lastly, in situ growth and pigment production can be very helpful in diagnosing melanoma.
From an immunohistochemical point of view, additional worthwhile points are listed in Table 2. Ultimately, however, the key to achieving a correct diagnosis is the integration of morphologic and immunohistochemical findings.
Virtually all malignant tumors occurring in the anal canal can become poorly differentiated and difficult to recognize. The author has no relevant financial interest in the products or companies described in this article.
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