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Graft-versus-Host Disease

Major salivary gland damage in allogeneic hematopoietic progenitor cell transplantation assessed by scintigraphic methods


Salivary gland dysfunction is a common sequela of hematopoietic progenitor cell transplantation (HPCT). The investigation of major salivary gland dysfunction with sodium pertechnetate scintigraphy is a non-invasive method that provides images of the parotid and submandibular glands. In this prospective trial, 20 HPCT patients were submitted to scintigraphic study with 99mTc-pertechenate and 67Ga in order to evaluate the major salivary glands early involvement following HPCT. Major salivary glands were evaluated prior to HCPT as well as at Days +30, +60 and +100 post transplant. Major salivary glands uptake and clearance of 99mTc-pertechenate results did not demonstrate any functional differences between pre- versus post transplant periods. Results of the 67Ga scan revealed inflammatory infiltration following HPCT, primarily in submandibular glands, suggest a persistent involvement of major salivary glands up to Day +100 after HPCT.


Salivary gland dysfunction is a common complication in the hematopoietic progenitor cell transplantation (HPCT) patient.1, 2 Salivary secretion rates can be substantially reduced during the conditioning regimen phase, likely due to high-dose therapy (HDT) plus total body irradiation (TBI) and other drugs utilized for supportive care.2, 3, 4

Effects of chemotherapy on minor salivary glands are well documented.5, 6 For example, a pilot study of patients with hematologic malignant diseases and who received chemotherapy demonstrated reduced secretion from the minor salivary glands compared to secretion from the major salivary glands.6 In addition, effects of radiation therapy in salivary glands are also well documented, primarily in head–neck cancer patients.7, 8

Recently, salivary gland scintigraphy has been refined such that quantitative data regarding glandular function after parenchymal insult can be obtained. Sodium pertechnetate scintigraphy is a minimally invasive procedure and provides images of the parotid and submandibular glands.9 Another radioactive isotope, gallium-67 (67Ga), has been widely utilized for the imaging study of various malignant tumors.10 Accumulation of 67Ga can be detected in inflammatory lesions that facilitate help on diagnosis of different major salivary gland diseases, as Sjögren's Syndrome.10

However, few studies regarding major salivary glands damage using scintigraphy were published. Most reports are directed to pediatric populations.11 In the current study, we performed a prospective evaluation of the major salivary glands up to +100 days post-HPCT in order to further study the early in the major salivary glands.

Patients and methods

This study enrolled 20 consecutive patients, 12 (60%) males and eight (40%) females, from March 2002 until November 2003 who were scheduled to receive allogeneic HPCT at BMT Unit of State University of Campinas (Unicamp) – Brazil. Table 1 shows the patients’ and donors’ characteristics, follow-up and the cell source. Seventeen out of 20 (85%) had chronic myelogenous leukemia (CML) and three (15%) severe aplastic anemia (SAA). Overall median age was 39 years old (range: 30–55). The study subjects had not received multi-chemotherapy regimens prior the study. CML patients were treated previously with hydroxyurea alone.

Table 1 Patients’ and donors’ characteristics, follow-up and cell source

Research ethics committee approval

Research Ethics Committee of Medical School – State University of Campinas approved the study protocol. All participants signed written informed consent.

HPCT features, conditioning regimen and GVHD prophylaxis

All transplants were allogeneic myeloablative and HLA-related full match according to Institutional practice. The conditioning regimen for CML included cyclophosphamide (CY) 120 mg/kg and busulfan (BU) 16 mg/kg. For SAA, the conditioning regimen consisted of CY 200 mg/kg plus BU 4 mg/kg.12 Cyclosporine-A and methotrexate were administered for GVHD prophylaxis, in accordance with current protocols at the University Hospital.

Supportive care

Supportive care was provided in single-bedrooms with high-efficiency particulate air (HEPA) filtration. Ceftazidime was administered to non-febrile patients whenever the neutrophils counts dropped below 0.5 × 109/l; the antibiotic regimen was modified according to the clinical course and maintained until bone marrow recovery. During neutropenia, all patients received fluconazole (200 mg/day) as antifungal prophylaxis.13 Pre-emptive ganciclovir therapy was administered for patients presenting two consecutive positive PCR assays and/or antigenemia for CMV.

Oral clinical examination

The oral mucosa, dentition, periodontium and orthopantographic radiograph were evaluated by the Dental Ambulatory Service prior to and during 100 days following HPCT. Acute dental infections were treated prior HPCT by the Dental Ambulatory Service.

Measurement of unstimulated salivary flow rate (USSFR)

An USSFR sample was collected prior to HPCT and again on Days +30, +60 and +100 following HPCT, 30 min after most recent dental brushing by the patient.14 The procedure consisted of a 5 min salivary expectoration into a sterile previously weighted glass bottle. Patients were asked not to swallow during the collection period. Salivary flow rates were calculated based of saliva collected per minute and converted to ml/min.3, 15 A USSFR 0.1 ml/min was considered low.3

Clinical features of xerostomia

Clinical signs of xerostomia subjectively assessed via (i) absence of the sublingual salivary pooling, (ii) adherence of a wooden tongue depressor to the buccal mucosa, (iii) dry lips and (iv) tongue snap.14

Major salivary glands scintigraphy

Major salivary gland scintigraphy was performed in order to assess: (1) major salivary glands uptake and salivary clearance using 99mTc-pertechenate scintigraphy, and (2) inflammatory activity using 67Ga scan. Scintigraphic studies were performed prior to HPCT and then Days +30, +60 and +100 days after transplant. 99mTc-pertechenate scintigraphy was obtained after intravenous injection of 370 MBq of 99mTc-pertechenate. Head and neck blood flow continuous images were acquired every 2 s during 80 s in the anterior projection. Static images with 500 000 counts in the anterior, right anterior oblique and left anterior oblique projections of the head were acquired 20 min after injection (prior stimulation images) and repeated in the same projections 2 min after stimulation with citric acid (two drops of lemon juice) for the same acquisition time of pre-stimulation images.

Regions of interest (ROI) were demarcated relative to submandibular and parotid glands and in adjacent areas for background count calculation. After acquisition, 99mTc-pertechnetate uptake by the major salivary glands was evaluated by two Nuclear Medicine physicians who were blinded to other study data and visually compared to thyroid uptake and considered as normal or decreased. In case of discordance, the final decision was obtained by consensus.

99mTc-pertechnetate salivary gland clearance was calculated for left parotid, right parotid, left submandibular and right submandibular by the following equation:

Demonstration of clearance of <50% was considered as evidence of impaired salivary gland function.

67Ga scan was performed 48 h after venous injection of 111 MBq of 67Ga citrate. Images were also acquired in the anterior, right anterior oblique and left anterior oblique projections of the head for 600 s. After acquisition, 67Ga uptake in the salivary glands was qualitatively evaluated by the two blinded Nuclear Medicine physicians and considered as physiologic or increased. In case of discordance, the final decision was obtained by consensus.

Statistical analysis

Fischer's exact test was utilized to compare major salivary glands scintigraphic data following HPCT to prior transplant and Wilcoxon rank-sum test was used to compare salivary flow rates following HPCT to rates observed prior transplant.


Oral clinical evaluation

Two out of 16 patients on Day +30, six out of 15 on Day +60 and six out of 14 on Day +100 presented mucosal erythema and xerostomia following HPCT. One patient developed cGVHD previously Day +100. Two patients developed clinically and microbiologically documented oral candidiasis between Days+30 and +60; these patients were treated with oral Fluconazole, according to Institutional protocol.

Clinical evaluation of xerostomia on Day +100

Seven out of 14 patients complained of xerostomia and all exhibited associated clinical features such as difficulties with food intake and oral erythema. One patient developed cGVHD and presented severe hyposalivation prior to Day +100.

Unstimulated salivary flow rates

Prior to HPCT::

median 0.76 ml/min (range: 0.69–4.72 ml/min);

Day +30::

median 0.69 ml/min (range: 0.46–1.96 ml/min);

Day +60::

median 0.67 ml/min (range: 0.30–1.68 ml/min);

Day +100::

median 0.65 ml/min (range: 0.30–120 ml/min).

99mTc-pertechnetate uptake prior and following HPCT

Prior to HPCT::

Three patients showed decreased uptake in the parotid glands and four patients in the submandibular glands;

Day +30::

Three patients showed decreased of uptake in the parotid glands and eight patients in the submandibular glands;

Day +60::

Two patients showed decreased of uptake in the parotid glands and five patients in the submandibular glands;

Day +100::

Two patients showed decreased uptake in the parotid glands and two patients in the submandibular glands.

Four patients died before Day +30, more 1 before Day +60 and more one before Day +100. Overall six patients were not evaluated during the study.

Range of 99mTc-pertechnetate clearance prior and following HPCT

Prior HPCT::

the clearance ranged between 50 and 60% (left parotid: 60%; right parotid: 56.5%; left submandibular 51.16% and right submandibular: 50%);

Day +30::

the clearance ranged between 40.3 and 60% (left parotid: 66%; right parotid: 59.5%; left submandibular 40.34% and right submandibular: 41.5%);

Day +60::

the clearance between 37 and 66% (left parotid: 66%; right parotid: 62.45%; left submandibular: 37% and right submandibular: 37%);

Day +100::

the clearance ranged between 43 and 64% (left parotid: 61.66%; right parotid: 64%; left submandibular: 43% and right submandibular: 45.5%).

67Ga scan

Table 2 shows the uptake of 67Ga prior and following HPCT.

Prior to HPCT::

one patient showed increased uptake in the submandibular glands, while no increase was observed in the parotid glands;

Day +30::

Three patients showed increased uptake in the parotid glands and six patients demonstrated an uptake increase in the submandibular glands;

Day +60::

Three patients showed increased uptake in parotid glands and seven patients in the submandibular glands;

Day +100::

Five patients showed increased uptake in parotid glands and eight patients in the submandibular glands.

Table 2 Results of uptake of 67Ga in major salivary glands

No statistical significance was observed in any of the comparative analyses.


Intact salivary gland function is essential to preserving oral health.16, 17 Hyposalivation refers to decreased measurable output of saliva; patients typically but not always complain of the symptom of dry mouth.17 It has not been clearly determined whether the subjective complaint of xerostomia in adults reflects actual salivary gland functional compromise.3

Adequate delivery to oral tissue minimizes or prevents xerostomia if the flow rate exceeds the rate of fluid loss by mucosal absorption and evaporation.18 Oral dryness occurred when the total salivary flow rate has been reduced to just <50% of normal.18 In the current study, although seven out of 14 (50%) of our patients complained xerostomia at Day +100, this study was not able to confirm the reduction of salivary flow rate.

The study data suggest an alteration in major salivary gland function following HPCT with a possible recovery on Day +100. These findings were reported previously.2 Patients in the current study presented a decreased unstimulated salivary output approximately Day +30. Despite that, apparent functional recovery was observed, on Days +60 and +100. However, no statistical significance was evident.

Functional compromise of the major salivary gland can be difficult to evaluate clinically. In transplanted patients it is a critical issue and may have influence in quality of life and infections complications. Trials, particularly in pediatric HPCT using 99mTc-pertechnetate were published.11, 19, 20 The scintigraphy may help us to clarify damage to the major salivary gland. However, few published studies have utilized salivary gland scintigraphy to assess salivary gland function in the early period following HPCT. Dynamic scintigraphy utilizes acquisition of images throughout the period of the scan reflecting blood flow to head and neck, perfusion, concentration, activation and clearance of salivary glands. 99mTc-pertechnetate uptake and clearance by major salivary glands correlate with salivary flow rates.21 It is like that 99mTc-pertechnetate uptake can be changed whether there is secretor unit damage. Concurrently, clearance may be reflecting a non-secretory ability, due to any drug use or compromised central nervous system stimulation. In this study, no difference was observed for uptake and/or clearance of 99mTc-pertechnetate in major salivary glands when compared to salivary flow rate. Moreover, submandibular glands presented evidence of major dysfunction characterized by 99mTc-pertechnetate and 67Ga scintigraphic images. This compromise of glandular function could quite possibly be responsible for the xerostomia as one of the major patients’ complaint following HPCT.2, 22

67Ga scans revealed an increase of inflammatory cell infiltrate on the submandibular glands when compared with findings associated with the parotid glands. The conditioning regimen can cause the release of inflammatory mediators IL-10, IL-6 and IL-2 in tissue.23 IL-2 may be responsible to decrease of function of parotid and submandibular glands.24 Nagler et al. using IL-2-based immunotherapy following HPCT demonstrated a major salivary gland dysfunction similar to chronic GVHD.24 In the current study, the increased uptake of 67Ga was observed on Day +30 and may be persistent up to Day +100. These data suggest a cumulative effect of conditioning regimen that may be responsible to patients’ complaint of xerostomia.

Salivary gland dysfunction is more pronounced in patients developing clinical GVHD; furthermore, degree of impairment positively correlated with severity of GVHD.2, 25, 26, 27, 28, 29, 30 Only one patient in the present study developed chronic GVHD, showing images patterns like described previously.19, 27, 28, 31, 32, 33 Major salivary glands showed uptake and clearance decreased, in association with the severe inflammatory process.

Results of USSFR suggest that on Day +100 the USSFR continue to decrease comparing to prior HPCT and may be due to persistent inflammatory cell infiltrate as demonstrated with 67Ga scans.

Owing to the relatively small sample size of this study, further research is needed to fully address the questions concerning the relationship between early major salivary glands dysfunction and HPCT.


  1. 1

    Dens F, Boogaerts M, Boute P, Declerck D, Demuynck H, Vinckier F et al. Caries-related salivary microorganisms and salivary flow rate in bone marrow recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996; 81: 38–43.

    CAS  Article  Google Scholar 

  2. 2

    Chaushu G, Itzkovitz-Chaushu S, Yefenof E, Slavin S, Or R, Garfunkel AA . A longitudinal follow-up of salivary secretion in bone marrow transplant patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995; 79: 164–169.

    CAS  Article  Google Scholar 

  3. 3

    Bagesund M, Winiarski J, Dahllof G . Subjective xerostomia in long-term surviving children and adolescents after pediatric bone marrow transplantation. Transplantation 2000; 69: 822–826.

    CAS  Article  Google Scholar 

  4. 4

    Dahllöf G, Bagesund M, Ringden O . Impact of conditioning regimens on salivary function, caries-associated microorganisms and dental caries in children after bone marrow transplantation. A 4-year longitudinal study. Bone Marrow Transplant 1997; 20: 479–483.

    Article  Google Scholar 

  5. 5

    Lockhart PB, Sonis ST . Alterations in the oral mucosa caused by chemotherapeutic agents. A histologic study. J Dermatol Surg Oncol 1981; 7: 1019–1025.

    CAS  Article  Google Scholar 

  6. 6

    Blomgren J, Jansson S, Rodjer S, Birkhed D . Secretion rate from minor salivary glands in patients with malignant haematological diseases receiving chemotherapy – a pilot study. Swed Dent J 2002; 26: 75–80.

    PubMed  Google Scholar 

  7. 7

    Berk LB, Shivnani AT, Small Jr W . Pathophysiology and management of radiation-induced xerostomia. J Support Oncol 2005; 3: 191–200.

    CAS  PubMed  Google Scholar 

  8. 8

    Sasse AD, de Oliveira Clark LG, Sasse EC, Clark OA . Amifostine reduces side effects and improves complete response rate during radiotherapy: Results of a meta-analysis. Int J Radiat Oncol Biol Phys 2006; 64: 784–791.

    CAS  Article  Google Scholar 

  9. 9

    Loutfi I, Nair MK, Ebrahim AK . Salivary gland scintigraphy: the use of semiquantitative analysis for uptake and clearance. J Nucl Med Technol 2003; 31: 81–85.

    PubMed  Google Scholar 

  10. 10

    Li N, Zhu W, Zuo S, Jia M, Sun J . Value of gallium-67 scanning in differentiation of malignant tumors from benign tumors or inflammatory disease in the oral and maxillofacial region. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003; 96: 361–367.

    Article  Google Scholar 

  11. 11

    Bagesund M, Richter S, Agren B, Ringden O, Dahllof G . Scintigraphic study of the major salivary glands in pediatric bone marrow transplant recipients. Bone Marrow Transplant 2000; 26: 775–779.

    CAS  Article  Google Scholar 

  12. 12

    Dulley FL, Vigorito AC, Aranha FJ, Sturaro D, Ruiz MA, Saboya R et al. Addition of low-dose busulfan to cyclophosphamide in aplastic anemia patients prior to allogeneic bone marrow transplantation to reduce rejection. Bone Marrow Transplant 2004; 33: 9–13.

    CAS  Article  Google Scholar 

  13. 13

    Nucci M, Andrade F, Vigorito A, Trabasso P, Aranha JF, Maiolino A et al. Infectious complications in patients randomized to receive allogeneic bone marrow or peripheral blood transplantation. Transplant Infect Dis 2003; 5: 167–173.

    CAS  Article  Google Scholar 

  14. 14

    Alborghetti MR, Correa ME, Adam RL, Metze K, Coracin FL, De Souza CA et al. Late effects of chronic graft-vs-host disease in minor salivary glands. J Oral Pathol Med 2005; 34: 486–493.

    CAS  Article  Google Scholar 

  15. 15

    Davies AN, Broadley K, Beighton D . Salivary gland hypofunction in patients with advanced cancer. Oral Oncol 2002; 38: 680–685.

    Article  Google Scholar 

  16. 16

    Dodds MW, Johnson DA, Yeh CK . Health benefits of saliva: a review. J Dent 2005; 33: 223–233.

    Article  Google Scholar 

  17. 17

    Kopittke L, Gomez R, Barros HM . Opposite effects of antidepressants on unstimulated and stimulated salivary flow. Arch Oral Biol 2005; 50: 17–21.

    CAS  Article  Google Scholar 

  18. 18

    Dawes C . How much saliva is enough for avoidance of xerostomia? Caries Res 2004; 38: 236–240.

    CAS  Article  Google Scholar 

  19. 19

    Nagler R, Marmary Y, Krausz Y, Chisin R, Markitziu A, Nagler A . Major salivary gland dysfunction in human acute and chronic graft-versus-host disease (GVHD). Bone Marrow Transplant 1996; 17: 219–224.

    CAS  Google Scholar 

  20. 20

    Bagesund M, Richter S, Agren B, Dahllof G . Correlation between quantitative salivary gland scintigraphy and salivary secretion rates in children and young adults treated for hematological, malignant and metabolic diseases. Dentomaxillofac Radiol 2000; 29: 264–271.

    CAS  Article  Google Scholar 

  21. 21

    Yagmur C, Miman MC, Karatas E, Akarcay M, Erdem T, Ozturan O . Effects of the chorda tympani damage on submandibular glands: scintigraphic changes. J Laryngol Otol 2004; 118: 102–105.

    CAS  Article  Google Scholar 

  22. 22

    Meurman JH, Laine P, Keinanen S, Pyrhonen S, Teerenhovi L, Lindqvist C . Five-year follow-up of saliva in patients treated for lymphomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997; 83: 447–452.

    CAS  Article  Google Scholar 

  23. 23

    Visentainer JE, Lieber SR, Persoli LB, Vigorito AC, Aranha FJ, De Brito Eid KA et al. Serum cytokine levels and acute graft-versus-host disease after HLA-identical hematopoietic stem cell transplantation. Exp Hematol 2003; 31: 1044–1050.

    CAS  Article  Google Scholar 

  24. 24

    Nagler A, Nagler R, Ackerstein A, Levi S, Marmary Y . Major salivary gland dysfunction in patients with hematological malignancies receiving interleukin-2-based immunotherapy post-autologous blood stem cell transplantation (ABSCT). Bone Marrow Transplant 1997; 20: 575–580.

    CAS  Article  Google Scholar 

  25. 25

    Dahllöf G, Bagesund M, Remberger M, Ringden O . Risk factors for salivary dysfunction in children 1 year after bone marrow transplantation. Oral Oncol 1997; 33: 327–331.

    Article  Google Scholar 

  26. 26

    Dicke KA . Late effects after allogeneic bone marrow transplantation. Bone Marrow Transplant 1994; 14 (Suppl 4): S11–S13.

    PubMed  Google Scholar 

  27. 27

    Levy S, Nagler A, Okon S, Marmary Y . Parotid salivary gland dysfunction in chronic graft-versus-host disease (cGVHD): a longitudinal study in a mouse model. Bone Marrow Transplant 2000; 25: 1073–1078.

    CAS  Article  Google Scholar 

  28. 28

    Medina JE, Frame R, Toth B, Nguyen L, Luna MH . Head and neck manifestations of the chronic graft vs host disease. Laryngoscope 1984; 94: 1145–1151.

    CAS  Article  Google Scholar 

  29. 29

    Nagler R, Marmary Y, Krausz Y, Chisin R, Markitziu A, Nagler A . Major salivary gland dysfunction in human acute and chronic graft-versus-host disease (GVHD). Bone Marrow Transplant 1996; 17: 219–224.

    CAS  Google Scholar 

  30. 30

    Yamauchi K, Noguchi K, Suzuki Y, Nagao T . Gallium-67 uptake in the salivary glands in chronic graft-versus-host disease after bone marrow transplantation. Clin Nucl Med 1989; 14: 330–332.

    CAS  Article  Google Scholar 

  31. 31

    Vogelsang GB . Graft-versus-host disease. Curr Opin Oncol 1990; 2: 285–288.

    CAS  Article  Google Scholar 

  32. 32

    Nagler RM, Nagler A . The molecular basis of salivary gland involvement in graft-vs-host disease. J Dent Res 2004; 83: 98–103.

    CAS  Article  Google Scholar 

  33. 33

    Nagler RM, Nagler A . Salivary gland involvement in graft-versus-host disease: the underlying mechanism and implicated treatment. Isr Med Assoc J 2004; 6: 167–172.

    PubMed  Google Scholar 

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We gratefully acknowledge the support and contributions of the staff of the Nuclear Medicine Service of University Hospital – Campinas State University, HPCT Unit. The expert data management by Mrs Eliana Miranda and Mrs Amanda Margelo is also sincerely appreciated. This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo-FAPESP-(The State of São Paulo Research Foundation) proc. 00/12188-4.

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Correspondence to C A De Souza.

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Coracin, F., Pizzigatti Correa, M., Camargo, E. et al. Major salivary gland damage in allogeneic hematopoietic progenitor cell transplantation assessed by scintigraphic methods. Bone Marrow Transplant 37, 955–959 (2006).

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  • major salivary glands
  • HPCT
  • 99mTc-pertechnetate and gallium-67 scintigraphy

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