TOPICAL REVIEW DOI 10.1111/j.1365-2133.2007.08253.x Paraneoplastic lanuginosa acquisita: uncommon or overlooked? P.H.T.J. Slee, R.I.F. van der Waal,* J.H. Schagen van Leeuwen, R.A. Tupker,* R. Timmer, C.A. Seldenrijk§ and M.A.M. van Steensel– Departments of Internal Medicine, *Dermatology, Obstetrics and Gynaecology, Gastroenterology and §Pathology, St Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, the Netherlands –Department of Dermatology, University Medical Hospital Maastricht, the Netherlands

Summary

Correspondence Acquired hypertrichosis lanugo-type or hypertrichosis lanuginosa acquisita (HLA) P.H.T.J. Slee. is often associated with metabolic and endocrine disorders and use of certain E-mail: [email protected] drugs. The occurrence of HLA with malignancy was first noted in 1865, and it has since been described in 56 patients as a paraneoplastic syndrome both in Accepted for publication 13 August 2007 women and in men. Sometimes HLA occurs concurrent with acanthosis nigri- cans, papillary hypertrophy of the tongue, and glossitis. The predominance of Key words female cases is striking. Malignancy-associated HLA seems to occur especially in acquired hypertrichosis lanugo-type, hypertrichosis the age group 40–70 years. In women with HLA the most frequent malignancy lanuginosa acquisita, malignancy, paraneoplastic is colorectal cancer, followed in order by lung cancer and breast cancer; in men Conflicts of interest lung cancer is the malignancy most frequently associated with HLA, followed by None declared. colorectal cancer. In 3 years we saw 10 patients with HLA, in whom the malig- nancy was usually metastasized. Only one patient had local disease; after removal of the primary tumour it took 2 years before the lanugo recurred. The aeti- ology of the syndrome is not clear: no specific hormonal or biochemical abnor- malities have been identified as yet. The difference between hirsutism and lanugo-type hypertrichosis is discussed. It is stressed that the appearance of lanugo-type hypertrichosis in body areas previously perceived by patients as ‘hairless’ is highly indicative of internal malignancy.

Hypertrichosis, defined as excessive hair growth, is a problem Lanugo physiologically grow in utero, contain no that may present itself in various clinical patterns. Recognition medulla, are not pigmented, are long and are shed during the of the type of hypertrichosis is very important for the diagno- last months of pregnancy up to the first months after birth.1 sis and therapy of the underlying disease. In contrast to hirsutism, lanugo-type hypertrichosis does not show a gender-specific distribution pattern. Patients with Hypertrichosis acquired hypertrichosis lanugo-type or hypertrichosis lanugin- osa acquisita (HLA) grow lanugo-type hair near their eye- Hypertrichosis may involve lanugo hair, or terminal brows and on their forehead, ears and nose. Some patients hair.1 Lanugo hairs are long, thin and unpigmented, like have extensive involvement that includes the extremities, axil- wool. Vellus or intermediate hairs are short, unpigmented lae and trunk, but the palmoplantar, suprapubic and genital hairs; they are variably medullated. Terminal hairs contain a areas are rarely involved.2 medulla, and are longer, thick, and pigmented. These hairs Hypertrichosis lanuginosa may occur as congenital or are involved in hirsutism, which is defined as an adult male- acquired forms. Only the lanugo-type of hypertrichosis will pattern hair overgrowth in children or women. Most authors be discussed here. For the other types excellent reviews are consider hirsutism as a subclass of hypertrichosis. This type of available.1 hypertrichosis appears predominantly on body areas with androgen-sensitive follicles, e.g. the chest, and mous- Hypertrichosis lanuginosa congenita tache regions. Hirsutism occurs as a result of androgen activ- ity: either as a consequence of elevated systemic androgen Hypertrichosis lanuginosa congenita or congenital lanugo levels, or by means of local elevated sensitivity for androgens, hypertrichosis (CLH) often represents a normal variation in or a combination of both mechanisms. In hirsutism endocrine premature neonates that have not gone through the in utero evaluation is warranted. shedding phase because of premature birth, but is rarely

2007 The Authors Journal Compilation 2007 British Association of Dermatologists • British Journal of Dermatology 2007 157, pp1087–1092 1087 1088 Paraneoplastic hypertrichosis lanuginosa acquisita, P.H.T.J. Slee et al. encountered in full-term children. In CLH the hair is spread epithelial tumours, e.g. proteins from the Wingless family and over the entire body, sparing only the palms, soles and b-catenin. Especially the latter is of interest, for it is capable of mucous membranes. It can be inherited as an autosomal dom- initiating de novo hair growth in adult mice.60 inant feature, but sporadic cases also occur.1,3 The recent observation that treatment with epidermal growth factor (EGF) receptor (EGFR) antagonists can result in 61 Hypertrichosis lanuginosa acquisita hypertrichosis is also quite intriguing in this respect. EGF signalling is known to play an important role in the regulation HLA may occur in metabolic and endocrine diseases, e.g. por- of growth and development. Mutations in the phyria and hypo- or hyperthyroidism, or may be induced by gene coding for the EGFR in the mouse cause disturbances of drugs such as ciclosporin, penicillamine, psoralens, glucocorti- hair growth.62 Considering the involvement of EGF signalling costeroids, diazoxide, interferon, minoxidil, phenytoin or in many solid malignancies such as lung cancer, it is tempting cetuximab.1,3 Furthermore, HLA can be associated with neo- to speculate that the production of EGFR ligands by the plastic disease, as outlined below (Tables 1 and 2). tumour could contribute to HLA. The skin symptoms that are associated with it, such as acanthosis nigricans, conceivably Hypertrichosis lanuginosa acquisita as reflect skin overgrowth caused by activation of EGF signalling. paraneoplastic manifestation The occurrence of lanugo-type hypertrichosis on body regions that a patient previously has perceived as ‘hairless’ should be In 1865, Turner reported the association of HLA with malig- interpreted as an important marker of an underlying malig- nancy in a woman with breast cancer.4 Several case reports nancy, after ruling out the above-mentioned other factors have appeared since, leading to a total of only 56 reported (hormones, drugs) that may be involved in HLA.19 Although patients to date.4–56 A comprehensive search of scientific pub- HLA may arise as a paraneoplastic manifestation in various lications via PubMed (1950–2005) and Google Scholar was cancers, it has predominantly been reported in lung and colo- carried out. The search terms used were [(‘hypertrichosis’) rectal cancer (Table 1). The predominance of these cancers AND (‘lanuginosa’ OR ‘lanugo’ OR ‘lanugo-type’)] AND may partially be explained by their higher prevalence rates. [‘acquisita’ OR ‘acquired’] AND [‘malignancy’ OR ‘Neo- Therefore, in patients with HLA in the absence of malignancy, plasms’ (Mesh) OR ‘paraneoplastic’]. All articles were checked the following work-up is advised, apart from history taking for related links and citations. Articles were checked to find and physical examination: blood examination, a chest X-ray out whether another aetiology was (more) reasonable. Essen- and colonoscopy.3 tial data of these patients are outlined in Table 1. HLA is strik- ingly predominant in women (female to male ratio 2Æ3) and, Own experience according to reported cases, it seems to occur mainly between ages 40 and 70 years (mean 54).4–56 In women, colorectal In the past 3 years 10 patients with paraneoplastic HLA were carcinoma is the most observed associated malignancy, fol- diagnosed in our hospital (Table 2). A combined pattern of lowed by lung cancer and breast cancer. In men, lung cancer lanugo-type hypertrichosis and hirsutism was encountered in is the most frequently encountered malignancy, followed three of them. Two of them had a sex cord stromal tumour of by colorectal carcinoma.4–56 Hair growth may occur from the ovary as underlying neoplasia, and a third was diagnosed 2Æ5 years before the tumour is identified up to 5 years after with an adrenocortical tumour. Production of androgens by diagnosis. Patients with HLA usually have metastatic disease at these three malignancies probably explains the combined pat- the time of diagnosis and, therefore, a poor prognosis. How- tern of hypertrichosis. Only one of the seven patients with ever, successful antitumour therapy is associated with regres- lanugo-type hypertrichosis without hirsutism had localized sion of the hair growth. disease. After removal of the primary tumour, an adenocarci- For reasons unknown, paraneoplastic HLA usually pro- noma of the endometrium, it took 2 years before the lanugo gresses in a craniocaudal direction and may be accompanied hair regrew. Data of all patients are presented in Table 2.63 by acanthosis nigricans, hypertrophy of tongue papillae, and A characteristic picture of patient 2 is given in Figure 1. glossitis.1 The pathogenesis of paraneoplastic HLA has not yet Hypertrichosis was also recognized in patients who were been elucidated. Hypothetically, tumour-produced cytokines previously treated with chemotherapy and who experienced may not only stimulate tumour growth, but may also promote alopecia. During regrowth of hair hypertrichosis was noted, as proliferation of other cells, including those of the hair folli- is reported in the literature. Such patients were not included cles. The concurrence of HLA and acanthosis nigricans might in Table 2. Currently, this is the largest series of patients with point towards the involvement of an insulin-like growth fac- paraneoplastic HLA in a single institution, bringing the total tor, but this has not been identified to date.57 Furthermore, number of reported patients to 63. In Table 3 an overview of various fibroblast growth factors (FGFs) are known to be all reported patients with paraneoplastic HLA is provided. In involved in the regulation and differentiation of hair view of the fact that this many patients were detected in just growth.58,59 FGF production has been demonstrated in lung 3 years, paraneoplastic HLA may be substantially under- tumours. Several other growth factors that play a role in the reported. This is probably mainly due to unfamiliarity of clini- initiation of hair follicle growth are produced by malignant cians with this particular paraneoplastic syndrome. Also,

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Table 1 Overview of all reported cases in the literature

Age Advanced First author (year) Sex (years) or localized Localization Malignancy Turner (1865)4 F 42 Adv Breast Carcinoma Lyell (1951)5 F 35 Adv Urinary bladder Transitional cell carcinoma Dingley (1957)6 F 56 Adv Ovary Adenocarcinoma Fretzin (1967)7 M 69 Adv Lung Anaplastic carcinoma Herzberg (1969)8 M 65 Adv Gallbladder Adenocarcinoma Hensley (1969)9 M 41 Adv Lung Small cell carcinoma Chadfield (1970)10 F 78 Adv Rectum Adenocarcinoma Djajadiningrat (1970)11 F 43 Adv Rectum Adenocarcinoma Hegedus (1972)12 F 45 Adv Colon Adenocarcinoma F 56 Adv Colon Adenocarcinoma van der Lugt (1973)13 F 73 Adv Colon Adenocarcinoma Anderson (1973)14 M 63 Adv Lung Squamous cell carcinoma Reinhold (1974)15 F 60 Adv Colon Adenocarcinoma Samson (1975)16 F 66 Adv Endometrium Adenoacanthoma F 35 Adv Mediastinum Histiocytic lymphoma Rzempoluch (1976)17 F 44 Adv Lung Anaplastic carcinoma Kaiser (1976)18 F 46 Adv Endometrium Adenocarcinoma Wadskow (1976)19 F 54 Loc Breast Carcinoma McLean (1977)20 F 19 Loc Pancreas Islet cell carcinoma Ikeya (1978)21 M 69 Loc Lung Undifferentiated carcinoma Davies (1978)22 F 59 Loc Colon Carcinoid Ricken (1979)23 F 24 Adv Leukaemia Chronic lymphocytic Goodfellow (1980)24 M 61 Loc Lung Polygonal cell carcinoma Gonza´lez (1980)25 M 71 Adv Urinary bladder Transitional cell carcinoma Shee (1981)26 M 57 Adv Lung Adenocarcinoma Knowling (1982)27 M 62 Adv Lung Adenocarcinoma F 51 Adv Lung Adenocarcinoma Sindhuphak (1982)28 F 32 Adv Unknown primary Adenocarcinoma Ulrich (1983)29 F 34 Adv Lung Carcinoma George (1983)30 F 46 Adv Breast Duct carcinoma Price (1985)31 F 63 Adv Colon Adenocarcinoma Kassis (1985)32 F 54 Loc Endometrium and lunga Anaplastic adenocarcinoma Jemec (1986)33 F 48 Adv Lymphoma Follicular Skaf (1986)34 F 62 Adv Colon Adenocarcinoma Hovenden (1987)35 F 76 Adv Lung Clear cell carcinoma Dyall-Smith (1987)36 M 48 Adv Colon Adenocarcinoma Carratala´ (1987)37 F 69 Adv Lung Adenocarcinoma Mengori (1989)38 M 69 Adv Colon Adenocarcinoma Rodriguez (1990)39 F 30 Adv Lung Carcinoma Salazar (1990)40 M 50 Adv Lung Undifferentiated carcinoma De Clercq (1990)41 F 58 Adv Breast Duct carcinoma McKenna (1992)42 F 65 Adv Endometrium Adenocarcinoma Begany (1992)43 F 32 Adv Skin Melanoma Brinkmann (1992)44 M 30 Loc Colon Adenocarcinoma Duncan (1994)45 M 69 Adv Kidney Renal cell carcinoma Toyoki (1998)46 M 75 Adv Rectum Adenocarcinoma Farin˜a (1998)47 F 66 Adv Breast Duct carcinoma Maier (1999)48 F 27 Adv Parotid gland Planocellular carcinoma Pe´rez-Losada (2001)49 F 62 Loc Sarcoma Extraskeletal Ewing sarcoma Bauer (2001)50 M 70 Adv Leukaemia Acute myeloid Sanchez-Estella (2005)51 F 50 Loc Cervix Squamous cell carcinoma Lorette (2006)52 F 68 Loc Rectum Adenocarcinoma Pruijm (2007)53 F 58 Adv Unknown primary Adenocarcinoma Saad (2007)54 F 51 Loc Stomach Adenocarcinoma Wyatt (2007)55 M 93 Adv Prostate Adenocarcinoma Vulink (2007)56 F 57 Adv Breast Adenocarcinoma

Loc, localized disease; Adv, advanced disease. aFour months later lung cancer was diagnosed.

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Table 2 Series of patients with paraneo- Age Tumour plastic hypertrichosis lanuginosa acquisita at Patient Sex (years) localization Tumour type St Antonius Hospital 1 F 53 Lung Advanced nonsmall cell carcinoma 2 F 62 Colon Advanced adenocarcinoma 3 F 27 Colon Advanced adenocarcinoma 4 F 61 Colon Advanced adenocarcinoma 5 F 60 Endometrium Localized adenocarcinoma 6 F 56 Breast Advanced adenocarcinoma 7 F 38 Breast Advanced neuroendocrine carcinoma 8 F 80 Ovary Localized sex cord stromal tumour 9 F 53 Ovary Advanced sex cord stromal tumour 10 F 63 Adrenal gland Advanced adrenocortical tumour

Table 3 Overview of all reported patients with paraneoplastic hypertrichosis laniginosa acquisita, including our series (in brackets)

Cumulative Tumour localization Men Women reported cases Lung 8 7a (+1) 16 Colorectum 4 10 (+3) 17 Breast 0 6 (+2) 8 Uterus 0 4a (+1) 5 Urinary bladder 1 1 2 Lymphoma 0 2 2 Chronic lymphocytic 01 1 leukaemia Acute myeloid 10 1 leukaemia Ovary 0 1 1 Unknown primary 0 2 2 Pancreas 0 1 1 Gallbladder 1 0 1 Melanoma 0 1 1 Kidney 1 0 1 Parotid gland 0 1 1 Ewing sarcoma 0 1 1 Cervix 0 1 1 Stomach 0 1 1 Prostate 1 0 1 Total 17 47 64

aThe case of endometrial and lung carcinoma32 has been coun- ted twice.

taking, physical examination and further diagnostics when HLA is diagnosed. If hypertrichosis is seen in an adult without Fig 1. Hypertrichosis in patient 2 (with permission of J Clin Oncol63). associated metabolic disorders or a history of taking a drug known to cause this phenomenon, it is imperative to search for a malignancy. hypertrichosis in men is less obvious against a more hairy background and is cosmetically more accepted than in women. This may be the reason why most cases reported so References far have been in women. Furthermore, in women hypertri- 1 Wendelin DS, Pope DN, Mallory SB. Hypertrichosis. J Am Acad chosis may be missed because of the ready availability of Dermatol 2003; 48:161–79. various techniques. 2 Poole S, Fenske NA. Cutaneous markers of internal malignancy. In this context Goethe is cited, who wrote: ‘What one II. Paraneoplastic dermatoses and environmental carcinogens. JAm knows, one sees.’ We reiterate the importance of history Acad Dermatol 1993; 28:147–64.

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