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Skin Signs of Internal Malignancy Fact, Fancy and Fiction Jeffrey P. Callen, MD Professor of Medicine (Dermatology) Chief, Division of Dermatology University.

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Presentation on theme: "Skin Signs of Internal Malignancy Fact, Fancy and Fiction Jeffrey P. Callen, MD Professor of Medicine (Dermatology) Chief, Division of Dermatology University."— Presentation transcript:

1 Skin Signs of Internal Malignancy Fact, Fancy and Fiction Jeffrey P. Callen, MD Professor of Medicine (Dermatology) Chief, Division of Dermatology University of Louisville

2 Disclosure I have no relevant disclosures in relationship to this presentation

3 Educational Objectives Following this session, the attendee will: Recognize the dermatological conditions associated with internal malignancy Understand criteria for associating a skin disorder with an internal malignancy Evaluate the strength of the relationship Construct an appropriate evaluation

4 “Recalcitrant” Psoriasiform lesions in a patient with Squamous Cell Carcinoma of the tonsil 67-year-old man Six month history of a psoriasiform rash than began on toes and progressed to involve the nasal tip, periungual fingers, and aural helices. Minimal pruritus An invasive, poorly differentiated squamous cell carcinoma of the left tonsil ( 4 x 3 x 2 cm) with cervical lymphadenopathy was diagnosed several weeks after the eruption began.

5 Diagnosis Acrokeratosis Paraneoplastica AKA Bazex Syndrome

6 Treatment and Course Chemotherapy and radiation induced remission of the tumor, however, only permitted partial improvement of the skin disease. After our evaluation of the patient, we recommended further evaluation for possible metastatic disease. Approximately two months later he developed hip pain and was found to have advanced disease with lytic metastatic involvement of the left ischium. The patient died six weeks later.

7 Acrokeratosis Paraneoplastica (AP) Originally described in 1965 occurring in a French man with typical skin lesions and a carcinoma of the pyriform sinus. The skin lesions cleared upon treatment of the tumor. Since then, AP has been recognized as a rare paraneoplastic condition most commonly associated with SCC of the head, neck, and upper “aerodigestive” tract.

8 Acrokeratosis Paraneoplastica (AP) The typical patient is a white male over 40 years old with a history of tobacco abuse but has been described in black men and women as well. Differential Diagnosis includes psoriasis, Reiter’s disease, dermatophytosis, lichen planus, acrodermatitis continua, dermatitis, porphyria cutanea tarda, epidermolysis bullosa acquisita and bullous pemphigoid when vesicles are present.

9 Acrokeratosis Paraneoplastica (AP) Classically, there are three clinical stages: I. Violaceous erythema and psoriasiform or spine-like scale of the fingers, toes, aural helices, and nose. II. The eruption spreads centripetally from the nail folds to involve the palms and soles with a violaceous keratoderma. III. The eruption may extend to involve the legs, knees, thighs, arms, and even trunk. The neoplasm is generally symptomatic by this stage.

10 Acrokeratosis Paraneoplastica (AP) Occasionally, vesicles and bullae may occur. Symmetric distribution Pruritus is usually minimal. Histopathology is relatively non-specific with hyperkeratosis, parakeratosis, acanthosis, significant spongiosis and a perivascular mononuclear infiltrate in the dermis Immunofluorescence is non-specific or negative. Minimal benefit with dermatologic therapies.

11 Acrokeratosis Paraneoplastica (AP) In a retrospective 1995 study by Bolognia et al., the psoriasiform lesions preceded the diagnosis of the associated malignancy in 67%, followed the diagnosis in 15%, and occurred simultaneously in 18% (n=109). The paraneoplastic nature of the disease was further supported by the fact that skin lesions in 93% of these patients either improved significantly (or resolved) when the underlying neoplasm was treated or they remained unchanged in the setting of persistent disease.

12 Skin signs of Internal Malignancy More than 50 dermatological conditions have been associated with systemic cancer Many may represent chance occurrences Curth in her work primarily with acanthosis nigricans proposed a set of criteria that are useful in assessing the interrelationship between dermatoses and cancer

13 “Curth’s” Criteria 1. The dermatosis is relatively uncommon 2. It occurs with a specific neoplasm 3. The two conditions are frequently observed together 4. The onset is concurrent 5. The clinical course is similar 6. Genetic predisposition

14 Some reasons for “false” associations Selection bias – unusual circumstances lead to referral of such patients to tertiary care centers Prevalence bias – the prevalence of a second disease is increased (Berkson’s bias) Diagnostic suspicion bias – More testing is done due to “known” association Anecdotal nature of first reports

15 Recognition of “false” associations will avoid: Waste of medical resources Complications of ‘unnecessary’ testing Psychological distress for the patient and family Medical-legal risks

16 Prototypic conditions Concurrent onset – Acanthosis nigricans Parallel course – Acute febrile neutrophilic dermatosis (Sweet’s syndrome) Specific tumor – Glucagonoma syndrome Extension of underlying cancer – Paget’s disease of the breast Statistical association - Dermatomyositis

17 Malignant Acanthosis Nigricans Hyperpigmented, velvety skin on intertriginous surfaces Asymptomatic Weight loss is frequent Widespread involvement is common Courtesy of Lawrence Sibrack

18 Acanthosis Nigricans – Differential Diagnosis Endocrinopathy (probably accounts for ‘hereditary’ and ‘psuedoAN’ cases) Insulin resistance – often accompanied by obesity Polycystic ovaries Addison’s disease Thyroid disease Malignancy Drug-related – hormones (DES, Corticosteroids) or nicotinic acid

19 Malignant Acanthosis Nigricans Tumors are commonly found within the abdomen – GI or GU Particularly adenocarcinoma of the stomach Epidermal growth factors (yet to be identified) are probably responsible for this disease With effective tumor therapy AN may resolve and may recur with recurrent cancer Poor prognostic sign

20 The Sign of Leser-Trelat Eruptive seborrheic keratoses or rapid growth or inflammation of existing lesions Unusually AN is also present Courtesy of Neil Fenske

21 Tripe Palms AN-like lesions of the palms Majority of patients do not have AN With AN – GI cancer is more common Without AN – lung cancer is associated Courtesy of Bruce Thiers, MD

22 Evaluation Acanthosis Nigricans GI & GU endoscopy and radiographs Leser-Trelat Same as AN Tripe palmsSame as AN in patient with AN, but CXR, cytology and possibly bronchoscopy for patients without AN

23 Acute Febrile Neutrophilic Dermatosis (Sweet’s Syndrome) Skin lesions often mimic an infection – cellulitis with classic AFND or impetigo/ecthyma with atypical PG-like lesions Fever Leukocytosis Polyarthritis

24 Malignancy-associated AFND Less frequent arthritis or conjunctivitis More frequent anemia & thrombocytopenia Associations: Myeloid preleukemia and leukemia Myeloma Hairy cell leukemia Lymphoma Solid tumors

25 Atypical Pyoderma Gangrenosum Superficial erosive lesions Frequently on the dorsal hands or face Bullous Blue-Gray margin Overlapping features with Sweet’s syndrome Strong association with hematologic malignancies and pre-malignant conditions

26 Pyoderma Gangrenosum and Cancer Classic lesions of Pyoderma gangrenosum are rarely associated with malignancy IgA paraproteinemia and occasionally IgA myeloma have been reported with PG Individual cases of PG with solid tumors have been reported

27 Evaluation of Patients with Neutrophilic Dermatoses Sweet’s syndrome – CBC Atypical PG – CBC and possibly SPEP PG - SPEP

28 Glucagonoma Syndrome Necrolytic migratory erythema Periorificial and intertriginous Erythema, scaling, blisters and erosions Other Features Angular cheilitis, glossitis, weight loss, depression, diarrhea Anemia, glucose intolerance

29 Glucagonoma Syndrome Caused by Alpha-cell tumor of the pancreas Differential diagnosis Seborrhea, Candidiasis, Intertrigo Acrodermatitis enteropathica, Zinc deficiency, Hepatic disease Evaluation – Glucagon levels, Scans or angiography Treatment – Removal of the tumor or chemotherapy Recently octreotide use has been associated with improvement of symptoms, however, it does not inhibit tumor growth

30 Paget’s Disease Erythematous, eczematous patch or plaque of the nipple and surrounding skin Differential diagnosis Eczema Psoriasis Contiguous ductal adenocarcinoma Axillary metastases are common

31 Extramammary Paget’s Disease Scaly, erythematous to eczematous patch or plaque in the perineal or perianal area Underlying malignancy in the GU or GI tract in about 40-50% of the patients

32 Dermatomyositis Inflammatory myopathy with characteristic skin lesions Gottron’s papules, Gottron’s sign, heliotrope rash, nailfold changes, scalp changes and photosensitive poikiloderma Proximal muscle weakness Elevated muscle enzymes

33 DM and Cancer – Scandinavian Studies NEJM 1992; 326: Population-based study PM – slight increase in cancer, explained by ‘diagnostic' suspicion bias DM – Statistically significant increase, greater with advancing age Overrepresentation of ovarian cancer No effects from DM therapy

34 DM and Cancer – Scandinavian Studies Cancer Causes and Control 1995; 6: 9-13 Danish study demonstrated that the risk was greatest in the first 2 years following the onset of disease By the 3 rd year the frequency of cancer had returned to baseline Arthritis & Rheum 1999; 42: S298 Overrepresentation of ovarian, lung and pancreatic cancer.

35 8% Adult Dermatomyositis and Malignancy

36 Malignancy Evaluation for the Patient with Dermatomyositis Careful history and physical examination Routine labs – CBC, U/A, CMP, CXR, stool hematest Chest X-ray, CT of Chest and abdomen, stool hematest – all patients Mammogram, pelvic ultrasound and or CT of the pelvis in women Repeat annual for three years Age-related evaluation after 3 years from onset Young patients evaluation is different than older adults

37 Bowen’s Disease Erythematous, scaly plaque, often with an undulating border In 1959 linked to cancer In the 1960s – felt that when it occurred on “non-exposed” surfaces the chance of malignancy was higher

38 Bowen’s Disease 1991 – population-based study disproved the association  JAMA 1991; 266: 816-9

39 Gardner’s Syndrome (MIM ) Autosomal dominant – APC (adenomatous polyposis coli) gene on 5q21-q22 The gene product regulates b-catenin, an adherens junction protein involved in cell migration and cell cycle control Epidermoid cysts, desmoid tumors Congenital hypertrophy of the retina is common Adenomatous polyps with a high chance of cancer – approaching 100%

40 Gardner’s syndrome Annual colonoscopy should begin at puberty for patients and family members who have not had genetic testing Consider prophylactic colectomy Consider genetic testing in first degree relatives along with careful skin examination for subtle changes

41 Peutz-Jeghers Syndrome (MIM ) Autosomal dominant – STK11/LKB1 gene on 19p13.3 This gene is a tumor suppressor gene encoding for serine/threonine kinase that affects cell cycle progression Pigmented labial macules, may also affect the acral skin Hamartomatous polyps 13% have GI cancer, 10-40% have other solid tumors

42 Peutz-Jeghers Syndrome GI endoscopy every 2 years with removal of large polyps Regular breast and gynecologic examination for women

43 Cowden’s Disease Multiple hamartoma syndrome Autosomal dominant – PTEN/MMAC1 gene on 10q22-23 (MIM ) This gene encodes a tyrosine phosphatase protein that regulates cell proliferation Facial trichilemmomas, acral keratoses, mucosal papillomas (HPV may be present in these lesions) Fibrocystic breast disease is present in nearly all women 22% of women have breast cancer, often bilateral

44 Cowden’s Disease Multiple hamartoma syndrome - II Hamartomatous GI polyps are present in 1/3 to 2/3 of the patients 62% - thyroid tumors, only 10% are malignant Endometrial cancer occurs in 5-10% Colon and lung cancers have also been reported

45 Cowden’s Disease Multiple hamartoma syndrome - III Self breast examination should begin at 18 years of age, bi-annual clinician examination and mammography or MRI at 25 Prophylactic mastectomy should be discussed Thyroid ultrasound beginning at age 18 Endometrial examination and aspiration might begin at age 35-40

46 Miscellaneous Conditions - 1 Primary Systemic Amyloidosis with myeloma

47 Miscellaneous Conditions - 2 Paraneoplastic pemphigus Associated with lymphoma, Castleman’s tumor

48 Miscellaneous Conditions - 3 Anti-epiligrin cicatricial pemphigoid About 1/3 of patients had a malignancy within a short time of the diagnosis of their bullous disease Lancet 2001; 357:1850-1

49 Miscellaneous Conditions – 4 Hypertrichosis lanuginosa or malignant down Glossitis is frequent Rule out endocrine disorder Courtesy of Ken Greer, MD

50 Miscellaneous Conditions - 5 Erythema gyratum repens Almost all have a cancer Courtesy of Don Lookingbill

51 Miscellaneous Conditions - 6 Bazex syndrome or acrokeratosis paraneoplastica Acral erythematous to violaceous eruption with scale Paronychia are common Can generalize Tumors of the upper “aero-digestive” tract

52 Miscellaneous Conditions – 7 Cutaneous Vasculitis Rare - <1% to 5% in some series Concurrent onset and parallel course may occur Evaluate the patient with unexplained recurrent episodes, fever, severe constitutional symptoms or lymphadenopathy

53 Miscellaneous Conditions – 8 Birt-Hogge-Dube Syndrome Autosomal dominant condition mapped to 17p11.2 gene that encodes for folliculin Increased incidence of renal cell (oncocytoma) and lung cysts which frequently cause spontaneous pneumothorax Family members should be offered screening examinations beginning at age 40

54

55 Miscellaneous Conditions – 9 Multiple Cutaneous Leiomyomas Multiple hereditary cutaneous leiomyomas (Reed syndrome) Autosomal dominant Presents in the 2 nd -4 th decade as multiple painful flesh colored-red papules/plaques on the trunk or extremities. May have associated uterine leiomyomas

56 Hereditary Leiomyomatosis/Renal Cell Cancer Syndrome Autosomal dominant condition characterized by multiple cutaneous and uterine leiomyomas in conjunction with papillary renal cell carcinoma Mutation of the fumarate hydratase gene, an enzyme involved in the tricarbolic acid cycle, mapped to 1q locus Screening of patients and family members should be offered

57 Multiple Cutaneous Leiomyomas Overlaps with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCCS) Develop a rare type II papillary renal cell cancer Etiology-heterozygous mutation of fumarate hydratase a tumor suppressor gene

58 Reports 5 generations of a family with cutaneous and uterine leiomyomas were evaluated 16 family members studied 8 presented with cutaneous leiomyomas (all 6 women also with uterine leiomyomas) 1 patients with papillary renal cell carcinoma with a defect in fumarate hydratase Cairey-Remonnay S et al Annales de Dermatologie et Venereologie Nov 2003;130:

59 Other hereditary syndromes with prominent cutaneous features and increased risk of malignancy Muir-Torre syndrome Sebaceous gland tumors, keratoacanthomas with visceral carcinoma, mostly in the colon Howell-Evans syndrome Tylosis and esophageal cancer Melanoma/Pancreatic Cancer syndrome Familial atypical moles with increase risk of melanoma and pancreatic carcinoma

60 Other hereditary syndromes with prominent cutaneous features and increased risk of malignancy Multiple mucosal neuroma syndrome (aka – MEN type 2b) Association of mucosal neuromas and medullary carcinoma of the thyroid as well as pheochromocytoma Neurofibromatosis type 1 Malignant Schwann cell tumor, malignant degeneration of neurofibromas, pheochromocytomas, and GI stromal tumors

61 P OEMS – Polyneuropathy Mixed sensorimotor Symmetric and ascending Numbness, not pain Both demyelination and axonal degeneration have been documented by EMG and sural nerve biopsy

62 P O EMS – Organomegaly Usually liver, spleen, lymph nodes Heart and kidneys have been documented Lymph node enlargement often reveals Castleman’s disease on biopsy (= angiofollicular lymph node hyperplasia) Seen in approximately 60% of biopsied nodes Castleman’s is characterized by benign lymphadenopathy throughout the body Splenic biopsy sometimes shows Castleman’s Liver biopsy often normal or non-specific

63 PO E MS – Endocrinopathy Findings are diverse Hypogonadism with low testosterone and erectile dysfunction most common endocrine complaint in men (79%)* Hypothyroidism, diabetes common Gynecomastia, amenorrhea, adrenal insufficiency, hyperprolactinemia also seen Frequently there are multiple endocrinopathies (54%)* *Mayo Clin Proc 2007; 82:

64 POE M S – Monoclonal gammopathy Paraproteinemia either IgG λ or IgA λ A few κ have been documented Osteosclerotic myeloma with sclerotic bone lesions seen in most patients (>90%) Bone marrow plasmacytosis in 5-20%

65 POEM S – Skin lesions Angiomas (glomeruloid, cherry, and tufted) Seen in approximately 1/3 of patients Most angiomas are cherry Most commonly seen over the trunk and proximal extremities Hyperpigmentation (usually diffuse, >90%) Hypertrichosis (in 78-85%, is usually generalized but most pronounced over the lower extremities) Hyperhidrosis, sclerodermoid features especially of the hands, digital clubbing, leukonychia, skin thickening Violaceous patches overlying plasmacytoma of bone have been seen

66 POEMS Syndrome Courtesy of Jean Bolognia

67 Conclusions This brief overview has highlighted only some of the possible skin signs of cancer By applying a set of criteria it is easier to study the true associations Evaluation may then be directed appropriately


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