Peutz-Jeghers Syndrome

Introduction :

Peutz-Jeghers syndrome (PJS) is a rare entity characterized by hamartomatous polyps, usually less than 100 in number, found throughout the GI tract in association with hypermelanotic macules in the perioral region, buccal mucosa, digits (hands, feet), perianal and genital regions.

In 1921, Peutz reported a familial syndrome of polyps of the gastrointestinal tract with pigmentation of the mouth and other parts of the body. Later, Jeghers and his colleagues established the syndrome by describing a number of cases.

Hamartomas are growths of tissue that can be of endodermal, mesodermal, and/or ectodermal origin, but with an epithelial covering typical of the bowel location where the polyp is found.

• Peutz-Jeghers polyps are also hamartomas, arising from smooth muscle in the muscularis mucosa.
  
• These lesions are hemispheric or finger-like protrusions, ranging in size from 0.1 to 10 mm, but they may grow up to 4 cm in diameter.
• On microscopy, a core of smooth muscle penetrating into the overlying lamina propria is seen.

Genetic considration :
This familial syndrome appears to be inherited as a single pleiotropic autosomal dominant gene with variable and incomplete penetrance.

• Germline mutations of the STK11/LKB1, a serine threonine kinase gene on chromosome 19p, cause this syndrome, but not all families with PJS are linked to this gene locus, suggesting genetic heterogeneity.

• Although it has been assumed that these cancers arise from rare foci of adenomatous epithelium that may develop within the Peutz-Jeghers polyps, recent evidence for loss of STK11/LKB1STK11/LKB1 gene itself might be the gatekeeper to carcinogenesis in this syndrome, much like APC gene is the gatekeeper in FAP.

• This disorder exhibits autosomal dominant inheritance with variable penetrance.
• Significant progress has been made in the identification of a specific genetic defect.
  
• The PJS putative tumor suppressor gene maps to the telomeric region of chromosome 19p at 19p13.3and encodes the serine threonine kinase LKB1/STK11.
  
• Germline mutations in LKB1/STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells, result in the phenotypic manifestations of the syndrome.

Clinical features :

Polyposis develops early in life and commonly presents clinically by age 20.

• In addition, polyps in the upper respiratory tract, biliary tract, and urinary tract have been reported.
  
• GI bleeding (acute or chronic) and bowel obstruction secondary to intussusception are the most common presentations, but unusual symptoms and signs indicative of biliary obstruction or gastric outlet obstruction are possible.

The polyps are found most frequently in the small bowel, particularly the jejunum, but they also can occur in the stomach, colon, and rectum.

• Small intestine — 48 %
• Stomach — 24 %
• Colon — 24 %
• Pancreas — 5 %

Cutaneous pigmentation usually is noted at birth or in infancy, but the skin changes may actually disappear after puberty.

• They consist of clusters of black or dark brown spots resembling freckles, 1 to 2 mm in diameter, on and around the lips and buccal mucosa, fingers, and toes.

The most common symptom and the one most difficult to manage is abdominal pain, often caused by intestinal obstruction.

• The obstruction is usually the result of a polyp or of an intussusception.
  
• The other frequent complaint is rectal bleeding.
  
• Additional signs and symptoms include prolapse of the polyp, passage of the polyp, hematemesis, and anemia.

Diagnosis :
Diagnosis of the syndrome can usually be made on the basis of family history, skin pigmentation, and gastrointestinal symptoms. Contrast studies in addition to endoscopy confirm the extent of the polypoid disease.
In case of Histopathologically confirmed hemartoma, the diagnostic requirement of PJS is any two findings of the following three :

1. Family history with concomitant autosomal dominant inheritance
2. Mucocutaneous hyperpigmentation
3. Small-bowel polyposis

Complete upper and lower endoscopy in addition to small bowel contrast studies or enteroscopy, if available, are indicated to identify gastrointestinal polyposis.

• Modern endoscopic techniques make surveillance and removal of polyps up to 150 cm beyond the ligament of Treitz possible.

• Genetic testing is available. Not all mutations associated with PJS have been identified. So in such a case, a negative genetic test does not exclude the diagnosis.

Pathology :

Macroscopically, the polyps vary in size.

• They may be as large as several centimeters in diameter, and with increasing size, they tend to become pedunculated.
  
• In visual appearance, they look very much like adenomatous polyps (see Polypoid Adenoma, Adenomatous Polyp, and Tubular Adenoma).

Microscopically, the polyps seem to originate from intestinal glandular epithelium along with a muscular branching framework that arises from the muscularis mucosa.

• The tubules of epithelium rest on the branching bands of smooth muscle in a relationship similar to that of the glandular epithelium with the muscularis mucosa of the normal bowel.
• Because there is no evidence of hyperplasia, cytologic variation, or loss of differentiation, Morson suggested that the lesion represents a hamartomatous process or malformation, rather than a neoplasm.

Relationship with Cancer :
In a review by Konishi and colleagues, 117 neoplasms were found in 103 patients.There were 50 carcinomas of the gastrointestinal tract, the colon and rectum being the most common site.

It was established that some of these tumors arose within a Peutz-Jegher polyp, but many probably originated in otherwise normal mucosa.

• Giardiello and colleagues investigated 31 patients with this syndrome and found that 48% developed a malignancy; this rate was 18 times greater than would be expected.

The increased frequency was noted for cancers of both gastrointestinal and nongastrointestinal origin.

• Hizawa and co-workers investigated 75 gastrointestinal polyps resected surgically or endoscopically from seven patients with this syndrome. Nine were accompanied by an adenomatous component, two of which demonstrated malignant transformation with pedicle invasion.

According to one author, that neoplastic transformation was not a rare event and that their results suggested a hamartoma-adenoma-carcinoma sequence in Peutz-Jeghers polyposis.

Linos and colleagues, conversely, reported the considerable Mayo Clinic (Rochester, MN) experience (48 patients) and failed to document one definite instance of cancer; the median follow-up period was 33 years. The authors, furthermore, found that survival was similar to that of the population at large. They recommended that every effort should be made to conserve intestine in the management of this condition. Another reason to be concerned about an aggressive surgical approach is the possibility of misinterpretation of the histologic appearance. Dippolito and colleagues suggested that careful evaluation may reveal most of these lesions to be, in reality, enteritis cystica profunda.

• Patients with PJS typically have several potential complications from hamartomatous polyps.
  • Not only is malignant transformation a concern, but the polyps can also ulcerate, bleed, infarct, and intussuscept.
    
  • After the age of 30 years, malignant complications become the major concern; by the age of 65 years, over 90% of patients will have a malignancy.
    
  • The most common GI cancers include
    • colon, with a lifetime risk of 39%,
      
    • pancreatic, with a lifetime risk of 36%,
      
    • gastric, and SB (Giardiello et al, 2000).
      
    Non-GI malignancies include
    
  • breast (54% lifetime incidence),
    
  • ovarian (21% lifetime incidence),
    
  • Sertoli cell tumors (9% lifetime incidence with 10 to 20% becoming malignant), and
    
  • lung (15% lifetime incidence).

The high rate of extra-intestinal cancers also deserves attention with regular examination of potentially involved organs. Specific symptoms require special attention and should lead to an aggressive workup to exclude a malignant cause.

Proctalgia Fugax

Proctalgia fugax is a common cause of pain in the rectum. Symptoms consistent with proctalgia fugax occur in 13 to 19 percent of the general population.
Proctalgia fugax is underrepresented in the medical literature, and many physicians are unaware of its existence. Lack of familiarity on the part of the physician can result in unnecessary diagnostic evaluation. Contributing to the relative lack of familiarity is the fact that most patients with proctalgia fugax do not seek medical attention because the pain is usually brief and often infrequent. Patients may also be reluctant to disclose the symptoms because they fear potentially painful diagnostic procedures or the possibility of a serious condition

• Anorectal pain is a relatively common symptom first described by the Romans.
• Patients will often delay consulting a healthcare practitioner about this problem due to embarrassment and fear of a sinister diagnosis, tolerating disturbing symptoms for long periods.
• There are two functional anorectal pain syndromes:
• Proctalgia fugax (PF) (fugax=fugitive/fleeting in Greek) and
• Levator ani syndrome (LAS)
• They are both characteristic, benign anorectal-pain syndromes of uncertain aetiology.
• Despite their benign nature, they can cause severe distress to the sufferer. There is even an account of marital disharmony caused by proctalgia fugax.

Aetiology

• They are thought to occur due to spasm of the anal sphincter (PF) or pelvic floor muscles (LAS) but are something of an enigma.
• They may be associated with irritable bowel syndrome. The two affected muscles are anatomically contiguous so the two conditions may co-exist, or be different manifestations of the same underlying dysfunction.
• The diagnosis of these conditions can usually be made on the basis of the symptoms.
• However, more serious diagnoses can present similarly. Thus, it is essential to conduct a thorough clinical assessment to exclude other pathology before offering reassurance.
• May be associated with low-fibre diet and irritable bowel syndrome. More than half of affected patients are aged 30–60 years and prevalence declines after age 45.⁶
• It has been associated with a variety of other pathologies which may have aetiological significance, for example pudendal nerve neuralgia.

Epidemiology

• PF is estimated to affect 8–18% of the population in the developed world, and LAS around 6%.
• LAS seems to affect women more than men.
• It is thought that only 20–30% of sufferers of these conditions consult a healthcare practitioner.

Differential diagnosis

• Irritable bowel syndrome
• Haemorrhoids ± thrombosis
• Anal fissure (usually causes intense localised pain associated with and following defecation) – should be visible on proctoscopy.
• Solitary chronic rectal ulcer
• Rectal carcinoma
• Perirectal abscess or fistula; hydradentis suppuritiva
• Proctitis (especially gonococcal/chlamydial infection)
• Crohn's/Ulcerative colitis.
• Rectal foreign body
• Pruritus ani.
• Diverticular disease
• Rectal prolapse
• Coccygodynia (neuralgic pain around the region of the coccyx)
• Retrorectal cysts
• Condylomata acuminata (anogenital warts)
• Testicular carcinoma
• Prostatitis
• Cystitis
• Psychological cause (some hypothesise that these conditions are psychological rather than physical in origin)
• Alcock's canal syndrome (pudendal neuralgia due to entrapment, may present similarly to PF/be aetiologically relevant)
• Hereditary anal sphincter myopathy
• Bilateral internal iliac artery occlusion

Proctalgia fugax

Presentation

• Symptoms:
• Recurrent episodes of sudden, severe cramping pain localised to the anus or lower rectum.
• Last from seconds to minutes and resolves completely.
• The patient is entirely pain free between the episodes.
• Symptoms often occur at night and may wake the sufferer. Attacks are infrequent (<5>
• Attacks may come in clusters (occurring daily) then abate for long periods.
• Signs:
• PF has no signs and the diagnosis is made on the basis of characteristic symptoms and the absence of signs of other pathology.
• Abdominal and digital rectal examination should constitute the minimum assessment of anal pain.
• Ideally, anoscopy/proctoscopy should be carried out.
• Consider gynae/scrotal examination if relevant.
• Further examination with a sigmoidoscope or colonoscope may be necessary in selected patients where there is suspicion of pathology higher in the colon.
• It is worth checking for signs of anaemia if GI bleeding is suspected.

Management

• Once the diagnosis is made, reassurance is usually sufficient.
• The symptoms are so transient that drug therapy is rarely needed.
• In patients who suffer frequent, severe, prolonged attacks, inhaled salbutamol has been shown to reduce their duration.
• Clonidine and amylnitrate have also been used but no evidence exists for their efficacy.