Original Article Liquid nitrogen: Cryo-sterilization Method for Free Bone Flap

Egyptian Journal of Neurosurgery Volume 29 / No. 1 / January - March 2014 25-32 Original Article Liquid nitrogen: Cryo-sterilization Method for Free Bone Flap 1 Tarek H Elserry*, 2 Iman Hewedi 1 Department of Neurosurgery, Ain Shams University Faculty of Medicine, Cairo, Egypt 2 Department of Pathology, Ain Shams University Faculty of Medicine, Cairo, Egypt ARTICLE INFO Received: 15 October 2013 Accepted: 16 November 2013 Key words: Liquid nitrogen Brain tumors Meningioma Simpson grading Craniotomy Bone flap ABSTRACT Objective: Several oncological sterilization methods involving autoclaving, irradiation, merging in antibiotic impregnated saline, or pasteurization have been developed for skull bone after an infiltrating tumor excision or compound skull fracture. Liquid nitrogen is nitrogen in a liquid state at a very low temperature, at atmospheric pressure; liquid nitrogen boils at 196 C ( 321 F). Nitrogen was first liquefied at the Jagiellonian University on 15 April 1883 by Polish physicists, ZygmuntWróblewski and Karol Olszewski. Several cranioplasty methods involving titanium mesh and acrylic used as bone substitute to achieve total removal of bone infiltrating aiming to introduce Liquid nitrogen (LN) as an efficient way of sterilization and eradication tool for the free craniotomy flap. Methods: This is a prospective study carried on 29 cases of convexity lesion. We merge the free flap craniotomy over the convexity in liquid nitrogen (LN2), bone specimens were obtained before and after merging in liquid nitrogen and sent to neuropathologists to document the presence of tumor cells before merging in liquid nitrogen (LN2). Follow up CT scan is done after 3 months to ensure bone viability and to exclude necrosis. Results: 22 cases established as WHO grade I with variable histological pattern. Three cases of grade II and one case grade III. One case of hemangiopericytoma grade III. 2 cases of Rosia-Dorfman disease. Neuropathology for the bone specimens of cases results revealed 22 positive specimens (84.6%) and negative for tumor cells in 4 cases (15.4%). Tumor cells was detected in the one case of hemangiopericytoma. Conclusion: LN2 is an efficient method of sterilization for free bone flaps in convexity tumors, providing a new concept of autologous bone flap.larger series and longer follow up is recommended to compare the rate of tumor recurrence for LNS sterilized bone flaps with other modality. 2014 Egyptian Journal of Neurosurgery. Published by MEDC. All rights reserved INTRODUCTION Extraaxial tumors are usually benign 1. Extraaxial tumors are uniquely interesting for brain tumor research for a number of reasons: They tend to be more homogeneous than parenchymal brain neoplasms such as glioma. The location of extraaxial tumors that is extrinsic to the brain encourages novel approaches to targeted therapy and facilitates extending the extent of resection to decrease rate of recurrence 2. Meningiomas are the most common supratentorial extraaxial tumor 1. The association between and hyperostosis was first described by Brissaud and Lereboullet in 1903 3. However, the cause of hyperostosis has remained controversial. It has been *Corresponding Author: Tarek H Elserry Department of Neurosurgery, Faculty of Medicine Ain Shams University, Cairo, Egypt E-mail:elserry@yahoo.com, Tel: +2/01223211156 hypothesized by several authors that hyperostosis may be a manifestation of tumor invasion 4. However, some believe that these bony changes represent nothing else but reactionary changes 5. As a common practice, neurosurgeons drill the hyperostotic bone and replace the bone flap in cases of intracranial s. Several studies aimed at determining whether the bony changes seen in can be attributed to tumor invasion and consequently leaving the bone flap in situ may be the same as leaving a part of the tumor behind 5. The primary treatment modality for s remains surgical resection, with the extent of resection being the primary factor influencing the recurrence rate. Simpson's 1957 classification of the extent of removal, which correlates well with rates of recurrence, continues to be a useful means of grading the extent of tumor removal 6 Liquid nitrogen (LN), stored at -197 C, is an effective cryogenic agent that can be used for either tissue preservation or destruction. A slow freeze and quick thaw allow tissue preservation, a quickfreeze and slow thaw lead to its destruction 7. Cryosurgery utilizing Egyptian Journal of Neurosurgery 25

LN is effective in the treatment of bone tumors 8 12. The formation of intracellular ice crystals and membrane disruptionare considered the main mechanisms of LN inducedcellular necrosis. Other mechanisms of cytotoxicity include electrolyte changes, denaturation of cellular proteins, and microvascular failure 13 17. Duringcryotherapy, the rapid freeze causes intracellularice crystals to form. As the temperature rises during thawing, these crystals coalesce and mechanicallydisrupt the cell membrane, causing celldeath 7,8. Three freeze-and-thaw cycles produce tumorcell death up to 2 cm from the cavity margin. This extent of bone destruction makes cryosurgery, which is by definition an intralesional surgical modality, as effective as a wide resection in the treatment of benign, aggressive, low-grade primary bone sarcomas, or metastatic lesions 14,18. Although nitrogen is nontoxic and inert, it can act as a simple asphyxiate by displacing the oxygen in air to levels below that required to support life. Inhalation of nitrogen in excessive amounts can cause dizziness, nausea, vomiting, loss of consciousness, and death. At low oxygen concentrations, unconsciousness and death may occur in seconds and without warning. However the amount of nitrogen required in the medical field is far away lower than the toxic doses and far away from the doses that cause hazardous effect on the handling personal. In this study we evaluate the Liquid nitrogen as a cryosterilization tool for craniotomy free bone flap in extraaxial dural based tumors excision; targeting a bone flap to remain viable during the follow up period. Hence we postulate this may be an economic method that would avoid complications of artificial mesh including infection. PATIENTS & METHODS In this study we included 29 cases with radiological evidence of convexity dural base extra-axial lesions that was evident by MRI to the brain. Preoperative evaluation: CT scan with bone window was done to all cases to diagnose positive or negative radiological evidence for hyperostosis, in addition to the always done MRI brain. Routine preoperative laboratory investigations were done to all cases including blood picture, coagulation profile, liver and kidney function. Fig., (1-A) Intraoperative: Craniotomy flap fashioned based on the bony anatomical land marks. We adopt the free bone flap. Infiltrated dura always excised with the tumor, extraarachnoidal removal fashion of the mass adopted in all cases gross total removal is ensured and good hemostasis. Dural graft was applied using autologous graft or synthetic duraform material. For the free bone flap; the gross tumor is removed with hand curettes, or high speed drilling according to availability after the neoplastic tissue has been curetted away from the inner table of the flap, cases in which the boney wallreveals irregular contour, Fig., (2). This irregularitymakes it virtually impossible to remove all the tissue from the inner reactive shell with a curette. The curettage material was preserved in 10% formaldehyde and sent to histopathology questioning the presence of tumor cells. Bone flap immersed in Liquid Nitrogen container until soft tissue Frozen then washed up by warm normal saline, three cycles was done which takes around 10-15 minutes, further curettage material was taken to histopathology questioning the effect of application of the LN2 on the bone, reapplying bone flap with hardware fixation in most of the cases, Fig., (3) Postoperative: Immediate postoperative period in intermediate care unite or intensive care upon anesthesia team recommendation, with follow up to vital data and neurological state. CT brain with bone window done at the intervals; first day and 3 months then a remote follow up. Fig., (1-B) A B Fig. 1: A. CT brain axial cuts post contrast study showing left frontal convexity extraaxial lesion with a noticeable thickening of the overlying skull bone; B. CT brain in a bone window sequence; a postoperative image for the same case in the 3 months follow up visit 26 Egyptian Journal of Neurosurgery

Fig. 2: Intraoperative capture for the craniotomy bone flap showing the irregular inner table surface A B Fig. 3: A. Intraoperative capture, a free bone flap merged in the liquid nitrogen; B. Warm normal saline washing up the bone flap after the liquid nitrogen bath RESULTS A total of 26 cases revealed to be with 22cases established as WHO grade I with variable histological pattern, 11cases transitional, 5 cases of meningiothelial, 2 cases of fibrous, 3 cases psamometous and 1 case lymphoblastocytic rich. Three cases of grade II, as 1 case of Chordoid, 2 cases of meningiothelial with evidence of atypia. One case grade III as Papillary. One case of hemangiopericytoma grade III. 2 cases of Rosia Dorfman disease with the notice that such a neoplastic like lesion is not categorized under the WHO grade (Table 1). We adopt to deal with the inner surface of the craniotomy bone flap by drilling versus curettage according to the availability with a preference to drilling strategy once available, 13 cases (44.8%) curettage of the inner table done versus 16 cases (55.2%) of drilling strategy (Table 1). Data received from the neuropathology department for the bone specimens of cases results reveal 22 positive specimens (84.6%) and negative for tumor cells in 4 cases (15.4%). Tumor cells was detected in the one case of hemangiopericytoma Hyperostosis detected in 18 cases (69.2%) of s with different histological pattern. With no hyperostosis detected in Rosia Dorfman or hemangiopericytoma casesno cases of radiological changes in the CT brain with bone window detected in the craniotomy flap, in the study done within 24 hours of the post-operative period. CT brain with contrast and with bone window ranges from 3 months to 48 months with a mean follow up of 34.9 months, with data received from the neuroradiology department of 2 cases of radiological evidence of recurrence in 18 and 10 months follow up in the meningiothelial with signs of atypia WHO grade II and papillary WHO grade III. No detected cases of resorbed bone in follow up CT scan, evidence of necrosis or infection. Egyptian Journal of Neurosurgery 27

Case Pathoogical diagnosis WHO grade Hyperostosis in preop. CT Curettage vs Drilling Tumor positivity in bone sample Changes in the immediate CT brain Max. follow-up period (months) Changes in remote CT brain 1 Transitional I Positive Curettage Positive Nil 40 Negative 2 Haemangiopericytoma II Negative Curettage Positive Nil 24 Negative 3 Lymphoplasmacyte-rich I Positive Drilling Positive Nil 29 Negative 4 Meningothelial II Positive Drilling Positive Nil 12 Negative 5 Meningothelial II Positive Drilling Positive Nil 18 Positive 6 Rosai-Dorfman disease Negative Drilling Negative Nil 36 Negative 7 Chordoid II Positive Drilling Positive Nil 46 Negative 8 Transitional I Positive Curettage Negative Nil 48 Negative 9 Psammomatous I Positive Drilling Positive Nil 48 Negative 10 Psammomatous I Negative Drilling Positive Nil 38 Negative 11 Meningothelial I Positive Curettage Positive Nil 46 Negative 12 Papillary III Positive Drilling Positive Nil 10 Positive 13 Transitional I Positive Curettage Positive Nil 42 Negative 14 Meningothelial I Positive Drilling Positive Nil 38 Negative 15 Transitional I Negative Drilling Negative Nil 40 Negative 16 Transitional I Positive Curettage Negative Nil 46 Negative 17 Transitional I Negative Drilling Negative Nil 39 Negative 18 Psammomatous I Positive Curettage Positive Nil 28 Negative 19 Rosai-Dorfman disease Negative Curettage Negative Nil 2 Negative 20 Meningothelial I Positive Drilling Positive Nil 28 Negative 21 Fibrous I Negative Drilling Positive Nil 32 Negative 22 Fibrous I Negative Curettage Positive Nil 46 Negative 23 Transitional I Negative Drilling Positive Nil 46 Negative 24 Transitional I Positive Drilling Positive Nil 29 Negative 25 Meningothelial I Negative Drilling Negative Nil 32 Negative 26 Transitional I Positive Curettage Positive Nil 40 Negative 27 Meningothelial I Positive Curettage Positive Nil 38 Negative 28 Transitional I Positive Curettage Positive Nil 48 Negative 29 Transitional I Negative Curettage Positive Nil 42 Negative 28 Egyptian Journal of Neurosurgery

DISCUSSION It was a point of difficulty in this study to plot previous experience in the use of LN2 in neurosurgery apart from the science-fiction dilemma of preserving brains and dead bodies for future researches. In this study we apply LN2 to 29 cases where convexity brain lesions were diagnosed in brain images 3 cases shows no gross morphological bone changes in the inner table of which was carrying the diagnosis of hemangiopericytoma, one case of papillary and the 3 cases bone curettage results shows no significant tumor cells. This goes with hemangiopericytoma with bone endostosis rather than exostosis, also raise the possibility to relay on the gross picture of the inner table to expect tumor invasion. We are offering an alternative to the use bone substitutes as acrylic and titanium mesh to get rid of the invaded bone and achieve a Simpson s grade one in removal of. Cryosurgery is the therapeutic use of cooling to induce tissue necrosis, for almost a century, cryosurgerywas practiced by a handful of surgeons in thefields of neurosurgery, gynecology, urology, andophthalmology. Solid carbon dioxide, cold airblast, and liquid nitrogen (LN) were used as cryogenicagents to treat various benign and malignantlesions 20. The first use of cryosurgery in conjunction withorthopedic surgery is attributed to MarcoveandMiller (1969) 21, who described an open system that entailed pouring LN directly into a tumor cavity. Liquid nitrogen was shown to achieve local tumorcontrol with minimal bone and function loss andcryosurgery was soon practiced in conjunction with surgery for a large variety of bone tumors 21,22. Despite its proven benefits, liquid nitrogen may cause substantial injury to the adjacent rim of bone, cartilage, and soft tissuesand result in secondary fracture, skin necrosis, infection, and temporary neuropraxia 21 23. In our study we tailored the use of liquid nitrogen in bone sterilization to be applied to free bone flap of the skull and it appeared to be a promising in getting rid of tumor cells invading bone structure. Histological evaluation of the bone cortex, immediately following cryosurgery, shows minimal changes. The extent of cortical injury does not become apparent until a week after application of LN; by this time, periosteum over the previously frozen cortex has disappeared, and the denuded bone appears dull white. The most dramatic effect of LN application may be seen in the bone marrow and is characterized by extensive necrosis, with minimal inflammation and subsequent liquefaction with progressive fibrosis. Large, thickened thrombosed vessels are occasionally seen 8,14,18,24,25.In our series we detected no bone resorption or necrosis in the follow up period but this will need further research to prove it. The association between and hyperostosis is well known.hyperostosis was present in 75% of cases of studied in a series of s involving the convexities and sphenoid wing 26. In our series we found 18 cases (69.2%) of hyperostosis in 26 cases of s. The cause of hyperostosis in has long been a matter of debate. There are various hypotheses which aim at explaining this phenomenon including preceding trauma, 27 irritation of the bone by the tumor without bony invasion, 28,29 stimulation of osteoblasts in normal bone by factors secreted by tumor cells, 30 production of bone by the tumor itself 31 and vascular disturbances caused by the tumor 32. In 1934, Echlin suggested a direct association between hyperostosis and tumor invasion of the bone 33. Since then, tumor invasion as a cause of hyperostosis has been gaining ground 34. This study shows the presence of tumor cells in the bone overlying a in 20% of the cases. In cases showing hyperostosis, the tumor cells were present in 23.3%. These results indicate that tumor invasion into the bone is present in a significant number of patients with, especially those showing hyperostosis. While the fact that tumor cells are seen in the overlying bone has been established by this study, it remains to be elucidated whether tumor invasion is the cause or the result of bony changes. The former scenario was appraised by another study in which a number of s not showing tumor invasion of the bone had hyperostosis on radiology (23 out of 32 cases not showing tumor invasion), thus negating the possibility that the invading tumor cells are responsible for the increased bone production. Also, the occasional occurrence of tumor invasion without hyperostosis (one out of ten) rules out the possibility of tumor invasion occurring as a result of hyperostosis. It is more likely that reactionary changes in the bone due to the close proximity to the tumor and their shared blood supply lead to production of growth factors which stimulate bone production, leading to hyperostotic changes with attendant release of chemotactic factors that attract the tumor cells into the bone matrix 5. It is hypothesized that there may be a common pathogenic pathway, yet to be explained, which leads to both the bony changes and tumor invasion into the bone.in our series with 18 cases of hyperostosis with, tumor cells was observed in inner surface of bone in 16 cases it does imply a strong association between hyperostosis and tumor bone invasion but we cannot prove causality with our results. In our study we observed 2 cases of Rosia Dorfman syndrome where there was no hyperostosis noticed and no tumor cells invasion in bone. O Raslan et al. detected no hyperostotic changes in 10 cases of Rosia Dorfman syndrome hence this can be a radiological clue to differentiate it from s 35. Egyptian Journal of Neurosurgery 29

In a clinical report of 9 cases of hemangiopericytoma no hyperostosis was found. In our study we found one case of hemangiopericytoma with no hyperostosis but tumor cells was found in pathology report of bone specimen, this may stand with that hyperostosis is not related to tumor invasion of bones. 36 In his landmark study published in 1957, Simpson elaborately described the importance of the degree of resection in preventing recurrence in s. He noted recurrence rates of 9, 19, 29 and 40% in Simpson Grade I through IV respectively 37,2 Although the series was reported prior to the advent of CT, MRI and micro neurosurgery, a number of subsequent studies on the rate of recurrence in have upheld the principle that clinical success in surgery is related to the extent of resection 34,38 47. Therefore, in order to achieve complete excision and ensure lower recurrence rate, one should also remove the bone infiltrated by the tumor. In our series we reported 2 cases of recurrence in 18 and 10 months follow up from a total of 26 s cases with maximum follow up of 48 months we can't conclude a recurrence risk rate from our study as we recommend a greater number of patients with longer period of follow up. Drawbacks of our study include; the few number of cases with different histological pattern and the relatively short follow up period, also we could not compare our rate of infection with other bone flap modalities, and we hope this can be solved in further research. However, it is not possible to predict which patients are likely to show bone invasion on the basis of either preoperative radiology or intra-operative pathological evaluation as invasion can occur without hyperostosis on radiology and frozen section examination of bone is not feasible. Therefore, in order to achieve higher Simpson grade of tumor excision, one should remove as much bone in contact with the tumor as possible whenever feasible. In skull base s, this can be achieved by drilling the bone, especially the hyperostotic areas. In cases of convexity, which showed the highest rate of tumor invasion into the bone; one should not replace the bone flap and instead use an artificial bone flap to cover the defect 5.Our study introduces sterilization of bone flap as a substitute for the use of artificial bone flap. CONCLUSION LN2 is an efficient method of sterilization for free bone flaps in convexity tumors, providing a new concept of utilizing autologous bone flap. Larger series and longer follow up is recommended to compare the rate of tumor recurrence for replantation of - extracorporeal Liquid nitrogen sterilized- craniotomy free bone flap modality. REFRENCES 1. Drevelegas, A. Extra-axial brain tumors. European Radiology 15, 453 67, 2005. 2. Oya, S. Erratum: Significance of Simpson grading system in modern surgery: integration of the grade with MIB-1 labeling index as a key to predict the recurrence of WHO Grade I s. Journal of Neurosurgery117, 806 806, 2012. 3. P., B. L. Two cases of hemicranios. Rev Neurol 537 40, 1903. 4. Pieper, D. R., Al-Mefty, O., Hanada, Y. & Buechner, D. Hyperostosis associated with of the cranial base: secondary changes or tumor invasion. Neurosurgery 44, 742 6; discussion 746 7, 1999. 5. Goyal, N., Kakkar, A., Sarkar, C. & Agrawal, D. Does bony hyperostosis in intracranial signify tumor invasion? A radio-pathologic study. Neurology India 60, 50 4, 2012. 6. De Monte, F. Current management of s. Oncology (Williston Park, N.Y.) 9, 83 91, 96; discussion 96, 99 101, 1995. 7. Gill, W., Fraser, J. & Carter, D. C. Repeated freezethaw cycles in cryosurgery. Nature 219, 410 3, 1968. 8. Gage, A. A., Greene, G. W., Neiders, M. E. & Emmings, F. G. Freezing bone without excision. An experimental study of bone-cell destruction and manner of regrowth in dogs. JAMA: The Journal of the American Medical Association 196, 770 4, 1966. 9. Schreuder, H.W., Conrad, E.U., Bruckner, J.D., Howlett, A.T. & Sorensen, L.S. Treatment of simple bone cysts in children with curettage and cryosurgery. Journal of Pediatric Orthopedics 17, 814 20 10. Schreuder, H.W., van Egmond, J., van Beem, H.B. & Veth, R.P. Monitoring during cryosurgery of bone tumors. Journal of Surgical Oncology 65, 40 5 1997. 11. Schreuder, H. W. et al. Aneurysmal bone cysts treated by curettage, cryotherapy and bone grafting. The Journal of Bone and Joint Surgery. British 79, 20 5, 1997. 12. Schreuder, H. W., Pruszczynski, M., Veth, R. P. & Lemmens, J. A. Treatment of benign and low-grade malignant intramedullary chondroid tumours with curettage and cryosurgery. European journal of Surgical Oncology: The Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology 24, 120 6, 1998. 13. Karow A R, W. W. R. Tissue freezing, a theory for injury and survival. Cryobiology 2, 99 108, 1965. 30 Egyptian Journal of Neurosurgery

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