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Mucosal Changes of the Free Jejunal Graft in Response to Radiotherapy
Mucosal Changes of the Free Jejunal Graft in Response to Radiotherapy William Ignace Wei, MS, FRCSE, DLO, FACS, Lai Kun Lam, FRCSE, FRACS, Po Wing Yuen, DLO, FRCSE, Dora Kwong, DMRT, FRCR, Kwok Wah Chan, FRCPath, Hong Kong, China
BACKGROUND: Microvascular free jejunal transfer was employed for reconstruction of pharyngeal defect resulting from circumferential resection of the hypopharynx. Postoperative radiotherapy to the neck might affect the graft, but this information was lacking. The mucosal changes of the jejunum in response to radiation were identified in this prospective study. METHODS: Normal jejunal mucosa was obtained at operation, and endoscopic jejunal mucosal biopsies were taken during and at completion of radiotherapy. Endoscopic biopsies were repeated at 1, 3, 6, 12, and 24 months afterwards. All jejunal biopsies were subjected to histologic and scanning electron microscopic (SEM) examinations. Nine patients had a complete set of biopsy while 5 other patients who received no radiotherapy also went through a similar sequence of biopsies as controls. RESULTS: Histologic examination showed mucosal edema and extensive blunting of jejunal villi at the completion of radiotherapy. Increased fibrosis with focal loss of glands was noticed at 3 months after radiotherapy, and this remained throughout the 2-year period. SEM revealed patchy loss of microvilli at completion and at 1 month after radiotherapy, but this feature was not apparent in biopsies taken at 3 months onwards, showing that it was only a transient event. CONCLUSIONS: Transient responses and persistent changes of jejunal mucosa to radiotherapy were identified and characterized. The presence of these mucosal lesions was not associated with any clinically significant adverse effect in the graft up to 2 years postradiotherapy. Am J
From the Departments of Surgery (WIW, LKL, PWY), Radiation Oncology (DK), and Pathology (KWC), The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. This work was presented at the 4th International Conference on Head & Neck Cancer, Toronto, July 1996. Supported by a research grant from CRCG, The University of Hong Kong (grant No. 335/048/0067 & 378/030/8132); RGC (grant No. 337/048/0012) and Sun Yat Sen Foundation Fund, The University of Hong Kong (grant No. 335/048/0067 & 378/030/ 8132). Requests for reprints should be addressed to Professor William I. Wei, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. Manuscript submitted January 3, 1997 and accepted in revised form April 29, 1997.
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© 1998 by Excerpta Medica, Inc. All rights reserved.
Surg. 1998;175:44 – 46. © 1998 by Excerpta Medica, Inc.
T
he treatment of hypopharyngeal tumor remains a therapeutic challenge as most patients present with extensive primary lesion. Combined surgical resection followed by postoperative irradiation as a management strategy is now practiced in many centers.1 Following total laryngectomy and circumferential pharyngectomy, microvascular free jejunal transfer is recognized as the optimal reconstructive option.2,3 When postoperative radiotherapy is delivered to the neck, it is well tolerated by the transposed jejunal loop,2,3 however, the response of the jejunal mucosa to radiation is not documented. Also whether the reaction of jejunum to radiation affects its function or intergrity is not known. The aim of our present study was to evaluate the changes of the jejunal mucosa after irradiation.
METHODS From 1991 to 1995, in the Head and Neck Division of the Department of Surgery, The University of Hong Kong at Queen Mary Hospital, Hong Kong, we have performed a total of 28 microvascular free jejunal grafts for reconstruction of circumferential pharyngeal defects created after extirpation of hypopharyngeal tumor. At the time of free jejunal transfer, a small piece of normal jejunum was kept aside as the nonirradiated sample. Subsequent biopsies of mucosa of the transposed jejunum were performed through a flexible upper gastrointestinal endoscope with a forward oblique viewing lens (GIFXK20, Olympus, Tokyo, Japan). Each biopsy was transferred from the jaws of the forceps to a flat piece of paper with a 25-guage needle, and the specimen was laid out with the mucosal surface facing upward. Every specimen was also flushed with saline to remove the mucus attached to it. For every patient, jejunal biopsies were taken at 3 weeks after commencement of radiotherapy and at its completion. Further sequential jejunal biopsies were taken at 1 month, 3 months, 6 months, 1 year, and 2 years after completion of radiotherapy. Some of the jejunal biopsies obtained were processed for histologic examination and others for scanning electron microscopic examination. Nine patients completed the study and had a whole set of biopsy material for examination. Their postoperative radiation dose ranged from 4600 to 6600 cGy (mean 5380 cGy). This sequence of jejunal biopsies were also carried out for 5 other patients who did not receive postoperative radiotherapy. Informed consent was obtained from all patients included in the study. There were 11 men and 3 women, and their ages ranged from 47 to 79 years (mean 0002-9610/98/$19.00 PII S0002-9610(97)00230-4
JEJUNAL GRAFT RESPONSE TO RADIOTHERAPY/WEI ET AL
Figure 1. Upper: At completion of radiotherapy, edema was marked in the lamina propria beneath the surface epithelium of the jejunal mucosa associated with shortening and blunting of jejunal villi (arrow). Lower: At 2 years after radiotherapy, persistent loss of villi with increased fibrosis and retraction of gland are noted (arrow). Abnormal branching of a gland is seen (arrow head). (Hematoxylin and eosin stain 380).
Figure 2. Scanning electron micrograph. Upper: Normal jejunal mucosal surface showing the boundaries (arrow). Lower: Pitted areas indicative of loss of microvilli (arrows).
crovilli completely disappeared in the biopsies taken at 3 months or longer after completion of radiotherapy.
COMMENTS 64). All the 14 patients were able to take normal oral diet at the time of the biopsies.
RESULTS Extensive loss of villi was an early histologic finding. After completion of radiotherapy, the jejunal mucosa showed edema. Subsequent biopsies showed thinning of jejunal mucosa, focal loss of glands, and increased inflammatory cellular infiltration; and the villi also showed blunting with reduction in height (Figure 1). Increased mucosal fibrosis with retraction of glands toward the mucosal surface was noticed at 6 months after radiotherapy, and this persisted throughout the following 2 years (Figure 1). None of the jejunal mucosal biopsies displayed any area of necrosis or ulceration. Scanning electron microscopic examination of jejunal biopsies taken after completion of the radiotherapy revealed patchy areas of microvilli loss over the mucosal surface when compared with controls (Figures 2 and 3). Occasionally there was loss of microvilli covering one cell but the underlying columnar cell was not affected (Figure 3). The goblet cells, however, remained unchanged in all the sequential jejunal biopsies. These areas of loss of mi-
In normal jejunum, the columnar epithelium that forms the mucosa is thrown up into minor projections, the villi. In between the villi are the intestinal glands, the crypts of Lieberku¨hn. Among the columnar cells are the mucussecreting goblet cells. To increase the surface area for absorption, the cell wall of columnar cells have multiple projections, the microvilli. The intestinal epithelial cells have high mitotic activities with a short turnover time. Within 24 hours of a radiation dose of 500 to 1000 cGy, the mitotic cells in the crypts showed maximum destruction. Reepithelization is extensive within 96 hours.4,5 In general, the small bowel can tolerate a radiation dosage of approximately 4,000 cGy with 180 cGy daily fraction at 5 days per week, although enteritis has been reported with a low dose of 3750 cGy.6 The risk of development of significant complications such as perforation or fistula formation is related to the total radiation dose delivered, the dose per fraction, and the volume of small intestine irradiated.7 Radiation of transposed jejunum in animal studies have shown that increased fibrosis may lead to circumferential constriction and stricture formation.8 Reports of the transposed jejunum in human subjects have, however, indicated that it tolerates postoperative radiotherapy without much sequel.3,9
THE AMERICAN JOURNAL OF SURGERY® VOLUME 175 JANUARY 1998
45
JEJUNAL GRAFT RESPONSE TO RADIOTHERAPY/WEI ET AL
of microvilli were seen. The parent columnar cell was not affected. All these changes were only detectable up to 1 month after completion of radiation and not later. This patchy loss of microvilli was probably only a transient event following radiotherapy. Radiotherapy apparently did not affect the goblet cells as revealed by the scanning electron microscopic examination. The continuous function of the goblet cells ensures that mucus secretion is adequate. Although the jejunal graft only serves as a conduit at times, ample mucous secretion is essential for smooth swallowing function. The clinical significance of the study is that when a curative dose of radiation was delivered to the neck region following circumferential pharyngectomy and free jejunal graft, the changes of the jejunal mucosa were only minor and transient. Radiotherapy aiming at tumor control should be given even though microvascular free jejunal transfer was used for reconstruction following tumor ablation.
REFERENCES
Figure 3. Scanning electron micrograph. Upper: Normal jejunal mucosal surface showing cell boundaries (arrows) and globlet cells (arrow head). Lower: Occasional loss of microvilli covering 1 cell (arrow) and patchy loss of microvilli (arrow head).
In the present study the initial change of mucosal edema is compatible with acute radiation enteritis. The changes of blunting and shortening of the jejunal villi, increased fibrosis, and inflammatory cell infiltrates were features of chronic inflammation and were probably related to the vasculitis caused by radiotherapy. The presence of fibrosis in the later periods is not extensive and is limited to the submucosal region. Radiotherapy at the dose delivered for tumor control should not account for stenosis or stricture of the jejunal graft. The loss of microvilli detected after completion of radiotherapy demonstrated the response of the jejunal epithelial cells to the radiation energy. There was very occasional loss of microvilli covering one cell; more frequently patchy loss
46
1. Kramer S, Gelber RD, Snow JB, et al. Combined radiation therapy and surgery in the management of advanced head and neck cancer: final report of study 73-03 of the Radiation Therapy Oncology Group. Head Neck Surg. 1987;10:19 –30. 2. Coleman JJ, Searles Jr JM, Hester TR, et al. Ten years experience with the free jejunal autograft. Am J Surg. 1987;154:394 –398. 3. Petruzzelli GJ, Johnson JT, Myers EN, et al. The effect of postoperative radiation therapy on pharyngoesophageal reconstruction with free jejunal interposition. Arch Otolaryngol Head Neck Surg. 1991;117:1265–1268. 4. Pascal RR, Kaye GI, Lane N. Colonic pericryptal fibroblast sheath: replication, migration and cytodifferentiation of a mesenchymal cell system in adult tissue. Gastroenterology. 1968;54:835– 851. 5. Trier JS, Browning TH. Morphologic response of the mucosa of human small intestine to x-ray exposure. J Clin Invest. 1966;45: 194 –204. 6. Ransom JL, Novak RW, Kumar APM, et al. Delayed gastrointestinal complications after combined modality therapy of childhood rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. 1979;5: 1275–1279. 7. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21: 109 –122. 8. Biel MA, Maisel RH. Gross morphologic and functional effects of postoperative radiation on free jejunal autografts. Laryngoscope. 1992;102:875– 883. 9. McCaffrey TV, Fisher J. Effect of radiotherapy on the outcome of pharyngeal reconstruction using free jejunal transfer. Ann Otol Rhinol Laryngol. 1987;96:22–25.-
THE AMERICAN JOURNAL OF SURGERY® VOLUME 175 JANUARY 1998
BACKGROUND: Microvascular free jejunal transfer was employed for reconstruction of pharyngeal defect resulting from circumferential resection of the hypopharynx. Postoperative radiotherapy to the neck might affect the graft, but this information was lacking. The mucosal changes of the jejunum in response to radiation were identified in this prospective study. METHODS: Normal jejunal mucosa was obtained at operation, and endoscopic jejunal mucosal biopsies were taken during and at completion of radiotherapy. Endoscopic biopsies were repeated at 1, 3, 6, 12, and 24 months afterwards. All jejunal biopsies were subjected to histologic and scanning electron microscopic (SEM) examinations. Nine patients had a complete set of biopsy while 5 other patients who received no radiotherapy also went through a similar sequence of biopsies as controls. RESULTS: Histologic examination showed mucosal edema and extensive blunting of jejunal villi at the completion of radiotherapy. Increased fibrosis with focal loss of glands was noticed at 3 months after radiotherapy, and this remained throughout the 2-year period. SEM revealed patchy loss of microvilli at completion and at 1 month after radiotherapy, but this feature was not apparent in biopsies taken at 3 months onwards, showing that it was only a transient event. CONCLUSIONS: Transient responses and persistent changes of jejunal mucosa to radiotherapy were identified and characterized. The presence of these mucosal lesions was not associated with any clinically significant adverse effect in the graft up to 2 years postradiotherapy. Am J
From the Departments of Surgery (WIW, LKL, PWY), Radiation Oncology (DK), and Pathology (KWC), The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. This work was presented at the 4th International Conference on Head & Neck Cancer, Toronto, July 1996. Supported by a research grant from CRCG, The University of Hong Kong (grant No. 335/048/0067 & 378/030/8132); RGC (grant No. 337/048/0012) and Sun Yat Sen Foundation Fund, The University of Hong Kong (grant No. 335/048/0067 & 378/030/ 8132). Requests for reprints should be addressed to Professor William I. Wei, Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China. Manuscript submitted January 3, 1997 and accepted in revised form April 29, 1997.
44
© 1998 by Excerpta Medica, Inc. All rights reserved.
Surg. 1998;175:44 – 46. © 1998 by Excerpta Medica, Inc.
T
he treatment of hypopharyngeal tumor remains a therapeutic challenge as most patients present with extensive primary lesion. Combined surgical resection followed by postoperative irradiation as a management strategy is now practiced in many centers.1 Following total laryngectomy and circumferential pharyngectomy, microvascular free jejunal transfer is recognized as the optimal reconstructive option.2,3 When postoperative radiotherapy is delivered to the neck, it is well tolerated by the transposed jejunal loop,2,3 however, the response of the jejunal mucosa to radiation is not documented. Also whether the reaction of jejunum to radiation affects its function or intergrity is not known. The aim of our present study was to evaluate the changes of the jejunal mucosa after irradiation.
METHODS From 1991 to 1995, in the Head and Neck Division of the Department of Surgery, The University of Hong Kong at Queen Mary Hospital, Hong Kong, we have performed a total of 28 microvascular free jejunal grafts for reconstruction of circumferential pharyngeal defects created after extirpation of hypopharyngeal tumor. At the time of free jejunal transfer, a small piece of normal jejunum was kept aside as the nonirradiated sample. Subsequent biopsies of mucosa of the transposed jejunum were performed through a flexible upper gastrointestinal endoscope with a forward oblique viewing lens (GIFXK20, Olympus, Tokyo, Japan). Each biopsy was transferred from the jaws of the forceps to a flat piece of paper with a 25-guage needle, and the specimen was laid out with the mucosal surface facing upward. Every specimen was also flushed with saline to remove the mucus attached to it. For every patient, jejunal biopsies were taken at 3 weeks after commencement of radiotherapy and at its completion. Further sequential jejunal biopsies were taken at 1 month, 3 months, 6 months, 1 year, and 2 years after completion of radiotherapy. Some of the jejunal biopsies obtained were processed for histologic examination and others for scanning electron microscopic examination. Nine patients completed the study and had a whole set of biopsy material for examination. Their postoperative radiation dose ranged from 4600 to 6600 cGy (mean 5380 cGy). This sequence of jejunal biopsies were also carried out for 5 other patients who did not receive postoperative radiotherapy. Informed consent was obtained from all patients included in the study. There were 11 men and 3 women, and their ages ranged from 47 to 79 years (mean 0002-9610/98/$19.00 PII S0002-9610(97)00230-4
JEJUNAL GRAFT RESPONSE TO RADIOTHERAPY/WEI ET AL
Figure 1. Upper: At completion of radiotherapy, edema was marked in the lamina propria beneath the surface epithelium of the jejunal mucosa associated with shortening and blunting of jejunal villi (arrow). Lower: At 2 years after radiotherapy, persistent loss of villi with increased fibrosis and retraction of gland are noted (arrow). Abnormal branching of a gland is seen (arrow head). (Hematoxylin and eosin stain 380).
Figure 2. Scanning electron micrograph. Upper: Normal jejunal mucosal surface showing the boundaries (arrow). Lower: Pitted areas indicative of loss of microvilli (arrows).
crovilli completely disappeared in the biopsies taken at 3 months or longer after completion of radiotherapy.
COMMENTS 64). All the 14 patients were able to take normal oral diet at the time of the biopsies.
RESULTS Extensive loss of villi was an early histologic finding. After completion of radiotherapy, the jejunal mucosa showed edema. Subsequent biopsies showed thinning of jejunal mucosa, focal loss of glands, and increased inflammatory cellular infiltration; and the villi also showed blunting with reduction in height (Figure 1). Increased mucosal fibrosis with retraction of glands toward the mucosal surface was noticed at 6 months after radiotherapy, and this persisted throughout the following 2 years (Figure 1). None of the jejunal mucosal biopsies displayed any area of necrosis or ulceration. Scanning electron microscopic examination of jejunal biopsies taken after completion of the radiotherapy revealed patchy areas of microvilli loss over the mucosal surface when compared with controls (Figures 2 and 3). Occasionally there was loss of microvilli covering one cell but the underlying columnar cell was not affected (Figure 3). The goblet cells, however, remained unchanged in all the sequential jejunal biopsies. These areas of loss of mi-
In normal jejunum, the columnar epithelium that forms the mucosa is thrown up into minor projections, the villi. In between the villi are the intestinal glands, the crypts of Lieberku¨hn. Among the columnar cells are the mucussecreting goblet cells. To increase the surface area for absorption, the cell wall of columnar cells have multiple projections, the microvilli. The intestinal epithelial cells have high mitotic activities with a short turnover time. Within 24 hours of a radiation dose of 500 to 1000 cGy, the mitotic cells in the crypts showed maximum destruction. Reepithelization is extensive within 96 hours.4,5 In general, the small bowel can tolerate a radiation dosage of approximately 4,000 cGy with 180 cGy daily fraction at 5 days per week, although enteritis has been reported with a low dose of 3750 cGy.6 The risk of development of significant complications such as perforation or fistula formation is related to the total radiation dose delivered, the dose per fraction, and the volume of small intestine irradiated.7 Radiation of transposed jejunum in animal studies have shown that increased fibrosis may lead to circumferential constriction and stricture formation.8 Reports of the transposed jejunum in human subjects have, however, indicated that it tolerates postoperative radiotherapy without much sequel.3,9
THE AMERICAN JOURNAL OF SURGERY® VOLUME 175 JANUARY 1998
45
JEJUNAL GRAFT RESPONSE TO RADIOTHERAPY/WEI ET AL
of microvilli were seen. The parent columnar cell was not affected. All these changes were only detectable up to 1 month after completion of radiation and not later. This patchy loss of microvilli was probably only a transient event following radiotherapy. Radiotherapy apparently did not affect the goblet cells as revealed by the scanning electron microscopic examination. The continuous function of the goblet cells ensures that mucus secretion is adequate. Although the jejunal graft only serves as a conduit at times, ample mucous secretion is essential for smooth swallowing function. The clinical significance of the study is that when a curative dose of radiation was delivered to the neck region following circumferential pharyngectomy and free jejunal graft, the changes of the jejunal mucosa were only minor and transient. Radiotherapy aiming at tumor control should be given even though microvascular free jejunal transfer was used for reconstruction following tumor ablation.
REFERENCES
Figure 3. Scanning electron micrograph. Upper: Normal jejunal mucosal surface showing cell boundaries (arrows) and globlet cells (arrow head). Lower: Occasional loss of microvilli covering 1 cell (arrow) and patchy loss of microvilli (arrow head).
In the present study the initial change of mucosal edema is compatible with acute radiation enteritis. The changes of blunting and shortening of the jejunal villi, increased fibrosis, and inflammatory cell infiltrates were features of chronic inflammation and were probably related to the vasculitis caused by radiotherapy. The presence of fibrosis in the later periods is not extensive and is limited to the submucosal region. Radiotherapy at the dose delivered for tumor control should not account for stenosis or stricture of the jejunal graft. The loss of microvilli detected after completion of radiotherapy demonstrated the response of the jejunal epithelial cells to the radiation energy. There was very occasional loss of microvilli covering one cell; more frequently patchy loss
46
1. Kramer S, Gelber RD, Snow JB, et al. Combined radiation therapy and surgery in the management of advanced head and neck cancer: final report of study 73-03 of the Radiation Therapy Oncology Group. Head Neck Surg. 1987;10:19 –30. 2. Coleman JJ, Searles Jr JM, Hester TR, et al. Ten years experience with the free jejunal autograft. Am J Surg. 1987;154:394 –398. 3. Petruzzelli GJ, Johnson JT, Myers EN, et al. The effect of postoperative radiation therapy on pharyngoesophageal reconstruction with free jejunal interposition. Arch Otolaryngol Head Neck Surg. 1991;117:1265–1268. 4. Pascal RR, Kaye GI, Lane N. Colonic pericryptal fibroblast sheath: replication, migration and cytodifferentiation of a mesenchymal cell system in adult tissue. Gastroenterology. 1968;54:835– 851. 5. Trier JS, Browning TH. Morphologic response of the mucosa of human small intestine to x-ray exposure. J Clin Invest. 1966;45: 194 –204. 6. Ransom JL, Novak RW, Kumar APM, et al. Delayed gastrointestinal complications after combined modality therapy of childhood rhabdomyosarcoma. Int J Radiat Oncol Biol Phys. 1979;5: 1275–1279. 7. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21: 109 –122. 8. Biel MA, Maisel RH. Gross morphologic and functional effects of postoperative radiation on free jejunal autografts. Laryngoscope. 1992;102:875– 883. 9. McCaffrey TV, Fisher J. Effect of radiotherapy on the outcome of pharyngeal reconstruction using free jejunal transfer. Ann Otol Rhinol Laryngol. 1987;96:22–25.-
THE AMERICAN JOURNAL OF SURGERY® VOLUME 175 JANUARY 1998