Bazex' syndrome

Bazex’ Syndrome JEAN L. BOLOGNIA, MD.

T wo different disorders have acquired the eponym Bazex syndrome. One is characterized by multiple basal cell epitheliomas, hypotricho- sis, and follicular atrophoderma’; the second,

acrokeratosis paraneoplastica, is the subject of this dis- cussion. The latter Bazex syndrome fulfills the criteria for a paraneoplastic eruption in that it has been associated with a neoplasm in all of the cases reported to date, plus in a review of 70 cases, the skin lesions in 91% of the patients either improved significantly following treatment of the underlying malignancy or did not improve in the setting of persistent tumor. 2 In addition, several patients have experienced recurrence of their skin lesions with recurrence of the underlying malignancy.*

History The first report of a psoriasiform eruption involving the ears, nose, cheeks, and distal extremities in association with a squamous cell carcinoma (SCC) of the tongue was made by Gougerot and Rupp in 19223; however, the rela- tionship between the skin lesions and the underlying tumor was speculative, and it was not until the mid-1960s that Bazex et al provided more evidence in support of a paraneoplastic process. *s5 One of their patients experienced a complete clearing of his psoriasiform lesions following the successful treatment of SCC of the tongue.

Incidence An estimated 100 cases of acrokeratosis paraneoplastica have been reported since 1965 .26-12 The majority of these

From the Department of Dermatology, Yale University School of Medi- cine, New Haven, Connecticut.

Address correspondence to: Jean L. Bolognia, MD, Department of Der- matology, 500 LCI, Yale Medical School, 333 Cedar Street, P.O. Box 3333, New Haven, CT 06510.

clinical descriptions have appeared in the French litera- ture; presumably, this reflects an increased awareness of Bazex syndrome among French physicians, as well as the incidence in this country of SCCs of the head and neck region. Because the cutaneous findings of acrokeratosis paraneoplastica can mimic more common disorders such as psoriasis and dermatitis, the true incidence of the disease is probably underestimated. Unless the clinician rec- ognizes the involvement of the nose, ears, and cheeks as characteristic of Bazex syndrome, the clinical diagnosis may not even be considered.

Clinical Manifestations The primary lesions in acrokeratosis paraneoplastica are erythematous to violaceous in color and usually have associated scale. Clinical descriptions of this scale have varied from fme and white to thick and adherent. The most common locations for these papulosquamous lesions are the nose and the helices of the ears (Table l), sites that are unusual for either psoriasis or dermatitis. In decreasing order of frequency, additional sites of involvement include the nails, hands, feet, elbows, and knees; this predilection for acral sites is reflected in the name acrokeratosis. When the palms and soles are involved, a relative sparing of their central portion is often observed (Fig. 1).

Erythema and swelling of the paronychium in association with nail dystrophy is also a characteristic finding in Bazex syndrome. The nail changes are quite common (Table 1) and include thickening, ridging, yellow discol- oration, and subungual debris, changes similar to those seen in psoriasis (Fig. 2). In dark-skinned individuals, the most striking finding can be macular hyperpigmentation in the same distribution as the papulosquamous lesions, that is, the nose, ears, and distal extremitiesz9J3 (Fig. 3).

Less often, crusts, vesicles, and bullae are observed, especially in acral areas.* Such bullous lesions have multi-

0 1993 by Elsevier Science Publishing Co., Inc. l 0738-081x/93/$6.00 37

38 BOLOGNIA Clinics in Dermatology 1993:11:37-42

Table 1. Sites of Cutaneous Involvement in 84 Patients With Bazex Syndrome*

Number of Patients O/o

Ears 66 Nails 63 Nose 53 Fingers1 51 Palmst 49 Hands 48 Soles+ 43 Feet 42 Toes+ 33 Knees 20 Elbows 16 Cheeks 16 Trunk5 11 Scalpll 6 Other7 <4

79 75 63 61 58 57 51 50 39 24 19 19 13

7

* Only patients with a detailed description of sites of inoolvement are included. t May be artificially low because some authors may have categorized involvement

of the fingers or palms as hand involvement. $ May be artificially low because some authors may have categorized involvement

of the toes or soles as foot involvement. g Includes back, shoulders, presacral area, and buttocks. 11 Includes alopecia. 7 Number of patients in parentheses: forehead W, eyebrows f3J, chin W, face (3),

neck (3), legs (3), arms (V, distal upper extremities (2). wrists CV, scrotum (V, thighs L?J, distal lower extremities (V, axillae (I), hips (I), eyelids (I), temples II), lips (I), periornl area (I), penis (IJ, periannl area (I), ankles (1).

Reproduced, with permission of Williams and Wilkins, from Bolognia et al2

ple etiologies including spongiosis or vacuolar degeneration as a component of the acrokeratosis paraneoplastica versus concomitant porphyria cutanea tarda, bullous pemphigoid, or epidermolysis bullosa acquisita.* Lastly, patients may have evidence of a second paraneoplastic process such as acquired ichthyosis,” dermatomyositis,15 or the sign of Leser - TrelaP in addition to the lesions of their Bazex syndrome.

Bazex and Griffiths” described three clinical stages in acrokeratosis paraneoplastica. In the first stage, the lesions are located on the nose, outer rim of the ears, distal digits, and nails and are not as well defined as in later stages. The associated tumor is usually asymptomatic during this first phase. Support for this latter statement comes from a review of 89 well-documented cases of Bazex syndrome in which 63% (n = 56) of the patients had skin lesions an average of 11 months prior to the onset of symptoms or diagnosis of the associated tumor.2 The second clinical phase is characterized by the appearance of symptoms related to the underlying malignancy and an extension of the eruption to involve the cheeks, palms, and soles. The third or final phase appears if the tumor grows unchecked and is notable for additional sites of involvement such as the elbows, knees, and dorsae of

Figure 1. Scaling and hyperpigmentation of the plantar skin with relative sparing of the central portion in a patienf with a carcinoma of the esophagus. Fungal culture and KOH examination of the scale were negative. Reproduced, with permission of Williams and Wilkins, from Bolognia et al.2

the hands and feet; these changes occur in association with systemic symptoms.

Histopathology

In a review of 61 skin biopsies done of psoriasiform lesions in 45 patients, the most common findings (in decreasing order) were hyperkeratosis, acanthosis, parakeratosis, dyskeratotic keratinocytes, and a perivascular lymphocytic infiltrate (Table 2). In addition, vacuolar degeneration and incontinent melanin were observedin several biopsy specimens, providing an explanation for the hyperpigmentation seen in dark-skinned individuals. As a group, these histologic findings were not specific and represented an overlap of changes associated with psoriasis, lichen planus, and dermatitis. Direct immunofluores- cence (IF) of 13 biopsies from nine patients were “posi- tive” for basement membrane deposits of IgM, IgG, IgA, and/or C3 in two patients; both of these individuals had

Clinics in Dermatology 1993;12:37-42

BOLOGNIA 39 BAZEX SYNDROME

Figure 2. Thickening of the fingernails with crumbling of the free edge in addition to horizontal and vertical ridging in the same patient. Reproduced, with permission of Will iams and Wilkins, from Bolognia et al2

bullous as well as papulosquamous lesions.2 Indirect IF was negative in the three cases in which it was tested.

Associated Malignancy The majority of associated malignancies are SCCs of the upper aerodigestive tract, which explains why the classic patient with Bazex syndrome is a male over the age of 40. In a series of 93 patients, 57 (61%) had an SCC of the oropharynx, larynx, or esophagus2 (Table 3). This is in addition to the 10 patients with cervical lymph node metastases secondary to a SCC of unknown origin, the majority of whom probably had an occult primary of the head and neck region. 18~19 The lack of cases of SCC of the cervix and the limited number of cases of SCC of the lung raise the possibility that the factor or factors responsible for acrokeratosis paraneoplastica are relatively specific for SCCs originating from the upper aerodigestive tract. In an additional group of patients,6-*2 this predominance of SCCs of the upper aerodigestive tract was also observed with five of seven patients having such tumors. Two unusual associated malignancies, prostate andmulti- ple myeloma, were also reported.‘J2

Laboratory Findings Other than a nonspecific elevation of the erythrocyte sedi- mentation rate or anemia, there are no specific serum abnormalities in patients with acrokeratosis paraneoplastica. Radiographic findings depend on the primary site of

Figure 3. Hyperpigmentation of the helix of the ear in the same patient. Reproduced, with permission of Will iams and Wilkins, from Bolognia et a1.2

the malignancy and can include lymphadenopathy, lung or liver nodules, and either radiodensities or radiolucen- ties secondary to bony metastases. Low serum levels of vitamin A have been reported in an occasional patient,20J1 but this finding has not been confirmed by other investigators.22

Differential Diagnosis The differential diagnosis of acrokeratosis paraneoplastica includes primarily psoriasis and dermatitis. It is not unusual for the patient to carry these clinical diagnoses for months to years before the diagnosis of Bazex syndrome is made.23 Fortunately, the nose or the helices of the ear are involved in over 80% of the patients,2 and this distribution pattern points away from the diagnosis of either psoriasis or dermatitis. When vesicles or bullae are present, they may be the result of spongiosis or vacuolar degeneration associated with the acrokeratosis paraneoplastica; however, concomitant porphyria cutanea tarda, bullous pemphigoid, or epidermolysis bullosa acquisita should also be considered.2 In cases where the hands and feet are involved as well as the nails, the possibility of a dermatophyte or saprophyte infection must be excluded.

40 BOLOGNIA Clinics in Dermatology 1993:12:37-42

Table 2. Histologic Findings in Biopsy Specimens of Papulosquamous Lesions in Patients With Bazex Syndrome (61 Biopsies in 45 Patients)

Number of Biopsies

Epidermis Hyperkeratosis 38 Acanthosis 27 Parakeratosis 18 Dyskeratotic keratinocytes 18 Vacuolar degeneration 12 Spongiosis 9 Exocytosis* 8 Papillomatosis 6 Other t

Dermis Infiltrate*

Perivascular 28 Diffuse 5 “Lichenoid” 4 Periadnexal 3 Lymphocytes and “histiocytes” 31

(mononuclear) Neutrophils 6 Eosinophils 6 Plasma cells 2 “Mixed’ 4

Incontinent pigment 11 Telangiectasias 8 Edema 2 Blood vessel@

“Nonspecific dermatitis” 11

l Cellular infiltrate: mononuclear (II = B neutrophilic (1). t Elongation of rete ridges (n = 5); increased pigment in the basal layer (3; thinned

suprapapillary plate (2); follicular hyperkeratosis (2); atrophic (1); irregular granulnr layer (I); increased granular layer, segmental (I); vacuolar degeneration with cleft formation (1); thickened basement membrane (1); epidermnl necrosis (1).

$ SuperficiuI (n = 77; deep (2). §Fibrinoiddegenerution (n = 4); cnpillaritis (2); nonspecificchanges( mildvnscu-

litis (I); swollen endothelinl cells (1). Reproduced, with permission of Williams and Wilkins, from Bolognia et nL2

Treatment The lesions of Bazex syndrome are notoriously resistant to therapy and it is this resistance that sometimes serves as the first clue to the diagnosis. Attempted treatments that have reportedly failed include topical keratolytics, corticosteroids, tar, antifungals, and antibiotics.2 A few successful therapies have been described such as oral etretinate*’ and oral prednisone,” but in general, eradica- tion of the underlying malignancy is required for clearing of the skin. In a review of 70 cases of acrokeratosis paraneoplastica, the cutaneous lesions in 91% of the patients were found either to improve significantly following treatment of the underlying malignancy or not to improve in the setting of persistent tumor.* Even if the tumor is successfully cured and the skin lesions disappear, the nail changes may persist indefinitely.2*26 Nail dystrophy,

therefore, should not be viewed as evidence of persistent tumor.

Pathogenesis One possible mechanism is cross-reactivity between antigens found in the tumor and antigens found in the epidermis or basement membrane zone of the skin, as has been described in tumor-associated bullous pemphigoid.13*27*28 An alternative explanation is the secretion of growth factors such as transforming growth factor (Y (TGF-cr) and insulin-like growth factor 1 by the tumor.* Both of these are autocrine growth factors for human keratinocytes and both have been shown to be secreted by squamous carcinoma cell lines (see Reference 2 for list of primary references). In addition, overexpression of TGF-(I! in nude mice resulted in benign hyperplasia of the keratinocytes. 29 Lastly, there have been reports of low serum levels of vitamin A in patients with Bazex syndrome, and this has been implicated in the dryness and scaling associated with the disease20,2*; however, the low serum levels of vitamin A have not been a consistent finding.22

Table 3. Primary Sites and Cell Types of Malignancies in 93 Patients With Acrokeratosis Paraneoplastica

1 1 2t

Poorly Number see Dif NA

Oropharynx/larynx 48 Tonsil 101 8 2 Pyriform sinus 9 7 1 Pharynx 8 6 1 Larynx 6 4 Tongue 6 6 Epiglottis 3 2 1 Soft palate 2 2 Floor of mouth 1 1 No specific site 3* 3

Unknown 16 11 4 1 Lung 14$ 3 3 3 Esophagus 9§ 3 4 2

see Adeno Liver 1 - - Prostate 1 + Stomach 1 + Thymus 1 + uterus 1 + Vulva 1 +

Abbreviations: SCC, squamous cell carcinoma; Poorly Difi poorly differentiated carcinoma; NA, not available; Adeno, adenocnrcinomn.

* Two patients also had an SCC of the esophagus; one 3 years later (tonsil) and one simultaneously (no specific site).

t One was an ndenocarcinoma. $ Also small cell carcinoma (2 patients), adenocarcinoma (2 patients), cnrcinoid (1

patient). 0 One patient also had a carcinoma of the pyriform sinus 6 months later. Reproduced, with permission of Williams and Wilkins, from Bolognia et ~1.~

Clinics in Dermatology 1993:11:37-42

Conclusion Bazex syndrome is characterized by psoriasiform lesions in acral sites including the ear, nose, and distal extremities that are related to an underlying neoplasm. The majority of the associated malignancies are SCCs of the upper aerodigestive tract, and in one review, the skin lesions in over 90% of the patients either improved significantly following treatment of the tumor or did not improve in the setting of persistent tumor.* The cutaneous eruption of acrokeratosis paraneoplastica was noted to precede the onset of symptoms or diagnosis of the malignancy by an average of 11 months in 63% (56/89) of the patients in this same series.* In the remainder of individuals, the appearance of the eruption either coincided with (21%) or followed (16%) the diagnosis of the tumor. The recog- nition of the cutaneous manifestations of Bazex syndrome provides the clinician the opportunity to treat the associated malignancy at an earlier asymptomatic stage.

References 1.

2.

3.

4.

5.

6.

7.

8.

9.

Bazex A, Dupre A, Christ01 B. Atrophodermie folliculaire, proliferations basocellulaires et hypotrichose. Ann Derma- to1 Syph 1966;93:241-54. Bolognia JL, Brewer YP, Cooper DL. Bazex syndrome (acrokeratosis paraneoplastica): An analytic review. Medicine 1991;70:269-80. Gougerot, Rupp. Dermatose Prythemato-squameuse avec hyperkbratose palmo-plantaire, porectasies digitales et cancer de la langue latent. Contribution B l’@tude des der- matoses monitrices de cancer. Paris Med 1922;43:234-7. Bazex A, Salvador R, DuprG A, et al. Syndrome parankoplas- ique Q type d’hyperkkratose des extr&niti%. Gu&ison apr& le traitement de I’bpithPlioma laryngh. Bull Sot Fr Dermatol Syph 1965;72:182. Bazex A, Salvador R, Duprb A, et al. Dermatose psoriasi- forme acromPlique d’etiologie can&reuse (Entitg paraneo- plasique originale). Bull Sot Fr Dermatol Syph 1967;74:130-5. Gonzilez Herrada CM, Frias J, Casanova JM, et al. Acro- queratosis paraneoplbsica de Bazex. Aportaci6n de un nuevo case. Actas Dermo-Sif 1984;75:301-6. Gaveau D, Rotteleur G, Bauters F, et al. AcrokPratose et ichtyose acquises associPes a un myGlome multiple. Ann Dermatol Venereol 1986;113:829-32. Gutierrez Salmeron MT, Naranjo Sintes R, Linares Solana J, et al. Acroqueratosis paraneoplisica de Bazex: Aspectos pe- culiares histol6gicos y ultraestructurales. Actas Dermo-Sif 1987;78:497-503. Espasandin J, Vignale RA. Acroqueratosis paraneoplisica de Bazex. Un case clinic0 con hiperpigmentaci6n. Med Cutan Ibero Lat Am 1990;18:257-62.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

BOLOGNIA 41 BAZEX SYNDROME

Platschek H, Lubach D, Niesert J. Akrokeratose Bazex. Med Klin 1990;85:54-5.

von Hintzenstem J, Kiesewetter F, Simon M Jr, et al. Para- neoplastische acrokeratose Bazex-verlauf unter pallia- tiver therapie eines zungengrundkarzinoms. Hautarzt 1990;41:490-3.

Yuste Chaves M, Gonzilez Moran A, Galvin Casas C, et al.Acroqueratosis paraneoplisica de Bazex asociada a adenocarcinoma de prbtata. Actas Dermo Syph 1991;82: 577-80.

Pecora AI, Landsman L, Imgrund SP, et al. Acrokeratosis paraneoplastica (Bazex’syndrome). Arch Dermatol 1983; 119:820-6.

Witkowski JA, Parish LC. Bazex’s syndrome. Paraneoplas- tic acrokeratosis. JAMA 1982;248:2883-4.

Amblard I’, Reymond JL, Jerome I’, et al. Double syndrome paran&oplasique dermatomyosite et acrokkratose de Bazex. Rev Med Alpes Fr 1979;8:39.

Rubisz-Brzezinska J, Zebracka T, Musialowicz D. Wspblist- nienie dwu zespol6w paraneoplastycznych-acrokeratosis Bazex oraz zespolu Lesera-TrPlata-w przypadku raka plaskonablonkowego krtani. Przegl Dermatol 1983;70: 205-8.

Bazex A, Griffiths A. Acrokeratosis paraneoplastica: A new cutaneous marker of malignancy. Br J Dermatol 1980; 102:301-6.

Coper DD, Casterline PF, Chambers RG, et al. Metastasis to lymph nodes of the head and neck from an unknown primary site. Am J Surg 1977;134:517-22.

Jesse RH, Perez CA, Fletcher GH. Cervical lymph node metastasis: Unknown primary cancer. Cancer 1973; 31:854-9.

Hagedorn M, Stengel R. Pathogenetischer beitrag zur akrokeratose Bazex. Dermatologica 1983;167:234-42.

Bazex A. Paraneoplastische akrokeratose. Hautarzt 1979; 30:119-23.

Jacobsen FK, Abildtrup N, Laursen SO, et al. Acrokeratosis paraneoplastica (Bazex’s syndrome). Arch Dermatol 1984; 120:502-4.

Brenner S, Brayer M, Toplisky M. Acrokeratosis paraneoplastica (Bazex) in a patient with bronchial carcinoid tumor. J Am Acad Dermatol 1987;17:517-8.

Wishart JM. Bazex’s paraneoplastic acrokeratosis: A case report and response to Tigason. Br J Dermatol 1986; 115:595-9.

Martin RW, Comitius TG, Naylor MF, et al. Bazex’s syndrome in a woman with pulmonary adenocarcinoma. Arch Dermatol 1989;125:847-8.

Bureau Y, Barriere H, Litoux P, et al. Acrokeratose paranbo- plasique de Bazex. Importance des l&ions ung&ales. A

42 BOLOGNIA Clinics in Dermatology 1993;11:37-42

propos de deux observations. Bull Sot Fr Dermatol Syph phigoid and transitional cell carcinoma of the bladder. Arch 1971;78:79-82. Dermatol 1983;119:704-5.

27. Keller F, Mazet J, Kleis V, et al. L’acrokeratose paraneoplas- ique (Syndrome de Bazex). J Med Strasbourg 1986;17:67-

29. Finzi E, Kilkenny A, Strickland JL, et al. (Y TGF stimulates growth of skin papil lomas by autocrine and paracrine mech-

70. anisms but does not cause neoplastic progression. Mol Car- 28. Tanaka T, Ogino A, Ogura K, et al. A case of bullous pem- cinogen 1988;1:7-12.

Documents

Bazex' syndrome