Appendix Table 1. Oral cancers and oral precancerous lesions in
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Appendix Table 1. Oral cancers and oral precancerous lesions in noninflammatory bowel disease patients. Author Drug(s) Patient(s) Underlying disease HIV+ Location of oral Ca Histology of oral Ca Candidiasis & leukoplakia Comments Hilton et al.1 152 Epstein et al.2 HAART (HIV therapy scheme) IS HIV + cohort Immunosu ppressed vs HC 1 HIV+ Oral cavity Malignant HIV+ Renal Tx Controls Panuveitis EBV-DNA(+) more in Tx than HIV CMV(-), HPV-DNA (+) more in HIV+ BCC adenoCa Oral lichen planus (OLP) OLP SCC OLP Areas of Tacrolimus application Tongue (left side) Oral cavity Geographical variation Hairy leukoplakia more in men After 52 months of CyA 5 ys after topical use 5 ys after topical use Successful treatment Amatuna et al.3 IS Ramchandani et al.4 CyA Mattsson et al.5 1 Chaklader et al.7 Tacrolimus topical Tacrolimus topical CyA Yamamoto et al.8 CyA 1 Psoriasis Oral cavity AdenoCa Koo et al.9 CyA 1 Psoriasis B-cell lymphoma Horie et al.10 MTX 60 M RA Maxillary sinus, orbit, palate Gingival ulcer Naidu et al.11 MTX 1 RA Many oral ulcers EBV+ Hodgkinlymphoma like Ishida et al.12 MTX 76 F RA Gingiva Hanakawa et al.13 MTX 67 M RA Oropharyngeal Lymphoproliferative disorder (LPD)EBV+ LPD Attard et al.14 MTX 1 RA Pastor-Nieto et al.15 MTX 79 F RA Oral mucocutaneous ulcer Oral ulcer LPD (probable) EBV+ - LPD Gono et al.16 MTX 1 RA Right submandibullar Diffuse large B-cell Mok et al.17 AZA 1 RA Parotid gland Dojcinov et al.18 AZA or MTX or CyA 26 16 / 26 with oral ulcers Hasegawa et al.19 Allogenic BMT 557 BMT Various autoimmune diseases Hematology related Ca Lymphoepithelioma -like Ca Large B-cell blasts Schmigelow et al.20 MTX or AZA children ALL Noguchi et al.21 IS 67 M Malignant Lymphoma Demarosi et al.22 AZA + CyA + Prednisone +colchicine 53 F Chien et al.23 AZA GVHD Cohort 1997-2010 BMT (for NonHodgkin lymphoma) BMT Becker et al.6 56 F 1 Oral cavity Labial SCC SCC Diffuse B-cell lymphoma EBV+ Increased incidence of oral Ca and NMSC Oral Ca (as secondary cancer) Left buccal mucosa SCC Oral SCC arising from GVHD-induced lesion s Oral cavity (+esophagus) Ca SIR=14.18 SCC Uncomplicated Remission after MTX withdrawal Differential diagnosis with Hodgkin lym[phoma DD with large B-cell lymphoma Remission after MTX withdrawal uncomplicated Remission after MTX withdrawal CHOP as no remission after MTX withdrawal Long-term AZA use EBV+ as secondary malignancies Increased incidence of second Ca Died postsurgery of sepsis 16 cases reported Need for oral screening Risk increased with cumulative doses of AZA Raut et al.24 IS 1 BMT Gingival ulcer Malignant lymphoma EBV+ IS to prevent GVHD Allen et al.25 IS 1 BMT Lower lip (vermillion zone) Verruciform xanthoma Surgery De Araujo et al.26 AZA+CyA +Tacrolimus +Prednisone IS 43 GVHD BMT Oral SCC 10 BMT Oral Hairy leukoplakia Koharazawa et al.28 CyA + Prednisone 31 M BMT -GVHD SCC both Curtis et al.29 Chronic GVHD therapy 183 501 BMT vs HC 2 cancers (1 mandibulargingival, 1 palate) Buccal cavity (or skin) P<0.001 GCHDprolonged multidrug EBV+ in 2 HPV+ in 3 3rd Ca esophagus Byun et al.30 IS 1 BMT-GVHD tongue SCC Abbas et al.31 IS 1 HSCT gingival Kaposi sarcoma Gummert et al.32 Tripple IS AZA + CyA + PrednIsone 45 M Heart Tx Tonsils Tonsilar SCC Rinaldi et al.33 AZA + CyA + PrednIsone 474 Heart Tx Oral cavity N=55 (6.5% of all Ca) Schmid-Westhanen et al.34 IS 50 20 Oral lesions EBV+ only in Tx not in HC O’ Connell et al.35 IS Rhinow et al.36 Azathioprine AZA+CyA 42 M 32/F 56/M Heart Tx vs HC Heart Tx Wimmer et al.37 CyA vs Tacrolimus 609 Heart Tx Myasthenia gravis Liver Tx Labial pappula (lower lip) Both Maxillary ridge alveolar / right edentulous ridge -Oropharyngeal (6.9% n=6/609) Acantholytic keratosis Diffuse large B-cell (NHL) lymphoma EBV+ NMSC (44.8%) Saigal et al.38 IS 1,140 Liver Tx 2 oropharyngeal SCC Broughton et al.39 IS 275 pediatric Liver Tx Tonsils (5/13 with changes at tonsillectomy, Tonsillar hyperplasia to large cell lymphoma Jain et al.40 Tacrolimus Liver Tx IS Liver Tx Oropharyngeal (X25.5 > general population) Oropharyngeal =7 SCC (de novo) Jain et al.41 185 ALD vs 649 non-ALD 1,000 Helenius-Hieblich et al.42 IS 84 Liver Tx Oral lesions Maraki et al.43 IS 1 Liver Tx Tongue OLP Candida Hairy leukoplakia In situ Ca Hernandes et al.44 FK506 +prednisone 1 M Liver Tx -GVHD Mouth floor Ca SCC (started from leukoplakia) Nure et al.45 Tacrolimus +MMF + prednisone Tacrolimus 225 Liver Tx 1 Tonsillar 1 Tongue SCC both 1 Liver Tx Oral ulcers GVHD-like lession et al.s Epstein et al.27 Bunetel et al.46 AZA major risk factor for SCC SCC Especially when combined to CyA/steroids Also KS in respiratory Pre-existing Ca? 1 month after Tx, smoke/alcohol Role of AZA and duration of IS uncomplicated 24 ys on AZA 7 wks after Tx Tacrolimus- is risk factor for oral Ca Increased in alcoholic livers Recommend tonsillectomy if increased size of tonsils In non-ALD Ca risk not increased x 7.6 higher than expected More in Tx than controls (43% vs 15%) Brush biopsy Rapid progression in 4 months of leukoplakia to SCC Plus 2 esophageal, 1 larynx Ca Due to tacrolimus Concentini et al.47 AZA+CyA 59 M Tx RenalPancreas 2 oral cancers -SCC -Spinocellular Keogh et al.48 IS 1 Renal Tx Oral NHL Quniby et al.49 CyA 1 Renal Tx gingiva Kaposi sarcoma Rosa-Gare et al.50 AZA + CyA + Prednisone CyA 190 Renal Tx Oral lesions 1 Renal Tx Oral Singh et al.52 AZA or CyA + PrednIsone 31 with Ca Renal Tx -6/31 oral Ca (20% of all Ca) More on combo AZA+CyA Gingival overgrowth Candidiasis Leukoplakia Lingual SCC, larynx, parotid Ca, tonsillar lymphoma Siegal et al.53 CyA 1 Renal Tx oral Kaposi sarcoma King et al.54 IS 160 Renal Tx oral leukoplakia=21 King et al.55 IS 159 160 Renal Tx vs HC Oral lesions more in Tx vs HC p<0.005) Zmonarski et al.56 AZA + CyA + Prednisone CyA 2 Renal Tx Hard palate Of 21, 13 dysplastic and 2 progressed in SCC Hairy leukoplakia Candidiasis Gingival hyperplasia Kaposi sarcoma 28 M 1 Renal Tx Gingiva Renal Tx Gingival (+skin) Al-Mohaya et al.51 Pan et al.57 Extramedullary plasmatocytoma Kaposi sarcoma Vlasic-Matas et al.58 AZA + CyA + Prednisone Varga et al.59 CyA 1 Renal Tx Oral Siegal et al.60 CyA 1 Renal Tx Bilinska-Petry et al.61 AZA + CyA + Prednisone CyA + Prednisone 25 M 500 Renal Tx Gingival (+skin) Lingual Ca Renal Tx 6 oral (1.2%) Van Zuuren et al.63 IS 1 Renal Tx Lip Ca De Visscher et al.64 IS 6 Renal Tx Lower lip SCC Gallagher et al.65 1 Renal Tx Head and neck 8 King et al.66 CyA or AZA +prednisone IS 160 Renal Tx Dysplasrtic or malignant Van Leeuwen et al.67 IS 8,162 Renal Tx Lip lesions increased risk Lip Ca (n=203) Darling et al.68 IS 1 Renal Tx Oral cavity Kaposi sarcoma Mihalov et al.69 IS 674 Madeleine et al.70 Tacrolimus 187,699 Tx Tx (solid organ) Tx (solid organs) Lip Ca and skin Ca increased risk Oropharyngeal (risk x2.1) SCC (HPV related) Karagas et al.71 Oral steroids 592 BCC Tx Risk x2.31 NMSC Lopez-Pintor et al.62 SCC (arising from gingival overgrowth) Kaposi sarcoma AZA stopped surgery-fatal, ex smoker Reduced IS gingival hyperplasia preceding Not a Ca study uncomplicated Without drawing IS prolonged survival alive uncomplicated In month 7 Regress tumor after stop AZA and low CyA uncomplicated After CMV infection SCC More men affected, sunlight exposure Mainly increased in Tx period uncomplicated Higher risk in Heart Tx Increase incidence of HPV-related Ca IS-related Ca 281 SCC by oral corticoids Reduced CyA dose Rolland et al.72 CyA 2 Tx Gingiva Rushing et al.73 IS 2 Tx Oral Post-Tx LPD (DD gingival overgrowth) Hairy leukoplakia Qunibi et al.74 CyA 2 Tx Gingival Kaposi sarcoma Thomas et al.75 IS 1 Tx Lower lip SCC Vargas et al.76 IS 8 Tx Tongue Verma et al.77 AZA 1 Tx Oral lichen planus fibroproliferative polyps of tongue benign Chaiben et al.78 IS 1 Tx Lower lip keratoacanthoma Successful treatment uncomplicated Lindelof et al.79 IS 5356 Tx NMSC Higher for men Väkevä L et al.80 CyA (n=272) 3 Kujken et al.81 Switch from AZA to CyA Tx (eczema) Tx Increased risk x 108.6 Mouth cancer Alexander et al.82 IS 8,000 Penn et al.83 IS 6,934 Tx HC Tx Miranda et al.84 IS 1 SLE surgery IS-related Medium CyA dose Better reduce IS dose Not reduced oral malignancies Lip Ca (7% Tx vs 0,3% HC) Lip Ca (Pediatric 29% > 13% adults) Oral cavity uncomplicated SCC Hairy leukoplakia Abbreviations used in the Table: ALD=alcoholic liver disease, ALL=acute lymphoid leukemia, AZA=azathioprine, BMT=bone marrow transplantation, BSC=basal cell cancer, Ca=Cancer, CyA=cyclosporine, GVHD=graft versus host disease, HSCT=Hemopoietic stem cell transplantation, HC=healthy controls, IS=immunosuppression, LPD=Lymphoproliferative disease MMF=mycophenolate mofetil, MTX=methotrexate, NMSC=non-melanoma skin cancer, OLP=oral lichen planus, RA=rheumatoid arthritis, SCC=squamous cell cancer, SLE=systemic lupus erythematosus, Tx=transplantation. uncomplicated
