Interesting Presentation

1. Cutaneous Manifestations of GI Malignancies
By
Mohammed Ezz El-din
Assistant Lecturer of Tropical Medicine & Gastroenterology
Faculty of Medicine, Assiut University
Email: squint_2008@yahoo.com

2. Brief Review of Dermatological Terminology…
You have to learn the
Terminology!

4. 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

5. 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.

6. Cutaneous Manifestations of
Hereditary Gastrointestinal Cancers

7. 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.

8. 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.

9. Sebaceous Adenoma on the scalp. Yellow Papule or Nodule

10. Sebaceous Adenoma. Yellow Papule or Nodule

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

12. • 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.

13. Sebaceous Carcinoma on the forearm

14. • Surveillance includes colonoscopy beginning at 25
years of age and repeated every 2 to 3 years.
• Regular dermatologic follow-up is recommended
annually.

15. 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.

16. • 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.

17. • 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.

18. Multiple Epidermoid Cysts on The Chest

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

20. • 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.

21. 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.

22. 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.

23. Hyperpigmentation of the tongue

24. Multiple Pigmentations on the lips and around the mouth

25. • 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.

26. 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.

27. • 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.

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

29. • 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.

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

31. Acral Keratosis

32. • 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.

33. 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.

34. • 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.

35. 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.

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

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

38. 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.

39. 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.

40. Neurofibromatosis. Café-au-Lait Macules and
Neurofibromas

41. 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.

42. (a) Nail dystrophy. (b) Onycholysis.

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

45. Paraneoplastic Syndromes Associated
with Gastrointestinal Malignancies

46. 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.

47. Malignant Acanthosis Nigricans. Hyperkeratotic, velvety,
hyperpigmented plaque presenting in the axilla in a
patient with gastric adenoacarcinoma.

48. • 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.

49. “Tripe palms” Keratoderma of the palms

50. “Tripe palms” Keratoderma of the palms

51. 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.

52. Sign of Leser-Trelat. Eruptive Seborrheic Keratosis

53. Sign of Leser-Trelat. Eruptive Seborrheic Keratosis

54. 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.

55. • 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.

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

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

58. 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.

59. Focal Palmoplantar Keratoderma

60. 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.

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

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

63. Koilonychia

64. 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

65. • 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.

66. Glucagonoma Syndrome and Necrolytic Migratory
Erythema. A: Annular, erythematous eruption with central
blisters. B: Angular cheilitis, glossitis and stomatitis.

67. Glucagonoma Syndrome. Necrolytic Migratory Erythema

68. • 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.

69. 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.

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

71. 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.

72. • 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.

73. Carcinoid Syndrome. Flushing

74. • 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.

75. 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

76. Paraneoplastic Dermatomyositis. Gottron Papules

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

78. • 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.

79. Nail Fold Telangiectasia and Ragged Cuticles

80. 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.

81. Paraneoplastic Pemphigus. Oral Erosions

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

83. 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.

84. Abdominal wall metastasis in a patient with adenocarcinoma
of the colon

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

86. 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.

87. References

89. http://www.dermnetnz.org/