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26 Anal Intraepithelial Neoplasms

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similarly to anal canal cancers, except that state T4 denotes invasion of deep structures such as bone and muscle. Similar to other cancers, T4 anal margin cancer patients should have CT examinations to look for metastases (see Chap. 27). Preferred treatment is CRT; APR is recommended for deep lesions (T2-T4 or N1), those involving the sphincter muscles, or incontinent patients. Prognosis is poorer for cancers at the anal margin.

Local excision is considered only when the lesion is small, supercial, distal to the anal canal in either the anal margin, at the verge, or in the perianal skin. If margins are inadequate or there is suspicion that a small number of tumor cells were left behind, low-dose chemotherapy is warranted.

Post-treatment surveillance is critical as persistence and recurrence are common. However, active surveillance cannot begin until 8–12 weeks after completion of CRT. A complete physical exam includes visual inspection, DRE, HRA, inguinal node palpation. Patients should be examined every 3–6months for the first 2years and every 6–12months until 5years after treatment.

If the cancer is detected within 6months of treatment, it is called persistent. Cancer detected past 6 months is considered recurrent. Persistence or recurrence after CRT occurs in 20–30% of patients and is associated with a higher stage at presentation, HIV seropositivity, and an inability to complete CRT.Persistent disease has a poorer prognosis than recurrent disease. If a local disease fails to respond to CRT, APR is recommended. Note that a rotational or pedicled ap should be used for reconstruction to decrease the chance of wound failure.

If salvage therapy fails for a local disease OR if CRT fails, systemic chemotherapy is indicated. In disease with distant metastases, cetuximab may prove helpful as an adjuvant therapy. Involved lymph nodes should be removed. Prognosis is poor in this subgroup, with a median survival of 9months.

Anal Conditions: Anal Margin Tumors

DavidA.Vivas andJillC.Genua

Refer toAlgorithm inFig. 27.1

A. Incidence

Anal cancer is a relatively rare, uncommon malignancy. Worldwide, the incidence of anal cancer has been increasing over the past 3–4 decades, particularly in developed countries. The true incidence of anal margin cancer is difcult to determine, as lesions of the anal canal and anal margin are often grouped together. Anal margin cancer is at least ve times less common than anal canal cancer. Generally, anal margin cancer is thought to follow a different clinical course with lower incidence, less aggressive biology, greater likelihood of local excision and a more favorable outcome.

B. Denition

The anal margin or perianal skin is identied by keratin containing epithelium containing hair follicles and encompasses a radius of 5cm from the anal verge. The anatomy of the anus can be confusing; in addition, body habitus of the patient and distortion of the area due to the pathology can hinder precise localiza-

D. A. Vivas Colon and Rectal Surgeon, Stony Brook, NY, USA

J. C. Genua (*) Division ofColon andRectal Surgery, Stony Brook School ofMedicine, Stony Brook University Medical Center, Stony Brook, NY, USA e-mail: jill.genua@stonybrookmedicine.edu

tion. The distinction between the anal margin/ perianal skin and the anal canal is important to avoid over or under treatment due to incorrect localization. The anal canal is divided into two regions: the anal canal proximal to the dentate line (columnar epithelium), and the anal canal distal to the dentate line (stratied squamous epithelium). The dentate line is dened as the demarcation between the columnar epithelium of the proximal canal and the stratied squamous epithelium of the distal canal. The anal verge is dened as the junction of the squamous epithelium with the perianal skin (anal margin) which is a keratinized squamous epithelium containing hair follicles. The anal margin is dened as the skin within 5cm from the anal verge. In order to eliminate discrepancy between practitioners, a more practical description has been proposed. Upon retraction of the buttock, the anal canal is not visualized, the anal verge is the part of the anal canal that remains closed, and anal margin/perianal lesions are completely visible within a 5cm radius of the anal opening. The dentate line also separates the pattern of lymphatic drainage; tumors below the dentate line and the anal margin drain into the inguinal and femoral lymph nodes.

C. Types of anal margin tumors

Anal margin tumors include squamous cell carcinoma (Fig.27.2), Bowen’s disease (perianal high grade squamous intraepithelial

https://doi.org/10.1007/978-3-319-65942-8_27

207

208

Fig. 27.1 Algorithm for diagnosis and treatment of anal margin tumors. DRE Digital rectal exam, RT Radiotherapy, HRA High resolution anoscopy, APR Abdomino perineal resection

D. A. Vivas and J. C. Genua

lesions, squamous cell carcinoma in situ), Paget’s disease (intraepithelial adenocarcinoma), basal cell carcinoma, verrucous carcinoma (giant condyloma, Buschke-Lowenstein tumor) and malignant melanoma. Of these, the most frequent tumor of the perianal skin is squamous cell carcinoma.

D. Presentation

The vast majority of patients presenting with anorectal complaints will have benign disease. Surgeons should evaluate these complaints thoroughly and consistently. Suspicious or atypical ndings must be recognized on physical exam and promptly biopsied. Symptoms at presentation most commonly include anorectal bleeding, pain, pruritus, discharge, palpable mass/lump, tenesmus, weight loss, perianal rashes and chronic non- healing processes. History should identify the following risk factors: HPV infection, smoking, prior radiotherapy, Crohn’s Disease, chronic anal wounds/drainage/stulas, abnormal PAP smear, history of

cervical carcinoma, immunosuppression following solid organ transplant, Hodgkin’s Disease, HIV infection, sexually transmitted diseases, multiple sexual partners, male homosexuality, anoreceptive intercourse, immunosuppression, anal condyloma, and Anal Intraepithelial Neoplasia (AIN). A history of benign lesions does not contribute to the development of anal cancer. Physical exam includes inspection of size, location and features, digital rectal examination, anoscopy, rigid proctosigmoidoscopy, and inguinal and femoral lymph node palpation. Colonoscopy, vaginal exam/PAP, and HIV testing can be considered at this time or as the diagnosis evolves. Important descriptive features of the anal lesion include location, size, proximal extent, ulceration or central depression, pigmentation, and characteristics of the edges (discrete, rolled, indistinct). Note whether the tumor is friable, supercial, rm, at, papillomatous or cauliower like (Fig.27.2).

27 Anal Conditions: Anal Margin Tumors

Fig. 27.2 Large squamous cell carcinoma of anal margin. With minimal retraction of the buttocks, the lesion is seen beginning at anal verge and centered in the 5cm radius, extending from the anal verge in the perianal region

E. Diagnosis

Diagnosis is determined by incisional or excisional biopsy depending on the size of the lesion and the likelihood of achieving adequate margins. Total excisional biopsy is recommended for lesions smaller than 1cm or isolated mucosal ndings; incisional biopsies are preferable for tumors larger than 1 cm. Excisional biopsy of large lesions or attempt to reduce the tumor burden at time of biopsy can lead to damage to the sphincter and should be avoided. Punch biopsy can assist with tissue biopsy of larger tumors, at lesions, or indistinct areas of chronic inammation. Excisional biopsy should include a 1cm margin. Anal ultrasound and MRI may provide helpful information such as tumor size, location, sphincter involvement or extent of penetration into deep or adjacent tissue. Operative exam under anesthesia may be required to dene the borders and obtain tis-

209

sue for pathology, particularly if the tumor is bulky and invading the anal canal.

F. Squamous cell carcinoma of anal margin/

perianal skin

Squamous cell carcinoma of the anal margin typically appears as an ulcerated lesion with rolled everted edges. The tumor starts as a slow-growing nodule conned in the perianal skin until later stages when the lesion may advance in to the anal canal. Once histology is conrmed as anal margin squamous cell carcinoma, CT of the chest, abdomen and pelvis is performed; colonoscopy, HIV status and gynecological exam in women are updated. The staging for cutaneous SCC is applied. T1 tumors are less than 2cm, T2 are 2–5cm or any tumor with high risk features, T3 tumors are greater than 5cm in size and T4 tumors involve invasion of deep extradermal structures (bone, striated muscle, cartilage). Lymph node metastasis is related to tumor size: 0% in tumors less than 2cm, 23% of tumors 2 to 5 cm and 67% of tumors greater than 5cm.

a. T1N0 anal margin SCC can be successfully

treated by wide local excision with a 1cm margin around the tumor and if there is no sphincter involvement. T1NO and early T2N0 lesions can also be treated with primary radiation therapy. Generally, wide local excision is preferred for small, well differentiated tumors, which avoids the inconvenience and morbidity that can result from radiation therapy. If the margins are inadequate, reexcision can be performed or consideration is given for radiation therapy +/− 5-FU or capecitabine-based chemo- therapy. Suspicious lymph nodes should be investigated with FNA or biopsy. Sentinel lymph node biopsy has been used for all T stages tumors for better treatment planning and to avoid unnecessary radiation in larger tumors but the results are too inconsistent to put this into routine practice. T2NO supercial, well to moderately differentiated anal margin squamous cell cancers can be treated with radiation alone to the primary lesion and the inguinal nodes. For

210

Paget’s disease (intraepithelial

D. A. Vivas and J. C. Genua

larger tumors (T3–T4) or any lymph node

involvement (N+), external beam radiation

to the primary tumor and inguinal/pelvic

lymph nodes with 2cycles of concomitant

adjuvant chemo (5-FU/mitomycin or mito-

mycin/capecitabine) are given. Abdomino-

perineal resection (APR) is considered for

signicant sphincter involvement, tumors

persisting after chemoradiation or salvage

following local recurrence.

G. Bowen’s disease (perianal high grade squa-

mous intraepithelial lesions, squamous carcinoma in situ)

Bowen’s disease was rst dened in 1912 as a premalignant dermatosis of the perianal region that developed an invasive component in less than 5% of cases. The terminology to describe anal dysplasia has undergone changes. Bowen’s disease is synonymous with high grade squamous intraepithelial lesion (HSIL), anal squamous carcinoma in situ, high grade anal intraepithelial neoplasia (HGAIN) and AIN II and AIN III. HSIL is the term most consistently used. HSIL is the immediate precursor to anal cancer with HPV related dysplastic changes as the causative agent. Appearance of HSIL may mimic dermatologic conditions appearing as a scaly plaque-like lesion, may be clinically unapparent, or may be detected incidentally such as in hemorrhoidectomy specimens. Goals of treatment should include eradication of primary and recurrent lesions, prevention of progression to cancer and minimizing morbidity. A variety of options exist with controversy as to which is superior. Traditionally, wide local excision and anal mapping to achieve negative histologic margins has been performed. This involves four quadrant biopsy of the anal canal, anal verge and perianal skin for 12–24 punch biopsies. These blind biopsies may heal by secondary intention, but if repeated biopsies are needed or the defects are large, then skin grafting or aps would be required. An alternative is high resolution anoscopy (HRA) which involves identication of the HSIL using acetic acid, Lugol’s solution and an operat-

ing microscope. HSIL is identied and targeted for destruction by electrocautery, laser or infrared coagulation. Common topical therapies include topical Imiquimod and topical 5-FU. Photodynamic therapy, radiation therapy, and laser therapy have been reported with some success. Although the preferred management of patients with HSIL varies, there is agreement that consistent follow- up, targeting excision or ablation of new lesions and patient compliance play an important role in preventing the progression of HSIL to invasive squamous cell cancer.

adenocarcinoma)

Perianal Paget’s is a rare intraepithelial adenocarcinoma, a precursor to invasive adenocarcinoma and a form of extramammary Paget’s disease which develops in apocrine glands. Perianal Paget’s usually presents as a slowly expanding, sharply demarcated, erythematous plaque that can be eczematous, crusting, scaling or ulcerated and causes pruritus, pain, burning and bleeding. As with many anal lesions, symptoms may be nonspecic, resulting in delayed diagnosis. Pathologic examination reveals Paget cells, which are malignant cells with enlarged, clear cytoplasm and large nuclei. Perianal Paget’s disease presents as two entities: primary anogenital extramammary Paget’s disease, or secondary to extension of a colorectal malignancy or to a remote gastrointestinal cancer. Approximately half of patients with anal Paget’s disease harbor a colorectal neoplasm, therefore full colonoscopic examination is mandatory with this diagnosis. Treatment of noninvasive Paget’s disease is local excision with clear margins. Preoperative or intraoperative mapping with random punch biopsies is often required to establish the boundaries of the lesion microscopically. The goal of excision is to achieve microscopic margins of 1cm. A variety of techniques for staged excision and skin grafting have been described to minimize morbidity as an alternative to tissue aps if the microscopic disease is circumferential or extensive. Invasive disease or peri-

27 Anal Conditions: Anal Margin Tumors

211

anal Paget’s disease with an associated invasive colorectal malignancy may require APR for radical resection, and/or combined modality with chemotherapy and radiation.

I. Basal cell carcinoma

Perianal basal cell carcinoma is a rare anal margin lesion and a rare site of cutaneous basal cell carcinoma. Full examination should be performed as patients often have basal cell carcinomas elsewhere in the body. It is typically a 0.5 to 5cm nodular or ulcerated nodular lesion; supercially extensive and inltrative patterns also occur. The risk of spread is low and complete excision is curative. For large perianal basal cell carcinoma, bilateral V-Y ap has been described for reconstruction of the perianal skin defect after curative resection. Deep invasion requiring radical resection with APR or local control would be extremely unusual. Basal cell carcinoma of the anal margin should be distinguished from basaloid squamous cell carcinoma of the anus which is a different pathologic entity.

J. Verrucous carcinoma (giant condyloma,

Buschke-Lowenstein tumor)

Verrucous carcinomas (also known as giant condylomas and historically labeled BuschkeLowenstein tumors) area lesions characterized by condylomatous features, large size, local invasion and lack of distant metastasis. They are associated with HPV, but a causal relationship has not been established. In the early clinical stages, they appear as verrucous, slow growing lesions, resistant or poorly responsive to topical therapy. Histologically they are benign: low grade, well differentiated, with minimal atypia and few mitotic cells. As they grow larger, the verrucous carcinomas invade the surrounding tissue causing destruction, necrosis and erosion. In this later stage, local tissue destruction may result in stulas and extension into the ischiorectal spaces. Despite this malignant, invasive behavior, verrucous carcinomas do not metastasize. Biopsies of multiple areas, including the base of the tumor, should be taken to rule out a true invasive component

which would then be viewed as invasive squamous cell carcinoma with metastatic potential. Treatment is wide local excision, preferably in the earlier stages. In the later stulizing stages or if the tumor degenerated to an invasive squamous cell carcinoma, abdominoperineal resection (APR) may be necessary. Combined modalities such as chemotherapy and radiation are not used for verrucous carcinoma unless there is a true invasive component.

K. Malignant melanoma

Anorectal melanoma is rare and more likely to begin in the anal canal than the anal margin. However, anal melanoma may be diagnosed based on a symptom or nding at the perianal skin. Anal melanoma carries a dismal prognosis as the diagnosis usually occurs at an advanced stage. APR offers no survival benet but is performed if bulky lesions cannot be locally excised, and to improve quality of life when tumors are responsible for local symptoms such as incontinence.

Invasive Anal Canal Neoplasia

DavidM.Schwartzberg andMichaelJ.Grieco

Refer toAlgorithm inFig. 28.1

A. Anal cancer accounts for a small percentage

(2.6–4%) of all lower gastrointestinal malignancies. There is a slight preponderance to females (incidence 2000 female, 1500 male), presenting most commonly in the sixthseventh decade of life, with the most common presenting symptoms of bleeding (27–74%) and/or anal discomfort (21–39%), but up to 20% are asymptomatic. The anal canal is dened as the terminal part of the large intestine, beginning at the upper surface of the anorectal ring and passing through the pelvic oor to the anus”. The “surgical anal canal” is dened as beginning at the puborectalis sling and extending to the anal verge/ intersphincteric groove, as the anal margin is dened as the perineal skin baring skin appendages and outward for 5cm.

B. A pertinent history and physical examination

are essential as part of the evaluation, as questions should include constitutional symptoms, blood per rectum, sexual prac-

D. M. Schwartzberg Donald and Barbara Zucker School of Medicine at Hofstra/Northwell; Harbor View Medical Services, Port Jefferson, NY, USA

M. J. Grieco (*) Division of Colon and Rectal Surgery, New York University, New York, NY, USA e-mail: michael.grieco@nyulangone.org

tices, smoking history, sexually transmitted diseases, genital warts and specically a known history of HIV/AIDs or HPV infection. Physical examination should include inspection with anoscopy and proctoscopy, digital rectal exam with assessment of sphincter function, exact document of the tumor for location, occupying percentage of anal circumference, xed or mobile, and size (as some lesions completely vanish in response to neoadjuvant treatment and for clinical T-stage) as well as a bilateral inguinal lymph node examination.

C. For pathologic diagnosis, one to two inci-

sional or punch biopsies from the edge of the lesion should be performed, excisional biopsies should be avoided due to risk of sphincter damage or causing delay of C-XRT due to wound healing. Examination under anesthesia is often necessary since a thorough ofce exam is often precluded by patient discomfort.

D. Anal squamous cell carcinoma (SCC) is

slightly more common in females and presents most commonly between the ages of 60–65years old. Recently, anal SCC has had an increasing incidence in males who have sex with other men (MSM), and those with HIV infection. It is often diagnosed up to 24months after the onset of symptoms, often because of prolonged treatment for benign conditions such as anal ssures or hemor-

https://doi.org/10.1007/978-3-319-65942-8_28

213

214

Fig. 28.1 Algorithm for invasive anal canal neoplasia. APR abdominoperineal resection

D. M. Schwartzberg and M. J. Grieco

rhoids by general practitioners, which ultimately accounts for a large percentage of advanced disease at initial diagnosis. Fortyve percent of patients present with rectal bleeding, followed by anal pain or mass in 30%, followed by pruritus ani, fecal incontinence, anal ssure, and change in bowel habits.

E. Metastatic workup includes CT chest/abdo-

men with PO and IV contrast and pelvic CT or MRI with contrast. If available, FDGPET/CT should be performed since anal SCC is 98% FGD avid and it has been demonstrated to identify metastases which were undetected by other imaging or physical exam in 17–25% of cases leading to a change of C-XRT plans in 5–19% of cases. Presence of neurologic symptoms should prompt CT head to assess for brain metastasis.

F. At presentation, 10–20% of anal SCC

patients have distant metastasis. The most common sites are liver, lung, extrapelvic lymph nodes, bone and subcutaneous tissues. Median survival is 9months. Metastatic disease should be treated with 5-FU (continuous infusion, 1000 mg/m

/d IV days 1–5) and

Cisplatin (100mg/m2 IV day 2), repeat every

4 weeks. C-XRT should be considered for local control of symptomatic bulky primary disease.

G. Treatment for locoregional disease varies

based on staging and location of disease burden. All stage patients receive C-XRT with Mitomycin-C (MMC) and 5-Fluorouracil (5-FU) tailored to tumor stage and location of lymph node involvement. For ≤T2N0 disease, an intermediate dose of radiation 42–45Gy to the inguinal nodes, pelvis, anus, and perineum is given, but for T3/4 or N1 disease an additional boost of 9–14Gy is given to the original primary tumor and involved nodes plus a 2–2.5 cm margin. The dosing and schedule is Mitomycin (10 mg/m2 IV bolus days 1 and 29)/5-FU (1000mg/m2/d IV days 1–4 and 29–32)(or Capecitabine 825mg/ m2 PO BID, Monday–Friday and on each day radiation is given, typically 28 treatment days) and external beam radiotherapy (45Gy in 1.8Gy fractions 5 fractions for 5weeks).

H. Regression of SCC is gradual after C-XRT so

patients should be examined starting at 6–12weeks after completion of neoadjuvant treatment with, digital rectal exam (DRE) and inguinal node palpation. Documentation

28 Invasive Anal Canal Neoplasia

215

of the lesion, including size, mobility and inguinal nodal status is mandatory. The presence of a mass at this stage is not a mandate to perform a resection (unless the tumor progressed during treatment), as chemoradiation therapy has continued effects beyond completion of the treatment.

I. If a patient had a documented regression

and subsequent complete clinical response, and biopsy proved SCC lesion is then detected on surveillance <6months of completing C-XRT, it is dened as locally recurrent. If locally recurrent, the patient should undergo full staging work-up with PET-CT and biopsy of the lesion and any palpable nodes. If there is no distant metastasis, the patient should undergo abdominoperineal resection (APR) with inguinal node dissection for positive nodes, and myocutaneous ap is often required to close the perineal defect. For clinically negative nodal disease inguinal node surveillance every 3–6months for 5years, with cross-sectional imaging of the chest/abdomen/pelvis annually for 3years.

J. Persistent disease is dened as locoregional

failure within 6 months of C-XRT completion in patients without a full initial clinical response. For disease that persists after completion of C-XRT, the lesion should be followed and re-evaluated at 4 week intervals until 6 months following completion of C-XRT.

K. If the lesion has regressed, or shows no pro-

gression during treatment, but there was not a complete clinical response, the tumor should continue to be observed and re-evaluated in 3month intervals[ss1] with DRE lasting and inguinal node palpation for 5 years, anoscopy every 6–12 months for 3 years, and chest/abdomen/pelvic cross-sectional imaging annually for 3years duration.

L. If there is a complete clinical response, fol-

low- up should be DRE every 3–6months for 5 years, inguinal node palpation every 3–6 months for 5 years, anoscopy every 6–12months for 3years, and reserved only for T3-T4 tumors and/or inguinal node posi-

tive patients, annual chest/abdomen/pelvis cross-sectional imaging for 3years duration.

M. After completion of C-XRT, if the patient

progressed during therapy and/or in the months after completion, they should be restaged.

N. If during re-evaluation the patient should

show signs of progression, they should be treated in the algorithm for progression and either receive APR (with ipsilateral inguinal lymphadenectomy for clinically positive nodes) if recurrent in the anus, an inguinal lymphadenectomy with external beam radiation (if groins were not in radiation eld from the C-XRT) and possibly chemotherapy if recurrent in the groin, or if metastatic, be treated with cisplatin-based chemotherapy or in a clinical trial.

O. Anal melanoma is as aggressive as it is rare,

with an estimated incidence of 1.7 cases per one million per year. Approximately 20% of patients will present with node-positive inguinal disease, and an additional 20–40% will present with distant metastasis. There is a median survival of less than 20months and a 5year survival of only 20%. Most anal melanoma patients die of distant metastasis.

P. The patient should be assessed for dermal

primary lesion to rule out mucosal metastasis. The most common site of melanoma metastasis is lung, followed by bone, liver, and brain so a CT head, chest, abdomen and pelvis should be obtained. As in cutaneous melanoma, PET-CT should be reserved for lesions that are indeterminate on CT.

Q. The surgical management is controversial

because of anal melanoma’s aggression and rarity, which precludes prospective trials. Retrospective reviews suggest that survival is equivalently poor for wide local excision compared to APR with or without inguinal lymphadenectomy. Incidentally discovered melanoma after hemorrhoidectomy with a negative margin does not require further surgery. Symptomatic patients can be offered local excision for palliation. APR should be considered for symptomatic patients whose locoregional disease cannot be resected by

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