Ivana Canjuga

Josip Galić

Marinka Mravak-Stipetić

Vlatko Kopić

English

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91	  Acta Dermatovenerol Croat                    2008;16(2):91-95                             CASE REPORTOral Acanthosis Nigricans: Case Report and Comparison with Literature ReportsIvana Canjuga1, Marinka Mravak-Stipetić2, Vlatko Kopić3, Josip Galić41Department of Oral Medicine, Zagreb University Hospital Center; 2Department of Oral Medicine, School of Dental Medicine, University of Zagreb,  Zagreb; 3Department of Maxillofacial Surgery; 4Department of Urology, Osijek University Hospital, Osijek, CroatiaCorresponding author: Ivana	Canjuga,	DMDDepartment	of	Oral	MedicineZagreb	University	Hospital	Center	and		School	of	MedicineGundulićeva 5HR-10000	ZagrebCroatiaivana.canjuga@gmail.com Received:	March	14,	2008Accepted:	April	30,	2008Summary	Acanthosis	 nigricans	 (AN)	 is	 a	 rare	 condition	 which	 may	affect	 oral	 cavity.	There	 are	 two	 forms	 of	AN:	 benign	 and	 malignant.	Benign	AN	may	be	hereditary,	or	may	be	related	to	systemic	diseases	or	 drugs.	 Malignant	AN	 is	 most	 often	 associated	 with	 gastric	 adeno-carcinoma	but	cancers	of	other	sites	and	 types	may	also	occur.	This	case	report	is	based	on	a	case	of	a	78-year-old	woman	suffering	from	invasive	bladder	papillary	 transitional	cell	carcinoma	accompanied	by	extensive	papillomatous	areas	of	normal	mucosal	color	and	soft	con-sistency	involving	the	lips,	buccal	mucosa	and	hard	palate.	Verrucous	changes	with	tiny	pigmented	macules	were	also	found	on	the	skin	of	the	right	ear	auricle.	Oral	lesions	occurred	after	the	tumor	had	been	diag-nosed, i.e. after third operation for tumor recurrence. The fifth operation for	 tumor	 recurrence	 resulted	 in	 slight	 improvement	 of	 oral	 changes.	It	 is	concluded	 that	 the	severity	of	oral	changes	 is	 in	correlation	with	tumor	progression.	The	occurrence	of	oral	lesions	may	be	an	indicator	of	tumor	progression.		Key wordS:	acanthosis	nigricans,	cancer,	oral	cavityINTroduCTIoNAcanthosis	nigricans	(AN)	is	a	mucocutaneous	disorder	 which	 is	 characterized	 by	 the	 presence	of	 hyperpigmented	 papillary	 lesions	 on	 the	 skin	and	 papillomatous	 lesions	 in	 the	 oral	 cavity	 (1).	There	are	two	forms	of	AN,	benign	and	malignant.	Benign	AN	may	be	hereditary,	or	may	be	related	to	 systemic	 diseases	 such	 as	 diabetes,	 obesity,	Cushing’s	syndrome	or	Addison’s	disease.	Certain	drugs	such	as	nicotinic	acid,	systemic	corticoste-roids,	estrogens,	insulin	and	fusidic	acid	may	play	a	 role	 as	 well	 (1).	 Insulin-resistant	 diabetes	 and	hyperinsulinemia	are	the	most	common	conditions	associated	with	the	benign	form	of	AN.	Malignant	AN	 is	a	 rare	 condition	 that	 is	 always	associated	with	 neoplasms.	 Searching	 through	 the	 Medline	we	found	8	cases	of	oral	AN	described	from	1999	to	2007	(2-9).Adenocarcinomas	are	 the	most	common	ma-lignancies	 found	 in	 patients	 with	 malignant	 AN	(10).		Malignant	AN	is	most	often	associated	with	gastric	adenocarcinoma	but	cancers	of	other	sites	and	types	may	also	occur	(1).	92The	 pathogenesis	 of	 malignant	 AN	 remains	unclear.	A	current	hypothetical	mechanism	is	 the	secretion	of	large	amounts	of	transforming	growth	factor	a	(TGF-a )	by	the	tumor	into	the	circulation,	which	is	thought	to	stimulate	keratinocyte	growth	via	an	endocrine	route	(11).	AN	is	characterized	by	hyperpigmented	plaques	commonly	affecting	 the	axillae,	nape	and	sides	of	the	neck.	Pruritus	and	hyperkeratosis	of	the	palms	and	soles	have	also	been	reported	(2).	Oral	AN	is	characterized	by	ex-tensive	papillomatosis	of	 the	 lips,	palate,	gingiva	and	tongue	(3).	Histologic	analysis	shows	hyper-keratosis	and	 irregular	acanthosis,	but	no	hyper-pigmentation	(2).	Papillary	hyperplasia	of	the	epi-thelial	lamina	is	also	present	(2-4,7,8).	This	report	is	based	on	a	case	of	a	patient	suffering	from	oral	AN	and	diagnosed	with	advanced	 invasive	blad-der	papillary	transitional	cell	carcinoma.CaSe rePorTIn	 September	 2006,	 a	 78-year-old	 woman	was	referred	to	the	Department	of	Oral	Medicine,	School	of	Dental	Medicine,	University	of	Zagreb,	Croatia,	for	evaluation	of	papillomatous	lesions	of	the	 vestibular	 and	 buccal	 oral	 mucosa,	 lips	 and	skin.	Her	medical	history	included	diabetes	melli-tus	and	hipercholesterinemia	as	well	as	taking	oral	antidiabetics	and	antilipemic	drugs.	Two	and	a	half	years	before	oral	lesions	developed,	the	diagnosis	of	invasive	papillary	transitional	cell	carcinoma	of	the	right	bladder	had	been	established.	Due	to	the	tumor	recurrence,	the	patient	was	surgically	treat-ed	four	times	within	2	years.	The	patient	refused	to	undergo	 the	 indicated	 radiotherapy,	 and	 chemo-therapy	was	not	performed.	Between	the	third	and	the	fourth	operation,	she	started	to	notice	discom-fort	 in	 the	 oral	 cavity.	 Shortly	 afterwards,	 due	 to	developed	changes	on	 the	oral	mucosa,	 the	pa-tient	was	referred	to	a	maxillofacial	surgeon	who	took	biopsies	from	the	lower	 lip	and	hard	palate.	Histologic analyses showed fibrovascular papillo-matous	connective	 tissue	covered	by	hyperkera-totic epithelium. These findings were consistent with the diagnoses of papilloma and fibroepithelial polyp.Clinical	 examination	 at	 our	 Department	 re-vealed	 extensive	 papillomatous	 areas	 of	 normal	mucosal	color	and	soft	consistency	 involving	 the	lips	 (Fig.	1a),	buccal	mucosa	 (Fig.	1b)	and	hard	palate.	 Verrucous	 changes	 with	 tiny	 pigmented	macules	were	also	present	on	the	skin	of	the	right	ear	auricle.	The	diagnosis	of	AN	was	established	according to clinical and histologic findings and the	patient’s	medical	documentation.The	 patient	 refused	 another	 biopsy	 due	 to	general	weakness.	A	swab	 for	Candida albicans	culture	and	cytobrush	smear	for	human	papilloma	virus	 (HPV)	 detection	 were	 obtained	 from	 papil-lomatous	 lesions.	 Candida albicans	 was	 highly	positive	by	semiquantitative	evaluation	according	to	the	previously	published	Budz-Jörgensen’s	cri-teria	 (12).	We	prescribed	 two-week	 therapy	with	miconazole	2%	oral	gel.	HPV	DNA	was	not	detect-ed	by	using	the	polymerase	chain	reaction	(PCR)	technique	on	the	cytobrush	smear	from	papilloma-tous	 lesions.	 Isotretinoin	 (0.5%) in Orabase was prescribed	for	local	therapy	for	its	antiproliferative	effect.	The	patient	noticed	slight	 improvement	of	oral	lesions.Figure 1.a	Papillomatous	changes	of	the	lips.Figure 1.b	Papillomatous	changes	of	the	buccal	mucosa.Canjuga et al.	 	 	 	 	 	 	 	 Acta	Dermatovenerol	CroatOral acanthosis nigricans       2008;16(2):91-95ACTA DERMATOVENEROLOGICA CROATICA93By	the	end	of	2006,	the	patient	underwent	her	fifth operation for tumor recurrence. Following the surgery,	oral	lesions	decreased	(Fig.	2);	however,	in	 May	 2007	 the	 patient	 died	 from	 tumor	 recur-rence	and	general	weakness.dISCuSSIoN In	this	case	report,	a	malignant	form	of	AN	ap-pearing	on	the	oral	mucosa,	perioral	skin	and	skin	of	 the	 right	 ear	 associated	 with	 advanced	 inva-sive	 bladder	 papillary	 transitional	 cell	 carcinoma	is	 described.	 In	 previous	 reports,	 malignant	 AN	has	been	most	commonly	associated	with	gastric	adenocarcinoma	(6-7,9,13-18).	Carcinomas	of	the	pancreas and biliary tract were also found (2,4,5).	Other	 carcinomas such	as	 those	of	 the	esopha-gus,	bladder,	testes,	breast,	uterus	and	lungs	have	been	reported	with	less	frequency.	In	the	report	by	Cairo	et al.	(3),	AN	was	associated	with	lung	and	bladder	carcinoma	in	the	same	patient.	As	the	lat-ter was at an early stage, confined to the super-ficial bladder epithelium, it seems reasonable to hypothesize	that	the	occurrence	of	malignant	AN	was	more	likely	linked	to	lung	carcinoma.	Addition-al	evidence	may	be	 the	 fact	 that	AN	progressed	despite	surgical	eradication	of	 the	bladder	 tumor	(3).	Bottoni	et al.	(8)	also	report	on	malignant	AN	associated	with	lung	carcinoma.AN	may	 involve	any	part	of	oral	mucosa	and	extend	 to	 pharyngeal	 and	 esophageal	 mucous	membranes	 (3).	 In	 previous	 reports,	 there	 has	been	 only	 one	 case	 report	 describing malignant	AN	limited	to	buccal	mucosa	(19).	Unlike	skin	le-sions,	oral	AN	seems	to	be	rarely	pigmented	or	not	pigmented	at	all	(1,2).Approximately	 40%	 of	 malignant	AN	 showed	oral	 lesions	 (20).	 During	 the	 1968-1998	 period,	there	 were	 14	 cases	 of	 malignant	 AN	 involv-ing	 oral	 cavity,	 as	 reported	 by	 Ramirez-Amador	et al.	 (2).	Eight	 cases	of	malignant	AN	 involving	oral	 cavity	 published	 by	 Medline	 from	 1999	 to	2007	are	shown	in	Table	1.	Although	the	number	of	described	cases	 in	comparison	with	 the	num-ber	of	 cases	 reported	by	Ramirez-Amador	et al.	(2)	has	increased,	gastric	adenocarcinomas	is	still	the	most	common	associated	malignancy	 (Table	2).	Our	assumption	is	that	the	discrepancy	in	the	number	of	cases	described	in	our	report	and	those	included	 in	Ramirez’s	 report	 is	more	 likely	 to	be	due	 to	 the	 fact	 that	we	had	an	easier	access	 to	Internet	 browsing	and	 literature	data	 than	 to	 the	actual	 increased	 prevalence	 of	 the	 disorder.	Ac-cording	 to	our	 report	 (Table	1),	 in	seven	of	eight	cases	 malignancy	 was	 diagnosed	 after	 AN	 had	developed.	 These	 data	 show	 the	 importance	 of	the	correct	diagnosis	of	oral	and	cutaneous	mani-festations	of	AN	and	additional	diagnostic	proce-dures	 in	 the	 detection	 of	 internal	 malignancy.	 It	has	been	recommended	that	patients	with	a	clini-cal	picture	of	AN,	apart	from	routine	hematological	and	biochemical	analyses,	should	undergo	chest	x-ray,	mammography,	cervical	cytology,	prostate-specific antigen assay and possibly endoscopy of the	complete	gastrointestinal	tract	(4).	Kleikamp	et al.	(6)	found	increased	levels	of	the	tumor	markers	CA	19-9,	CA	72-4	and	CEA	in	serum	of	a	patient	with	malignant	AN.Histological	 analysis	 of	 the	 previous	 reports	on	AN	 in	 the	oral	 cavity	 showed	hyperkeratosis,	acanthosis and finger-like structures of epithe-lial	lamina	(2-4).	These histological findings corre-spond	well	to	the	histological	data	in	our	case. In	our	patient,	PCR	typing	of	HPV	showed	no	reactivity	for	HPV.	In	the	study	by	Ramirez-Ama-dor	et al.	(2),	PCR	typing	of	HPV	showed	weak	re-activity for HPV type 35. Bottoni et al.	(8)	found	no	HPV	using	PCR	technique.	Other	authors	(13,16)	found	no	HPV	antigens	using	immunohistochem-istry	 either.	The	 result	 of	 Ramirez-Amador	 et al.	may be considered as an incidental finding (2).Since	the	lesions	of	malignant	AN	are	clinically	indistinguishable	from	the	benign	forms,	 this	 fact	addresses	the	importance	and	necessity	of	addi-tional	diagnostic	procedures	in	the	detection	of	in-ternal	malignancy.	In	our	case,	a	reduction	of	oral	lesions	was	observed	after	operative	cancer	treat-ment,	which	was	consistent	with	previous	obser-vations	on	AN	to	decrease	following	chemothera-py administration (5,9). The occurrence of clinical signs	and/or	aggravation	of	oral	AN	may	suggest	recurrence	or	metastasis	of	the	primary	tumor,	as	shown	in	our	case.Figure 2.	Decreased	 lesions	of	 the	 lips	after	 the	fifth operationCanjuga et al.	 	 	 	 	 	 	 	 Acta	Dermatovenerol	CroatOral acanthosis nigricans       2008;16(2):91-95ACTA DERMATOVENEROLOGICA CROATICA94Table 1.	Oral	acanthosis	nigricans	(AN)	published	by	Medline	1999-2007AuthorYear	of	publication	(ref.	no.)Diagnosis	of	AN	(before/after	diagnosis	of	malignancy)Oral	signs	and	symptomsOther	signs	and	symptomsAssociated	malignancyRamirez-Amador	et al.	1999	(2) BeforePapillomatosis	of	upper	vermilion	and	lip	mucosa,	buccal	mucosa,	hard	and	soft	palate,	gingiva	and	dorsum	of	the	tongueDiscrete	hyperpigmented	cutaneous	plaques;	papillomatous	lesions	on	the	esophagus;	palm	hyperkeratosisGallbladder	adenocarcinoma	Anderson	et al.1999	(9) BeforePapillomatous	lesions	on	perioral	area	and	palatePruritus;	generalized	warty	growths;	papillomatous	lesions	of	the	eyelids;	discharge	and	pain	of	perineum;	acanthotic	areas	on	the	chest	wall	and	nipplesGastric	adenocarcinomaBottoni	et al.	2000	(8) Before	Papillomatous	and	verrucous	lesions	on	lips	and	mouthDiffuse	hyperpigmentation;	hyperkeratosis	of	the	nipples;	papillomatous	and	verrucous	lesions	of	the	conjunctivaeLung	carcinomaScully	et al.	2001	(4) BeforeMild	gingival	swelling,	diffuse	thickening	of	lower	labial	mucosa	Generalized	pruritic	skin	papules,	of	the	axillae	and	groin;	slightly	keratotic	palms	and	solesGallbladder	adenocarcinomaCairo	et al.2001	(3) BeforePapillomatosis	of	vestibular	mucosa,	dorsum	of	the	tongue,	palate	and	gingiva;	burning	sensationsSubtle	changes	on	the	neck	skin,	axillae,	internal	surface	of	the	tighs,	with	hyperpigmented	and	thickened	areasBladder	and	lung	carcinomaPentenero	et al.	2004		(7) AfterPapillomatosis	of	lips,	buccal	mucosa	and	palate;	sore	palateVerrucous,	slightly	pigmented	papules	in	the	axillae	and	on	the	dorsal	surface	of	the	hand;	small,	brown	hyperkeratotic	exophytic	lesions	on	the	back	Gastric	adenocarcinomaMcGinness	and	Greer	2006 (5)BeforeVerrucous	papillomatous	papules	and	plaques	on	the	vermilion,	buccal	mucosa	and	tongueTripe	palms Pancreatic	adenocarcinomaKleikamp	et al.	2006	(6) BeforePapillomatous	to	verrucous	lesions	of	the	lips	and	buccal	mucosaHyperkeratosis	of	the	palms	and	solesGastric	adenocarcinomaCanjuga et al.	 	 	 	 	 	 	 	 Acta	Dermatovenerol	CroatOral acanthosis nigricans       2008;16(2):91-95ACTA DERMATOVENEROLOGICA CROATICA95Table 2.	 Comparison	 of	 literature	 data	 according	 to	 the	 incidence	 of	 gastric	 adenocarcinoma	 during	observation	periodAuthor	(ref.	no.) Period	(yrs)No.	of	acathosis	nigricans	cases	describedIncidence	of	associated	gastric	adenocarcinomaRamirez-Amador	et	al.	(2)	 30 14 6/14	(42%)Canjuga	et al. 8 8 3/8 (37.5%)	It	 is	concluded	 that	 the	occurrence	of	oral	 le-sions	may	be	an	indicator	of	tumor	progression.references1.	 		Schwartz	 RA.	 Acanthosis	 nigricans.	 J	 Am	Acad	Dermatol	1994;31:1-19.2.	 		Ramirez-Amador	V,	Esquivel-Pedraza	L,	Ca-ballero-Mendosa	 E,	 Berumen-Campos	 J,	Orozco-Topete	 R,	 Angeles-Angeles	 A.	 Oral	manifestations	 as	 a	 hallmark	 of	 malignant	acanthosis	 nigricans.	 J	 Oral	 Pathol	 Med	1999;28:278-81.3.	 		Cairo	F,	Rubino	I,	Rotundo	R,	Pini	Prato	G,	Fi-carra	G.	Oral	Acanthosis	Nigricans	as	a	Mar-ker	of	 Internal	Malignancy.	A	Case	Report.	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Oral Acanthosis Nigricans: Case Report and Comparison with Literature Reports

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