Cutaneous Manifestations of GI Malignancies

By Mohammed Ezz El-din

Assistant Lecturer of Tropical Medicine & Gastroenterology

Faculty of Medicine, Assiut UniversityEmail: squint_2008@yahoo.com

Brief Review of Dermatological Terminology…

You have to learn the Terminology!

Agenda

Hereditary GI disorders

•Lynch syndrome and Muir-Torre syndrome

•Familial adenomatous polyposis and Gardner syndrome

Hamartomatous syndromes

•Peutz-Jeghers syndrome•Juvenile polyposis syndrome.

•Cowden syndrome•Cronkhite-Canada syndrome.

•Bannayan-Riley-Ruvalcaba syndrome

•Neurofibromatosis

Paraneoplastic dermatological disorders

•Malignant acanthosis nigricans •Leser-Trelat sign•Tylosis•Plummer-Vinson syndrome•Glucagonoma syndrome and necrolytic migratory erythema

•Perianal extramammary Paget disease•Carcinoid syndrome•Paraneoplastic dermatomyositis•Paraneoplastic pemphigus

Cutaneous metastasis of gastrointestinal malignancy

•Sister Joseph nodule

GI – Skin Interaction

• Because the gastrointestinal (GI) and cutaneous systems have closely linked developmental origins, concurrent pathologic diseases are frequently present.

• This underscores the important role of dermatologists in the diagnosis, detection, monitoring, and treatment of these disorders while consulting and interacting with their GI colleagues.

Cutaneous Manifestations of Hereditary Gastrointestinal Cancers

Hereditary Nonpolyposis Colon Cancer or Lynch Syndrome

• Lynch syndrome is an autosomal dominant disorder. • Lynch syndrome is associated with colon cancer and also

has an increased risk of developing endometrial, urologic, small bowel, ovarian, hepatobiliary, and brain cancers.

• The disease appears to have a male predominance, with a male to female ratio of 3:2.

Muir-Torre Syndrome

• Muir-Torre syndrome is a variant of Lynch syndrome. The vast majority of cutaneous findings associated with Lynch syndrome are found in this variant.

• These findings include sebaceous adenomas, epitheliomas, and carcinomas together with multiple keratocanthomas.

• Sebaceous adenomas are the most common skin lesion found in Muir-Torre syndrome, presenting as yellow papules or nodules predominantly on the face.

Sebaceous Adenoma on the scalp. Yellow Papule or Nodule

Sebaceous Adenoma. Yellow Papule or Nodule

Keratoacanthoma. A skin-colored, shiny nodule with telangiectases and a central horny plug covered by a crust

• Malignant transformation results in sebaceous carcinoma with the histologic features of pleomorphism and anaplasia.

• These are commonly found on the eyelids as yellow nodules with a propensity toward ulceration and are locally aggressive in nature.

Sebaceous Carcinoma on the forearm

• Surveillance includes colonoscopy beginning at 25 years of age and repeated every 2 to 3 years.

• Regular dermatologic follow-up is recommended

annually.

Familial Adenomatous Polyposis and Gardner Syndrome

• Familial adenomatous polyposis (FAP) and Gardner syndrome (GS) are autosomal dominant disorders.

• FAP is a syndrome that is characterized by hundreds to thousands of adenomatous colon polyps beginning at a mean age of 16 years.

• FAP is the second most commonly inherited CRC syndrome, with a prevalence of 1:10,000.

• These patients develop CRC at a mean age of 39 years.

• Attenuated FAP is characterized by the development of significantly fewer colonic adenomas (<100) compared to classic FAP.

• Congenital hypertrophy of retinal pigmented epithelium (CHRPE) can be an early sign of this syndrome.

• CHRPE is a patch of darkly pigmented retinal epithelium necessitating an ophthalmologic examination for its detection.

• Gardner syndrome (GS), a variant of FAP, is characterized by numerous gastrointestinal adenomatous polyps.

• Cutaneous manifestations include epidermoid cysts, lipomas, and desmoid tumors as well as dental abnormalities.

• Epidermoid cysts are usually multiple, typically manifesting on the face or extremities, and frequently predate the appearance of intestinal polyps.

Multiple Epidermoid Cysts on The Chest

• Patients with FAP and GS are predisposed to malignancies, including duodenal, thyroid, brain (most often medulloblastomas), adrenal, and liver cancers in addition to CRC.

• Annual colon screening should begin at 10 to 15 years of age for classic FAP, and 18 years of age for attenuated FAP until the recommendation for surgery is made.

• Upper GI endoscopy is recommended every 1 to 3 years beginning at 25 to 30 years of age along with an annual thyroid examination that should be performed because of an increased risk of thyroid cancer.

• Prophylactic total proctocolectomy remains the only means to prevent the development of CRC in FAP.

Hamartomatous Polyposis Syndromes

• Hamartomatous polyposis syndromes are a heterogeneous group of disorders that are characterized by hamartomatous polyps of the GI tract and have an autosomal dominant mode of inheritance.

Peutz-Jeghers Syndrome

• PJS is an autosomal dominant disorder.• PJS is characterized by hamartomatous polyposis,

mucocutaneous pigmentation, and an increased risk of visceral malignancy.

• Cutaneous lesions of PJS include small melanocytic macules commonly seen on the labial mucosa, lips, palate, and tongue, but also in other areas, including the perianal region.

• The most common malignancies in patients with PJS are small intestinal, colorectal, gastric, and pancreatic adenocarcinomas.

Hyperpigmentation of the tongue

Multiple Pigmentations on the lips and around the mouth

• Surveillance should begin in childhood because of a tendency for polyps to cause intussusception or bleeding, with colonoscopy being initiated during the late teenage years.

• Annual transvaginal ultrasound, endoscopic ultrasound for evaluation of pancreatic malignancy, computed tomographic scans of the abdomen, and assays for CA-125 biomarkers are also recommended.

Cowden Syndrome (Multiple Hamartoma Syndrome)

• CS is a highly variable autosomal dominant disease with an age at diagnosis ranging from 13 to 65 years with a female preponderance.

• GI involvement occurs in 70% to 85% of CS patients, with a predilection for the esophagus, stomach, and colorectal structures. The small bowel is rarely involved. Polyps are usually small and < 5 mm in size.

• Multiple hamartomas of the bones, central nervous system, eyes, and genitourinary tract may be present.

• Orocutaneous juvenile retention hamartomas and ganglioneuromas may also be found in CS, as is macrocephaly.

• Mucocutaneous lesions are found in almost all patients with CS, and include trichilemmomas, oral papillomatosis, facial papules, and acral keratoses.

• Trichilemmomas, a benign hamartomas of the outer sheath of hair follicles, are flesh-colored smooth papules, ranging from 1- to 5-mm in size and are present predominantly on the face, head, and neck, close to the hairline.

Trichilemmomas. Multiple 2- to 3-mm small papules on the nose and cheek

• Papillomatous papules are benign mucocutaneous lesions usually seen on the face, oral mucosa, and acral surfaces. They produce a cobblestone appearance on the buccal and gingival mucosa.

• Keratosis punctata may be seen on the palms and sides and soles of the feet.

• Lipomas are seen in 30% of the patients and café au lait spots in 9% of patients with CS.

(a) Skin-colored warty facial papules. (b) Acral keratoses. (c) Cobblestone tongue.

Acral Keratosis

• Sebaceous hyperplasia and fibromas may also present in the orofacial region.

• Other mucocutaneous lesions include hemangiomas, scrotal and furrowed tongue, neuromas, xanthomas, vitiligo, acanthosis nigricans, perioral and acral lentigines, and speckled pigmentation of the penis.

• Breast, colon, and thyroid cancers are most common malignancies associated with Cowden syndrome.

• A baseline colonoscopy should be initiated at 50 years of age.

Bannayan-Riley-Ruvalcaba Syndrome (BRRS)

• Bannayan-Riley-Ruvalcaba syndrome is characterized by hamartomatous gastrointestinal polyps, macrocephaly, hemangiomas, and developmental delay.

• The disease is usually diagnosed at a young age, with a 68% male predominance.

• Hyperpigmented macules involving the glans penis or vulva are the most specific cutaneous finding.

• Less common lesions include facial verrucous papules, lipomas, acanthosis nigricans, and vascular malformations.

• Ocular abnormalities involving the retina (Schwalbe lines) and cornea occur in 35% of patients.

• The recommendations for BRRS screening include examination of the glans penis of any male with macrocephaly and/or mental retardation.

• Surveillance recommendations are similar to those described for CS.

Juvenile Polyposis Syndrome

• Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder that is characterized by multiple juvenile polyps in the gastrointestinal tract.

• Juvenile polyposis syndrome can occasionally present in combination with hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease) and, as a result, have the characteristic cutaneous features of HHT.

• Patients should be examined for facial and digital telangiectasias.

• The presence of digital clubbing in a JPS patient should prompt additional evaluation for HHT.

A. Telangiectasia on the lower lip (arrow)B. Clubbing of the fingernails

Hereditary Hemorrhagic Telangiectasia. (a) Telangiectasia of the oral mucosa. (b) Telangiectasia of the palms.

Neurofibromatosis

• Neurofibromatosis involves the gastrointestinal tract in 25% of patients, predominantly the jejunum and stomach but also the colon, along with the characteristic cutaneous findings and Lisch nodules in the iris.

• Cutaneous and ocular manifestations include Café au lait spots, axillary and inguinal freckling, dermal neurofibromas, and iris Lisch nodules.

• On rare occasions, neurofibromas may undergo malignant transformation into neurofibrosarcomas.

Neurofibromatosis. A: Multiple skin-colored, dome shaped nodules on the trunk along with wing scapula. B: Lisch nodules, Yellow-brown oval to round papules on the surface of iris.

Neurofibromatosis. Café-au-Lait Macules and Neurofibromas

Cronkhite-Canada Syndrome

• Cronkhite-Canada syndrome is characterized by diffuse gastrointestinal polyposis (with sparing of the esophagus).

• The cutaneous manifestations of the disease possibly result from malabsorption and malnutrition and include nail dystrophy (present in 98% of affected individuals), alopecia, and diffuse hyperpigmentation.

• The disease typically manifests in the sixth decade of life with a male to female ratio of 3:2.

• Up to 55% of patients die from this syndrome.

(a) Nail dystrophy. (b) Onycholysis.

Cronkhite-Canada syndrome. A: Onycholysis. B: Alopecia.

Paraneoplastic Syndromes Associated with Gastrointestinal Malignancies

Malignant Acanthosis Nigricans (AN)

• Arises spontaneously.• Progresses rapidly. • Most frequently associated with gastrointestinal

adenocarcinomas. Other malignancies include bladder, breast, pancreatic, hepatobiliary, and lung cancer.

• AN presents as hyperpigmented and hyperkeratotic velvety, slightly elevated plaques, frequently associated with acrochordons.

• Lesions are present in intertriginous areas, such as axillary, inguinal, and neck folds, but may progress to mammary, umbilical, and anogenital regions.

Malignant Acanthosis Nigricans. Hyperkeratotic, velvety, hyperpigmented plaque presenting in the axilla in a

patient with gastric adenoacarcinoma.

• Palmoplantar keratoderma or ‘‘tripe palms’’ is a feature of paraneoplastic AN.

• Palmoplantar keratoderma associated with AN has been described in the setting of gastric adenocarcinoma and squamous cell carcinoma in contradistinction to tripe palms alone, which are typically perceived to be associated with lung cancer.

• Benign AN is associated with endocrinopathies, such as obesity and insulin-resistant diabetes mellitus, and is normally limited to certain body areas, such as the neck and axillae.

“Tripe palms” Keratoderma of the palms

“Tripe palms” Keratoderma of the palms

Sign of Leser-Trѐlat

• Acute onset of multiple, eruptive seborrheic keratoses presenting initially on the trunk and subsequently on the extremities and face with an associated internal malignancy.

• The acute onset and rapid development of seborrheic keratoses should, however, prompt practitioners to search for an underlying malignancy.

Sign of Leser-Trelat. Eruptive Seborrheic Keratosis

Sign of Leser-Trelat. Eruptive Seborrheic Keratosis

Acrokeratosis Paraneoplastica (Bazex Syndrome)

• Bazex syndrome is a rare, acral psoriasiform dermatosis that is associated with internal malignancy, including those of the upper gastrointestinal tract.

• Classical dermatologic findings include well-defined erythematous to violaceous plaques covered by fine to thick adherent psoriasiform-like scale, symmetrically distributed on the acral areas, ear helices, and nasal and malar surfaces.

• In later stages, the limbs and trunk become involved.

• Other cutaneous findings include hyperpigmentation, palmoplantar keratoderma, and paronychia.

• Involved nails show ridging, thickening, yellowish discoloration, and onycholysis.

• Bulbous enlargement of distal phalanges with nail dystrophy is a characteristic finding.

Bazex Syndrome (Acrokeratosis Paraneoplastica). Keratoderma of the (A) palms and (B) soles.

Acrokeratosis paraneoplastica. Scaly, psoriasiform plaques involving the hands (a) and ears

(b)

Tylosis

• Tylosis is an autosomal dominant condition resulting in focal non frictional and non epidermolytic palmoplantar hyperkeratosis.

• Two types have been described: Type A occurs between 5 and 15 years of age and is

associated with a high incidence of esophageal carcinomas (Howel-Evans syndrome).

Type B occurs in the first year of life and is generally benign.

Focal Palmoplantar Keratoderma

Plummer-Vinson Syndrome

• Plummer-Vinson syndrome is a rare syndrome that is characterized by the classic triad of dysphagia, iron deficiency anemia, and esophageal webs.

• This disease typically affects middle aged women.• Fibrous band or web-like strictures are present in the

lower pharynx or upper esophagus.• Plummer-Vinson syndrome is associated with squamous

cell carcinoma of the esophagus.

Plummer-Vinson syndrome. Radiographic results revealing a fibrous band present in the lower pharynx as shown by the

arrow.

An endoscopic view of an esophageal web in Plummer-Vinson syndrome. A thin membranous constriction is typical

Koilonychia

Glucagonoma Syndrome and Necrolytic Migratory Erythema

• Glucagonoma syndrome is a rare glucagon secreting pancreatic alpha cell tumor associated with :

Cutaneous findings known as necrolytic migratory erythema (NME)

Elevated serum glucagon levels Abnormal glucose tolerance Weight loss Anemia Aminoaciduria Diarrhea, Steatorrhea Thromboembolic disease Psychiatric disturbances

• NME is a painful, pruritic, annular, erythematous eruption with central blisters leading to secondary erosions, crusting, and subsequent hyperpigmentation.

• Areas subject to friction and pressure, such as the perineum, ischial surfaces, groin, and lower abdomen are favored locations, but NME can also occur in a periorofacial distribution.

• Angular cheilitis, glossitis and stomatitis, alopecia, and brittle nails are frequently present.

Glucagonoma Syndrome and Necrolytic Migratory Erythema. A: Annular, erythematous eruption with central blisters. B:

Angular cheilitis, glossitis and stomatitis.

Glucagonoma Syndrome. Necrolytic Migratory Erythema

• NME identified in patients without glucagonoma is referred to as pseudoglucagonoma. This is seen in intestinal malabsorption syndromes, cirrhosis, inflammatory bowel disease, pancreatitis, and nonpancreatic malignancies.

• Presence of NME, new onset diabetes mellitus, and unexplained weight loss strongly suggest the diagnosis of glucagonoma.

Perianal Extramammary Paget Disease

• Perianal Paget disease is a rare intraepithelial adenocarcinoma with a high rate of recurrence and invasiveness, located in and around the anal verge and below the dentate line.

• The mean age of diagnosis is 69 years with an equal number of male and female patients.

• A unilateral, eczematous-like lesion in the perianal region is the most common initial complaint.

• Perianal Paget disease associated with underlying anorectal carcinoma.

Extramammary Perianal Paget Disease. Large Hemorrhagic Ulcer involving the gluteal cleft.

Carcinoid Syndrome

• Carcinoid syndrome classically refers to an intestinal carcinoid with hepatic metastases.

• Fifty percent are located in the appendix, with the remainder located in the small intestine.

• Carcinoid tumors confined to the intestinal tract are asymptomatic, because the various mediators are inactivated by the liver as they pass through portal circulation.

• Hepatic metastases or extraintestinal carcinoids lead to carcinoid syndrome.

• Carcinoid syndrome has several stages of cutaneous involvement.

• It includes : Flushing and rosacea; Pellagra-like changes from niacin deficiency; A sclerodermoid variant; Cutaneous metastases.

• Bright red flushing of the face, neck, and upper aspect of the trunk lasting for 1 to 2 minutes is a characteristic cutaneous finding.

Carcinoid Syndrome. Flushing

• Scleroderma is a feature of carcinoid tumor arising in the gut. In contrast to classical scleroderma, these patients have an absence of the Raynaud phenomenon, sparing of acral areas with lower limb involvement before involvement of the upper limbs.

• 24-hour 5-hydroxyindoleacetic acid testing is the criterion standard for diagnosis.

• Chromogranin A is considered to be a preferable marker.

Paraneoplastic Dermatomyositis (DM)

• Between 15% and 40% of adults over 40 years of age with dermatomyositis may have an underlying malignancy, including a gastrointestinal malignancy.

• Cutaneous manifestations seen in paraneoplastic DM are similar to classic DM and include :

A heliotropic rash with periorbital edema Gottron papules on the finger joints Violaceous poikiloderma overlying the chest, upper

aspect of the back, elbows, and knees

Paraneoplastic Dermatomyositis. Gottron Papules

Periorbital Heliotrope Erythema and Edema in a patient with Paraneoplastic Dermatomyositis.

• Other findings include characteristic nail findings, such as ‘‘ragged cuticle’’ and nail fold telangiectases.

• Autoantibodies are present in a high percentage of patients with DM without malignancy.

• Therefore, the absence of autoantibodies may be predictive of an occult malignancy.

Nail Fold Telangiectasia and Ragged Cuticles

Paraneoplastic Pemphigus

• Paraneoplastic pemphigus (PNP) is an acantholytic mucocutaneous blistering disease distinct from pemphigus vulgaris and pemphigus foliaceus.

• Extensive mucosal involvement is an early, hallmark feature of PNP, with hematologic malignancies seen in the majority along with adenocarcinoma of the colon.

Paraneoplastic Pemphigus. Oral Erosions

Violaceous plaques with erosions on the trunk of a patient with Paraneoplastic Pemphigus.

Cutaneous Metastasis of Gastrointestinal Malignancy

• GI malignancies can also metastasize to the skin, typically to the overlying upper abdominal wall.

• Gastric adenocarcinoma is classically associated with a Sister Joseph nodule on the umbilicus.

• Cutaneous metastases may also initially present along the surgical incision site.

Abdominal wall metastasis in a patient with adenocarcinoma of the colon

Sister Mary Joseph's nodule. Red papular lesions in the umbilicus

Capsule Summary

• Hereditary gastrointestinal diseases and paraneoplastic syndromes manifest distinct cutaneous features.

• Hereditary malignancies include nonpolyposis and polyposis colorectal cancer, hamartomatous polyposis, and Cronkhite-Canada syndrome.

• Paraneoplastic syndromes do not have direct malignant infiltration, but primary tumor and cutaneous progression is typically parallel.

• Identification of these cutaneous findings is necessary for timely diagnosis, surveillance, and treatment of the underlying gastrointestinal pathology.

References

http://www.dermnetnz.org/