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Inflammatory processes and non-neoplastic lesions
A number of inflammatory and infectious processes may affect the anal canal; the histologic findings of anal fissures and ulcers, abscesses, and fistulas are not particularly distinctive and are discussed only briefly. Infectious agents that can affect the anorectum include human papillomavirus (HPV; discussed later in the condyloma and squamous dysplasia sections), herpes simplex virus (HSV), Treponema pallidum (syphilis), chlamydia, Neisseria, and Enterobius vermicularis . These infectious lesions are described in depth in Chapter 9 . Lesions such as inflammatory cloacogenic polyps and anal Crohn’s disease, as well as degenerative and reactive lesions such as hemorrhoids and anal tags, are considered in depth.
Anal fissures are thought to result from tearing of the anal mucosa during the passage of large or hard stools; individuals with low dietary fiber intake appear to be at increased risk for developing fissures. Even though anal fissures may be seen in any age group, they are especially common in young, otherwise healthy, adults, with no gender preference. The typical symptoms are pain during or after defecation and the passage of bright red blood per anus, separate from the stool. The bleeding is usually minor. Fissures are typically located in the posterior midline of the anal canal from the dentate line to the anal verge and are pear shaped on direct examination. Most represent superficial injuries and heal spontaneously within 6 weeks with dietary modification to increase fiber and with stool softeners; however, some fissures persist and progress to a larger, deeper chronic anal ulcers. Chronic fissures and ulcers may develop subsequent to childbirth, usually in the anterior midline of the anal canal. The treatment of chronic lesions is aimed at reducing spasm of the internal anal sphincter and pressure in the anal canal. This may be accomplished by surgical dilation or sphincterotomy or, more recently, by the use of organic nitrates, calcium channel blockers, α-adrenergic antagonists, β-adrenergic agonists, or botulinum toxin. Histologic examination is rarely used in the assessment of acute anal fissures; chronic lesions may be examined via biopsy to exclude inflammatory bowel disease or an underlying malignancy. The microscopic appearance is not distinctive, demonstrating the usual features of a mucosal ulcer. Chronic fissures may be associated with other anal abnormalities, including hemorrhoids, and the so-called sentinel tag, a fibroepithelial polyp resulting from hypertrophy of the anal papilla at the proximal end of the lesion.
Suppurative disease of the anal canal is thought to derive from infection of an anal duct, beginning as an abscess, with the duct providing the framework for the formation of a fistula from the perianal soft tissues to the anal canal. The purulent process can also tract along various planes in the anorectal area to give rise to ischiorectal abscesses when it tracts along the internal and external sphincter muscles, as well as intramuscular or “submucosal” abscesses when the infection tracks superiorly between the muscle layers of the anorectal wall. Histologic features of abscesses and fistulas include acute and chronic inflammation, granulation tissue, and fibrosis; a foreign body giant cell reaction to fecal material may be present. Although most abscesses and fistulas are infectious or idiopathic, they may develop in patients with Crohn’s disease, hidradenitis suppurativa, or carcinoma.
Crohn’s disease
Inflammatory bowel disease is discussed in depth in Chapter 10 . Ulcerative colitis of the anus is histologically nonspecific and is usually characterized by superficial acute inflammation. On occasion, patients exhibit anal fissures, abscesses, or fistulas, but these are uncommon findings. Crohn’s disease, on the other hand, commonly affects the anal canal, exhibits a distinctive microscopic appearance, and is often complicated by the inflammatory lesions discussed previously.
Clinical features
The incidence of anal involvement in Crohn’s disease is approximately 25% of patients with small bowel disease and 50% to 80% of patients with colonic disease. Even though anal involvement usually is concurrent with or follows the diagnosis of intestinal Crohn’s disease, in 20% to 36% of patients, perianal lesions precede intestinal disease. Perianal manifestations of Crohn’s disease include fissures (21% to 35% of patients), anal tags and hemorrhoids, deep anal ulcers (2% to 5%), abscesses (23% to 62%), fistulas (6% to 34%, most often anovaginal), anorectal strictures, and carcinomas (0.7%). The clinical presentation reflects the particular type of perianal lesion and may include perianal pain, bloody diarrhea, incontinence, and sepsis.
Crohn’s disease may manifest at any age, but most patients are diagnosed in the third and fourth decades of life. White individuals of Anglo-Saxon descent are the most frequently affected, and some familial cases suggest a genetic predisposition. It is postulated that Crohn’s disease represents an abnormal immune response to gastrointestinal flora, although proof of this theory is lacking; there has been some evidence for the role of probiotic therapy.
Definition
- ■
A chronic idiopathic ulceroinflammatory process that may involve any portion of the gastrointestinal tract, as well as extraintestinal sites
Incidence and location
- ■
Anal involvement in 25% of patients with small bowel disease; in 50% to 80% of patients with colonic disease
- ■
Precedes intestinal disease in 20% to 36% of patients
- ■
Anal canal, perianal skin
Morbidity and mortality
- ■
High morbidity with high relapse rate after therapy
Gender, race, and age distribution
- ■
No gender predominance
- ■
Whites of Anglo-Saxon descent most often affected
- ■
Any age affected; most common in third and fourth decades of life
- ■
Possible familial predisposition in some cases
Clinical features
- ■
Symptoms vary with type of lesion: perianal pain, bleeding, bloody diarrhea, sepsis, incontinence
- ■
Manifestations: fissures; anal tags and hemorrhoids; deep anal ulcers; abscesses; fistulas; anorectal strictures; rarely carcinomas
Prognosis and therapy
- ■
Anal lesions poorly responsive to usual medical therapy for intestinal Crohn’s disease, such as steroids and aminosalicylates
- ■
Antibiotics, immunomodulators (e.g., cyclosporin A, azathioprine) useful in managing fistulas
- ■
Surgical: drainage of abscesses, fistulotomy, flap or graft repair of fistulas, resection of intestinal disease, proctectomy
- ■
Prognosis guarded; high relapse rate makes “cure” unlikely, regardless of therapeutic modality
Pathologic features
Gross findings
Crohn’s disease of the anal canal and perianal region has a spectrum of gross appearances, from reddened, eroded mucosa to abscesses and fistulas, all of which may be seen in settings not associated with inflammatory bowel disease. External clues include thickened and discolored perianal skin, fissures, fistulous openings in or around the anal canal, and prominent anal tags. Multiplicity of lesions is a common finding.
Microscopic findings
Although the gross findings are nonspecific in perianal Crohn’s disease, the presence of sarcoid-like granulomata closely associated with the anal mucosa is highly suggestive of the diagnosis ( Fig. 15-1 ). Many anal biopsies of patients with Crohn’s disease, however, demonstrate only acute or chronic inflammation and reactive changes in the mucosa.
Gross findings
- ■
Spectrum of lesions from reddened, eroded mucosa to abscesses and fistulas in anal canal
- ■
Thickened perianal skin, may have fistulous openings
- ■
“Sentinel tag,” a fibroepithelial polyp
Microscopic findings
- ■
Abscesses and fistulas nonspecific, with acute and chronic inflammation and granulation tissue
- ■
Key feature suggesting Crohn’s disease is sarcoid-like granulomata in the mucosa, especially immediately adjacent to the epithelium
Differential diagnosis
- ■
Mycobacterial infection
- ■
Sarcoidosis
- ■
Adenocarcinoma arising in fistula
Differential diagnosis
Idiopathic anal abscesses, fissures, and fistulas may be difficult to distinguish from anal Crohn’s disease in a patient without an established diagnosis of inflammatory bowel disease, especially when sarcoid-like granulomata are missing. Foreign body giant cells, common in idiopathic fistulas, abscesses, and other anal inflammatory lesions, should not be overinterpreted as evidence of Crohn’s disease. If granulomatous inflammation is present, tuberculosis should be considered in the differential diagnosis but is usually characterized by caseating granulomata and positive acid-fast stains or mycobacterial cultures.
The incidence of anal carcinoma arising in Crohn’s disease is small. In particular, adenocarcinoma developing in a chronic fistula is described in the background of anal Crohn’s disease; those patients who have severe inflammatory disease in this region are most at risk. There is virtually no increase in the incidence of squamous cell carcinoma between patients with Crohn’s disease and the general population .
Prognosis and therapy
A variety of medical and surgical treatments are available for the perianal lesions of Crohn’s disease, especially abscesses and fistulas. These lesions are typically nonresponsive to steroids and oral aminosalicylates, which are mainstays of therapy for intestinal Crohn’s disease. Antibiotics are frequently successful in controlling abscesses and fistulas, although relapse is common after cessation of therapy. Immunomodulators, such as mercaptopurine, azathioprine, methotrexate, and cyclosporin A, have also demonstrated favorable results in managing fistulas, but again relapse is common. Surgical drainage of an abscess is the most common operative procedure in the management of perianal Crohn’s disease and is usually semiemergent for elimination of the septic focus. Abscesses are often followed by fistulas, which may require placement of drains or diversion of the fecal stream to allow clearing of the underlying infection. Definitive surgical therapy for a Crohn’s disease fistula is controversial due to the risk for poor wound healing and incontinence. Operative procedures include fistulotomy, placement of flaps or grafts to repair the defect, resection of proximal intestinal disease, a permanent diverting colostomy, and, as a last effort, proctectomy.
The prognosis for patients with perianal Crohn’s disease is, as with intestinal disease, guarded. There is a high incidence of recurrence of lesions, and “cure” is not a realistic goal in most cases; quality-of-life issues must be considered a high priority in the management of these patients.
Inflammatory cloacogenic polyp; mucosal prolapse syndrome
Inflammatory cloacogenic polyps are considered to be part of the spectrum of manifestations of mucosal prolapse, which includes solitary rectal ulcer syndrome, rectal prolapse, intussusception, and rectocele. The clinical features and, to some degree, the pathologic changes of these disorders are similar, suggesting a common etiology. The inflammatory cloacogenic polyp is thought to result from mucosal prolapse, which produces local trauma and ischemic injury followed by inflammation, repair, and regenerative changes. The polyps usually develop along the anterior aspect of the anorectal junction, where the loosely attached rectal mucosa meets the more firmly seated anal mucosa.
Clinical features
Inflammatory cloacogenic polyps occur at the anterior anorectal junction. They may be seen in any age group but are most common in middle age, with no gender predominance. While they commonly present with bright red rectal bleeding, other symptoms associated with mucosal prolapse syndrome may be noted. These include rectal pain, passage of mucus, excessive straining, tenesmus, and constipation or diarrhea.
Definition
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A manifestation of mucosal prolapse syndrome (solitary rectal ulcer syndrome) characterized by a hyperplastic and ulcerative lesion in the anal canal
Incidence and location
- ■
Estimated annual incidence 1 to 3.6 per 100,000, for solitary rectal ulcer syndrome, of which this is a subset
- ■
Anterior wall of anorectal junction
Morbidity and mortality
- ■
Chronic disorder, requiring conservative approach to manage patient discomfort
- ■
Rare instances of massive hemorrhage
Gender, race, and age distribution
- ■
Males equal to females, or slight female predominance
- ■
Occurs at any age, but 80% younger than 50 years; average age 49 years
- ■
Less common in cultures with high dietary fiber content
Clinical features
- ■
History of straining with defecation, constipation (55%) or diarrhea, rectal bleeding, rectal pain, tenesmus
- ■
Some patients with underlying psychological disorder, such as obsessive-compulsive disorder
Prognosis and therapy
- ■
Chronic disorder, frequently recurs after therapy
- ■
Medical therapy includes increase in dietary fiber, topical treatment with human fibrin sealant, biofeedback, psychological counseling, pelvic floor exercises
- ■
Surgical treatment last resort due to high recurrence rate
Pathologic features
Gross findings
Inflammatory cloacogenic polyps are frequently diagnosed by biopsy; intact lesions may be either sessile or pedunculated, ranging in size from 1 to 2 cm. They are indistinguishable from tubular adenomas. The surface may be eroded or may demonstrate a patchy exudate.
Microscopic findings
The key features of inflammatory cloacogenic polyps are surface erosion or ulceration with underlying granulation tissue, reactive and reparative alterations, and hyperplastic glandular epithelium. The reparative surface epithelium is often thinned and flattened, with nuclear enlargement and prominent nucleoli. The lack of dysplastic nuclear changes readily distinguishes these inflammatory polyps from tubular and villous adenomas.
A fibrinous inflammatory exudate forms a cap on the surface of the polyp, overlying a bed of granulation tissue ( Fig. 15-2 ). The lamina propria of the underlying mucosa is altered by the proliferation of fibromuscular tissue; the smooth muscle cells are particularly conspicuous by their presence above the muscularis mucosa. The glandular structures appear disorderly and may be dilated and branched or cystic. In some instances the surface of the polyp assumes a villous configuration. Glandular epithelial hyperplasia is present, with glands lined by columnar epithelium with an abundance of mucinous cytoplasm, folding and protruding into the crypt lumen. Colitis cystica profunda may be present, with distorted cystic glands filled with mucin embedded in the fibromuscular stroma deep to the muc osa.
Gross findings
- ■
Sessile or pedunculated polyp
- ■
Surface erosion, ulceration, or adherent exudative fibrin cap
Microscopic findings
- ■
Surface erosion with adherent cap of fibrin and neutrophils
- ■
Granulation tissue with reactive atypia and reparative changes (may be marked)
- ■
Villiform architectural changes in the glandular mucosa
- ■
Ingrowth of fibromuscular tissue into lamina propria
- ■
Hyperplastic epithelial alterations with irregular branching of glands
- ■
Underlying colitis cystica profunda with mucus-filled epithelial-lined cysts may be present
Differential diagnosis
- ■
Colonic adenoma
- ■
Adenocarcinoma
- ■
Dysplasia
Differential diagnosis
Inflammatory cloacogenic polyps with florid proliferative changes may be mistaken for villous adenomas, especially in small biopsy specimens. The progression from very proliferative and perhaps somewhat atypical epithelium deep in the crypts to mature and orderly surface epithelium in the inflammatory cloacogenic polyp contrasts with the deep and surface dysplasia of the adenoma. The presence of a surface cap of fibrin and granulation tissue may also suggest the inflammatory nature of this lesion.
Cases with underlying colitis cystic profunda can be especially treacherous; the underlying fibromuscular stroma that replaces the normal elements of the lamina propria can be suggestive of a desmoplastic reaction. This combination of findings may mimic an invasive adenocarcinoma.
A few cases with histologic changes identical to mucosal prolapse syndrome have been described in association with an invasive carcinoma. In most of the cases these changes were detected in superficial biopsy specimens and the carcinoma was infiltrating the underlying submucosa. The mechanism for the mucosal prolapse-like changes is postulated to be localized ischemia related to the malignancy.
Prognosis and therapy
Simple removal is generally adequate treatment of an inflammatory cloacogenic polyp. The underlying abnormality of rectal prolapse syndrome, however, must be addressed separately. Such treatment might include dietary modification with increased fiber and fluid intake, pelvic floor exercises, use of laxatives, and psychological counseling, reserving surgery as a last option. Surgical approaches aim at fixation of the rectal mucosa but may aggravate the underlying cause of the syndrome in some cases.
Hemorrhoids and anal tags
The impact of hemorrhoids on the well-being of humans is evident through historical references from every age, from ancient Egypt to the Age of Enlightenment. The gravity of the problem is reflected by the designation of St. Fiacre as the patron saint of hemorrhoid sufferers. Many theories regarding the cause of hemorrhoids have been espoused over the centuries, including, in the last century, that they represent hyperplasia or varicosities of the mucosal venous plexus. Current evidence, however, suggests that hemorrhoids represent a “sagging” or “slippage” of the normal cushions of hemorrhoidal fibrovascular tissue found in the anal canal. The large venous channels seen in hemorrhoids are no different from those seen in the normal submucosal connective tissue; rather, changes seem to occur in the fibromuscular supportive tissue of these cushions. Once the slippage begins, it is apparently exacerbated by the stress of defecation and increased pelvic pressure.
“Internal” hemorrhoids arise in the anal canal and are subclassified on the basis of whether they prolapse out of the canal and on the persistence of the prolapse. Hemorrhoids that are permanently prolapsed are prone to thrombosis and infarction. External hemorrhoids are contiguous with the normal venous plexus located below the dentate line. Thrombosis is also common in external hemorrhoids.
Anal tags are polypoid masses of anal mucosa, usually squamous type, with underlying submucosal tissue; these correspond to cutaneous fibroepithelial polyps or “skin tags.” They lack the vascular component of hemorrhoids but are often clinically mistaken for such.
Clinical features
Hemorrhoids are a common problem, although the true incidence is difficult to determine because patients often refrain from seeking medical attention. They appear to be evenly distributed between the sexes, with most people seeking medical assistance during middle age. The incidence of hemorrhoids is not increased in individuals with portal hypertension. Symptomatic hemorrhoids are a common complaint during pregnancy, although the actual incidence is not known. Factors that may account for the apparent increase in symptoms during pregnancy include hormonal influences, constipation, pelvic pressure and congestion, and increased blood volume.
The most common complaint associated with hemorrhoids is painless bleeding, which is usually minor. Anal discomfort or pain on defecation may be noted. Infarction or thrombosis results in acute exacerbations of pain and usually requires more urgent medical attention.
Definition
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Enlarged and edematous masses of hemorrhoidal (perianal) soft tissue associated with the anal mucosa, thought to result from slippage or sagging of the normal tissue in this region
Incidence and location
- ■
Variable data, incidence reported from 4.4% to 36%
- ■
More than 1000 physician visits per 100,000 population per year in the United States and United Kingdom
Morbidity and mortality
- ■
Not a significant cause of mortality, but a common cause of discomfort and expense
Gender, race, and age distribution
- ■
Males equal to females, although males more likely to seek medical attention
- ■
Historical evidence in virtually all cultures
- ■
Wide age range, peaking in middle age and declining thereafter
Clinical features
- ■
Painless bleeding most common symptom; also anal discomfort on defecation
- ■
Acute pain exacerbations with thrombosis and infarction
- ■
Commonly symptomatic during pregnancy
- ■
Anal tags are merely fibroepithelial polyps; may be associated with hemorrhoids or other anal disease as a reactive process
Prognosis and therapy
- ■
Medical therapy is primary approach: increases in dietary fiber, injection sclerotherapy, banding, ablative photocoagulation, electrocoagulation, laser ablation, and cryotherapy
- ■
Surgical therapy is reserved for the 5% to 10% who fail conservative measures
- ■
Surgical excision should include only symptomatic hemorrhoidal tissue to protect continence
- ■
Recurrence rate fairly high
Pathologic features
Gross findings
Hemorrhoids are edematous masses of pale connective tissue covered by gray to tan mucosa. Infarcted or thrombosed hemorrhoids are dark purple and firm. Sectioning reveals dilated vascular spaces, frequently with evidence of thrombosis. Typical excised hemorrhoidal tissue measures a few centimeters in aggregate.
Anal tags are covered by thin tan mucosa; the cut surface may be edematous and soft or dense and fibrotic. The prominent dilated vessels of hemorrhoidal tissue are absent.
Microscopic findings
The epithelial lining of hemorrhoids may be columnar, transitional, or nonkeratinizing squamous type. The submucosa contains dilated thick-walled vessels and thin sinusoidal spaces in a loose and often edematous fibrous tissue, sometimes with chronic inflammation ( Fig. 15-3 ). Thrombosis is common, and hemosiderin deposits in the connective tissue indicate previous trauma and hemorrhage. Organization of intravascular thrombi may produce cellular masses of granulation tissue, which nearly obliterate vascular lumina. When the intravascular proliferation is florid, it may suggest a neoplastic lesion, such as angiosarcoma or Kaposi’s sarcoma; the low-power pattern highlights the intravascular distribution within large vessels and the underlying thrombosis with recanalization indicative of a reactive process. Excised hemorrhoidal tissue should always be examined microscopically to exclude an inflammatory, infectious, or neoplastic process with a clinical appearance mimicking hemorrhoids, or an associated epithelial dysplasia, although such findings are rare (<2%).
Anal tags resemble cutaneous fibroepithelial polyps, with a squamous epithelial lining over loose fibrovascular submucosal tissue. They lack dilated veins and sinusoids, containing instead smaller branching thin-walled vessels ( Fig. 15-4 ). The stroma contains fibroblastic cells, which may be small, inconspicuous spindle cells or, especially if the lesion has been traumatized or irritated, enlarged stellate cells with bizarre or multiple nuclei. Such stellate cells are evenly distributed within the collagenous stroma and reflect a reactive or reparative atypia of no clinical significance.
Gross findings
- ■
Usually 1 to 3 cm in diameter
- ■
Edematous masses of pale connective tissue covered by thin gray-to-tan mucosa
- ■
Infarcted or thrombosed hemorrhoids are dark purple and firm
- ■
Cut surface with dilated vascular spaces, some with thrombi
- ■
Anal tags are edematous or firm masses of pale connective tissue covered by thin tan mucosa
Microscopic findings
- ■
Epithelium columnar, transitional, or squamous
- ■
Submucosa with edematous stroma and dilated thick-walled vessels and thin sinusoidal spaces
- ■
Vessels may contain thrombi, with intravascular and perivascular hemosiderin deposits and intravascular granulation tissue, often with marked reactive changes
- ■
Anal tags have thin squamous epithelium over edematous stroma, without dilated vasculature
Differential diagnosis
- ■
Gross differential diagnosis includes neoplasms such as melanoma and squamous cell carcinoma among others
- ■
Histologic differential diagnosis of thrombosed hemorrhoids with organization includes angiosarcoma and Kaposi’s sarcoma
Differential diagnosis
Although the clinical differential diagnosis of hemorrhoids includes neoplastic lesions such as condyloma, squamous cell carcinoma, and melanoma, the histologic differential diagnosis is limited. As noted previously, hemorrhoids with organizing thrombi may be associated with florid intravascular granulation tissue, suggesting a vascular neoplasm.
Prognosis and therapy
Although hemorrhoids may be a great nuisance to humanity, the extent of their morbidity is rather circumscribed. Thrombosis or infarction may lead to acute pain requiring surgical excision, but there are many treatment options available to most patients. These include simple increases in dietary fiber content, injection sclerotherapy and banding to induce fibrosis and fixation of the sagging tissue, and ablative techniques such as photocoagulation, electrocoagulation, laser ablation, and cryotherapy. Surgical excision is reserved for the 5% to 10% of patients who fail more conservative measures. Excision of only symptomatic hemorrhoidal tissue is favored to maintain continence; enlarged asymptomatic hemorrhoidal tissue should be left alone. There is no advantage to the traditional three-position hemorrhoidectomy procedure, which removes the right lateral, left lateral, and anterior hemorrhoidal tiss ue.
Anal tags are easily removed by a snare or snip excision. They are significant only for cosmetic concerns and for potential clinical resemblance to a hemorrhoid or neoplasm.
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Neoplastic lesions
Hidradenoma papilliferum
Hidradenoma papilliferum is an uncommon benign cutaneous neoplasm that is almost exclusively seen in the vulvar and perianal region. Although traditionally considered a cutaneous (sweat gland) adnexal tumor, there is convincing morphologic and immunohistochemical evidence to support development from ectopic mammary tissue.
Clinical features
Most examples have occurred in white women in the fourth to sixth decades of life. The most common site involved is the labium majus; other sites include the labium minus, interlabial sulcus, clitoris, posterior fourchette, mons pubis, and perineum; perianal examples are rare. The typical lesion is a few millimeters in diameter, although rare cases up to 2 cm have been described. They are located in the dermis, with no surface epithelial connection in most cases. Rarely surface erosion or ulceration may be present.
Definition
- ■
Benign cutaneous neoplasm thought to originate from either sweat glands or ectopic breast tissue
Incidence and location
- ■
Incidence uncertain—uncommon at any site
- ■
Most occur in labium majus; other sites include labium minus, interlabial sulcus, clitoris, posterior fourchette, mons pubis, perineum, and perianal region
Morbidity and mortality
- ■
Benign lesion with limited morbidity, readily treated
Gender, race, and age distribution
- ■
Exclusively in females
- ■
Fourth to sixth decades of life most frequent
- ■
Most occur in whites
Clinical features
- ■
Dermal nodule covered by intact skin in most cases
- ■
Occasionally skin eroded or ulcerated
- ■
May be discovered incidentally on gynecologic examination
Prognosis and therapy
- ■
Benign lesion; conservative excision usually curative
- ■
Extremely rare reports of possible malignant change
Pathologic features
Gross findings
A small excisional biopsy specimen is usually received, demonstrating a dermal nodule covered by unremarkable skin. As noted previously, rare cases are associated with epidermal erosion or ulceration. The cut surface of the lesion is usually tan to brown and, in larger examples, may have a papillated appearance. The lesion is unencapsulated but circumscribed.
Microscopic findings
Microscopically the lesion has a complex papillary pattern of fibrovascular cores, sometimes within a cystic structure ( Fig. 15-5 ). The papillae are lined by a double layer: a luminal layer of cuboidal to low columnar epithelial cells with faintly eosinophilic cytoplasm demonstrating occasional apical snouts (decapitation secretion), overlying a flattened myoepithelial layer. The luminal cells may be slightly pleomorphic and stratified. The lesion is within the dermis but may be accompanied by erosion or ulceration of the epidermis. A lymphoplasmacytic inflammatory infiltrate is common.
Gross findings
- ■
Firm, ill-defined mass within dermis, with normal or ulcerated overlying skin
- ■
Cut surface yellow-tan to brown
- ■
Size ranges from few millimeters (typical) to 2 cm (rare)
Microscopic findings
- ■
Complex papillary pattern with arborizing fibrovascular cores
- ■
Double cell lining: outer low columnar cells with apocrine snouting; inner flattened myoepithelial cells
- ■
Chronic inflammation common
- ■
No connection with epidermis
Differential diagnosis
- ■
Gross differential diagnosis: cutaneous cyst, hemorrhoids, polyps, carcinoma (if ulcerated)
- ■
Histologic differential diagnosis includes adenocarcinoma
Differential diagnosis
Although hidradenoma papilliferum is characterized by a distinctive histologic pattern, an erroneous diagnosis of adenocarcinoma may be made on a small biopsy. The presence of the double epithelial-myoepithelial layer should prevent this mistake. The clinical differential diagnosis is more extensive, including cutaneous cysts, hemorrhoids, and polyps; ulcerated examples may suggest malignancy.
Prognosis and therapy
Hidradenoma papilliferum is a benign lesion that is adequately treated by conservative excision. There are reports of malignant transformation to adenocarcinoma or adenosquamous carcinoma, but this must be exceedingly rare.
Granular cell tumor
A granular cell tumor is a benign tumor of nerve sheath, or Schwann cell, origin, common in the skin, upper respiratory tract, and gastrointestinal tract, but rather rare in the anal region.
Clinical features
Granular cell tumors lack specific clinical features; rather, the presentation is generally due to the effects of a mass relative to its location. They may be incidental findings, but anal lesions may present with perianal discomfort and bleeding. The lesions vary in size; they are located in the dermis or subcutis and are covered by normal skin.
Definition
- ■
A benign neoplasm of Schwann cell origin, characterized by granular eosinophilic cytoplasm due to abundant cytoplasmic lysosomes
Incidence and location
- ■
Common in skin, upper respiratory tract, and gastrointestinal tract but rare in the anal region
- ■
May be in submucosa or in perianal skin
Morbidity and mortality
- ■
Almost always benign, with excellent cure rate following conservative excision
- ■
Malignant examples are rare but may metastasize
Gender, race, and age distribution
- ■
Females more than males
- ■
No clear racial difference; multiple lesions more common in blacks
- ■
Can occur at any age but most in adults
Clinical features
- ■
Anal lesions present as polyps or subcutaneous or submucosal nodules
- ■
Symptoms related to effect of mass; some ulcerate and cause rectal bleeding or perianal discomfort
- ■
May be mistaken for hemorrhoids
Prognosis and therapy
- ■
Complete conservative excision
- ■
Low recurrence rate with adequate excision
Pathologic features
Gross findings
Although most granular cell tumors are small, but they may reach 5 cm in diameter. They are firm and poorly circumscribed, usually submucosal; occasional examples present as polypoid masses. The perianal skin or mucosa of the anal canal may be involved; one case within the internal anal sphincter has been reported.
Microscopic findings
Granular cell tumors often are observed growing in and around peripheral nerves. They are composed of large round to ovoid cells with abundant brightly eosinophilic, and slightly refractile, granular cytoplasm ( Fig. 15-6 ). The cell borders are distinct; the nucleus is round, with a dense chromatin pattern, and is usually centrally placed within the cell. The cytoplasmic granules are small and uniform in size, admixed with occasional large eosinophilic droplets. The cytoplasm is positive for periodic acid-Schiff reagent and is diastase resistant. If the tumor is close beneath an epithelial surface, such as skin or squamous mucosa, the overlying epithelium may proliferate, with pseudoepitheliomatous hyperplasia sometimes mimicking squamous cell carcinoma. Mitotic figures are rare .
Gross findings
- ■
Firm yellow-to-white, submucosal, subcutaneous, or polypoid mass, poorly circumscribed
- ■
Size usually 1 to 2 cm but may be up to 5 cm
Microscopic findings
- ■
Large round cells with abundant eosinophilic granular cytoplasm and occasional large eosinophilic cytoplasmic droplets
- ■
Dark, homogeneous, centrally placed nuclei; inconspicuous nucleoli
- ■
Distinct cell borders
- ■
Cytoplasmic granules PAS positive and diastase resistant
- ■
Overlying skin or squamous mucosa may demonstrate pseudoepitheliomatous hyperplasia.
Ultrastructural findings
- ■
Electron microscopy rarely used for diagnosis
- ■
Large number of lysosomes correlates with cytoplasmic granules
Immunohistochemistry
- ■
S-100 protein positive
Differential diagnosis
- ■
Squamous cell carcinoma (if pseudoepitheliomatous hyperplasia present)
- ■
Alveolar soft part sarcoma
- ■
Adult rhabdomyoma
Ancillary studies
Immunohistochemistry
The tumor cells are usually positive with S-100 protein immunohistochemistry, which, combined with periodic acid-Schiff with diastase (PASD), is the most frequently used study for confirmation of the diagnosis. Other immunohistochemical study results reported as positive in granular cell tumor include laminin, inhibin, calretinin, and myelin basic protein.
Electron microscopy
The cytoplasm of tumor cells is filled with an abundance of lysosomes, which impart the granular appearance on light microscopy.
Differential diagnosis
Considerations in the differential diagnosis of granular cell tumor include rhabdomyoma, a benign tumor with skeletal muscle differentiation, and alveolar soft part sarcoma, a malignant neoplasm of uncertain histogenesis. Rhabdomyoma is composed of round cells with eosinophilic cytoplasm and superficially bears a striking resemblance to granular cell tumor. However, the presence of multiple nuclei, peripherally placed, and readily identified cross-striations usually makes the distinction clear on closer examination. Rhabdomyomas are positive for immunohistochemical markers of muscle differentiation, including desmin, muscle-specific actin, Myo D1, and myoglobin.
Alveolar soft part sarcoma is also characterized by round large cells with abundant granular eosinophilic cytoplasm. The classic alveolar pattern and the degree of nuclear atypia, with vesicular nuclei and prominent nucleoli, should exclude granular cell tumor from the differential diagnosis. Like granular cell tumor, alveolar soft part sarcoma has cytoplasmic positivity for PASD, but the pattern is more coarsely granular to crystalline; the tumor cells are sometimes, but not reliably, positive for smooth muscle and sarcomeric actin, desmin, and other markers of muscle differentiation.
Prognosis and therapy
Granular cell tumors require conservative local excision for cure in most instances. Rare cases of malignant behavior are reported, with metastatic disease; these lesions are characterized by mitotic activity and nuclear pleomorphism.
Condyloma
Condyloma is a common lesion of the anogenital region, caused by HPV (usually low-risk genotypes 6 and 11), with a low propensity for progression to malignancy, but with an etiologic kinship to premalignant and malignant squamous epithelial lesions. Even though the classification of condyloma as an infectious process versus a neoplastic process might be controversial, it is discussed here to emphasize the spectrum of HPV-induced lesions of the anus and the differential diagnostic distinction among them.
Clinical features
Condyloma is the most common manifestation of sexually transmitted HPV. The incidence and demographics of anal condylomata parallel the recent increase in anal cancers, particularly among young males.
Anal condylomata, like genital lesions, are found in sexually active adults of both genders, but with a high incidence in males who practice receptive anal intercourse, whether bisexual or homosexual. Other associations that increase the incidence of anal condylomata include human immunodeficiency virus (HIV) seropositivity, immunosuppression in the organ transplant population, cigarette smoking, alcohol use, other sexually transmitted diseases (including cervical intraepithelial neoplasia in females), and low socioeconomic status. Most patients present with visible or palpable polypoid perianal lesions.
Definition
- ■
Exophytic papillomatous lesion of squamous epithelium caused by HPV, with low propensity for progression to malignancy
Incidence and location
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Most common manifestation of infection with HPV. High incidence in general population, with marked increase in young males in past two decades
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Anal condylomata are particularly common in males who practice anal-receptive intercourse.
Morbidity and mortality
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Most condylomata are completely benign, although they may occasionally become very large, especially in the immunosuppressed population.
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Recurrence is frequent, but malignant transformation is uncommon in clinically typical condylomata, most of which are associated with the low-risk HPV genotypes (6 and 11).
Gender, race, and age distribution
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Formerly higher in females; the incidence in young males is increasing, particularly in the homosexual population
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No clear racial predilection is identified, but low socioeconomic status is clearly linked to a higher incidence.
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The age range is broad, encompassing sexually active males and females
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Other associations with the incidence of anal condylomata include HIV seropositivity, immunosuppression in the transplant population, cigarette smoking, alcohol use, and other sexually transmitted diseases
Clinical features
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Most patients present with visible or palpable polypoid lesions
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Very large lesions may become ulcerated
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Coexisting lesions of the vulva are common in women, as is the presence of cervical intraepithelial neoplasia; penile lesions are frequently encountered in males
Prognosis and therapy
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Most condylomata are associated with nononcogenic HPV genotypes and pursue a benign course
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Immunosuppressed individuals, including organ transplant patients, HIV-positive patients, and particularly those with a low CD4 count, have a high risk for recurrence and development of high-grade intraepithelial neoplasia in association with anal condylomata.
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Primary treatment is with topical agents such as podophyllin for usual condylomata; extensive lesions may require intralesional interferon.
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Surgical excision reserved for persistent or recurrent lesions
Pathologic features
Gross findings
Condylomata are white to skin-colored rubbery lobulated polypoid masses ranging in size from a few millimeters to 2 cm or more; they are often reminiscent of cauliflower florets ( Fig. 15-7 ). Large lesions should prompt a thorough histologic assessment to exclude verrucous carcinoma.
Microscopic findings
Condylomata are characterized by a papillary proliferation of acanthotic squamous epithelium overlying elongated rete ridges, which may develop arborizing fibrovascular cores, with variable surface keratinization ( Fig. 15-8 ). Koilocytotic features are usually most evident in the superficial layers of the epithelium, where enlarged cells with one or two, and occasionally more, nuclei are observed. The koilocytes are defined by a large central cytoplasmic vacuole that contains the central nucleus or nuclei; the rim of the vacuole is outlined by a ribbon-like condensation of cytoplasm. The nuclei are often either slightly hyperchromatic or pyknotic and may have an irregular raisin-like contour. There is slightly disordered nuclear polarity in the areas of koilocytotic change. The lower layers of epithelial cells exhibit basal cells one to three cells deep, with orderly maturation above them. Mitotic figures, if present, are restricted to the basal zone in ordinary condylomata.
