WHO 2016 updated classification of medulloblastomas.
\r\n\t
",isbn:"978-1-83968-727-3",printIsbn:"978-1-83968-726-6",pdfIsbn:"978-1-83968-728-0",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"625b869ee498e8ac2159ddaf9fb4a906",bookSignature:"Dr. Sonia Soloneski and Dr. Marcelo L. Larramendy",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10368.jpg",keywords:"Biomarkers, Safety Testing, Pesticides, Biomolecules, Medical Devices, Nanomaterials, Drugs, Radiation, Apoptosis, Autophagy, Cytotoxicity Testing, Standardized Procedures",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 7th 2020",dateEndSecondStepPublish:"October 5th 2020",dateEndThirdStepPublish:"December 4th 2020",dateEndFourthStepPublish:"February 22nd 2021",dateEndFifthStepPublish:"April 23rd 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"An Assistant Professor of Molecular Cell Biology at the National University of La Plata (Argentina) that authored more than 380 contributions in the field, including scientific publications in peer-reviewed journals and research communications.",coeditorOneBiosketch:"Head of the Laboratory of Molecular Cytogenetics and Genotoxicology at the National University of La Plata (Argentina) and author of more than 450 contributions, including scientific publications, research communications, and conferences worldwide.A recipient of several national and international awards.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"14863",title:"Dr.",name:"Sonia",middleName:null,surname:"Soloneski",slug:"sonia-soloneski",fullName:"Sonia Soloneski",profilePictureURL:"https://mts.intechopen.com/storage/users/14863/images/system/14863.jpeg",biography:"Sonia Soloneski has a Ph.D. in Natural Sciences and is an Assistant Professor of Molecular Cell Biology at the School of Natural Sciences and Museum of La Plata, National University of La Plata, Argentina. She is a member of the National Scientific and Technological Research Council (CONICET) of Argentina in the genetic toxicology field, the Latin American Association of Environmental Mutagenesis, Teratogenesis, and Carcinogenesis (ALAMCTA), the Argentinean Society of Toxicology (ATA), the Argentinean Society of Genetics (SAG), the Argentinean Society of Biology (SAB), and the Society of Environmental Toxicology and Chemistry (SETAC). She has authored more than 380 contributions in the field, including scientific publications in peer-reviewed journals and research communications. She has served as a review member for more than 30 scientific international journals. She has been a plenary speaker in scientific conferences and a member of scientific committees. 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He is a former member of the Executive Committee of the Latin American Association of Environmental Mutagenesis, Teratogenesis, and Carcinogenesis. He is the author of more than 450 contributions, including scientific publications, research communications, and conferences worldwide. He is the recipient of several national and international awards. Prof. Larramendy is a regular lecturer at the international A. Hollaender courses organized by the IAEMS and a former guest scientist at NIH (USA) and the University of Helsinki, (Finland). He is an expert in genetic toxicology and is, or has been, a referee for more than 20 international scientific journals. He was a member of the International Panel of Experts at the International Agency for Research on Cancer (IARC, WHO, Lyon, France) in 2015 for the evaluation of DDT, 2,4-D, and Lindane. 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From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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They reported 29 cerebellar vermis tumor in children and young adults. Later they renamed as “medulloblastoma” as the term “Spongioblastoma multiforme” was described by Globus and Strauss in 1925 for various adults cerebral tumors in which feature of considerable cellular differentiation was seen. This picture was found absent in tumors of cerebellar origin [1, 2]. World Health Organization (WHO) defined medulloblastoma as “invasive malignant embryonal tumor of the cerebellum with commonest manifestation seen in children”. These neuroepithelial tumors have inherent tendency to spread through the cerebrospinal fluid to cranial and spinal subarachnoid spaces [3].
\nInjuries followed by malignancy are the second leading cause of mortality among children. After leukaemia’s, brain tumors are the most common in children accounting for ‘25%’ of all malignancies in children [4]. Most common malignant CNS tumor in children is medulloblastoma (MB) constituting 20% of primary brain tumors and approximately 40% of all tumors of the posterior fossa [5]. The incidence of medulloblastoma in adults is relatively low as compared to pediatric population. This constitutes 1% of all CNS tumors and this may be the cause of scanty data available in adult MB group [6]. U.S data showed the incidence of the medulloblastoma is 1.5–2 cases/100,000 population. Three hundred and fifty new cases in the United States are seen each year. The peak incidence is seen in 1st decade of life and incidence is noted higher in the pediatric age group 3–4 years followed by 8–10 years of age.
\nCBTRUS (Central Brain Tumor Registry of the United States) showed that incidence is higher in males as compared to females (Males: 0.16 vs. Females: 0.12). But this trend is different in children who are less than one year old. There is rising trend of higher incidence (APC: 1.7, 95% CI −0.4, 4.0) and death risk (Hazard Ratio for Survival: 0.74 with p value 0.09) seen in black race compared to whites which is non-significant [7, 8].
\nThere is rapid initiation of clinical symptoms are secondary to the rapid proliferation of these cellular malignant tumors. Symptoms of medulloblastomas vary with age. Earlier age of onset is associated with behavioral changes. Other symptoms may include listlessness, moodiness or irritability, vomiting, and lack of social interactions. As medulloblastoma is rapidly growing tumor, this results in obstructive hydrocephalus which manifests as raised intracranial pressure (ICP). Children may be seen with macrocephaly, fullness of fontanelle, and delayed developmental milestones. Older children and adults have symptoms of raised intracranial pressure like headache, vomiting, especially upon awakening in the morning hours. Headache usually gets better during the day. As anatomical location of medulloblastoma is cerebellum but symptoms slightly vary within various sites of cerebellum. Truncal ataxia result from tumors located in midline of cerebellum and appendicular ataxia is associated with the hemispheric located tumors [1]. There can be stretching of sixth cranial nerve because of hydrocephalus resulting in double vision. Meningeal irritation causes tilting of head and stiffness of neck due to the tonsillar herniation. Trochlear nerve palsy related to tumor compression is another reason of head tilt. Patients with spinal metastasis had symptoms of backache, weakness of bilateral lower limb and loss of bowel and bladder control. Metastatic disease symptoms depend upon the site involvement [9]. Majority are sporadic cases but there are associated syndromes like Gorlin syndrome (nevoid basal-cell carcinoma syndrome), Blue rubber-bleb nevus syndrome, Rubinstein-Taybi syndrome and Turcot syndrome (glioma polyposis syndrome) [10].
\nAlthough radiology is good contributor of diagnosis still detailed history and physical examination remained important and has to be done before proceeding for any investigations. Alteration of child behavior, persistent symptoms and focal neurological deficit are warning signs and should be proceeded with neuroimaging for diagnosis.
\nComputed tomographic (CT) appearance of a medulloblastoma is seen as well-defined vermian cerebellar mass which is hyperattenuated with surrounding vasogenic edema and sometimes evidence of hydrocephalus is seen. Contrast enhanced images show homogeneous enhancement.
\nMRI imaging of the entire neuraxis, brain and spine is recommended for suspected cases. MRI images show “Low-to-intermediate signal intensity” on T1-weighted images and “moderately high signal intensity” on T2-weighted images, compared to cerebellar white matter. Intratumoral haemorrhage, peritumoral oedema, tonsillar herniation, hydrocephalus and calcification are other associated findings. Multivoxel MR spectroscopy (MRS) of the primary tumor can assess the tumor metabolites like ‘elevated Choline peaks and decreased Creatine and N-acetyl acetate peaks’. Even without frank necrosis, a small amount of lipid-lactate peak sometimes observed indicating an increase in metabolic activity. Due to densely packed cells within the tumor and nuclear: cytoplasm ratio is higher, MB causes restriction of diffusion. There is restriction of diffusion of water particles in the tumor. So there is high signal of the tumor in diffusion-weighted MR images [11]. As frequency of spine seeding is 35% at diagnosis, to rule out any leptomeningeal metastases, Sagittal fat-suppressed post- gadolinium contrast MRI of the spine should be performed prior to surgery (Figure 1). Guang-Yao Wu et al. published data showed that proton magnetic resonance spectroscopy (1H-MRS) and Diffusion Weighted Imaging are helpful for qualitative diagnosis of medulloblastoma [12].
\nShowing preoperative MRI. (A) T1 weighted image post- gadolinium with tumor arising from midline of cerebellum. (B) T2 FLAIR with mild hyper intensity and voxel showing the tumor area of interest for spectroscopy. (C) Drop metastasis. (D) Significantly increased choline peaks with decreased NAA and Cr peaks on Spectroscopy.
Baseline hearing status with tests like Audiometry, IQ Testing and hormonal levels with Serum TSH and GH can be tested.
\nMostly medium and large sized tumors in posterior fossa are associated with hydrocephalus. In routine practice, prior to definitive surgery, ventriculo-peritoneal (VP) shunt should generally be avoided as definitive resection of tumor efficiently relieves the obstruction by opening the CSF pathways. Ideal surgery of any tumor is complete surgical resection, but feasibility and safety is priority. In such circumstances, it is recommended to attempt maximal safe resection and residual disease can be left behind rather than aggressive surgical resection approach that can precipitate significant morbidity. Benefit to risk ratio of complete surgical removal of tumor has to be assessed preoperatively [13, 14].
\nIdeal timing of post surgery MRI imaging should be obtained immediately, within 24–48 h of tumor resection, for accurately identification of the extent of surgical resection and quantification of the status of the residual tumor. If immediate post surgery MRI imaging has not been obtained, then recommendation is to wait for at least 2–3 weeks, but no more than 4-weeks, for resolution of post surgical changes and this will further prevent false positive results. Recommendations for timing of postoperative CSF analysis for malignant cells are also same, at least 2–3 weeks post surgery to prevent errors like false positive results [15, 16].
\nClassification of most of the CNS tumors are still relying on only histopathological features but in medulloblastomas, integration of additional molecular information has updated WHO classification from 2007 to 2016. Medulloblastoma is classified now by an integrative diagnosis including a histologically as well as genetically defined compound as shown in Table 1 [17].
\nHistopathologically defined MB | \nGenetically defined MB | \n
---|---|
Medulloblastoma, classic | \n\n
| \n
Desmoplastic/nodular medulloblastoma | \n\n
| \n
Medulloblastoma of extensive nodularity | \n\n
| \n
Large cell/anaplastic medulloblastoma | \n\n
| \n
Medulloblastoma, not otherwise specified (NOS) | \n\n
| \n
WHO 2016 updated classification of medulloblastomas.
Molecular classification provides additional clinical and prognostic information which has the potential for identification of innovative strategies and research for the management of this disease (Table 2) [18, 19].
\n\n | Wingless activated (WNT) MB | \nSonic hedgehog (SHH) subgroup | \nGroup 3 | \nGroup 4 | \n
---|---|---|---|---|
Cell of origin | \nDorsal brainstem (lower rhombic lip) neuronal progenitors | \nCerebellar external granular layer, neuron precursors | \nVentricular zone neural progenitors | \nCerebellum progenitors (upper rhombic lip) | \n
Prevalence | \n10% | \n30% | \n25% | \n35% | \n
Male:female | \n1:1 | \n1:1 | \n2:1 | \n3:1 | \n
Common age | \nOlder children | \n<3 year and >16 year, adult group | \nInfants and children <16 year | \nInfants/children/adults | \n
Histopathology | \nClassic. In few case, large cell and anaplastic | \nNodular desmoplastic histology, classic, large cell and anaplastic | \nClassic, large cell and anaplastic | \nClassic, large cell and anaplastic | \n
Genetic aberrations | \nCTNNB1 DDX3X SMARCA4 | \nMYCN, GLI2, PTCH1, SUFU, MLL2, SMO, TP53, BCOR1, LDB1, GABRG1 | \nMYC, PVT1, OTX2, MLL2, SMARCA4, CHD7 | \nOTX2, DDX31, CHD7, SNCAIP, MYCN, CDK6 GFI1/GFI1B, MLL2, KDM6A, MLL3, ZMYM3 | \n
Chromosome | \n−/6 | \n3q gain, 9q loss, 10q loss | \n1q gain, 5q loss, 10q loss | \nIsochromosome 17q chr X loss, 17p loss | \n
Molecular markers | \nBeta-catenin | \nSFRP1or GAB1 | \nMYC activation in 50% of this subtype | \nUnknown | \n
Metastasis | \nRarely present | \nNot common | \nHigh | \n35–40% at presentation | \n
Recurrence | \nRarely seen | \nLocal | \nMetastasis | \nMetastasis | \n
5 year overall survival | \n95% | \n75% | \n50% | \n75% | \n
Future strategy | \nReduction in therapy | \nSHH pathway inhibitors | \nIntensified therapy, novel therapeutics | \nRobust and large data research | \n
Medulloblastoma as a group of molecularly distinct subtypes.
Medulloblastomas originally were staged only on surgical basis but “Modified Chang Staging” is the current standard and there is addition of imaging [20] explained in Figure 2.
\nModified Chang’s staging system.
Risk stratification based on clinico-radiological analysis is still widely practiced and remains valid for Radiation planning in institutions. COG and SIOP Group accepted the clinical prognostic variables [21] shown in Figure 3. Although with the inclusion of molecular sub-grouping and genetic analysis of disease, more robust information about risk stratification and outcome of disease can be concluded to some extent but this required availability of these facilities with expertise in institutions. Incomplete neuraxis staging should be classified as high risk disease.
\nThe stratifying medulloblastoma patients clinically into high risk and standard (average) risk based on variables like age, resection and metastasis.
Medulloblastoma, the embryonal tumors of the central nervous system, are highly radiosensitive tumors. After 200 cGy, the survival fraction has been reported to be 27%. Although Dargeon in 1948 stated that “medulloblastomas … have a consistently unfavourable prognosis” but later careful observation of Edith Paterson regarding pattern of disease spread brings hope to this disease. Radiating brain and spinal cord in one undivided volume principle mentioned by Edith Paterson and Farr. was based on the post-mortem findings of brain and spinal cord deposits in untreated cases. In 1953, at the Christie Hospital a five-year survival rate for children who were treated with kV irradiation reported by Paterson and Farr was 41%. Since then the practice to irradiate the entire craniospinal axis is universally adopted [22, 23].
\nAfter resection of tumor, entire craniospinal axis irradiation followed by whole posterior fossa or tumor bed boost irradiation is recommended irrespective of clinically detectable disease. Being Radiosensitive, Radiotherapy is curative up to 70% of standard risk patients. For this pediatric age group disease, linear accelerators are better than telecobalt machines and these children should preferably be referred in time to well equipped higher center with radiotherapy facility and infrastructure to prevent unnecessary side effects. As treatment delays beyond 6–7 weeks result in worse outcome, cobalt-60 therapy may be offered in those areas where linacs are not available. To prevent the adverse effects of radiotherapy in the developing nervous system, radiotherapy is avoided initially in children up to 3 years of age. CSI technique required accurate reproducibility and complex field matching techniques. Long and complex shaped target volume homogeneity is a technically challenging process.
\nTiming of radiotherapy
\nImproved survival for patients is associated with a shorter interval from surgery to the start of radiation therapy. After definitive surgery, treatment should be started within 4–7 weeks. International Society of Paediatric Oncology (SIOP) trials showed that increase in the risk of relapse is seen if radiotherapy treatment is delivered after 7 weeks [24].
\nYounger brains are much more sensitive to damage caused by radiotherapy. CT based conformal radiation therapy, 3DCRT, is standard of care exists for many years. Patient can be in the supine or prone position during CSI treatment. Over the years, prone position was used universally. Nowadays supine position is used increasingly.
\nAdvantages of supine position [25]
Target volume coverage is more easily assured and delivery more reproducible.
Patient is more comfortable due to stable position.
Technically, there is better shielding of cribriform plate and inferior temporal lobes.
For younger pediatric patients who require anaesthesia, there can be better management of airways and cardiopulmonary complications can be reduced.
Limitations of supine position
Without adequate portal imaging, setup accuracy is difficult.
Old couches contain metal inserts and beam entrance posteriorly through the head rest and treatment couch is not possible.
Advantages of prone position is the junction between the spinal and cranial fields can be better visualized.
\nFor younger children, good sedation may be required. Expert play therapist may help in treatment for radiotherapy without sedation.
\nIn 2-dimensional planning, fluoroscopic guidance two-dimensional simulation is done. Immobilization is done with thermoplastic cast and universal prone head-rest is used. CSI board with Lucite base plate having semicircular Lucite structures are available for head rest and chin rest. Various degrees of neck extensions is possible which will prevent the exit of superior border of spinal field through the oral cavity. Chest wall can be supported by thermocols.
\nThis complex 2-dimensional CSI technique fundamentals are:
Two parallel opposed lateral portals for cranium and upper cervical spinal cord.
Posterior spinal field matching with the cranial fields.
In case of adults or larger children, matching of upper posterior spinal field with the separate lower posterior spinal field.
Craniospinal junction can be placed at higher level: C1/C2 interspace or lower level C5-C7. At higher level, overdose to spinal cord is low. Shoulders are excluded from the lateral fields by keeping the craniospinal junction at lower level (C5-C7). Also the exit dose to mandible, thyroid, pharynx and larynx is lowered. Inferior edge of S2 is mostly the anatomical landmark where lower border of spinal field (SF) is set. Single Craniospinal junction is set for smaller children. If length is >36 cm, two junctions are required which are craniospinal and spinal-spinal (SS) junction. Mostly SS junction is place at L2-L3 interspace. Multi-leaf collimators or custom made lead blocks are utilized for orofacial region shielding. In order to know the divergence of spinal fields, the spinal fields are simulated first.
\nVarious techniques used for matching craniospinal junction are:
For matching the beam divergence of the lateral head portals with the superior beam edge of SF, Collimator rotation is done 7–10°.
Couch rotation 6°.
Half beam blocks
Asymmetric jaws
Penumbra trimmers
The craniospinal junction should be feathering/moving weekly during craniospinal irradiation for homogenous dose distribution and further minimizing the hot or cold spots resulted from the gap-junction or set-up errors. With each shift, spinal field can be extended superiorly, and cranial fields can be decreased inferiorly by 0.5–1 cm. Similarly LB (lower border) of “superior spinal field” and SB (superior border) of “inferior spinal” field can be shifted superiorly. This all is done for spread out of dose homogeneity. Still the contribution of human errors is seen in many studies. As there is direct visualization of the optical field light on the skin surface in prone position, verification of beam delivery of CSI is relatively simple (Figure 4A) [26, 27].
\n(A) Gap feathering during craniospinal irradiation (CSI). Junction movement across the long treatment length allows homogenous dose distribution by reducing the overlap hot spot and gapping cold spots. If field length <35 cm, 100 cm SSD is used and for field length >35 cm, 120 cm SSD is used. (B) Posterior fossa boost volume including whole infratentorial compartment.
The posterior fossa (PF) boost volume
\nDepending on the risk-stratification of the disease, volume of the posterior fossa boost is decided. Those cases which are considered low risk and standard risk medulloblastomas, posterior fossa target volume includes pre-operative tumor bed with adequate margins. Most institutions add 1–1.5 cm margin to the tumor bed. Cases of high risk and very high risk disease require irradiation of the entire posterior fossa. Posterior fossa irradiation can easily be planned based on fluoroscopic imaging in low and middle income countries where there is no availability of multileaf collimators.
\nConventional portals for PF boost
\nThe PF boost is given using two lateral opposing fields. Anterior radiotherapy borders are formed by the posterior clinoids, posteriorly by internal occipital protuberance, superiorly extended up to mid-point of foramen magnum and vertex (or 1 cm above tentorium) and inferiorly extended up to C2-C3 interspace (Figure 4B) [28].
\nIn case of pediatric patients who are potential long term survivors, critical structures are better spared by conformal techniques.
\nImmobilization is done in supine position and patient is aligned straight keeping neck in the neutral position. A 4-clamp thermoplastic immobilization cast for the head and shoulder region along with appropriate neck rest should be used. A five point orfit for immobilization along with hyperextended head and depressed both shoulders can result in optimal sparing of the upper esophagus and laryngeal structures.
\nTraditionally, axial planning images of 5 mm thickness on CT simulator from the vertex till the upper thigh region were preferred. But in this era of high precision radiotherapy where CTV accuracy is important for optimal outcome, CT slice thickness is reduced in some anatomical sites of CSI field. Slice Thickness of 1–2.5 mm from the vertex to the inferior border of third cervical vertebrae (C3) and 2–5 mm from the lower border of third cervical vertebrae (C3) to the upper anatomical region of the femur should be obtained. Skull base foramina delineation is of utmost important and for their identification, “1 mm slice thickness at the base of skull” is preferred. To improve better identification of cranial nerves dural sheaths, co-registration of planning imaging CT to MRI can be done [29]. CSF extensions within the dural reflections are better demonstrated by FIESTA (Fast Imaging Employing Steady-State Acquisition) MRI sequences [30].
\nTreatment volumes
\nDue to the risk of CSF dissemination, entire arachnoid space is included in the clinical target volume (CTV).
\nThe frontal lobe and the cribriform plate must be included in the clinical target volume. Inclusion of superior orbital tissue is must in the radiation field for the adequate coverage of the frontal lobe and cribriform plate. As per SIOPE guidelines, “the geometric edge of shielding should extend at least 0.5 cm inferiorly below the cribriform plate and at least 1 cm elsewhere below the base of the skull”.
\nDelineation of CTVcranial
Brain along with its covering meninges are contoured till second cervical vertebrae (C2). For outlining the inner table of the skull, CT bony window setting is used with window/level: 1500–2000/300–350 suggested by SIOPE group.
The most critical sites are the ‘cribriform plate’, the ‘most inferior parts of the temporal lobes’, and the ‘whole pituitary fossa’. They all to be included in the CTVcranial delineation. For cribriform plate CT window/level suggested is 3000/400.
For inclusion of CSF within the dural sheath of cranial nerves, CTVcranial is modified. For second cranial (optic) nerve, window width 350/level 40 is to be used
Foramina or canals of skull base which are significant for delineation of CTVcranial are cribriform plate, optical canal of sphenoid, superior orbital fissure, foramen ovale, internal auditory meatus (IAM), jugular foramen and hypoglossal canal. Entire components length of the optic nerves in the CTVcranial is included in most institutions where photons are used. But in those institutions where medulloblastomas are treated by protons, for prevention of any potential optical retinopathy risk, only the posterior length components of the optic nerves is included [31, 32].
\nAs CSF flows up to the posterior aspect of eyeball which is better observed in MRI images, it is better to include whole optic nerves in CTV in routine practice of photon beam based radiotherapy in these cases. The cranial nerves which are wrapped without dural cuff are the third, fourth and sixth (oculomotor, trochlear and abducens) nerves. Nobel et al. studied the flow of cerebrospinal fluid beyond the inner table of skull into the IAM (internal auditory meatus), juglar foramen (JF) and hypoglossal canal (HC). Their study (on basis of 96 FIESTA MRI sequences) concluded that the CSF extension was up to ‘16 mm’ in the internal auditory meatus which is not very far away from the cochlea. So the cochlear sparing by CSF exclusion within the internal acoustic canal should not be attempted. Their data also showed that the CSF extension was up to 11 mm in the juglar fossa from inner table of skull. There is no extension of CSF within these dural sheaths outside the outer table of the skull. It is not so easy to delineate dural sheath CSF on MRI but CT images with 1 mm thickness along the base of skull can show skull foramina and canals and they can easily be contoured on bony windows (Figure 5) [29].
CTV brain: brain and its covering meninges till lower border of C2. PTV brain: 5 mm isotropic margin around CTV brain. CTV spine: entire arachnoid space with nerve roots. PTV spine: 5–8 mm isotropic margin is recommended around the CTV-spine | \n
Showing conformal planning. (A) Cribriform plate is in close proximity to ocular structures. Shielding edge should be at least 0.5 cm below the cribriform plate and 1 cm elsewhere below base of skull to cover the temporal fossa and skull base foramina. (B) The petrous part of temporal bone showing Internal acoustic canal (IAC). (C) Various skull base foramina contoured in CTVcranial including dural cuffs of cranial nerves. (D) Cribriform plate must be in target volume. (E) Entire subarachnoid space, including nerve roots laterally must be included in CTVspinal. SFOP, French Paediatric Oncology Society; CP, cribriform plate; SOF, superior orbital fissure; FO, foramen ovale.
Issues of the cribriform plate (CP)
\nAccording to a 1982 report from MSKCC, 15% of recurrences are subfrontal in medulloblastomas [33]. Hypothesis given by Donnal et al. was that the pooling of cells secondary to gravitational effect of prone position with maximum shielding of eyes can result in the recurrences at the region of cribriform plate [34].
\nThe CTVSpinal (spinal target volume) includes the complete dural or thecal sac. Lateral extension of delineation is must to cover the intervertebral or neural foramina with their exiting nerve roots from the C2 cervical spine till the lower end of the thecal sac. Lower border of CTVSpinal is appreciated by the latest spinal MRI imaging. Children Oncology Group (ACNS0332, ACNS 0331, ACNS 0122) recommended the inferior border of CTVSpinal is ‘2 cm below the termination of the subdural space’ which is usually at bottom of second sacral vertebrae. The other SIOPE group trials recommended that the lower border of CTVSpinal must be determined by the spinal MRI imaging of the termination of the thecal or dural sac. This border should be kep. 1 cm inferior to this. Root canals in the Sacral CTVSpinal can be excluded. This recommendation is based on a MRI study conducted on ten volunteers who were healthy proved that there was no CSF around the nerve roots of sacral segments.
\nIf patients are to be treated by protons, then for skeletally immature patients, CTVSpine should include the vertebral bodies. This will decrease the risk of unequal vertebral growth. In skeletally mature patients, spinal TV should include the subarachnoid space of spine with a margin of 3–5 mm is summed up to the body of vertebrae for set up uncertainties/variation (interfraction) [29].
\nDelineation of posterior fossa boost volume
\nHigh Risk and Very High Risk disease: The clinical target volume PF (CTVPF) boost encompassed the whole PF. The boost CTVPF extends superiorly up to the tentorium cerebelli, inferiorly to the foramen magnum, and posterolaterally to the occipital bony walls and temporal fossa. BS (Brain Stem) anterior border and midbrain cover the components of the posterior fossa anteriorly. The geometric margin of 0.5 cm around the CTVPF is taken for delineation of the PTV posterior fossa (PTVPF). PTVPF is limited to the bony confines of the skull, except at the foramen magnum where it extended to the level of C1. The PTVPF contoured anteriorly up to the posterior clinoids and inferiorly to the C1-C2 junction. PTV is modified at sella and pituitary gland is excluded from anterior extension of PF boost planning.
\nFor low risk and standard risk, tumor bed, as defined on CT images, delineation with a margin of 1–2 cm is recommended. For three-dimensional planning, two lateral opposing portals with editing/shaping using the multileaf collimators (MLCs) is recommended. Finally, these craniospinal and boost plans must be summated to produce a composite treatment plan and final dose-distribution is calculated [35, 36].
\nChildren and adults are two different groups as far as radiotherapy treatment in medulloblastoma is concerned. Proliferating tissues are more in children as compared to the adults. IMRT for adult population is a used as a routine practice for numerous malignancies but for pediatric patients, IMRT has to be used with great caution in view of low dose volumes. Spinal irradiation during CSI results in increased doses delivered to anterior thoracic and abdominal structures with conventional plans. Parker et al. published data showed that the PTV and dose homogeneity was better for the medulloblastoma CSI, IMRT plans. Dosimeteric analysis showed V95% for IMRT was 100%, 3D planning was 96% and 2D planning was 98%. Also V107% for IMRT was 3%, 3D planning 38% and 2D was 37%. The IMRT plans provided better sparing of heart and liver in terms of V (10 Gy) and above. Integral Dose analysis showed the IMRT plans were superior for liver and heart and the 3D plan were better for the body contour. Tomotherapy may be helpful in reducing high dose regions in OAR, but low dose of radiation to a large volume is a concern for pediatric patients [37].
\nIMRT planning
\nIMRT for craniospinal irradiation in adult medulloblastomas is delivered after summation of PTV brain plan and PTV spine plan. Usually the spinal PTV planning is done first with ‘inverse planning technique’ using the 5 posterior fields with 0°, ±20° and ± 50°gantry angles. For the craniocaudal direction, the isocenter is kept at the “geometrical center of the PTV_spine”. For the depth and lateral position, it is usually set at the “midline and midplane” at the level of the interphase of second and third cervical vertebral body. Dose prescription and normalization is to the isocenter of the spine. For the cranial target, a separate plan is created. Cranial fields isocenter is set at the inferior most slice of the PTV brain. MLC positions can be modified for dose reduction to the nearby OARs and adequate coverage of the target volume. The geometric center of the PTV_brain is defined as the reference point for dose prescription and normalization. Final composite plan for the whole cranio-spinal axis is obtained after dosimetrically summation of spinal and cranial plans. For taller patients, for upper and lower spine, IMRT plans are created separately [38].
\nIntensity modulated radiotherapy for posterior fossa boost
\nMeenu et al. re-planned seven previously irradiated patients of MB with seven field inverse planning IMRT for whole posterior fossa boost. Equidistant gantry angles (0°, 50°, 100°, 150°, 210°, 260°, 310°) were used with step and shoot IMRT on 6MV energy LINAC. Treatment isocenter was set at the geometrical center of the planning target volume. They compared with 3DCRT plan delivered by two lateral opposing beams with multileaf collimators for shaping. Their dosimeteric results showed there were decreased mean dose to most critical organ at risk, cochlea, with IMRT compared to the three dimensional radiotherapy plans with significant p values i.e. 0.032 for the cochlea of right ear and 0.020 for the left sided cochlea (Figure 6) [35] Similar results are found in published clinical studies conducted by Huang et al. where 13% of the IMRT group had grade 3 or 4 hearing loss as compared to 64% for the conventional group [39].
\nCoursey JCRT. Meenu et al. mid-axial dose distributions with (a) 3DCRT (b) IMRT for one of the representative case of entire posterior fossa boost. Yellow represents 100%, red 95% and blue 70% of the isodose lines. IMRT is advantageous over 3DCRT for cochlear sparing. 3DCRT, three dimensional conformal radiotherapy; IMRT, intensity modulated radiotherapy.
Organ at risk
\nOAR as demarcated on axial CT images include brain, eyes, lens, optic nerves, optic chiasma, cochlea, parotids, mandible, thyroid, esophagus, lungs, heart, breasts, liver, kidneys, bowel bag, rectum, bladder, gonads (ovary or testes), vertebral bodies, uterus plus pelvis (red bone marrow).
\nBerry et al. reported a five year survival rate of 47% with lesser doses and ten year DFS of 77% once the posterior fossa doses delivered were >52 Gy [40]. Abacioglu et al. showed in adult medulloblastomas, control rate was 33% at 5 year with doses <54 Gy native to 91% in those patients on whom higher doses were delivered [41]. CSI dose reduction is feasible with the addition of chemotherapy as level 1 evidence based data released by Children’s Cancer Study Group showed that the reduction of doses from 36- to 23.4 Gy resulted in significantly higher risk of recurrences outside the posterior fossa [42].
\nRadiotherapy doses to CSI depends upon the risk stratification of the disease at presentation. If risk stratification or accurate staging is incomplete then patient can be treated as high-risk disease. Radiation therapy doses according to the risk stratification are shown in Table 3 [43]. There are different long term toxicities between the adult and children. CSI dose reduction approach is avoided for adult patients. Still big data is required to justify the addition of adjuvant chemotherapy to radiotherapy in average risk adult patients as data showed that 70–80% of these patients have no progression of disease at 5 years when RT is used as a sole modality. Also there are issues of hematological toxicities in adult patients.
\nVarious risk stratification | \nVolume and doses of radiation therapy | \nConcurrent or adjuvant chemotherapy | \n
---|---|---|
High risk and very high risk disease | \nCSI: 36 Gy/ 20 fractions, 5 days a week Boost to posterior fossa: 19.8 Gy/ 11 fractions, 5 times/week Gross metastatic deposits: Boost dose of 5.4–9 Gy/3–5 fractions | \nConcurrent carboplatin followed by adjuvant six cycles of systemic chemotherapy | \n
Standard risk | \nChildren <18 year CSI: 23.4 Gy/13 fractions, 5 days a week Boost to whole posterior fossa (or tumor bed): 30.6 Gy/17 fractions, 5 times/week Adults CSI: 36 Gy/20 fractions, 5 days a week Boost to posterior fossa: 19.8 Gy/11 fractions, 5 times/week | \nChildren <18 year Weekly vincristine followed by adjuvant six cycles of systemic chemotherapy | \n
Low risk | \nCSI: 23.4 Gy/13 fractions, 5 days a week Boost to whole posterior fossa (or tumor bed): 30.6 Gy/17 fractions, 5 times/week | \nReduced intensity chemotherapy | \n
Radiotherapy doses according to risk stratification.
Pediatric age is more sensitive to radiation induced carcinogenesis as compared to adults by a factor of at least 10 [44].
\nAs children anatomy is small so critical organs are very much close to the target volume. Also the scatter from the treatment volume is highly significant in children having small body area as compared to large body of adults. Particle beam therapy is a potential powerful tool for improving the therapeutic ratio. Goal of pediatric radiation oncologists is integral dose minimization to whole body and organs at risk. Advantage of protons over the photons is that they can modulate the dose to avoid very close OARs. For CSI, advantages of protons are because of absorption of low dose on tissue entry and the point of maximum dose deposition at the Bragg-peak. This results in the avoidance of dose deposition to anterior organs like thyroid, lungs, heart, gut, liver, esophagus, kidneys and urinary bladder. Also critical brain structures such as the lens, optic chiasma, pituitary, cochleae are better spared. In grown up children, sparing the anterior portion of the vertebral body results in minimization of bone marrow dose (Figure 7).
\nCSI Schematic Model. (A) Photons are absorbed and secondary electrons have large range in mm resulting in doses beyond the target volume. (B) Advantage of stopping of protons is due to the Bragg peak curve resulting in lower doses to OARs with proton therapy.
Consensus report from the Stockholm pediatric proton therapy conference showed that treatment of choice for medulloblastoma is proton therapy [45]. Based on the review of the existing theoretical and early clinical outcomes evidence, results showed that proton craniospinal irradiation provide similar control of tumor with potentially decreased doses to the normal structures thus reduces the risk of side effects when compared with photon existing data [46]. Spot-scanned intensity-modulated proton therapy (IMPT) is advantageous over the photon therapy in terms of all radiobiological risk estimation [47].
\nWeight changes in medulloblastoma and adaptive proton therapy are coming up but at present there is scanty data available. Patient selection is of utmost important in proton therapy. Limitations of patients with their families to travel in these centers, the proton center capacity to treat children and the availability of expertise and support structures must be evaluated by the referral physicians.
\nChemotherapy is integral part of treatment and in standard risk cases CSI doses can be reduced. Children less than 3 years, chemotherapy is recommended till the child will attain the age of 3 years. Drugs like carboplatin, cyclophosphamide and etoposide is recommended. There are various regimens recommended (Box 1). In a published database analysis of medulloblastoma children (n = 816) age 3–8 years who received adjuvant chemotherapy after surgery, overall rate of RT deferral after surgery was 15.1%. Their practice was associated was decreased overall survival in this pediatric population even in the well-established era of chemotherapy. [48] At present, recommendations of chemotherapy are:
Following RT as adjuvant settings
In Infant medulloblastoma, to defer RT, till the age of 3-years
Autologous stem-cell rescue accompanied with high-dose chemotherapy with
Concurrent chemotherapy with radiotherapy
As a salvage therapy in cases of relapsed of recurrent medulloblastoma.
Chemotherapy regimens (adjuvant) in MB children >3 years of age [49, 36].
\n\n
A detailed discussion about the chemotherapy and late effects of radiochemotherapy, management of adverse effects are outside the scope of this chapter. It is recommended and important to have multidisciplinary follow-up with pediatric radiation oncologists and endocrinologists.
\nFollow up counseling is mandatory prior to initiation of treatment. MRI brain may be performed every three months and MRI spine may be obtained every six months in standard risk category of standard risk patients for the initial two years. These two investigations can be performed every 6 months up to five years, and then repeated every year. In high-risk group, MRI of whole brain and spine may be repeated every three months for the initial two years. Thorough clinical examination with every visit is necessary. In case of pediatric or adolescence groups following radiotherapy, neuroendocrine follow-up with evaluation of serum hormonal levels should be performed every six months.
\nAuthors are grateful to Prof. Sunil Saini, Director Cancer Research Institute, Swami Rama Himalayan University for providing motivation and necessary facilities for writing this book chapter.
\nThe authors declare that this chapter was written in the absence of any commercial or financial relationships that could elucidate as a potential conflict of interest.
\nThe role of the general as well as oral pathology and microbiology laboratory is essential to the successful provision of patient care. Appropriate, professional and knowledgeable interaction with the dental or head and neck surgeon can benefit the patients by achieving accurate diagnosis as well as effective treatment approaches. Acquiring proper laboratory data allows the dental practitioner to arrive at a definitive diagnosis for further referral in a timely manner as oral cavity often presents the first signs of a systemic illness. The pathologist plays a valuable role in education and documentation of the learned information for future cases with similar presentation for he/she presents the final verdict.
The oral pathology laboratory is the most resourceful place for the diagnosis of oral lesions. A multitude of lesions are encountered in the oral and maxillofacial regions that need a sound knowledge of how to approach their diagnosis, and it begins with a good clinical history and examination. The basic requirements of a useful diagnostic technique are ease of use, patient acceptance and sufficient specimen collection. The ideal diagnostic procedure should also be highly sensitive and specific, simple, and not time-consuming and have a potential for automation [1]. Oral tissue examination includes a wide range such as oral biopsy (for routine formalin fixed and fresh tissue), saliva, swabs, cytology smears and fine needle-aspirated, cystic fluid and microbiology.
When a patient with a particular lesion is seen, a list of differential diagnosis is formulated, and biopsy is useful at arriving at a definitive diagnosis or to confirm the clinical diagnosis. Oral biopsy was and still is the gold standard for oral diagnostic procedures. It is an invasive procedure with procedural limitations and a psychological effect on patients. It is important that the biopsy specimen be a true representation of the entire lesion. A carefully selected area involving normal as well as pathologic areas can produce good diagnostic specimen.
Take tissue specimen, and put it into a wide-mouth container with 10% formalin at least 20 times the volume of the surgical specimen. Care should be taken to be sure that the tissue has not become lodged on the wall of the container above the level of the formalin.
Incisional biopsy specimens should be taken from each area showing different characteristics. Even if the lesion clinically looks uniform, it is still wise to sample different areas of a large lesion. Multiple samples must be adequately labeled.
Vigorous manipulation of lesion should be avoided if it is suspected to be tumor as it can increase the tumor cell emboli in venous drainage.
The tissue should never be put on gauze, cotton or paper, as it can lead to dehydration of the tissue specimen.
If culture is desired, take the material for bacteriologic study before fixing the specimen.
On the other hand, if the lesion is a large one with variations in its clinical appearance multiple biopsies could be planned for better sampling.
Even though the pathologist would like to receive the biggest specimen possible, the minimum size of the biopsy should not be less than 5 mm in diameter, to enable the pathologist to obtain well-prepared slides.
In majority of cases, the most active part of the lesion and, therefore, the most representative are located peripherally. If the biopsy specimen is taken from a necrotic part of the tumor, the diagnosis rendered by the oral pathologist can be only the “necrotic tissue.” Therefore, as a rule, it is unwise to biopsy the center of a lesion, which is probably its least active part [2, 3].
It is extremely important to place the biopsy specimen into proper fixative immediately after removal from the patient. Ten percent formalin is the standard fixative used to prevent autolysis, distortion and destruction of the tissues. Most oral pathology laboratories will provide mailing containers, specimen bottles filled with 10% formalin, and history-biopsy request sheet. Table 1 is a list of fixatives with reference to oral tissue.
List of fixatives with reference to oral tissue.
If the fixative in the mailing container has evaporated, leaving a white powder residue, it cannot be reconstituted by adding water.
Another container must be used or the fixative prepared by getting formalin (formaldehyde 37–40%) and mixing 10 parts of formalin solution with 100 parts of tap water.
The biopsy specimen must not dry out on the bracket table while one is finding the fixative, bottles and the like.
Everything should be ready in advance so that the tissues can be properly fixed and a diagnosis can be rendered and to avoid the statement “improper fixation, unable to render diagnosis.”
The biopsy specimen should never be submitted in normal saline or water, as the tissues become completely degenerated by autolysis.
In an emergency, when 10% formalin cannot be obtained, 70% alcohol may be used. Alcohol causes hardening of the specimen to the degree that cutting may be difficult, so on the biopsy request form it should be noted that the specimen is submitted in alcohol. The histology technician can then transfer the specimen to 10% formalin, hopefully before 48 h, so that the tissue will not become too hard to cut.
Preserving the specimen. The specimen—a tooth, piece of bone, or soft tissue—is at once placed in a bottle containing a fixing solution, such as 10% formalin, Zenker’s solution, or Carnoy’s solution. Most pathologists prefer 10% formalin solution.
It should be promptly sent to a pathologist for examination. The latter should be given all the information gained by clinical study and X-ray examination, or other laboratory tests, as this will facilitate diagnosis in difficult cases.
A consultation between the pathologist and the dentist will be particularly helpful and will also give the opportunity for discussing the method of procedure in the treatment of the patient.
It is also very important that the completed history form be sent with the biopsy specimen [3].
During winter months in climates where the temperature drops to freezing or below, there is a danger that the biopsy specimens dropped in a mailbox may freeze. The freezing of the tissue forms ice crystals within the cells. These crystals disrupt cell membranes and cause great distortion and introduction of artifacts into the specimen. Thus interpretation of the tissue specimen becomes very tenuous.
Before mailing biopsy specimens during cold weather, one must make sure that they are fixed in 10% formalin at room temperature for at least 2 h before mailing.
Biopsy specimens can display tissue changes that might interfere with the accurate diagnosis by the use of electrocautery. The frying action of the electric current generating high temperatures in the tissues results in changes.
In the case of a biopsy of an oral mucosa lesion, an eosinophilic homogenization of the fibrous tissue can be seen histologically. Thus, it is especially important not to use electrocautery for excision of small lesions. It is preferable to use a surgical scalpel to remove the biopsy specimen followed by the use of electrocautery to control bleeding [3].
Oral exfoliative cytology was developed as a potential diagnostic tool for early detection of malignant lesion. It is relatively simple, easy to master and least invasive and has high patient acceptance [1]. Though it has been always used as an adjunct to oral biopsy in oral cancer diagnostics, it holds potential in diagnosis of oral dermatosis and certain microbial infections. The specimen obtained can be used for cytomorphometry, DNA cytometry and immunocytochemical studies [1].
Toluidine blue should be used as a supravital stain before the site selection and smear preparation.
Label one end of the slide with patient’s name, date, and area from which material is to be obtained. Wipe the slide clean.
Use a clean cotton tip applicator or wooden spatula for the collection of the smear. If the area to be scraped is dry, moistened the applicator or spatula.
Collect the material using a slight rolling motion or scraping of the lesion. (Inadequate slides may be obtained if there is a pseudomembrane, thick saliva, no moisture or excess bleeding).
Immediately apply the scraping to the center area of the slide previously marked.
Alcohol (70%) is adequate for fixation. Equal parts of ether and 95% ethyl alcohol give superior staining qualities.
Immediately immerse the slide in fixative or put the fixative on the slide with a dropper. Do not allow any drying of the smear before fixation.
Keep the slide in fixative for a minimum of 30 min.
At this point, the slides can be air dried and sent for staining and screening, or it can be left in the fixative.
Very good, easy, rapid, painless and bloodless procedure.
Adjunct to biopsy, better to take cytology first, and then if necessary advice biopsy.
Creates less psychological trauma and fear.
Useful in follow-up after radio- and chemotherapy.
Recurrence can be known very easily without taking biopsy.
Mainly used for ulcerative epithelial lesion; intact epithelium gives false negative result.
Also used for dermatological condition like pemphigus vulgaris, Darier’s disease, and viral infections like herpes simplex as well as aphthous ulcers, etc.
Deeper lesions are not identified by this technique, and for that another technique called fine needle aspiration cytology (FNAC) is used.
Fine needle aspiration biopsy or cytology is an effective tool in evaluating and diagnosing suspect lumps or masses. The name indicates this biopsy technique uses aspiration to obtain cells or fluid from a superficial or deep palpable mass. A quick diagnosis means that tumor is detected early, or benign lumps are diagnosed without the need for multiple surgeries [4]. The success of perfect FNAC depends on the technique for collection and preparation of samples along with a detailed clinical history and clinical impression. If an infectious process is suspected, often a portion of the specimen is submitted for microbiology in an appropriate sterile medium or transport container.
FNAC is indicated in head and neck lesions, which include salivary gland lesions, thyroid and parathyroid lesions, cervical lymph nodes and intraosseous lesions.
Alcohol wipe; 4 × 4-inch gauze pads; 10-ml plastic syringes; 25-gauge 1 1/2-inch stiff, noncutting, bevel-edged needles; glass slides; alcohol bottles; pistol-grip mechanical syringe holder.
Procedure:
Explanation of procedure to the patient before doing FNAC ensures the patient’s cooperation.
For head and neck biopsies, a chair with head rest is essential.
Prebiopsy sedation is usually not required, except in the deep aspirations in very anxious patients or for deep biopsies.
The patient is placed in a comfortable position—with mass readily palpable and easily graspable.
The lesion is grasped with one hand usually between two fingers with an attempt to determine the location and surrounding tissue.
The syringe pistol with attached needle is laid against the surface of the lesion at determined puncture site and angle.
The needle is inserted quickly and advanced into the mass.
The suction is applied to syringe, about one third the length of syringe barrel observing the junction of the hub and needle for appearance of any specimen.
Multiple short 5-mm “in-and-out” motions are made till tissue material is seen coming into the hub of the needle.
At first appearance of any sample at junction, the syringe pistol is released, letting the vacuum equate to normal, and the needle is withdrawn slowly.
Pressure is applied to the puncture site with sterile gauze pad.
The above procedure can be repeated again using a clean needle for a second pass (and more passes if needed).
The needle is removed quickly from the syringe. Five milliliters of air is aspirated into the syringe, and the needle is placed back on the syringe. With the needle bevel facing down, 1–2 drop of aspirated material is expelled onto each of several marked glass slides.
Preparation of smear: A drop of aspirate is placed at the center of plain glass slide. A second slide is inverted over the drop, and the slides are gently pulled apart vertically or horizontally once. Fix immediately in 95% ethyl alcohol for a wet smear. For studying and evaluating cytoplasmic features or background elements of smear, air drying is preferred. Until all the material in the needle is used, continue making more slides. Or a drop is placed near the frosted end of slide held in the left hand; the bloody material is spread along the edge of the slide held in the right hand. The material is pulled gently down the slide in a manner of making a blood smear.
Alternatively the expressed specimen is sent directly to the laboratory in a 50% ethyl alcohol fixative or Hank’s balanced salt solution for slide preparation. If a cyst is aspirated, the laboratory will have to spin the specimen for concentration.
Modifications:
Often needle biopsy without aspiration based on capillary pressure in a fine needle is sufficient to keep the scraped cells inside the lumen. A 25-gauge needle is held directly with finger tips and is inserted into the target lesion and is moved back and forth in various directions. This procedure offers the advantage of better feel of tissue consistency and less admixture of blood and is valuable for tiny lymph nodes.
Cell block preparation: It refers to formalin fixing and paraffin embedding of aspiration biopsy that help reinforce some tissue patterns that may be seen on smears—aids in specific diagnosis especially for immunoperoxidase cytology staining.
Flow cytometry, electron microscopy and molecular diagnostic studies such as ELISA and FISH can be performed on FNAC specimens.
Storage instructions: Refrigerate in a fixative if there is delay.
Causes for rejection: Improper labeling, improper fixation and air-drying artifact.
The cervical and supraclavicular lymph nodes of the neck are in the drainage path of many infectious and malignant diseases; an examination should be made by FNAC. FNAC of cervical lymph nodes is a well-accepted diagnostic test of choice in both adult and pediatric patients for reliably distinguishing between benign/reactive and malignant processes and guiding patient management with simple observation or antimicrobial therapy for infections, chemotherapy and radiation therapy or the need for more sample tissue like core biopsies or excisional biopsy of the lymph node itself [5].
Thus FNAC is recommended as a safe, quick and inexpensive tool in the diagnosis of head and neck lesions.
Collection of human saliva offers a noninvasive method for monitoring the disposition of unbound (free) drugs and many endogenous biomarkers. Human genomic DNA extracted from buccal epithelial cells and white blood cells found in saliva can be used in various applications in diagnostics. The correlations between blood and saliva biomolecule/biomarker concentrations range from good to excellent. Methods of collecting saliva range from simply spitting into a collection cup or using absorbent pads or swabs or the trademarked collecting devices. Freeze-thaw techniques are often employed to help break up the mucin protein that is responsible for the sticky, foamy saliva. There are few inherent drawbacks for using saliva as an ideal biofluid. In some cases, the drug, metabolites or other compounds being assayed may bind to absorbent materials, thus reducing recovery or giving a misleading result [6].
Saliva is useful for testing:
As an index to metabolic processes
For caries activity tests
For detection of various metabolites in smokers
Whole saliva is commonly collected by draining, spitting, suction, and swab or absorbent method. Common stimuli used are chewing on paraffin wax and chewing gum at a fixed rate. As described by Wong D, the proposal for standardized collection of whole and glandular saliva can be followed for saliva sample collection.
Collect saliva samples at the same time of the day between 9:00 and 11:00 a.m.
Patient should refrain from eating and drinking at least 90 min before advised collection.
If present, drug usage should be stopped that might affect salivary secretion for at least 1 day.
Rinse mouth with preferably deionized water prior to the saliva collection.
Collect saliva for 10 min [6].
Collection of saliva into ice-cooled vials is recommended to slow down the activity of hydrolytic enzymes present in saliva in air-cooled preset environment. Proprietary collection vials contain a cocktail of protease inhibitors and bacteriostatic chemicals. Bacteria and cellular debris have to be removed directly after collection by centrifugating for 5 min at 10,000 g, or 20 min at 3000 g or by non-cotton-based filtration or vortexing (2 min, maximal speed).
After collection, salivary samples must be snapped frozen in liquid nitrogen. In the absence of liquid nitrogen, freezing in dry ice is a practical choice when samples are collected. For a prolonged storage, −80°C temperature is preferred over storage at−20°C. The salivary samples can be diluted with glycerol (1:1) before storage. For immunochemical analysis such as ELISA, the saliva can be stored frozen after dilution (e.g., 1:100) in the assay buffer, usually PBS—0.5% Tween-20. To maintain the integrity of the proteins, before testing, the deep-frozen samples must be thawed as quickly as possible. Analysis of pH (H+ and HCO4−) and viscoelastic properties is best analyzed in fresh saliva samples. Storage of salivary DNA and RNA is similar to that of a salivary protein sample [6].
Rationale: The idea of culturing microorganisms is not new or foreign to the practice of dentistry. There are situations in dentistry where it is not only important to know whether microorganisms are present in a lesion but also the type of microorganism. It follows from this that to best treat these infections the dentist needs to know what antibiotic would be most effective against the particular organism. Thus the culture and sensitivity test for bacterial organism is indispensable [7]. The biggest challenge today will be the transition from culture-based microbiological testing to molecular-based testing.
The success of oral bacteriologic/fungal identification procedures depends to a great extent on the manner in which the specimen is collected.
Lack of care and faulty methods of collection and handling of the specimen make the laboratory procedures valueless.
Because most of the microorganisms encountered in dental or head and neck infections are caused by facultative anaerobic or obligate anaerobic bacteria, the laboratory may prefer the use of a reducing transport media.
The biopsy for culture is similar to the surgical biopsy for tissue diagnosis. A 5 × 5 × 5-mm piece of tissue is excised from the lesion with aseptic technique (here, it is undesirable to biopsy the normal tissue border, as there will not be any organisms in the normal tissues).
The biopsy specimen is placed in a sterile test tube containing sterile physiologic saline as the transport media (formalin is not used). The cap is secured and the specimen sent to the laboratory, along with the completed history sheet request form.
At the laboratory, using the sterile tissue grinders, the specimen is ground into suspension, which is left to settle. The supernatant fluid is then used for the inoculation of appropriate media [8].
For examination of surface lesions or exudates from a fistula or cyst, a specimen is procured by the means of a sterile platinum wire or a sterile exploring point. A sample of deposit or plaque on a tooth is gathered by the platinum loop, by exploring point or by a pipette. Root canal specimens may be taken with a sterile point. The specimen is then smeared on a glass slide. It is allowed to dry in the air and is fixed on the slide by drawing it three times through a Bunsen flame, when it is ready to be stained. For the proper collection of specimens, the precautions are:
Do not use antiseptic or disinfectants for cleaning the site from which the culture specimen is taken; just dry the site with sterile gauze.
The sterile swab moistened with sterile saline should be introduced into the wound or lesion and removed without touching the adjacent tissues.
The sterile swab should be immediately put into the sterile test tube and the part of the swab handle touched by the fingers and hand in grasping should be broken off and discarded. Some commercials have plastic cap that covers the end of the swab handle and also serves as a cap for the test tube. Two cultures should be taken from each site so that one can be grown under aerobic conditions and the other under anaerobic conditions.
The cover of the test tube should then be screwed on tightly and the tube titled to saturate the swab with the transport media.
Sterile swabs in empty tubes. These are not to be used as they may cause death of organisms and alteration of flora [9].
Discharge from gingival abscess shows various types of pyogenic bacteria (Staphylococcus, Streptococcus pyogenes and pneumococcus species). Discharge from fistulae and gingival pockets may in addition show a large number of leukocytes. Appleton gives the following method of obtaining a specimen from the gingival pockets:
Isolate the area with sterile cotton rolls.
Stroke the gingival wall of the pocket to milk out the grosser quantity of microorganisms. With a sterile cotton pledget, wipe away the exudates.
Paint the gingival margin with tincture of iodine 1 part, acetone 1.5 parts and glycerin 0.5 part.
With a sterile flat platinum needle, collect material from the very depth of the pocket or draw a bit of the material into the capillary pipet.
Examine the specimen on a slide or else inoculate a number of deep test tubes of semi-liquid medium as ascitic fluid or ordinary nutrient agar plus a piece of fresh, sterile rabbit kidney tissue. This is satisfactory for the cultivation of many anaerobes [10, 11].
The technique for culture from pulp canals is:
Drying the canal with two or three sterile absorbent points.
Inserting a fresh sterile absorbent point and leaving it until the tip is moistened with the exudate (usually 1 min).
Removing the point with cotton pliers and, with one hand, opening the test tube of the medium held in the other hand.
Flaming the test tube lip, dropping the point into the tube, and plugging or covering. Make certain that the point is in the medium.
Incubating for 48 h.
If the medium is clear after the incubation, it is assumed that there is no growth of organism although a smear may be taken as a check. If the medium is cloudy or a precipitate is seen, assume that infection is still present. In questionable cases a second culture is taken [10, 11].
These are used if bacteremia or septicemia is suspected. Streptococci, Staphylococci or Pneumococci may be found. In patients with multiple osteomyelitis, with extreme lesions in mandible, blood cultures showed that streptococcal septicemia was the cause. In chronic cases at least 15–30 cc. of blood should be taken for the test; in acute cases, 5 cc. is sufficient.
In actinomycosis the discharge pressed out from the fistula contains the so-called sulfur granules. When soft, these granules can be pressed between two slides and examined without staining. The granules appear as rosette-like masses with dense centers and a network of mycelium. Bulbous clubs or rays extend from the periphery.
Where thrush is suspected, moist preparations may be used, placing scrapings from the suspected lesion directly on a microscopic slide. A 10% solution of potassium hydroxide is added, and the slide is heated slightly and inspected under the microscope. The slide is examined for the branching mycelia and for spores of Candida albicans [11].
Cysts contain a fluid or semi-fluid material, which for diagnostic purposes is aspirated by the means of glass syringe and hypodermic needle. The anesthetized place where the needle is to be inserted or the bone perforated with a sterilizing agent is prepared; the area with sterile gauze should be isolated. The cystic content is then aspirated and examined on a slide or cultured [10].
With the increasing specimen loads and collection centers now at the remotest parts of the country, transportation of the pathology specimen plays a crucial role in timely diagnosis. Thus specimen transport needs special care and attention to detail and appropriately filled laboratory requisition form guidelines that are usually issued by the national authorities, e.g., Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM) or Indian Council for Medical Research (ICMR) and the World Health Organization (WHO), are to be strictly followed.
For any hand-carried specimen that is transported over a short distance, the specimen needs to be placed upright in appropriate bottles with sufficient fixatives in appropriate racks. For long-distance cross country or different countries, the triple packing system has been advocated specially for infectious substances [12].
The triple packing system contains three layers as (1) primary container/receptacle that has the specimen and is leak proof with a screw cap and (2) secondary container that is durable, waterproof and made of metal/plastic with a screw cap. It contains absorptive material, and details of the specimen are pasted on the outside of the container. (3) The outer packing or tertiary container is made of wood or card-box and withstands the transportation shocks. Dry ice is normally kept between the outer two containers with provision for carbon dioxide gas release vents. A biohazard label is a must [12].
A laboratory should always consider strict rules on the basis of which an oral specimen could be rejected. This important decision must be taken with full conviction of doing the right thing to save time and laboratory resources. Such decision should be taken when the following criteria are not fulfilled:
Inappropriate test requests (incomplete, duplicate, missing or inconsistent information)
Errors in transport and handling (light exposure, delayed transport time or broken sample bottles)
Misidentification of specimen (unlabeled or mismatched)
Improper or wrong container
Insufficient specimen quantity for the quantity of preservative or insufficient quantity for the test requested transport media
Contamination of specimen
Incorrect storage
Hemolyzed sample [13]
Thus a continuous effort must be made in order to ensure proper collection and transportation of clinical specimens by all involved. A sound understanding of contemporary principles and practices of various methods of collection and transport of specimens is of critical importance to the clinician dealing with oral and maxillofacial infections.
The author K.S.S would like to thank her teachers Dr. Jyoti Chawda and Dr. Raksha Shah.
The authors declare no conflict of interest.
Authors are listed below with their open access chapters linked via author name:
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