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Nonfamilial diffuse palmoplantar keratoderma associated with bronchial carcinoma
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2 11. Alexander CB, Guillermo AH,JaffeK,etal.Blackthyroid; clinical manifestations, ultrastructural findings, and possiblemechanisms. Hum Patho11985;16:72-8. 12. Reid JD. The black thyroid associated with minocycline therapy. Am J Clin Pathol 1983;79:738-46. 13. SaulSR, Dekker A, Lee RE, et al. Theblack thyroid: its relation to minocycline usein man. Arch Pathol Lab Med 1983;107:173-7. 14. Argenyi ZB,Finelli L,Bergfeld WF,etal.Minocycline-related cutaneous hyperpigmentation as demonstrated by light microscopy andelectron microscopy andx-rayenergy spectroscopy. J Cutan Pathol1987;14:176-80. 15. Ridgway HA,Sonnex TS,Kennedy eTC, etal.Hyperpig-
.Minocycline hyperpigmentation mentation associated withoralminocycline. Br J Dermato1 1982;107:95-102. 16. Okada N, Moriya K, Nishida K, et al. Skinpigmentation associated with minocycline therapy. Br J Dermatol 1989;121:247-54. 17. Granstein RD, Sober AJ. Drug- and heavy metal-induced hyperpigmentation. JAM ACAD DERMATOL 1981;5:1-18. 18. McGrae JD, Zelickson AS. Skin pigmentation secondary to minocycline therapy. Arch Dermatol1980;116:1262-5. 19. Fenske NA, Millns JL, Greer KE. Minocycline-induced pigmentation at sites of cutaneous inflammation. JAMA 1980;244: 11 03-6.
Nonfamilial diffuse palmoplantar keratoderma associated with bronchial carcinoma Sandeep K. Khanna, MD,a Frank A. Agnone, MD,b Alan I. Leibowitz, MD,b Robert A. Raschke, MD,b and Manju Trehan, MDc Los Angeles, California, and
Phoenix, Arizona A 61-year-old black woman had epidermoid carcinoma of the lung and the recent onset of diffusehyperkeratosisofthe palmsand soles. Thesefindingssuggestedan association between internal malignancy and palmoplantar hyperkeratosis. This report discusses the palmoplantar keratodermas, including those associated with malignancy. (J AM ACAD DERMATOL 1993;28:295-7.) The terms hyperkeratosis, keratosis, and tylosis appear, often interchangeably, to describe palmaplantar keratoderma (PPK), a thickening of the palms and soles caused by excessive keratin. 1 PPK may be heritable or acquired. Both forms have been associated with malignant tumors. We describe a woman in whom carcinoma of the bronchus was associated with the recent onset of diffuse palmoplantar hyperkeratosis. CASE REPORT
A 61-year-oldblack woman had a 7-month history of severe pain in the left shoulder radiating down the arm,
From the Division of Nuclear Medicine, Department of Radiologic Sciences" and the Departmentof Medicine;UCLA School ofMedieine, and the Department of Internal Medicine, GoodSamaritan Regional Medical Center." Reprint requests: Alan I. Leibowitz, MD, Department of Internal Medicine, GoodSamaritan Regional MedicalCenter, 1111 E. MeDowell Rd., Phoenix, AZ 85006. Copyright@ 1993 by the AmericanAcademy of Dermatology. 0190-9622/93 $1.00+.10 16/4/41054
occasional hemoptysis, and weight loss. She also had a recent increasein the thickness of her palms and solesthat was associatedwith decreased strength in her left hand. She had smoked 20 cigarettes per day for 40 years. She denied any family history of cancer or similar skin disorders. On examinationshe had left-sided, normal-reacting miosis with partial ptosis, which indicated Horner's syndrome. The palms and soles were diffuselythickened and yellow (Fig. 1). The skin was more hyperkeratotic in pressure areas. She had left ulnar and median nervepalsy and marked bilateral clubbing. Findings of a bone scan revealed hypertrophic pulmonary osteoarthropathy. A chest x-ray film revealed a large left upper lobe mass. Findings of a transthoracic needle biopsy specimen revealed poorly differentiated epidermoid carcinoma. The patient received radiation therapy (6540 rads to the tumor and 5000 rads to the mediastinum). Her shoulder pain resolved somewhat, and modest improvement in her palmoplantar keratosis occurred. Her condition gradually deteriorated, and she died 10 months later. DISCUSSION The association between hereditary diffuse PPK (tylosis) and carcinoma of the esophagus was first
295
Journal of the American Academy of Dermatology February 1993
296 Khanna et al.
Fig. 1. Diffuse hyperkeratosis of the palms.
reported by Howel-Evans et al.? in 1958 in two Liverpool families, in which 17 of 48 members with tylosis developed squamous cell carcinoma of the esophagus. This association, especially the "late onset" variety of tylosis.! was later confirmed by several observers.v 5 Hereditary diffuse PPK (tylosis) has also occasionally been associated with esophageal stricturesf oral leukoplakia." squamous cell carcinoma of the tylotic skin," and carcinoma of the larynx and stomach.? The nonfamilial or acquired form of PPK also may be associated with neoplasia. Usually it involves both the palms and soles. Parnell and Johnson 10 first reported this acquired diffuse PPK in association with cancer of the esophagus and the bronchus. Subsequently, several reports supported this relationship by demonstrating acquired diffuse PPK in association with cancer of the esophagus, lung, breast, urinary bladder, and stomach.P'l'' These hyperkeratotic lesions have a characteristic cobblestone pattern with disruption of the dermatoglyphic palmar skin markings.'! This contrasts with familialhyperkeratosis (tylosis), which is usually smooth with retention of the normal dermatoglyphic pattern. 2 Punctuate palmar hyperkeratosis, of the palms only, is a distinct form of acquired keratoses that consists of pearly, yellow or flesh-colored, translucent, hyperkeratotic papules sometimes surrounded by a collarette of scales. 15 A greater than expected
risk of breast, uterus, lung, bladder, colon, and other cancers has been reported in patients who have this punctuateform ofpalmar hyperkeratosis. 15, 16 However, the existence of this relationship has been refuted by some authors. 17-19Arsenic exposure could explain the apparently increased risk of malignancy in these patients. 2o However, subsequent studies failed to reveal a history ofincreased arsenic exposure in patients who had punctuate palmar keratoses.l'' The pathogenesis of both the hereditary and acquired hyperkeratoses is unknown. Tyldesley and Hughes 7 found histologicchanges of preleukoplakia or leukoplakia in 16 of the 17 tylotic patients originally described by Howel-Evans et al.2 Tyldesley and Kempsorr" later demonstrated intranuclear electron-dense particles in epithelial cells obtained from esophageal carcinoma and oral leukoplakia in these patients. Yesudian et al.8 reported the development of squamous cell carcinoma in the tylotic palmar skin. These studies suggest a genetic association between the esophagus and the skin of the palms and soles that predisposes both sites to the development of squamous cell carcinoma.! It is likely that acquired, diffuse PPK represents a paraneoplastic response to the visceral malignancy, as either a solitary cutaneous manifestation 14 or as part of a syndrome such as pachydermoperiostosis,22 Bazexsyndrome, or acanthosis nigricans. 23, 24 Elevated levels of immunoreactive human growth hormone have been reported in these patients. Im-
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2
munoreactive human growth hormone, produced by the malignant tumor, has been proposed to induce proliferation of the palmoplantar skin.!' This was, unfortunately, not measured in our patient. Improvement of the skin lesions after radiation therapy in our patient, as previously reported," makes it likely that acquired diffuse hyperkeratosis represent a paraneoplastic response to the underlying malignancy. REFERENCES 1. Arnold HL Jr, Odom RB, James WD. Andrews' diseases of the skin: clinicaldermatology. 8th ed.Philadelphia: W B Saunders, 1990:219. 2. Howel-Evans W, McConnell RB, Clarke CA, et al. Carcinoma of the oesophagus with keratosis palmaris et plantaris (tylosis). Q J Med 1958;27:413-29. 3. Harper PS. Genetic heterogeneity in hyperkeratosis palmaris et plantaris. Birth Defects 1971;7:50-1. 4. Shine I, Allison PRoCarcinoma of the oesophaguswith tylosis(keratosis palmaris et plantaris). Lancet 1966;1:951-3. 5. Harper PS, Harper RM, Howel-Evans AW. Carcinoma of the oesophagus with tylosis. Q J Med 1970;39:317-33. 6. Thambiah AS, Yesudian P, Augustine SM, et al. Tylosis following post-corrosive stricture of the oesophagus. Br J DermatoI1975;92:219-21. 7. Tyldesley WR, Hughes RO. Tylosis, leukoplakia, and oesophageal carcinoma [Letter]. BMJ 1973;4:427. 8. Yesudian P, Premalatha S, Thambia AS. Genetic tylosis with malignancy: a study of a south Indian pedigree. Br J DermatoI1980;102:597-600. 9. Haines D. Primary carcinoma duplex associatedwith tylosis. J R Nav Med Serv 1967;53:75-8. 10. Parnell DD, Johnson SA. Tylosis palmaris et plantaris: its occurrence with internal malignancy. Arch Dermatol 1969;100:7-9.
Nonfamilial diffuse palmoplantar keratoderma 297 11. Millard LG, Gould DJ. Hyperkeratosis of the palms and soles associated with internal malignancy and elevated levels of immunoreactive human growth hormone. Clin Exp Dermatol 1976;1:363-8. 12. Costello MJ, Gibbs Re, Scott MJ. Palms and soles in medicine. Springfield: Charles C. Thomas, 1967:121-3. 13. Powell F, Mackey JP. Bronchial carcinoma and hyperkeratosis palmaris et plantaris. Postgrad Med J 1981;57:57-9. 14. Kuchmeister B, Rasokat H. Acquired disseminated papulous palmar keratoses-a paraneoplastic syndrome in cancers of the urinary bladder and lung? Z Hautkr 1984; 59:1123-4. 15. Dobson RL, Young MR, Pinto JS. Palmar keratoses and cancer. Arch DermatolI965;92:553-6. 16. Cuzick J, Harris R, Mortimer PS. Palmar keratoses and cancers of the bladder and lung. Lancet 1984;1:530-3. 17. Bean SF, Foxley EG, Fusaro RM. Palmar keratoses and internal malignancy. Arch DermatoI1968;97:528-32. 18. Stoman LP, Kopf AW, Garfinkel L. Are palmar keratoses a sign of internal malignancy? Arch Dermatol 1970; 101:52-5. 19. Rhodes EL. Palmar and seed keratoses and internal malignancy. Br J Dermatol 1970;82:361-3. 20. Sommers SC, McManus RO. Multiple arsenical cancers of skin and internal organs. Cancer 1953;6:347-59. 21. Tyldesley WR, Kempson SA. Ultrastructure of the oral epithelium in leukoplakia associated with tylosisand esophageal carcinoma. J Oral Pathol Med 1975;4:49-58. 22. Thompson OW III. Pachydermoperiostosis (hypertrophic osteoarthropathy). In: Demis DJ, Dobson RL, McGuire J, eds. Clinical dermatology. 10th ed. Hagerstown: Harper & Row, 1984:1-2. 23. Bazex A, Griffiths A. Acrokeratosis paraneoplastica-a new cutaneous marker of malignancy. Br J Dermatol 1980;103:301-6. 24. Breathnach SM, Wells G'C, Acanthosis palmaris: tripe palms. A distinctive pattern of palmar keratoderma frequently associated with internal malignancy. Clin Exp DermatoI1980;5:181-9.
.Minocycline hyperpigmentation mentation associated withoralminocycline. Br J Dermato1 1982;107:95-102. 16. Okada N, Moriya K, Nishida K, et al. Skinpigmentation associated with minocycline therapy. Br J Dermatol 1989;121:247-54. 17. Granstein RD, Sober AJ. Drug- and heavy metal-induced hyperpigmentation. JAM ACAD DERMATOL 1981;5:1-18. 18. McGrae JD, Zelickson AS. Skin pigmentation secondary to minocycline therapy. Arch Dermatol1980;116:1262-5. 19. Fenske NA, Millns JL, Greer KE. Minocycline-induced pigmentation at sites of cutaneous inflammation. JAMA 1980;244: 11 03-6.
Nonfamilial diffuse palmoplantar keratoderma associated with bronchial carcinoma Sandeep K. Khanna, MD,a Frank A. Agnone, MD,b Alan I. Leibowitz, MD,b Robert A. Raschke, MD,b and Manju Trehan, MDc Los Angeles, California, and
Phoenix, Arizona A 61-year-old black woman had epidermoid carcinoma of the lung and the recent onset of diffusehyperkeratosisofthe palmsand soles. Thesefindingssuggestedan association between internal malignancy and palmoplantar hyperkeratosis. This report discusses the palmoplantar keratodermas, including those associated with malignancy. (J AM ACAD DERMATOL 1993;28:295-7.) The terms hyperkeratosis, keratosis, and tylosis appear, often interchangeably, to describe palmaplantar keratoderma (PPK), a thickening of the palms and soles caused by excessive keratin. 1 PPK may be heritable or acquired. Both forms have been associated with malignant tumors. We describe a woman in whom carcinoma of the bronchus was associated with the recent onset of diffuse palmoplantar hyperkeratosis. CASE REPORT
A 61-year-oldblack woman had a 7-month history of severe pain in the left shoulder radiating down the arm,
From the Division of Nuclear Medicine, Department of Radiologic Sciences" and the Departmentof Medicine;UCLA School ofMedieine, and the Department of Internal Medicine, GoodSamaritan Regional Medical Center." Reprint requests: Alan I. Leibowitz, MD, Department of Internal Medicine, GoodSamaritan Regional MedicalCenter, 1111 E. MeDowell Rd., Phoenix, AZ 85006. Copyright@ 1993 by the AmericanAcademy of Dermatology. 0190-9622/93 $1.00+.10 16/4/41054
occasional hemoptysis, and weight loss. She also had a recent increasein the thickness of her palms and solesthat was associatedwith decreased strength in her left hand. She had smoked 20 cigarettes per day for 40 years. She denied any family history of cancer or similar skin disorders. On examinationshe had left-sided, normal-reacting miosis with partial ptosis, which indicated Horner's syndrome. The palms and soles were diffuselythickened and yellow (Fig. 1). The skin was more hyperkeratotic in pressure areas. She had left ulnar and median nervepalsy and marked bilateral clubbing. Findings of a bone scan revealed hypertrophic pulmonary osteoarthropathy. A chest x-ray film revealed a large left upper lobe mass. Findings of a transthoracic needle biopsy specimen revealed poorly differentiated epidermoid carcinoma. The patient received radiation therapy (6540 rads to the tumor and 5000 rads to the mediastinum). Her shoulder pain resolved somewhat, and modest improvement in her palmoplantar keratosis occurred. Her condition gradually deteriorated, and she died 10 months later. DISCUSSION The association between hereditary diffuse PPK (tylosis) and carcinoma of the esophagus was first
295
Journal of the American Academy of Dermatology February 1993
296 Khanna et al.
Fig. 1. Diffuse hyperkeratosis of the palms.
reported by Howel-Evans et al.? in 1958 in two Liverpool families, in which 17 of 48 members with tylosis developed squamous cell carcinoma of the esophagus. This association, especially the "late onset" variety of tylosis.! was later confirmed by several observers.v 5 Hereditary diffuse PPK (tylosis) has also occasionally been associated with esophageal stricturesf oral leukoplakia." squamous cell carcinoma of the tylotic skin," and carcinoma of the larynx and stomach.? The nonfamilial or acquired form of PPK also may be associated with neoplasia. Usually it involves both the palms and soles. Parnell and Johnson 10 first reported this acquired diffuse PPK in association with cancer of the esophagus and the bronchus. Subsequently, several reports supported this relationship by demonstrating acquired diffuse PPK in association with cancer of the esophagus, lung, breast, urinary bladder, and stomach.P'l'' These hyperkeratotic lesions have a characteristic cobblestone pattern with disruption of the dermatoglyphic palmar skin markings.'! This contrasts with familialhyperkeratosis (tylosis), which is usually smooth with retention of the normal dermatoglyphic pattern. 2 Punctuate palmar hyperkeratosis, of the palms only, is a distinct form of acquired keratoses that consists of pearly, yellow or flesh-colored, translucent, hyperkeratotic papules sometimes surrounded by a collarette of scales. 15 A greater than expected
risk of breast, uterus, lung, bladder, colon, and other cancers has been reported in patients who have this punctuateform ofpalmar hyperkeratosis. 15, 16 However, the existence of this relationship has been refuted by some authors. 17-19Arsenic exposure could explain the apparently increased risk of malignancy in these patients. 2o However, subsequent studies failed to reveal a history ofincreased arsenic exposure in patients who had punctuate palmar keratoses.l'' The pathogenesis of both the hereditary and acquired hyperkeratoses is unknown. Tyldesley and Hughes 7 found histologicchanges of preleukoplakia or leukoplakia in 16 of the 17 tylotic patients originally described by Howel-Evans et al.2 Tyldesley and Kempsorr" later demonstrated intranuclear electron-dense particles in epithelial cells obtained from esophageal carcinoma and oral leukoplakia in these patients. Yesudian et al.8 reported the development of squamous cell carcinoma in the tylotic palmar skin. These studies suggest a genetic association between the esophagus and the skin of the palms and soles that predisposes both sites to the development of squamous cell carcinoma.! It is likely that acquired, diffuse PPK represents a paraneoplastic response to the visceral malignancy, as either a solitary cutaneous manifestation 14 or as part of a syndrome such as pachydermoperiostosis,22 Bazexsyndrome, or acanthosis nigricans. 23, 24 Elevated levels of immunoreactive human growth hormone have been reported in these patients. Im-
Journal of the American Academy of Dermatology Volume 28, Number 2, Part 2
munoreactive human growth hormone, produced by the malignant tumor, has been proposed to induce proliferation of the palmoplantar skin.!' This was, unfortunately, not measured in our patient. Improvement of the skin lesions after radiation therapy in our patient, as previously reported," makes it likely that acquired diffuse hyperkeratosis represent a paraneoplastic response to the underlying malignancy. REFERENCES 1. Arnold HL Jr, Odom RB, James WD. Andrews' diseases of the skin: clinicaldermatology. 8th ed.Philadelphia: W B Saunders, 1990:219. 2. Howel-Evans W, McConnell RB, Clarke CA, et al. Carcinoma of the oesophagus with keratosis palmaris et plantaris (tylosis). Q J Med 1958;27:413-29. 3. Harper PS. Genetic heterogeneity in hyperkeratosis palmaris et plantaris. Birth Defects 1971;7:50-1. 4. Shine I, Allison PRoCarcinoma of the oesophaguswith tylosis(keratosis palmaris et plantaris). Lancet 1966;1:951-3. 5. Harper PS, Harper RM, Howel-Evans AW. Carcinoma of the oesophagus with tylosis. Q J Med 1970;39:317-33. 6. Thambiah AS, Yesudian P, Augustine SM, et al. Tylosis following post-corrosive stricture of the oesophagus. Br J DermatoI1975;92:219-21. 7. Tyldesley WR, Hughes RO. Tylosis, leukoplakia, and oesophageal carcinoma [Letter]. BMJ 1973;4:427. 8. Yesudian P, Premalatha S, Thambia AS. Genetic tylosis with malignancy: a study of a south Indian pedigree. Br J DermatoI1980;102:597-600. 9. Haines D. Primary carcinoma duplex associatedwith tylosis. J R Nav Med Serv 1967;53:75-8. 10. Parnell DD, Johnson SA. Tylosis palmaris et plantaris: its occurrence with internal malignancy. Arch Dermatol 1969;100:7-9.
Nonfamilial diffuse palmoplantar keratoderma 297 11. Millard LG, Gould DJ. Hyperkeratosis of the palms and soles associated with internal malignancy and elevated levels of immunoreactive human growth hormone. Clin Exp Dermatol 1976;1:363-8. 12. Costello MJ, Gibbs Re, Scott MJ. Palms and soles in medicine. Springfield: Charles C. Thomas, 1967:121-3. 13. Powell F, Mackey JP. Bronchial carcinoma and hyperkeratosis palmaris et plantaris. Postgrad Med J 1981;57:57-9. 14. Kuchmeister B, Rasokat H. Acquired disseminated papulous palmar keratoses-a paraneoplastic syndrome in cancers of the urinary bladder and lung? Z Hautkr 1984; 59:1123-4. 15. Dobson RL, Young MR, Pinto JS. Palmar keratoses and cancer. Arch DermatolI965;92:553-6. 16. Cuzick J, Harris R, Mortimer PS. Palmar keratoses and cancers of the bladder and lung. Lancet 1984;1:530-3. 17. Bean SF, Foxley EG, Fusaro RM. Palmar keratoses and internal malignancy. Arch DermatoI1968;97:528-32. 18. Stoman LP, Kopf AW, Garfinkel L. Are palmar keratoses a sign of internal malignancy? Arch Dermatol 1970; 101:52-5. 19. Rhodes EL. Palmar and seed keratoses and internal malignancy. Br J Dermatol 1970;82:361-3. 20. Sommers SC, McManus RO. Multiple arsenical cancers of skin and internal organs. Cancer 1953;6:347-59. 21. Tyldesley WR, Kempson SA. Ultrastructure of the oral epithelium in leukoplakia associated with tylosisand esophageal carcinoma. J Oral Pathol Med 1975;4:49-58. 22. Thompson OW III. Pachydermoperiostosis (hypertrophic osteoarthropathy). In: Demis DJ, Dobson RL, McGuire J, eds. Clinical dermatology. 10th ed. Hagerstown: Harper & Row, 1984:1-2. 23. Bazex A, Griffiths A. Acrokeratosis paraneoplastica-a new cutaneous marker of malignancy. Br J Dermatol 1980;103:301-6. 24. Breathnach SM, Wells G'C, Acanthosis palmaris: tripe palms. A distinctive pattern of palmar keratoderma frequently associated with internal malignancy. Clin Exp DermatoI1980;5:181-9.