M U LT I P L E P R I M A R Y C A R C I N O M A S O F T H E T O N G U E
CASE HISTORY REPORT
ABSTRACT Hepatitis C virus (HCV) infection has been implicated as a risk factor for development of oral squamous cell carcinoma (SCC). Multiple primary sites of oral SCC associated with HCV infection occurs infrequently. This case report describes a rare presentation of multiple primary SCCs of the tongue in a patient with recurrent HCV cirrhosis status post liver transplant that required interdisciplinary medical and surgical management. It is important for oral health care providers to understand the local and systemic implications of HCV infection and perform routine clinical examinations to monitor for development of oral lesions and associated complications.
KEY WORDS: Oral squamous cell carcinoma, tongue, hepatitis C
A rare presentation of multiple primary squamous cell carcinoma of the tongue in a patient with recurrent hepatitis C infection Eric T. Stoopler, DMD, FDS RCSEd;1* Ying Wai Sia, DMD;2 Ara A. Chalian, MD;3 Bert W. O’Malley Jr., MD;4 Faizan Alawi, DDS5 1
Associate Professor of Oral Medicine, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania; 2Faculty Lecturer, Department of Oral Diagnosis Science, Faculty of Dentistry, McGill University, Montreal, Province of Quebec; 3Associate Professor of Otorhinolaryngology, Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine of the University of Pennsylvania, Pennsylvania; 4Gabriel Tucker Professor and Chairman of Otorhinolaryngology, Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine of the University of Pennsylvania, Pennsylvania; 5Associate Professor of Pathology, Department of Pathology, University of Pennsylvania School of Dental Medicine, Pennsylvania. *Corresponding author e-mail: [email protected] Spec Care Dentist 34(2): 96-99, 2014
Hepatitis C virus (HCV) is an RNA virus and one of the most common causes of chronic liver disease throughout the world.1 HCV infection is reported to cause significant organ damage beyond the liver itself.2 Oral and maxillofacial conditions that have been reported in association with HCV infection include sialadenitis, salivary gland lymphoma, lichen planus, and rare cases of pemphigus.1,3 Chronic HCV status post liver transplant has also been associated with extrahepatic tumor development, including oral squamous cell carcinoma (SCC).2,4,5 In brief, oral SCC is a malignant process often with a multifactorial etiology. The median age at diagnosis is 62 years with the tongue and floor-of-the mouth reported as the most commonly affected intraoral sites.6,7 A more comprehensive review of oral SSC is beyond the scope of this article.
Multiple primary sites of SCC of the tongue associated with recurrent HCV status post liver transplant is rarely observed clinically. We report a well-documented case of a patient with recurrent HCV cirrhosis status post liver transplant who developed multiple primary SCCs of the tongue that required interdisciplinary medical and surgical management.
C a s e R ep or t
A 60-year-old Caucasian male was referred to the Oral Medicine service at
96 S p e c C a r e D e n t i s t 3 4 ( 2 ) 2 0 1 4
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the University of Pennsylvania Medical Center for evaluation of painful bilateral tongue lesions of at least 4 months duration. He described the tongue lesions as “white mounds” surrounded by redness. Otherwise, he denied any other affected mucosal or cutaneous surfaces. His past medical history was significant for recurrent HCV cirrhosis status post liver transplant (performed 9 years prior to presentation), Type 2 diabetes, hypertension and anxiety/depression. Medications prescribed were alprazolam, atenolol, furosemide, insulin injection, tacrolimus,
© 2013 Special Care Dentistry Association and Wiley Periodicals, Inc. DOI: 10.1111/scd.12030
19/02/14 12:42 PM
M U LT I P L E P R I M A R Y C A R C I N O M A S O F T H E T O N G U E
Figure 1. (A) Erythroleukoplakic erosion on the right lateral tongue approximately 1 cm in diameter. (B) Erythroleukoplakic erosion on the left lateral tongue approximately 0.75 cm in diameter.
gabapentin, zolpidem, oxycodone/acetaminophen, and dietary supplements. True drug allergies included aspirin and erythromycin. The patient’s family history was significant for cancer; i.e., the patient’s mother died at age 63 of cancer of the soft palate and his father died at age 64 of lung cancer (oat-cell type). His social history was unremarkable for tobacco, alcohol, or history of intravenous or recreational drug use. Review of systems was positive for odynophagia. Extraoral exam did not reveal lymphadenopathy or salivary gland enlargement.
Intraoral examination revealed distinct erythroleukoplakic lesions on the right posterior lateral tongue (Figure 1A) and left posterior lateral tongue (Figure 1B) that were symptomatic on palpation. No other masses, lesions, or ulcers were noted on clinical examination. The clinical differential diagnosis consisted of erosive lichen planus versus dysplasia and a biopsy was recommended for both tongue lesions. Laboratory studies were ordered to determine medical stability for the procedure and included a complete blood
Table 1. Abnormal laboratory results. Elevated values Procedure
Value
Reference range
Prothrombin time (PT)
13.3
9.0–13.2 seconds
INR
1.3
0.9–1.2
Chloride
109
98–107 mmol/L
Glucose
113
70–99 mg/dL
33
6–20 mg/dL
Blood urea nitrogen (BUN) Creatinine
1.40
0.70–1.30 mg/dL
Total bilirubin
2.0
0.2–1.2 mg/dL
Aspartate aminotransferase (AST)
72
15–41 U/L
Decreased values Red blood cells (RBC)
3.60
4.11–5.35 × 106/uL
Hemoglobin
12.0
12.7–16.7 g/dL
Hematocrit
34.3
38.0–50%
Platelets
89
150–450 × 103/uL
Albumin
3.0
3.4–4.8 g/dL
Stoopler et al.
scd12030.indd 97
count, comprehensive metabolic panel, prothrombin time (PT)/INR and partial thromboplastin time (PTT). The patient had multiple abnormal laboratory values that indicated the severity of his medical conditions (Table 1). In consultation with the patient’s medical providers, it was determined that the patient did not require any peri-operative modifications for the procedure and punch biopsies of both tongue lesions were performed under local anesthesia without complications. Histopathologic analysis of both specimens was consistent with primary SCC; the right tongue lesion was moderately to poorly differentiated (Figure 2A), while the left tongue lesion was moderately differentiated (Figure 2B). The patient was promptly referred to the Otorhinolaryngology service for consultation. A magnetic resonance imaging (MRI) scan with gadolinium was obtained and demonstrated a 2.4 cm mass of the left lateral tongue which extended to the midline without e xtension to the floor of mouth or contralateral spread (Figure 3). There was no definite imaging abnormality with respect to the known right-sided neoplasm. No cervical lymphadenopathy was identified on the MRI. Surgical planning included a limited right partial glossectomy and left near hemi-glossectomy with left neck dissection and left radial forearm free flap reconstruction, skin graft from thigh, tracheostomy and peg tube placement. Since there were no obvious neck metastases by physical exam on either side nor identified by imaging, the patient was recommended for only a left neck dissection because of the larger size and depth of invasion of the left-sided neoplasm. The tumors were completely resected though there were close, deep margins on the left-sided specimen, and the neck dissection revealed one positive neck node for metastases. The patient was therefore recommended for radiation therapy to include both sides of the neck though with the standard postoperative lower dose. After surgical management however, the patient developed significant oropharyngeal complications, ascites, multiple necrotic cervical lymph
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M U LT I P L E P R I M A R Y C A R C I N O M A S O F T H E T O N G U E
Figure 2. (A) Histopathology of right lateral tongue lesion demonstrating moderately to poorly differentiated squamous cell carcinoma (hematoxylin and eosin, 200× magnification). (B) Histopathology of left lateral tongue lesion demonstrating moderately differentiated squamous cell carcinoma (hematoxylin and eosin, 200× magnification).
Figure 3. An enhanced axial, fat-suppressed, T1-weighted MRI of the neck reveals a 2.5 × 1.5 cm mass of the left lateral tongue (arrows), which extends to the midline and base of tongue.
nodes, and enlargement of nodular opacities in the lower lobe of the right lung that were suspicious for metastases. At that time, the patient declined further medical management and succumbed to the disease within seven months of the initial diagnosis of tongue SCC.
D is cu s s io n
Several reports have indicated HCV infection as a risk factor for SSC in the
98 S p e c C a r e D e n t i s t 3 4 ( 2 ) 2 0 1 4
scd12030.indd 98
oral and maxillofacial region.3,5,8,9 In a 2009 retrospective study from Japan, the incidence of multiple primary carcinomas in oral SSC patients infected with HCV was significantly higher than in those individuals who were not infected with the virus.5 In addition, patients status post transplant who are chronically immunosuppressed appear to be at increased risk for developing secondary malignancies, including oral SCC.10 Multiple primary sites of SSC affecting the tongue in association with recurrent HCV cirrhosis status post liver transplant is a rare clinical scenario that may pose significant treatment challenges. It is critical for oral health care providers (OHCPs) to understand the widespread implications of this disease. As previously described, the patient had several abnormal laboratory values indicating the severity of his medical conditions, which could have potentially impacted peri-operative management and procedure outcomes in a significant manner. It is important for OHCPs to recognize the importance of obtaining and interpreting appropriate laboratory values and consulting with the patient’s medical provider(s) to appropriately manage and treat medically complex patients,11
such as described in the p resent case. Routine laboratory tests, including a complete blood count with differential, coagulation studies, and a comprehensive metabolic panel, should be evaluated to determine presence of anemia, thrombocytopenia, and coagulopathy, as well liver function, in patients with hepatitis C prior to provision of care.12 In addition, it is imperative for OHCPs to perform routine clinical examinations for patients with HCV infection for detection of oral mucosal lesions. The authors recommend an incisional biopsy and microscopic analysis of any oral lesion that has been present for greater than 2 weeks. Patients with oral SSC often require interdisciplinary medical and/or surgical management in order to maintain quality of life and to achieve optimal treatment outcomes.
References 1. Carozzo M. Oral diseases associated with hepatitis C virus infection. Part 1: sialadenitis and salivary gland lymphoma. Oral Dis 2008;14:123-30. 2. Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond
Multiple primary carcinomas of the tongue
19/02/14 12:42 PM
M U LT I P L E P R I M A R Y C A R C I N O M A S O F T H E T O N G U E
the liver. Clinical Gastroenterol Hepatol 2010;8:1017-29. 3. Carozzo M. Oral diseases associated with hepatitis C virus infection. Part 2: lichen planus and other diseases. Oral Dis 2008;14:217-28. 4. Scheifele C, Reichart PA, Hippler-Benscheidt M, Neuhaus P, Neuhaus R. Incidence of oral, pharyngeal, and laryngeal squamous cell carcinomas among 1515 patients after liver transplantation. Oral Oncol 2005;41: 670-6. 5. Nagao Y, Sata M. High incidence of multiple primary carcinomas in HCV infected
Stoopler et al.
scd12030.indd 99
patients with oral squamous cell carcinoma. Med Sci Monit 2009;15:CR453-459. 6. Johnson NW, Jayasekara P, Amarasinghe AAHK. Squamous cell carcinoma and precursor lesions of the oral cavity: epidemiology and aetiology. Periodontology 2000 2011;15:19-37. 7. Natarajan E, Eisenberg E. Contemporary concepts in the diagnosis of oral cancer and precancer. Dent Clin North Am 2011;55:63-88. 8. Nagao Y, Sata M, Tanikawa K, Itoh K, Kameyama T. High prevalence of hepatitis C virus antibody and RNA inpatients with oral cancer. J Oral Pathol Med 1995;24:354-60.
9. Yoshida M, Nagao Y, Sata M, Kusukawa J, Kameyama T. Multiple primary neoplasms and hepatitis C virus infection in oral cancer patients. Hepatol Res 1997;9:75-81. 10. Shah AT, Wu E, Wein RO. Oral squamous cell carcinoma in post – transplant patients. Am J Otolaryngol 2013;34:176-9. 11. Brown RS, Farquharson AA, Pallasch TM. Medical consultations for medically complex dental patients. J Calif Dent Assoc 2007;35:343-9. 12. DePaola LG. Managing the care of patients infected bloodborne diseases. J Am Dent Assoc 2003;134:350-8.
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CASE HISTORY REPORT
ABSTRACT Hepatitis C virus (HCV) infection has been implicated as a risk factor for development of oral squamous cell carcinoma (SCC). Multiple primary sites of oral SCC associated with HCV infection occurs infrequently. This case report describes a rare presentation of multiple primary SCCs of the tongue in a patient with recurrent HCV cirrhosis status post liver transplant that required interdisciplinary medical and surgical management. It is important for oral health care providers to understand the local and systemic implications of HCV infection and perform routine clinical examinations to monitor for development of oral lesions and associated complications.
KEY WORDS: Oral squamous cell carcinoma, tongue, hepatitis C
A rare presentation of multiple primary squamous cell carcinoma of the tongue in a patient with recurrent hepatitis C infection Eric T. Stoopler, DMD, FDS RCSEd;1* Ying Wai Sia, DMD;2 Ara A. Chalian, MD;3 Bert W. O’Malley Jr., MD;4 Faizan Alawi, DDS5 1
Associate Professor of Oral Medicine, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania; 2Faculty Lecturer, Department of Oral Diagnosis Science, Faculty of Dentistry, McGill University, Montreal, Province of Quebec; 3Associate Professor of Otorhinolaryngology, Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine of the University of Pennsylvania, Pennsylvania; 4Gabriel Tucker Professor and Chairman of Otorhinolaryngology, Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine of the University of Pennsylvania, Pennsylvania; 5Associate Professor of Pathology, Department of Pathology, University of Pennsylvania School of Dental Medicine, Pennsylvania. *Corresponding author e-mail: [email protected] Spec Care Dentist 34(2): 96-99, 2014
Hepatitis C virus (HCV) is an RNA virus and one of the most common causes of chronic liver disease throughout the world.1 HCV infection is reported to cause significant organ damage beyond the liver itself.2 Oral and maxillofacial conditions that have been reported in association with HCV infection include sialadenitis, salivary gland lymphoma, lichen planus, and rare cases of pemphigus.1,3 Chronic HCV status post liver transplant has also been associated with extrahepatic tumor development, including oral squamous cell carcinoma (SCC).2,4,5 In brief, oral SCC is a malignant process often with a multifactorial etiology. The median age at diagnosis is 62 years with the tongue and floor-of-the mouth reported as the most commonly affected intraoral sites.6,7 A more comprehensive review of oral SSC is beyond the scope of this article.
Multiple primary sites of SCC of the tongue associated with recurrent HCV status post liver transplant is rarely observed clinically. We report a well-documented case of a patient with recurrent HCV cirrhosis status post liver transplant who developed multiple primary SCCs of the tongue that required interdisciplinary medical and surgical management.
C a s e R ep or t
A 60-year-old Caucasian male was referred to the Oral Medicine service at
96 S p e c C a r e D e n t i s t 3 4 ( 2 ) 2 0 1 4
scd12030.indd 96
the University of Pennsylvania Medical Center for evaluation of painful bilateral tongue lesions of at least 4 months duration. He described the tongue lesions as “white mounds” surrounded by redness. Otherwise, he denied any other affected mucosal or cutaneous surfaces. His past medical history was significant for recurrent HCV cirrhosis status post liver transplant (performed 9 years prior to presentation), Type 2 diabetes, hypertension and anxiety/depression. Medications prescribed were alprazolam, atenolol, furosemide, insulin injection, tacrolimus,
© 2013 Special Care Dentistry Association and Wiley Periodicals, Inc. DOI: 10.1111/scd.12030
19/02/14 12:42 PM
M U LT I P L E P R I M A R Y C A R C I N O M A S O F T H E T O N G U E
Figure 1. (A) Erythroleukoplakic erosion on the right lateral tongue approximately 1 cm in diameter. (B) Erythroleukoplakic erosion on the left lateral tongue approximately 0.75 cm in diameter.
gabapentin, zolpidem, oxycodone/acetaminophen, and dietary supplements. True drug allergies included aspirin and erythromycin. The patient’s family history was significant for cancer; i.e., the patient’s mother died at age 63 of cancer of the soft palate and his father died at age 64 of lung cancer (oat-cell type). His social history was unremarkable for tobacco, alcohol, or history of intravenous or recreational drug use. Review of systems was positive for odynophagia. Extraoral exam did not reveal lymphadenopathy or salivary gland enlargement.
Intraoral examination revealed distinct erythroleukoplakic lesions on the right posterior lateral tongue (Figure 1A) and left posterior lateral tongue (Figure 1B) that were symptomatic on palpation. No other masses, lesions, or ulcers were noted on clinical examination. The clinical differential diagnosis consisted of erosive lichen planus versus dysplasia and a biopsy was recommended for both tongue lesions. Laboratory studies were ordered to determine medical stability for the procedure and included a complete blood
Table 1. Abnormal laboratory results. Elevated values Procedure
Value
Reference range
Prothrombin time (PT)
13.3
9.0–13.2 seconds
INR
1.3
0.9–1.2
Chloride
109
98–107 mmol/L
Glucose
113
70–99 mg/dL
33
6–20 mg/dL
Blood urea nitrogen (BUN) Creatinine
1.40
0.70–1.30 mg/dL
Total bilirubin
2.0
0.2–1.2 mg/dL
Aspartate aminotransferase (AST)
72
15–41 U/L
Decreased values Red blood cells (RBC)
3.60
4.11–5.35 × 106/uL
Hemoglobin
12.0
12.7–16.7 g/dL
Hematocrit
34.3
38.0–50%
Platelets
89
150–450 × 103/uL
Albumin
3.0
3.4–4.8 g/dL
Stoopler et al.
scd12030.indd 97
count, comprehensive metabolic panel, prothrombin time (PT)/INR and partial thromboplastin time (PTT). The patient had multiple abnormal laboratory values that indicated the severity of his medical conditions (Table 1). In consultation with the patient’s medical providers, it was determined that the patient did not require any peri-operative modifications for the procedure and punch biopsies of both tongue lesions were performed under local anesthesia without complications. Histopathologic analysis of both specimens was consistent with primary SCC; the right tongue lesion was moderately to poorly differentiated (Figure 2A), while the left tongue lesion was moderately differentiated (Figure 2B). The patient was promptly referred to the Otorhinolaryngology service for consultation. A magnetic resonance imaging (MRI) scan with gadolinium was obtained and demonstrated a 2.4 cm mass of the left lateral tongue which extended to the midline without e xtension to the floor of mouth or contralateral spread (Figure 3). There was no definite imaging abnormality with respect to the known right-sided neoplasm. No cervical lymphadenopathy was identified on the MRI. Surgical planning included a limited right partial glossectomy and left near hemi-glossectomy with left neck dissection and left radial forearm free flap reconstruction, skin graft from thigh, tracheostomy and peg tube placement. Since there were no obvious neck metastases by physical exam on either side nor identified by imaging, the patient was recommended for only a left neck dissection because of the larger size and depth of invasion of the left-sided neoplasm. The tumors were completely resected though there were close, deep margins on the left-sided specimen, and the neck dissection revealed one positive neck node for metastases. The patient was therefore recommended for radiation therapy to include both sides of the neck though with the standard postoperative lower dose. After surgical management however, the patient developed significant oropharyngeal complications, ascites, multiple necrotic cervical lymph
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M U LT I P L E P R I M A R Y C A R C I N O M A S O F T H E T O N G U E
Figure 2. (A) Histopathology of right lateral tongue lesion demonstrating moderately to poorly differentiated squamous cell carcinoma (hematoxylin and eosin, 200× magnification). (B) Histopathology of left lateral tongue lesion demonstrating moderately differentiated squamous cell carcinoma (hematoxylin and eosin, 200× magnification).
Figure 3. An enhanced axial, fat-suppressed, T1-weighted MRI of the neck reveals a 2.5 × 1.5 cm mass of the left lateral tongue (arrows), which extends to the midline and base of tongue.
nodes, and enlargement of nodular opacities in the lower lobe of the right lung that were suspicious for metastases. At that time, the patient declined further medical management and succumbed to the disease within seven months of the initial diagnosis of tongue SCC.
D is cu s s io n
Several reports have indicated HCV infection as a risk factor for SSC in the
98 S p e c C a r e D e n t i s t 3 4 ( 2 ) 2 0 1 4
scd12030.indd 98
oral and maxillofacial region.3,5,8,9 In a 2009 retrospective study from Japan, the incidence of multiple primary carcinomas in oral SSC patients infected with HCV was significantly higher than in those individuals who were not infected with the virus.5 In addition, patients status post transplant who are chronically immunosuppressed appear to be at increased risk for developing secondary malignancies, including oral SCC.10 Multiple primary sites of SSC affecting the tongue in association with recurrent HCV cirrhosis status post liver transplant is a rare clinical scenario that may pose significant treatment challenges. It is critical for oral health care providers (OHCPs) to understand the widespread implications of this disease. As previously described, the patient had several abnormal laboratory values indicating the severity of his medical conditions, which could have potentially impacted peri-operative management and procedure outcomes in a significant manner. It is important for OHCPs to recognize the importance of obtaining and interpreting appropriate laboratory values and consulting with the patient’s medical provider(s) to appropriately manage and treat medically complex patients,11
such as described in the p resent case. Routine laboratory tests, including a complete blood count with differential, coagulation studies, and a comprehensive metabolic panel, should be evaluated to determine presence of anemia, thrombocytopenia, and coagulopathy, as well liver function, in patients with hepatitis C prior to provision of care.12 In addition, it is imperative for OHCPs to perform routine clinical examinations for patients with HCV infection for detection of oral mucosal lesions. The authors recommend an incisional biopsy and microscopic analysis of any oral lesion that has been present for greater than 2 weeks. Patients with oral SSC often require interdisciplinary medical and/or surgical management in order to maintain quality of life and to achieve optimal treatment outcomes.
References 1. Carozzo M. Oral diseases associated with hepatitis C virus infection. Part 1: sialadenitis and salivary gland lymphoma. Oral Dis 2008;14:123-30. 2. Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond
Multiple primary carcinomas of the tongue
19/02/14 12:42 PM
M U LT I P L E P R I M A R Y C A R C I N O M A S O F T H E T O N G U E
the liver. Clinical Gastroenterol Hepatol 2010;8:1017-29. 3. Carozzo M. Oral diseases associated with hepatitis C virus infection. Part 2: lichen planus and other diseases. Oral Dis 2008;14:217-28. 4. Scheifele C, Reichart PA, Hippler-Benscheidt M, Neuhaus P, Neuhaus R. Incidence of oral, pharyngeal, and laryngeal squamous cell carcinomas among 1515 patients after liver transplantation. Oral Oncol 2005;41: 670-6. 5. Nagao Y, Sata M. High incidence of multiple primary carcinomas in HCV infected
Stoopler et al.
scd12030.indd 99
patients with oral squamous cell carcinoma. Med Sci Monit 2009;15:CR453-459. 6. Johnson NW, Jayasekara P, Amarasinghe AAHK. Squamous cell carcinoma and precursor lesions of the oral cavity: epidemiology and aetiology. Periodontology 2000 2011;15:19-37. 7. Natarajan E, Eisenberg E. Contemporary concepts in the diagnosis of oral cancer and precancer. Dent Clin North Am 2011;55:63-88. 8. Nagao Y, Sata M, Tanikawa K, Itoh K, Kameyama T. High prevalence of hepatitis C virus antibody and RNA inpatients with oral cancer. J Oral Pathol Med 1995;24:354-60.
9. Yoshida M, Nagao Y, Sata M, Kusukawa J, Kameyama T. Multiple primary neoplasms and hepatitis C virus infection in oral cancer patients. Hepatol Res 1997;9:75-81. 10. Shah AT, Wu E, Wein RO. Oral squamous cell carcinoma in post – transplant patients. Am J Otolaryngol 2013;34:176-9. 11. Brown RS, Farquharson AA, Pallasch TM. Medical consultations for medically complex dental patients. J Calif Dent Assoc 2007;35:343-9. 12. DePaola LG. Managing the care of patients infected bloodborne diseases. J Am Dent Assoc 2003;134:350-8.
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