Multifocal epithelial hyperplasia: Clinical features, diagnosis and management challenges

Table 1 Results chronological table of the studies on multifocal epithelial hyperplasia included (2025→2021)

Ref.	Year	Prevalence	Molecular diagnostic methods	Immunohistochemical markers	Number of patients
Bravo et al[6]	2024	Increased prevalence in small populations of Native American descent	PCR for HPV13/32; Genomic sequencing (phylogenetic analysis of AlphaPVs); In situ hybridization	p16 INK4a (not always overexpressed); Ki-67; Keratins (differentiation)	Not specified (narrative review)
Conde-Ferráez et al[3]	2024	38.1% (Peru); 13% (Colombia); 22% vs 2%	PCR (HPV13/32); Sequencing (GenBank). Serology	Not specified	3877 children (Peru); 138 schoolchildren
Di Spirito et al[2]	2023	51.37%	In situ hybridization; PCR; Biopsy + molecular techniques	Not specified	75/146 oral lesions (in 153 children)
Dommisch et al[10]	2023	Endemic in Inuit and South American natives; women: 5:1 ratio	PCR for HPV-13 and 32	Not specified	Not specified
Wang et al[1]	2023	Rare in Asia (0.02%-35% depending on region); Underdiagnosed in China	PCR (GP5+/6+, MY09/11); Sanger sequencing; RDB genotyping	Not specified	1 clinical case
Sethi et al[4]	2021	32.3% (Nahuatl, Mexico); 7.4%-13% (indigenous); 0.11% (Sweden)	PCR (HPV13/32 primers); DNA sequencing; In situ hybridization; Microscopy	Cytokeratin 4/13; sensitivity 80%, specificity 70%	95 cases: 54 women, 41 men

PCR: Polymerase chain reaction; HPV: Human papillomavirus.

Table 2 Geographical distribution of multifocal epithelial hyperplasia in the studies included

Country	Ref.	Study	Total patients	Sex distribution	Ethnic origin	Place of study
North America
Canada	Jarvis and Gorlin[14]	Focal epithelial hyperplasia in an Eskimo population	1591 surveyed; prevalence 86%-12.7% (approx. 137-202 cases)	Not provided	Eastern Arctic Eskimos	University of Minnesota, Minneapolis, United States
Canada	Landells and Prendiville[15]	Oral mucosal lesions in a Somali boy	1 + 1 uncle (Somalia)	Male (patient)	Somali	Vancouver, Canada
Mexico	Tan et al[16]	Focal epithelial hyperplasia in a Mexican Indian	1	Male (12 years)	Mexican Indian	Illinois, United States (patient origin Mexico)
Mexico	Sandi et al[17]	Comparative treatment of multifocal epithelial hyperplasia	20	11 male, 9 female	Not specified	Hospital Infantil de Mexico, Mexico City
Mexico	Lopez-Villanueva et al[18]	HPV-13 in a Mexican Mayan community with MEH	53	75% female, 25% male	Mayan (Yucatán)	Yaxchachén, Yucatán
Mexico	González-Losa et al[19]	MEH in a Mayan community	57 (44 fully studied)	61.3% female, 38.6% male	Mayan (Chemax)	Chemax, Yucatán
Mexico	Lama-Gonzalez et al[20]	HPV-13 detection in MEH patients and relatives	16	9 female, 7 male	Likely Mayan or Mestizo	Mérida, Yucatán and Quintana Roo
Mexico	Gonzalez-López[21]	FEH in two communities of Estado de México	61 children + 25 relatives	Mestizo: 18 female/13 male; Mazahua: 17 female/13 male	Mestizo and Mazahua	Estado de México
Mexico	Jiménez Aguilar et al[22]	HPV diversity in MEH outbreak	21	10 female, 11 male	Not specified (indigenous predisposition noted)	Navolato, Sinaloa and Mexico City
United States	Waldman and Shelton[23]	FEH in an adult Caucasian	1	Female (56 years)	Caucasian	Fort Bragg, NC, United States
United States	Archard et al[24]	FEH in Indian children	19	13 female, 6 male	Navajo, Eskimo (Alaska), Xavante (Brazil)	Gallup, New Mexico
Central and South America
Bolivia	Decker and De Guzmán[25]	FEH in Mestizos from Cochabamba	4	All male	Mestizo	University San Simón, Cochabamba
Brazil	Witkop and Niswander[26]	FEH in Indians and Ladinos	7	6 female, 1 male	Xavante Indians	Brazil
Brazil	Borborema-Santos et al[27]	Oral FEH: 5 cases	5	2 female, 3 male	Indigenous (Central Amazonia)	Manaus, Brazil
Brazil	Rosa et al[28]	FEH clinical case	1 + sister	1 male, sister also affected	Caucasian	Porto Alegre, Brazil
Colombia	Gomez et al[29]	FEH in Colombian family	7	5 female, 2 male	Mestizo (Black admixture)	Medellín, Colombia
Colombia	Estrada[30]	Caramanta Indians oral findings	3	Not specified	Caramanta Indians	Colombia
Colombia	Estrada[31]	Katíos Indians oral findings	3	Not specified	Katíos Indians	Chocó, Colombia
El Salvador	Witkop and Niswander[26]	FEH in Ladinos	2	1 male, 1 female	Ladino	Santa Ana, El Salvador
Guatemala	Carlos and Sedano[32]	MPVEH study	110	76 female, 34 male	Not specified	Guatemala City and rural areas
Guatemala	Witkop and Niswander[26]	FEH in Quiché-Maya	5	3 male, 2 female	Quiché-Maya	Santa María Cauqué
Paraguay	Fischman[33]	FEH case report (Paraguay and Peru)	1	Male (30 years)	Not specified	Yaguaron, Paraguay
Peru	Fischman[33]	FEH reports (Paraguay and Peru)	≥ 3	Not specified	Amazon Indians (Iquitos), 1 Lima resident	Peru (Iquitos and Lima)
Peru	Guevara et al[34]	Prevalence in Mórrope schoolchildren	1465 of 3877	685 female, 780 male	Rural schoolchildren (Indigenous/mestizo)	Mórrope, Lambayeque
Surinam	Starink and Woerdeman[35]	FEH cases in Surinamese patients	2 + 1	1 female/1 male + 1 male	Black Surinamese	Amsterdam, Netherlands (patients born in Surinam)
Venezuela	Navarro et al[36]	Prevalence in Sanema and Yekuana	79 of 862	37 female, 42 male	Sanema, Yekuana	Bolívar State, Venezuela
Venezuela	Soneira and Fonseca[37]	Study in Indigenous girls	54 of 160	All female	Indigenous	Venezuela
Europe
Germany	Binder et al[38]	FEH in Black child	1	Male	Black African	Cologne/Graz
Germany	Meissner et al[39]	FEH in Crohn’s disease patient	1	Male	Not specified	Frankfurt am Main
Germany	Kreuter and Silling[40]	FEH in 7y boy	1	Male	Angolan	Witten and Cologne
Greece	Bassioukas et al[41]	Oral FEH	1	Female	Caucasian	Greece
Greece	Laskaris et al[42]	First Greek case	1	Female (56 years)	White (Caucasian)	University of Athens
Italy	Bon et al[43]	FEH (siblings)	2	1 female, 1 male	Italian	Zürich (patients born Switzerland)
Italy	Bombeccari et al[44]	FEH PCR case	1	Male	Bolivian	Milan
Italy	Galanakis et al[45]	FEH in HIV patient	1	Male	African	Rome
Lithuania	Puriene et al[46]	FEH case report	1	Female (15 years)	Not specified	Vilnius
Netherlands	Starink and Woerdeman[35]	FEH cases	2 + 1	1 female/1 male + 1 male	Black (Surinamese origin)	Amsterdam
Poland	Obalek et al[47]	Sporadic cases in girls	2	Female	Polish	Warsaw
Poland	Kubiak and Stępień[48]	FEH in adult male	1	Male	Caucasian	Wrocław
Spain	Segura-Saint-Gerons et al[49]	FEH cases	2	1 female 1 male	Saharan; Ecuadorian	Córdoba and Barcelona
United Kingdom	Bradnum[50]	FEH case	1	Male (36 years)	Scottish	Newcastle
United Kingdom	Gusterson and Greenspan[51]	Multiple polypoid oral conditions	1	Female (65 years)	Caucasian	London
United Kingdom	Goodfellow and Calvert[52]	FEH case	1	Male	West Indian	Reading
Africa
Ghana	Nartey et al[53]	Six cases from Ghana	6	5 female, 1 male	West African	University of Ghana
Kenya	Chindia et al[54]	FEH in Kenyan children	3	All female	Kenyan	Kenya
Nigeria	Sawyer et al[55]	Early West African reports	3	Not specified	West African	Nigeria
South Africa	Harris and van Wyk[56]	Longitudinal study	143	Varied (25 female, 19 male in Garies)	Khoi-San descendants	Garies and Kamieskroon
South Africa	Feller et al[57]	FEH in HIV+ child	1	Not specified	Not specified	South Africa
Sudan	Ghandour[58]	Case report	1	Female (girl)	Not specified	Sudan
Asia
China	Wang et al[1]	FEH in Chinese man (case + review)	4	1 female, 3 male	Chinese	Zhejiang University, Hangzhou
Middle East
Afghanistan (patients in Iran)	Ghalayani et al[59]	3 Afghan immigrant cases	3	1 female, 2 male	Afghan	Isfahan University, Iran
Iran	Mansouri et al[60]	Extensive FEH case report	1	Male	Iranian	Tehran
Israel	Buchner and Mass[61]	Israeli family with FEH	4 (of 11 children)	3 male, 1 female	North African origin	University of Tel Aviv
Turkey	Köse et al[62]	FEH treated with interferon α2a	1	Male	Caucasian	Ankara
Turkey	Akyol et al[63]	MPVEH treated with CO2 Laser and IFN	5 (1 + 2 sisters + 2 cousins)	1 male, 2 female, 2 unknown	Turkish	Ankara
Turkey	Artac et al[64]	FEH in ADA deficiency	1	Female (12 years)	Turkish	Konya
Turkey	Gültekin et al[65]	Oral FEH with HPV sequencing	3	2 female, 1 male	Turkish	Ankara
Turkey	Ozden et al[66]	Case report with PCR	1	Female (girl)	Caucasian	Samsun and Ankara
Turkey	Akoğlu et al[67]	FEH in Turkish family (HLA-linked)	4	2 male, 2 female	Turkish (Anatolia)	Ankara

FEH: Focal epithelial hyperplasia; PCR: Polymerase chain reaction; HPV: Human papillomavirus; ADA: Adenosine deaminase; IFN: Interferon alpha-2b; HIV: Human immunodeficiency virus; MPVEH: Multifocal papillomavirus epithelial hyperplasia; MEH: Multifocal epithelial hyperplasia.

Table 3 Summary of the studies¹

Continent	Number of countries	Total patients (approx.)	Year range of reports
North America	3 (Canada, United States, Mexico)	Approximately 1760 (Canada: Survey of 1591 individuals, with 137-202 cases diagnosed with MEH + 169 Mexican and United States cases)	1965-2023
Central and South America	10 (Bolivia, Brazil, Colombia, El Salvador, Guatemala, Paraguay, Peru, Venezuela, Surinam)	Approximately 1757 (includes 1465 in Peru, 110 from Guatemala, 79 from Venezuela	1956-2015
Europe	9 (Germany, Greece, Italy, Lithuania, Netherlands, Poland, Spain, Sweden, United Kingdom)	Approximately 28 (mostly isolated case reports and small series)	1970s-2015
Africa	5 (Ghana, Kenya, Nigeria, South Africa, Sudan)	Approximately 156 (includes 143 in South Africa longitudinal study + small series elsewhere)	1964-2000s
Asia	1 (China)	4 (cases reported in literature review + current case)	2000s-2010s
Middle East	4 (Afghanistan, Iran, Israel, Turkey)	Approximately 22 (Turkey family clusters + Israel family + Iran/Afghan series)	1973-2010s
Arctic (Greenland)	1 (Greenland)	89 (epidemiological study of 460 examined)	1970
Total	31 countries	Approximately 3816 patients	1956-2023

¹The highest case numbers come from Peru (1465), Canada (approximately 137-202 cases, extrapolated from a survey of 1591 individuals), and South Africa (143). Many countries in Europe and the Middle East have only 1-3 cases. The full-time range extends from Estrada's first report in Colombia (1956) to the outbreak studied in Mexico (Aguilar-Jiménez, 2023).

MEH: Multifocal epithelial hyperplasia.