Presentation on theme: "Skin Signs of Internal Malignancy Fact, Fancy and Fiction"— Presentation transcript:
1Skin Signs of Internal Malignancy Fact, Fancy and Fiction Jeffrey P. Callen, MDProfessor of Medicine (Dermatology)Chief, Division of DermatologyUniversity of Louisville
2DisclosureI have no relevant disclosures in relationship to this presentation
3Educational Objectives Following this session, the attendee will:Recognize the dermatological conditions associated with internal malignancyUnderstand criteria for associating a skin disorder with an internal malignancyEvaluate the strength of the relationshipConstruct an appropriate evaluation
4“Recalcitrant” Psoriasiform lesions in a patient with Squamous Cell Carcinoma of the tonsil 67-year-old manSix month history of a psoriasiform rash than began on toes and progressed to involve the nasal tip, periungual fingers, and aural helices.Minimal pruritusAn 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.
6Treatment and CourseChemotherapy 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.
7Acrokeratosis 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.
8Acrokeratosis 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.
9Acrokeratosis Paraneoplastica (AP) Classically, there are three clinical stages:Violaceous erythema and psoriasiform or spine-like scale of the fingers, toes, aural helices, and nose.The eruption spreads centripetally from the nail folds to involve the palms and soles with a violaceous keratoderma.The eruption may extend to involve the legs, knees, thighs, arms, and even trunk. The neoplasm is generally symptomatic by this stage.
10Acrokeratosis Paraneoplastica (AP) Occasionally, vesicles and bullae may occur.Symmetric distributionPruritus is usually minimal.Histopathology is relatively non-specific with hyperkeratosis, parakeratosis, acanthosis, significant spongiosis and a perivascular mononuclear infiltrate in the dermisImmunofluorescence is non-specific or negative.Minimal benefit with dermatologic therapies.
11Acrokeratosis 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.
12Skin signs of Internal Malignancy More than 50 dermatological conditions have been associated with systemic cancerMany may represent chance occurrencesCurth 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 The dermatosis is relatively uncommon It occurs with a specific neoplasmThe two conditions are frequently observed togetherThe onset is concurrentThe clinical course is similarGenetic predisposition
14Some reasons for “false” associations Selection bias – unusual circumstances lead to referral of such patients to tertiary care centersPrevalence bias – the prevalence of a second disease is increased (Berkson’s bias)Diagnostic suspicion bias – More testing is done due to “known” associationAnecdotal nature of first reports
15Recognition of “false” associations will avoid: Waste of medical resourcesComplications of ‘unnecessary’ testingPsychological distress for the patient and familyMedical-legal risks
16Prototypic conditions Concurrent onset – Acanthosis nigricansParallel course – Acute febrile neutrophilic dermatosis (Sweet’s syndrome)Specific tumor – Glucagonoma syndromeExtension of underlying cancer – Paget’s disease of the breastStatistical association - Dermatomyositis
17Malignant Acanthosis Nigricans Hyperpigmented, velvety skin on intertriginous surfacesAsymptomaticWeight loss is frequentWidespread involvement is commonCourtesy of Lawrence Sibrack
18Acanthosis Nigricans – Differential Diagnosis Endocrinopathy (probably accounts for ‘hereditary’ and ‘psuedoAN’ cases)Insulin resistance – often accompanied by obesityPolycystic ovariesAddison’s diseaseThyroid diseaseMalignancyDrug-related – hormones (DES, Corticosteroids) or nicotinic acid
19Malignant Acanthosis Nigricans Tumors are commonly found within the abdomen – GI or GUParticularly adenocarcinoma of the stomachEpidermal growth factors (yet to be identified) are probably responsible for this diseaseWith effective tumor therapy AN may resolve and may recur with recurrent cancerPoor prognostic sign
20The Sign of Leser-Trelat Eruptive seborrheic keratoses or rapid growth or inflammation of existing lesionsUnusually AN is also presentCourtesy of Neil Fenske
21Tripe Palms AN-like lesions of the palms Majority of patients do not have ANWith AN – GI cancer is more commonWithout AN – lung cancer is associatedCourtesy of Bruce Thiers, MD
22Evaluation Acanthosis Nigricans GI & GU endoscopy and radiographs Leser-Trelat Same as ANTripe palms Same as AN in patient with AN,but CXR, cytology and possiblybronchoscopy for patientswithout AN
23Acute Febrile Neutrophilic Dermatosis (Sweet’s Syndrome) Skin lesions often mimic an infection – cellulitis with classic AFND or impetigo/ecthyma with atypical PG-like lesionsFeverLeukocytosisPolyarthritis
24Malignancy-associated AFND Less frequent arthritis or conjunctivitisMore frequent anemia & thrombocytopeniaAssociations:Myeloid preleukemia and leukemiaMyelomaHairy cell leukemiaLymphomaSolid tumors
25Atypical Pyoderma Gangrenosum Superficial erosive lesionsFrequently on the dorsal hands or faceBullous Blue-Gray marginOverlapping features with Sweet’s syndromeStrong association with hematologic malignancies and pre-malignant conditions
26Pyoderma Gangrenosum and Cancer Classic lesions of Pyoderma gangrenosum are rarely associated with malignancyIgA paraproteinemia and occasionally IgA myeloma have been reported with PGIndividual cases of PG with solid tumors have been reported
27Evaluation of Patients with Neutrophilic Dermatoses Sweet’s syndrome – CBCAtypical PG – CBC and possibly SPEPPG - SPEP
28Glucagonoma Syndrome Necrolytic migratory erythema Other Features Periorificial and intertriginousErythema, scaling, blisters and erosionsOther FeaturesAngular cheilitis, glossitis, weight loss, depression, diarrheaAnemia, glucose intolerance
29Glucagonoma Syndrome Caused by Alpha-cell tumor of the pancreas Differential diagnosisSeborrhea, Candidiasis, IntertrigoAcrodermatitis enteropathica, Zinc deficiency, Hepatic diseaseEvaluation – Glucagon levels, Scans or angiographyTreatment – Removal of the tumor or chemotherapyRecently octreotide use has been associated with improvement of symptoms, however, it does not inhibit tumor growth
30Paget’s DiseaseErythematous, eczematous patch or plaque of the nipple and surrounding skinDifferential diagnosisEczemaPsoriasisContiguous ductal adenocarcinomaAxillary metastases are common
31Extramammary Paget’s Disease Scaly, erythematous to eczematous patch or plaque in the perineal or perianal areaUnderlying malignancy in the GU or GI tract in about 40-50% of the patients
33DM and Cancer – Scandinavian Studies NEJM 1992; 326: Population-based studyPM – slight increase in cancer, explained by ‘diagnostic' suspicion biasDM – Statistically significant increase, greater with advancing ageOverrepresentation of ovarian cancerNo effects from DM therapy
34DM and Cancer – Scandinavian Studies Cancer Causes and Control 1995; 6: 9-13Danish study demonstrated that the risk was greatest in the first 2 years following the onset of diseaseBy the 3rd year the frequency of cancer had returned to baselineArthritis & Rheum 1999; 42: S298Overrepresentation of ovarian, lung and pancreatic cancer.
36Malignancy Evaluation for the Patient with Dermatomyositis Careful history and physical examinationRoutine labs – CBC, U/A, CMP, CXR, stool hematestChest X-ray, CT of Chest and abdomen, stool hematest – all patientsMammogram, pelvic ultrasound and or CT of the pelvis in womenRepeat annual for three yearsAge-related evaluation after 3 years from onsetYoung patients evaluation is different than older adults
37Bowen’s DiseaseErythematous, scaly plaque, often with an undulating borderIn 1959 linked to cancerIn the 1960s – felt that when it occurred on “non-exposed” surfaces the chance of malignancy was higher
38Bowen’s Disease1991 – population-based study disproved the associationJAMA 1991; 266: 816-9
39Gardner’s Syndrome (MIM 175100) Autosomal dominant – APC (adenomatous polyposis coli) gene on 5q21-q22The gene product regulates b-catenin, an adherens junction protein involved in cell migration and cell cycle controlEpidermoid cysts, desmoid tumorsCongenital hypertrophy of the retina is commonAdenomatous polyps with a high chance of cancer – approaching 100%
40Gardner’s syndromeAnnual colonoscopy should begin at puberty for patients and family members who have not had genetic testingConsider prophylactic colectomyConsider genetic testing in first degree relatives along with careful skin examination for subtle changes
41Peutz-Jeghers Syndrome (MIM 175200) Autosomal dominant – STK11/LKB1 gene on 19p13.3This gene is a tumor suppressor gene encoding for serine/threonine kinase that affects cell cycle progressionPigmented labial macules, may also affect the acral skinHamartomatous polyps13% have GI cancer, 10-40% have other solid tumors
42Peutz-Jeghers Syndrome GI endoscopy every 2 years with removal of large polypsRegular breast and gynecologic examination for women
43Cowden’s Disease Multiple hamartoma syndrome Autosomal dominant – PTEN/MMAC1 gene on 10q22-23 (MIM )This gene encodes a tyrosine phosphatase protein that regulates cell proliferationFacial trichilemmomas, acral keratoses, mucosal papillomas (HPV may be present in these lesions)Fibrocystic breast disease is present in nearly all women22% of women have breast cancer, often bilateral
44Cowden’s Disease Multiple hamartoma syndrome - II Hamartomatous GI polyps are present in 1/3 to 2/3 of the patients62% - thyroid tumors, only 10% are malignantEndometrial cancer occurs in 5-10%Colon and lung cancers have also been reported
45Cowden’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 25Prophylactic mastectomy should be discussedThyroid ultrasound beginning at age 18Endometrial examination and aspiration might begin at age 35-40
46Miscellaneous Conditions - 1 Primary Systemic Amyloidosis with myeloma
47Miscellaneous Conditions - 2 Paraneoplastic pemphigusAssociated with lymphoma, Castleman’s tumor
48Miscellaneous Conditions - 3 Anti-epiligrin cicatricial pemphigoidAbout 1/3 of patients had a malignancy within a short time of the diagnosis of their bullous diseaseLancet 2001; 357:1850-1
49Miscellaneous Conditions – 4 Hypertrichosis lanuginosa or malignant downGlossitis is frequentRule out endocrine disorderCourtesy of Ken Greer, MD
50Miscellaneous Conditions - 5 Erythema gyratum repensAlmost all have a cancerCourtesy of Don Lookingbill
51Miscellaneous Conditions - 6 Bazex syndrome or acrokeratosis paraneoplasticaAcral erythematous to violaceous eruption with scaleParonychia are commonCan generalizeTumors of the upper “aero-digestive” tract
52Miscellaneous Conditions – 7 Cutaneous Vasculitis Rare - <1% to 5% in some seriesConcurrent onset and parallel course may occurEvaluate the patient with unexplained recurrent episodes, fever, severe constitutional symptoms or lymphadenopathy
53Miscellaneous Conditions – 8 Birt-Hogge-Dube Syndrome Autosomal dominant condition mapped to 17p11.2 gene that encodes for folliculinIncreased incidence of renal cell (oncocytoma) and lung cysts which frequently cause spontaneous pneumothoraxFamily members should be offered screening examinations beginning at age 40
55Miscellaneous Conditions – 9 Multiple Cutaneous Leiomyomas Multiple hereditary cutaneous leiomyomas (Reed syndrome)Autosomal dominantPresents in the 2nd-4th decade as multiple painful flesh colored-red papules/plaques on the trunk or extremities.May have associated uterine leiomyomas
56Hereditary Leiomyomatosis/Renal Cell Cancer Syndrome Autosomal dominant condition characterized by multiple cutaneous and uterine leiomyomas in conjunction with papillary renal cell carcinomaMutation of the fumarate hydratase gene, an enzyme involved in the tricarbolic acid cycle, mapped to 1q locusScreening of patients and family members should be offered
57Multiple Cutaneous Leiomyomas Overlaps with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCCS)Develop a rare type II papillary renal cell cancerEtiology-heterozygous mutation of fumarate hydratase a tumor suppressor gene
58Reports5 generations of a family with cutaneous and uterine leiomyomas were evaluated16 family members studied8 presented with cutaneous leiomyomas (all 6 women also with uterine leiomyomas)1 patients with papillary renal cell carcinoma with a defect in fumarate hydrataseCairey-Remonnay S et al Annales de Dermatologie et Venereologie Nov 2003;130:
59Other hereditary syndromes with prominent cutaneous features and increased risk of malignancy Muir-Torre syndromeSebaceous gland tumors, keratoacanthomas with visceral carcinoma, mostly in the colonHowell-Evans syndromeTylosis and esophageal cancerMelanoma/Pancreatic Cancer syndromeFamilial atypical moles with increase risk of melanoma and pancreatic carcinoma
60Other 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 pheochromocytomaNeurofibromatosis type 1Malignant Schwann cell tumor, malignant degeneration of neurofibromas, pheochromocytomas, and GI stromal tumors
61POEMS – Polyneuropathy Mixed sensorimotorSymmetric and ascendingNumbness, not painBoth demyelination and axonal degeneration have been documented by EMG and sural nerve biopsy
62POEMS – Organomegaly Usually liver, spleen, lymph nodes Heart and kidneys have been documentedLymph node enlargement often reveals Castleman’s disease on biopsy (= angiofollicular lymph node hyperplasia)Seen in approximately 60% of biopsied nodesCastleman’s is characterized by benign lymphadenopathy throughout the bodySplenic biopsy sometimes shows Castleman’sLiver biopsy often normal or non-specific
63POEMS – Endocrinopathy Findings are diverseHypogonadism with low testosterone and erectile dysfunction most common endocrine complaint in men (79%)*Hypothyroidism, diabetes commonGynecomastia, amenorrhea, adrenal insufficiency, hyperprolactinemia also seenFrequently there are multiple endocrinopathies (54%)**Mayo Clin Proc 2007; 82:
64POEMS – Monoclonal gammopathy Paraproteinemia either IgG λ or IgA λA few κ have been documentedOsteosclerotic myeloma with sclerotic bone lesions seen in most patients (>90%)Bone marrow plasmacytosis in 5-20%
65POEMS – Skin lesions Angiomas (glomeruloid, cherry, and tufted) Seen in approximately 1/3 of patientsMost angiomas are cherryMost commonly seen over the trunk and proximal extremitiesHyperpigmentation (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 thickeningViolaceous patches overlying plasmacytoma of bone have been seen
67ConclusionsThis brief overview has highlighted only some of the possible skin signs of cancerBy applying a set of criteria it is easier to study the true associationsEvaluation may then be directed appropriately