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and multimodal treatment, prognosis of OMM remainsvery poor.3 Also, because of the rarity of this tumor,there is lack of definite proof regarding etiology, patho-

DerialRe201221doi

Vol. 116 No. 4 October 2013st be established in all cases.Melanomas are malignant neoplasms arising fromlanocytes, originating from the neural crest cells.

elanocytes are primarily present in the basal portionthe epidermis at the dermo-epidermal junction. Pri-ry malignant melanoma has been described in vir-lly all sites and organ systems where neural crest

lls migrate. One of the unusual sites is the upperrodigestive tract.

genesis, treatment protocol, and prognostic factors forOMM. This paper reports 2 cases of OMM treated atA. B. Shetty Memorial Institute of Dental Sciences,Mangalore, and a review of literature in an endeavor toestablish current understanding on various aspects ofOMM.

CASE REPORTSCase 1

A 60-year-old woman reported to our department withcomplaint of swelling in the palate for 3 months. It wasinsidious in onset and growing in size. It was not associatedwith any pain, ulceration, or bleeding. The patient had ahistory of breast carcinoma 8 years prior, for which she hadundergone surgery followed by radiotherapy, detailed recordswhich were not available. There was no recurrence noted atthe time of thorough physical examination. On examination,

partment of Oral and Maxillofacial Surgery, A. B. Shetty Memo-Institute of Dental Sciences, Mangalore, India.

ceived for publication Apr 3, 2011; returned for revision Oct 30,1; accepted for publication Nov 9, 2011.

2013 Elsevier Inc. All rights reserved.2-4403/$ - see front matter:10.1016/j.oooo.2011.11.034ral malignant melanoma: systemport of two cases

uralee Mohan, MDS, DNB, Vihang Y. Sukhadia, MDSangalore, IndiaB. SHETTY MEMORIAL INSTITUTE OF DENTAL

jective. Oral malignant melanoma (OMM) is a rare tumor of tplementation of an aggressive treatment. This paper aims to shdy Design. We report 2 cases of OMM treated at our institurrent understanding on various aspects of OMM.sults. Both patients in our study are showing good local conneeded to rule out distant metastasis.nclusions. Because late diagnosis and advanced disease at trough clinical and pathologic workup of any suspected megnosis and aggressive multimodal treatment are the only meth OMM. (Oral Surg Oral Med Oral Pathol Oral Radiol 201

mented lesions in the oral cavity may be classifiedmelanotic or nonmelanotic lesions. Melanotic le-ns are more common than nonmelanotic ones. Me-ocytes may be found in the oral mucosa but may notnoticeable because of their low level of pigmentduction. However, when they are active in pigmentduction or proliferation, they may be responsible foreral oral pigmentations ranging from focal to diffuse

d physiologic to malignant neoplasm.Diffuse pigmentations are mostly systemic-related,g-induced, or caused by exogenous pigments,ereas most focal pigmentations are brought about byerproduction of melanin. Although most pigmentedions are benign, it is necessary to distinguish thegin of pigmentation for melanocytic lesions whichc review of literature and

pak Pai, MDS, and Smitha Bhat, MDS,

NCES

l cavity with very poor prognosis despite thee light on current evidence for management of OMM.a review of the literature in an endeavor to establish

th aggressive multimodal treatment. Long-term follow-up

e of diagnosis are the only sure predictors of outcome,lesion should be carried out to diagnose OMM. Earlyailable to surgeons to provide better outcome to patientse247-e254)

Primary mucosal melanoma of the head and neck israre entity, occurring much less frequently than itstaneous relatives. It constitutes 1% of all melano-s and 10% of head and neck melanomas.1 Itsidence is thought to be stable, contrary to its cuta-

ous counterpart, which has been rapidly increasing.2me authors think that oral malignant melanoma hasial growth phase and appears to be similar to acraltiginous melanoma of the skin, whereas others thinkt oral malignant melanoma is a separate entity fromcutaneous counterpart and should be classified sep-tely.3Surgery remains the main treatment modality, withded radiotherapy and/or chemotherapy to preventurrence and metastasis. Despite aggressive resectione247

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ORAL AND MAXILLOFACIAL SURGERY OOOOe248 Mohan et al. October 2013ingle 3 3 cm smooth-surfaced swelling was noted in theddle of the palate with slightly darker pigmentation aroundBlackish discoloration of anterior alveolar mucosa was alsosent. Lesion was nontender and firm to hard in consis-cy. Incisional biopsy was performed and was reported aslignant melanoma with fibrous hyperplasia. A thoroughysical examination was undertaken to detect any skin le-n and in the absence of that, the oral lesion was labeled asmary malignant melanoma. Systemic examination was car-d out with chest x-ray, ultrasonography of the abdomen,

computerized tomography (CT) scan of the cervical arearule out any metastatic lesion. After a thorough work-up,patient was scheduled for surgery and low-level maxil-

tomy was performed with 2 cm gross soft tissue margin allund the lesion. The defect was closed with split-thicknessn graft, and a temporary obturator was placed intraopera-ely (Figure 1).The histopathology report showed atypical cells whichembled melanocytes infiltrating into connective tissue andgrating upward into superficial layers of epithelium. Thepical melanocytes were epitheloid in the superficial region

spindle shaped in the deeper regions of connective tissuegure 2). The tumor cells showed hyperchromatism, pleo-rphism, multinucleation, increased nuclear-cytoplasmicio, and atypical mitoses. Resected margins were free from

or cells.Two months later, the patient reported with neck swellingthe right side. The primary lesion had healed well andwed no evidence of recurrence, with 100% take-up of skinft. Fine-needle aspiration cytology of the neck swellingealed it to be metastatic lymphadenopathy. CT scan was

ne which revealed bilateral submandibular lymph nodeargement. Modified radical neck dissection was performedboth sides and the patient recovered well with no postop-tive sequelae. Histopathologic examination revealed onlye positive lymph node in the right side specimen at level II

ph node. Patient was given adjuvant radiotherapy after thegery. At the time of writing this paper the patient wasease-free with no locoregional recurrence or metastasis forost 20 months. The patient is under regular follow-up atonth intervals.

. 1. Case 1. A, Typical clinical presentation of oral malignargins. C, Postresection view showing split thickness graft stse 2A 40-year-old female patient reported to our departmentth chief complaint of blackish discoloration/patch in max-ry anterior gingivae for 4 months which was rapidly grow-in size. The patient consulted a local hospital, where she

s advised to undergo incisional biopsy for diagnostic pur-se. But she declined and visited our department for per-al reasons. On examination, an elevated black to brownch of approximately 5 3 cm was noted involving max-ry attached gingivae extending from right central incisor tot second premolar area. Superoinferiorly it was involving

whole of gingivae extending up to the mucogingivalction (Figure 3). The lesion was firm in consistency andder on palpation. It was also extending onto the palateere a black to brown discoloration of approximately 4 3was present in the anterior half of the palate on the left

e which was crossing midline in incisive papillae regiongure 3). Small brown spots were also noted on the righte of palate. The lesion was asymmetric with irregularrders along with color variegation present, and it wasarging in size. These are characteristic features of malig-t melanoma along with the fact that lesion was also

vated. Therefore, keeping OMM as provisional diagnosis,rough physical examination, oropharyngeal examination,

chest radiography were done to rule out any metastatic

. 2. Histopathologic section of case 1.

noma. B, Resected specimen showing adequate clearanced with surgical splint.thejuntenwhcm

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OOOO CASE REPORTVolume 116, Number 4 Mohan et al. e249ion. No clinically palpable lymphnodes were detected onk examination. CT scan showed no gross bony invasion,cervical lymph node involvement was ruled out.

Excision of the lesion was performed under general anes-sia with Le Fort I level maxillectomy and adequate soft

sue margin of 1.5 cm all around the lesion (Figure 4).lateral buccal pad of fat was mobilized to cover the max-ry sinus and the entire area of defect was covered withniotic membrane (Figure 4). The postoperative period waseventful, and the patient was discharged on postoperative

8 with a temporary obturator.Histopathologic examination revealed stratified squamousakeratinized epithelium with long and narrow rete ridges.oid and spindle-shaped tumor cells were seen at junction asll as infiltrating into underlying connective tissue (Figure 5).reased junctional activity was noted along with pleomor-

ism of tumor cells. Numerous large melanophages were seenthe vicinity, along with dense chronic inflammatory cellsinly in the form of plasma cells and lymphocytes. Margins ofspecimen were free from the tumor cells.

At 1 month follow-up, the surgical site had healed well andlocal or regional recurrence was noted, and the patient waserred for adjuvant chemoradiotherapy. At the time of thisiting, the patient had been closely followed for 1 year withointments every 3 months for local examination and chestiography to rule out metastasis.

SCUSSIONmented lesions of melanocytic origin is a rare oc-

rrence in the oral cavity, and they can span a spec-

. 3. Case 2. A, Clinical presentation. B, Palatal view.

. 4. Case 2. A, B, Resected specimen. C, Postresection viewm ranging from innocuous lesions, such as orallanotic macule, and various benign nevi to life-eatening malignant melanoma of oral mucosa.erefore, meticulous clinical and pathologic examina-n must be made of any suspicious lesion to avert thegress of a malignant melanoma.

OMM is an extremely rare and very aggressive tu-r of melanocytic origin. Apart from oral mucosalignant melanoma can affect mucous membranes ofse and paranasal sinuses, pharynx, and conjunctiva.

a group, mucosal melanomas invade and spread

ing amniotic membrane dressing.

. 5. Histopathologic section of case 2.trume

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ORAL AND MAXILLOFACIAL SURGERY OOOOe250 Mohan et al. October 2013re quickly and metastatize more frequently, and arerefore associated with much poorer prognosis than

taneous melanomas.After conjunctiva, oral cavity and sinonasal tract aresecond most common affected sites in the head and

ck region.4 In the oronasal region approximatelye-half of melanomas occur in the oral cavity (48%)d the remaining portions are located in the nasalvity (44%) and sinuses (8%).2,3 OMM accounts forly 0.5% of all oral malignancies,5 and oral melanomaresents 0.2%-8.0% of all melanomas.5 OMM usu-

y occurs in the fourth to sixth decades of life and istremely rare before 30 years of age.6 Some studiesve shown a male predilection of 2:1, whereas otherdies show no sex predilection.3,7 OMM is known tocur more frequently in Japanese, African, and North

erican Indian populations than in European popula-ns.8-13 Most commonly involved intraoral site islate and maxillary alveolar gingiva.7,9,13,14 and they

labeled as high-risk sites for OMM.5 Other sites lessquently affected include the labial and buccal mu-sa, tongue, and floor of mouth.5Etiology of OMM is essentially unknown. Unliketaneous melanoma, no definite risk factors for OMMve been defined, and tobacco use as well as chronicitation from ill-fitting dentures has been mentioned asssible risk factors.12 Also, a possible role of ingestedd inhaled environmental carcinogens at higher inter-l body temperature has been suggested.15 Most

Ms are thought to arise de novo from apparentlyrmal mucosa. But it has been shown that one-third oftients have a history of preexisting oral pigmentation

several months or even years before diagnosis oflignant melanoma.12 Some of these flat precursorions actually consist of atypical melanocytes andresent radial growth phase of malignant melanoma,ereas others represent benign proliferation of mela-cytes. Exact mechanism for transformation of benignlanocytic nevus to melanoma is not known, but

pressions of some melanoma-associated antigensve been implicated.3 p53 protein alterations haveen identified in two-thirds of OMMs, and a recentdy demonstrates loss of heterozygosity at 12p13 ands of p27KIP1 protein expression contributing to mel-oma progression.3The most common presenting symptom is a pig-nted swelling. Hemorrhage and ulceration are usu-y late findings when the lesion has entered verticalwth phase.3,5 OMM can be uniformly brown orck, or variable pigmentation may be present whichges as black, brown, gray, purple, red, and/or white.e lesions are asymmetric, irregular in outline, andcasionally multiple, which represents satellite le-ns.5 Umeda et al. noted that on close examinationical OMM usually presents with 3 distinct compo-nts: a nodular component usually affecting the cen-; a flat or slightly elevated, deep brownish-blackmented plaque component; and a nonelevated lightwn macular component.16 Approximately 10% of

ses are known to be amelanotic in nature, lackingcular component, thus posing a difficulty in diagno-.17 Induration is usually absent in cases with pro-ged radial growth phase or with minimal invasion.

her presenting signs and symptoms include bleeding,fitting dentures, pain, increased mobility of teeth,d delayed healing of extraction sockets.5Tanaka et al.18 identified 5 types of OMM based onnical appearance: pigmented nodular type, nonpig-nted nodular type, pigmented macular type, pig-nted mixed type, and nonpigmented mixed type.Mucosal melanoma can be primary or metastatic. Ittherefore very important to rule out any other primarylignant melanoma elsewhere in the body. Green etgave criteria for diagnosis of primary OMM as

lows19:

Demonstration of clinical and microscopic tumor inthe oral mucosa.Presence of junctional activity in the oral mucosa.Inability to show any other primary site.

th of our patients fulfilled all of these criteria.Diagnosis of OMM can be made based on clinicalsentation of the pigmented lesion with the so-calledCD checklist (asymmetry, border irregularities,

lor variegation, and diameter 6 mm) that is com-nly used for cutaneous melanomas. Deferential di-

nosis includes melanoma, melanotic macule, oralmented nevus, smokers melanosis, amalgam tattoo,

d Kaposis sarcoma.5It has often been suggested that cutting into an

M, either for incisional biopsy or other invasivecedures, may lead to seeding of tumor cell into

jacent tissue or even into bloodstream or lymphatics,ding to dissemination of tumor cells and increasede of metastasis. Umeda et al.16 in his study con-ded that 5-year survival rate of patients who under-nt some surgical procedures, such as incision, bi-sy, or tooth extraction, before definitive surgery wasor (25.9%) compared with those who did not un-rgo such procedures (91.7%). Similar results wereown by Rampen et al. and Austin et al.20 However,ny authors believe that biopsy of an undiagnosedion, pigmented or nonpigmented, occurring in highk sites for OMM should be done, because benefitsined by a definite diagnosis of OMM far more out-igh the risk of distant metastasis which is not yetly established.21-23 According to Batsakis,24 there isevidence that a preliminary biopsy of the primary

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OOOO CASE REPORTVolume 116, Number 4 Mohan et al. e251ion increases the risk of metastatic dissemination orfavourably affects prognosis. Excisional biopsy ofall lesion should be performed and incisional biopsym the thickest and darkest area is recommended forger lesions.25Apart from biopsy, radiologic examination through, magnetic resonance imaging, or positron-emissionography could be useful for evaluation of primaryor invasion and regional or distant metastases. Rob-Marx et al. recommends a chest radiograph as the

mary diagnostic tool for metastatic workup and onery 6-month follow-up after surgery to assess fortant metastasis, because lungs and liver are the mostmmonly affected organs with OMM metastases.26 Inth of our patients, CT scan was done to assess themary lesion and its invasion of bone along withessment of neck for regional spread. Case 1 showedny invasion of palate, and both patient had no re-nal involvement of neck nodes.

No definite classification for OMM exists, in contrastcutaneous melanoma which is divided into clinicallyd pathologically well defined varieties. In the past its thought that OMM represented a mucosal counter-rt of acral lentiginous melanoma, based on similartopathologic findings, but it was observed that OMMs a very different biologic growth pattern and veryor prognosis. Therefore, it was thought that cleartinction should be made between cutaneous melano-s and OMM. During the Workshop on OMM, con-

ned at the Western Society of Teachers of Oralthology annual meeting in 1995, the authors agreedthe fact that oral lesions should be considered sep-tely from cutaneous melanomas until definitive in-mation on cause and natural history of OMM isthcoming. In situ OMM, invasive OMM, invasivelanoma with in situ component, and atypical melano-

tic proliferation are the preferred descriptive terms.5TNM staging for cutaneous melanoma does not pro-e specific guidelines for OMM. A simple clinicalging system for head and neck mucosal melanomascommonly used and has been shown to be of prog-stic value. Prasad et al.27 has proposed histopatho-ic microstaging for stage I tumor (Table I).

Microscopically, two patterns have emerged for thecosal melanomas: an in situ pattern in which the

oplasm is limited to the epithelial-connective tissueerface; and an invasive pattern in which the neo-sm was found within the supporting connective tis-

e. Also, a combined pattern of invasive melanomath in situ component is typical of most advancedions. Varied types of neoplastic cells, including spin-d, plsmacytoid, and epitheloid, are seen in invasivelanoma. They are usually arranged in either sheet-e, organoid/alveolar, neurotropic, or desmoplasticttern. Approximately 10% of cases are amelanotic,which diagnosis requires immunohistochemical

ining. Various markers commonly used are S-100tein, HMB45, and Melan-A.3

Measurement of tumor thickness should also be in-ded in the report, because it is shown to be a strongdictor of prognosis.28 Breslow measurement for tu-r thickness is usually used, in which tumor thickness

determined with the use of a micrometer in the oculara microscope (Table II).26Usually, OMM tends to present at a more advancedge compared with cutaneous melanomas, with 70%stage I and 83% of stage II tumors presenting with ackness 4 mm, leading to poor prognosis.29Most authors think that the mainstay of treatment for

M is surgery with wide clear margins; however, mostthe time proximity of vital structures makes this objec-e difficult. Also, most OMM presents at a more ad-nced stage, when the tumor has entered vertical growthase with deep invasion of surrounding tissue and bone,uiring extensive resection to achieve clear margins. Formost common site, the palate, surgery usually consist

a type of maxillectomy with 3-5-cm margins and some-es it is necessary to extend the excision to the soft

late and tonsillar pillar, and into the pterygomaxillaryce. No particular guidelines for the surgical treatmentOMM exist, and treatment of most patients is left to thecretion of the individual surgeon. Umeda and Shi-da29 suggested a protocol for management of OMMich refers to the extent of margins:

Excision of the primary lesion, preferably using anintraoral approach and involving at least 1.5 cm ofhealthy tissue.

ble I. Clinical staging system for oral malignant mel-oma with histopathologic microstaging for stage Ige I Primary tumor present only (Tany N0 M0)

Level I: pure in situ melanoma without evidence ofinvasion or in situ melanoma withmicroinvasion

Level II: invasion up to the lamina propriaLevel III: deep skeletal tissue invasion into skeletal

muscle, bone, or cartilagege II Tumor metastatic to regional lymphnodes (Tany

N1 M0)ge III Tumor metastatic to distant sites (Tany Nany M1)

ble II. Breslow scale for the measurement of tumorckness of oral malignant melanomaickness (mm) Risk of recurrence0.76 Low risk0.76-1.50 Low to intermediate risk1.50-3.99 Intermediate to high risk4.00 High risk

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ORAL AND MAXILLOFACIAL SURGERY OOOOe252 Mohan et al. October 2013Excision of any lymph node metastasis (stage II).Consider chemotherapy.

naka et al.30 reported that primary lesion was con-lled in 92.3% of cases with surgery, whereas in ansurgery group treated with radiotherapy, only 53%ses had controlled primary lesion. This clearly cor-ates with the traditional opinion of surgery being theatment of choice, with radiotherapy and chemother-y having only adjunctive roles. During the 1995orkshop on OMM, it was concluded that there isrrently no compelling new information that wouldggest that another approach would be better. More-er, they also advised that serious considerationould be given to combination therapy in primarytient care, because of the high recurrence rate asso-ted with OMM.5Another area of controversy in OMM is regarding

issue of prophylactic neck dissection. Various au-rs have reported lymph node metastasis in primaryM at approximately 25%-50%.3,30,31 According to

ah et al., regional metastases at the time of presen-ion do not affect the survival of patients with OMM,ereas other authors think that it carries a negativegnostic value.29,32 According to most authors, necksection should be reserved for cases with preopera-ely confirmed lymph node metastasis, and the choicethe neck dissection modality should be guided by thetent and the level of nodes. There is no proof thatphylactic neck dissection improves survival.30,33

Both of our patients were treated with surgical re-tion of palate with 1.5-cm macroscopic margin allund the lesion which is as per the guidelines givenUmeda and Shimada et al.29 The patient of case 1

veloped neck node involvement after 2 months,ugh local recurrence was not present. According toow et al., lymph node metastases rarely developthout local recurrence after initial treatment of pri-ry lesion. But this was not the case in our patient;

en Tanaka et al reported good loco-regional controlth surgery alone or surgery combined with otheratments.30 Bilateral neck dissection was performedthis patient.Very few studies are done on the effect of primaryiotherapy for OMM, and it does not show any ap-

rent advantage over surgery based on survival rated local control.30 Postoperative radiotherapy is rec-mended in cases with positive surgical margins or a

ong likelihood of local or regional recurrence.4 Var-s studies have shown that postoperative radiother-

y was useful for increasing local control,34-36 but ites not seem to improve survival rate.3 It has beenggested that local failure is a harbinger of distanttastases in mucosal melanoma, because the majoritypatients who die of distant metastases have also localregional recurrent disease. Therefore, efforts to im-ve loco-regional control by adding postoperativeiotherapy might also result in higher survival rates.other role of radiotherapy is in advanced disease,ere it is used as a primary treatment modality for

lliation. Radiotherapy is the most effective treatmentdality for unresectable disease.37

Role of adjuvant chemotherapy in management ofM does not seem to influence survival.3 Umeda and

imeda et al.29 reported that adjuvant chemotherapyth dimethyl triazeno imidazole carboximide, nimus-e hydrochloride, vincristine, and biologic responsedifier OK-432 was effective for OMM and showsproved survival rate. Another recent retrospectivedy showed that adjuvant chemotherapy decreasedrelapse rates of both local and distant metastasis

ease.38 But further studies are necessary to assess thefinitive role of adjuvant chemotherapy in OMM.Most of patients die owing to distant metastases togs, brain, liver, and bones despite good locoregional

ntrol. Because many patients dies of disseminatedease, it makes sense to add a systemic therapy whenating advanced OMM. Systemic immunotherapyth interleukin-2 and other cytokines has not shownry encouraging results, and further research is re-ired to develop some sort of definitive targeted sys-ic therapy.3

There is no disagreement regarding prognosis ofM, and a majority of reported case series attest to

t. OMM carries a quite poor prognosis comparedth its cutaneous counterpart. The average survivale after diagnosis has varied from 13% to 20% inrious case series, and mean survival for OMM is 28nths.39 Various prognostic factors have been putward for OMM, but to date only clinical staging atsentation has been affirmed by all as the most im-

rtant factor determining outcome. Other independentk factors are thickness of the tumor (5 mm), cer-al lymph node metastases, anatomic site (palate be-poorer than gingiva), and presence or absence of

eration.3 The reasons for poor prognosis are notown with certainty, but various probable reasons aret forward, the most important of them being lategnosis of OMM due to nonspecific symptoms. Oth-include anatomic location, because mucosal tumors

n easily invade the deeper structures, such as bone.so, there is high vascularity of oral mucous mem-ne, which along with earlier bone invasion can con-

bute to the high incidence of distant metastases.31so because of anatomic location, sometimes it isficult to achieve clear margins during resection. Pos-e surgical margins are seen in 43% of OMM4 and

ve been shown to be associated with poor outcome.

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OOOO CASE REPORTVolume 116, Number 4 Mohan et al. e253NCLUSIONalignant melanoma is a rare tumor of the oral cavity,th very poor prognosis. Local, regional, and distanttastases occur in OMM despite the implementationaggressive multimodal treatment. Because late diag-sis with advanced disease at the time of diagnosis is

only sure predictor of outcome, thorough clinicald pathologic work-up of any suspected melanoticion should be carried out to diagnose OMM in itsrly stages. Early diagnosis and aggressive multi-dal treatment are the only means available to sur-

ons to provide better outcome to a patient withM. There is also need for pooling of data from

rious centers to analyze key determinants of outcomed thereby establish a treatment policy.

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Vihang Y. Sukhadia, MDSSurgical FellowDr. Jeysekharan Centre for Cleft CareK P RoadNagercoil629 003TamilnaduIndiavihangsukhadia@gmail.com

ORAL AND MAXILLOFACIAL SURGERY OOOOe254 Mohan et al. October 2013

Oral malignant melanoma: systematic review of literature and report of two casesCase ReportsCase 1Case 2

DiscussionConclusionReferences