1. SALIVARY GLAND NEOPLASMS

2. STRUCTURAL ELEMENTS OF THE SALIVARY GLAND UNIT

3. ETIOLOGY  Not fully understood.  Two theories predominate: (A) Bicellular stem cell theory (B) Multicellular theory  Bicellular stem cell theory : Tumors arise from 1 of 2 undifferentiated stem cell  (A) Excretory duct reserve cell-squamous cell and mucoepidermoid carcinomas,  (B) Intercalated duct reserve cell- pleomorphic adenomas, oncocytomas, adenoid cystic carcinomas, adenocarcinomas, and acinic cell carcinomas. -

4. CONTD  Multicellular theory:Each tumor type arises from a specific differentiated cell within the salivary gland unit.  Squamous cell carcinomas - excretory duct cells,  pleomorphic adenomas -intercalated duct cells  oncocytomas -striated duct cells,  acinic cell carcinomas -acinar cells.

5. RISK FACTORS  Radiation –Mucoepidermoid carcinoma(mc among malignant),Warthins (mc among benign)  Viral –EBV-lymphoepithelial carcinoma  Tobacco smoking- Warthin tumors  Increased incidence of second primary tumor in patient with thyroid cancer treated with radioiodine.  Controversy:mobile phones- electromagnetic waves-H/N neoplasm

6. CONTD.  Occupational exposure – Silica dust - 2.5-fold increased risk of cancer Rubber workers( nitrosamines)  Iatrogenic-Radiation therapy to the head and neck  Latency period - 11 years for malignant tumors and 21.5 years for benign  Possible protective effect - Diet high in polyunsaturated fatty acids

7. GENETIC ALTERATION AND SALIVARY GLAND NEOPLASM  Tumor suppressor genes- p53 family  Increased expression- p63 and p73( Benign salivary neoplasms, pleomorphic adenomas, myoepitheliomas, and basal cell adenomas).  Overexpression of MDM2(Murine double minute 2 ) along with high-mobility group protein gene (HMGIC) - carcinoma ex pleomorphic adenoma.

8. CONTD.  PLAG1, translocations,band 8q12-pleomorphic adenomas.  Allelic loss of 19q -adenoid cystic carcinoma  Mucoepidermoid carcinomas -loss of chromosomal arms 2q, 5p, 12p, and 16q.  Increased expression of erb-2 is associated with salivary gland neoplasm.

9. CONTD.  Matrix metalloproteinase-1, tenascin-C, and beta-6 integrin help in tissue invasion by malignant tumors.  In adenoid cystic carcinoma, increased immunoreactivity for nerve growth factor and tyrosine kinase A -correlated with perineural invasion.

10. INCIDENCE  Relatively uncommon 2% of head and neck neoplasms  Distribution Parotid: 80% overall; 80% benign Submandibular: 15% overall; 50% benign Sublingual/Minor: 5% overall; 40% benign

11. MINOR SALIVARY GLAND DISTRIBUTION

12. PATIENT EVALUATION  Clinical Features  Both benign or malignant tumors of the parotid gland -painless swelling.  Benign tumors have a slow growth rate.  A rapid increase in size -suspicion of malignant transformation  Mass in the parotid->Metastasis-from skin cancer (melanoma)- >So examination of facial skin and scalp is mandatory.

13. EXAMINATION  Benign tumors of the parotid gland -usually well-defined, nontender, and freely mobile.  Locates in the "tail" of the parotid gland-superficial or deep lobe.  Dumbbell tumor :Extend from the superficial to the deep lobe through stylomandibular tunnel.  Deep lobe and dumbbell tumor -> parapharyngeal space extension-> medial displacement of oropharyngeal wall

14. DUMBBELL TUMOR

16. DEEP LOBE TUMORS OF PAROTID

17. SUBMANDIBULAR GLAND TUMOR LOCATION  Benign tumors of the submandibular gland painless, mobile mass in the submandibular triangle.

18. SUSPICION OF MALIGNANCY  Facial nerve paresis  Ipsilateral weakness or numbness of the tongue indicates involvement the hypoglossal or lingual nerves(malignant tumor of SMG)  pain  Fixation of the mass to the overlying skin or underlying structures (to the mandible in malignant tumor of SMG)  Cervical adenopathy

19. SUSPICION OF MALIGNANCY

20. FINE-NEEDLE ASPIRATION BIOPSY BENIGN TUMORS:  sensitivity -85.5% to 99%  specificity -96.3% to 100%.  Ultrasound-guided FNAB enhance the overall diagnostic accuracy. MALIGNANT LESION:  Accuracy is less in comparision to benign lesion.  Sensitivity-60% to 73%

21. FNAB MIMICRY  Basal cell adenomas- Adenoid cystic carcinoma particularly the solid (anaplastic) type.  Mucoepidermoid carcinoma-Benign salivary gland duct obstruction.  Large cell epithelial lesions of low nuclear grade: oncocytic proliferations and acinic cell carcinoma.

22. IMAGING  CT-SCAN  MRI-SCAN  USG  MRI is better than CT(Dental artifacts obscure vital details of gland in CT-scan)  Pleomorphic adenoma-calcification (CT-SCAN)  Tumor composition better defined in T2 than T1.

23. IMAGING  CT better than MRI in defining cortical bony involvement  Disadvantage of CT-ionizing radiation and requiring contrast for vascular detail.  Disadvantage of MRI: Bony-soft tissue interface is often not clearly distinguishable

24.  Deep lobe tumors  Dumb-bell tumors  Parotid tumors with facial weakness  Indication of malignancy  Congenital parotid masses  SMG tumors with mandibular fixation  Tumors of the palate with suspected involvement of nose or maxillary antra  Any tumors with clinically ill defined margins. INDICATIONS OF CT/MR IMAGING MAJOR GLANDS MINOR GLANDS

25. MR SCAN SHOWING PLEOMORPHIC ADENOMA OF DEEP LOBE OF PAROTID

26. PLEOMORPHIC ADENOMA  Most common of all salivary gland neoplasms 70% of parotid tumors 50% of submandibular tumors 45% of minor salivary gland tumors 6% of sublingual tumors  4 th -6 th decades  F:M = 1.4:1(overall) 1.7:1(SMG)

27. PLEOMORPHIC ADENOMA  Slow-growing, painless mass  Parotid: 80% in superficial lobe, most in tail of gland  Minor salivary gland: most common site- palate. second most common site -upper lip. Other sites – buccal space base of tongue retropharyngeal space pterygopalatine fossa lateral nasal wall nasal septum maxillary bone facial skin trachea lung breast

28. PLEOMORPHIC ADENOMA  Despite the abundance of minor salivary glands in the lower lip, pleomorphic adenoma is very rare.  Pleomorphic adenoma is the most common benign tumor of the lacrimal gland.

29.  Gross pathology Smooth Well-demarcated Solid Cystic changes Myxoid stroma Capsule:present (major salivary glands) absent (minor salivary glands ) PLEOMORPHIC ADENOMA  Histology Mixture of epithelial, myopeithelial and stromal components Epithelial cells: nests, sheets, ducts, trabeculae Stroma: myxoid, chrondroid, fibroid, osteoid Tumor pseudopods

30. PLEOMORPHIC ADENOMA GROSS PATHOLOGY

31. PLEOMORPHIC ADENOMA  Treatment: complete surgical excision Parotidectomy with facial nerve preservation Submandibular gland excision Wide local excision of minor salivary gland  Avoid enucleation and tumor spill

32. RECURRENT PLEOMORPHIC ADENOMA  One fourth of pleomorphic adenomas demonstrate pseudopodia from thin capsules.  A cuff of normal tissue should be excised for complete removal of these pseudopods.  Failure to remove these pseudopods –a high chance of recurrence.  Multicentric pattern is characteristic of recurrent pleomorphic adenoma.

33. MR SCAN OF RECURRENT PLEOMORPHIC ADENOMA

34. RECURRENT PLEOMORPHIC ADENOMA  Progesterone receptors are present.  Potential target for hormone treatment.  Increased risk for facial nerve injury with revision surgery.  Neutron radiotherapy

35. BASAL CELL ADENOMA  96% in the parotid gland and 4% in the other salivary glands  painless and slow growing.  7 th decade  M:F =1:1  Upper lip mc site of the minor salivary gland basal cell adenomas

36. BASAL CELL ADENOMA  Four histologic growth patterns : solid, trabecular, tubular, and membranous.  Basal cell adenoma may be difficult to distinguish from the solid variety of adenoid cystic carcinoma.  Treatment is surgical excision with a cuff of normal surrounding tissue

37. CANALICULAR ADENOMA 7 th decade F:M – 1.8:1 Most common in minor salivary glands of the upper lip (74%) Painless submucosal mass

38. CANALICULAR ADENOMA  Histology Tubular structures lined by columnar or cuboidal cells Vascular stroma TREATMENT:  Enucleation or surgical excision can be done.  Recurrence is rare

39. WARTHIN’S TUMOR  AKA: papillary cystadenoma lymphomatosum  6-10% of parotid neoplasm  M:F=1.5:1  10% bilateral or multicentric  3% with associated neoplasms(mc with Pleomorphic Adenoma)  Development:neoplastic proliferation of ectopic salivary gland ducts within intraparotid and periparotid lymph nodes during encapsulation of the parotid gland.  T- and B-cell markers positivity support this pathogenetic origin.

40. WARTHIN’S TUMOR  Gross pathology Encapsulated Smooth/lobulated surface Cystic spaces of variable size, with viscous fluid Solid areas with white nodules representing lymphoid follicles

41. WARTHIN’S TUMOR

42.  Histology Papillary projections into cystic spaces surrounded by lymphoid stroma (Papillary cystadenoma lymphomatosum) Eithelium : double cell layer Luminal cells Basal cells Stroma: mature lymphoid follicles with germinal centers

43. WARTHIN’S TUMOR

44.  Basal cuboidal cells contain small dark nuclei and abundant granular pink cytoplasm (oncocyts).  The granular eosinophilia of oncocytes is due to abundant mitochondria present in the cytoplasm.  Oncocytes selectively incorporate technetium (Tc)-99m pertechnetate and appear as hot spots on radionucleotide scintigraphy

45. (TC)-99M PERTECHNETATE

46. WARTHIN’S TUMOR  Treatment :surgical excision, parotidectomy with facial nerve preservation.

47. ONCOCYTOMA  Rare: 2.3% of benign salivary tumors  6 th decade  M:F = 1:1  Parotid: 78%  Submandibular gland: 9%  Minor salivary glands: palate, buccal mucosa, tongue

48. ONCOCYTOMA  Presentation Enlarging, painless mass  Technetium-99m pertechnetate scintigraphy Mitochondrial hyperplasia  Gross Encapsulated Homogeneous, smooth Orange/rust color

49. ONCOCYTOMA  Electronmicroscopy Mitochondrial hyperplasia 60% of cell volume

50. ONCOCYTOMA  A true oncocytoma contains no lymphoid tissue.  Although histologically benign, they have a destructive potential  Treatment of choice for benign oncocytomas is surgical excision

51. MYOEPITHELIOMA  <1% of all salivary neoplasms  3 rd -6 th decades  No gender predilection  Minor salivary glands > parotid > submandibular gland  Presentation: asymptomatic mass

52. MYOEPITHELIOMA  Histology Spindle cell Uniform, central nuclei Eosinophilic granular or fibrillar cytoplasm Plasmacytoid cell Polygonal Eccentric oval nuclei

53. MYOEPITHELIOMA  D/D based on histology:  plasmacytomas  Any tumors with spindle cells neurilemoma fibroma meningioma leiomyoma.  Treatment is surgical excision

54. SIALOADENOMA PAPILLIFERUM  Rare, benign salivary gland tumor  Resembles skin tumor syringocystadenoma papilliferum on gross pathologic and microscopic examination.  Major and minor salivary glands,  men >60 years  cell of origin -pluripotential myoepithelial cell.

55. SIALOADENOMA PAPILLIFERUM  D/D-papillary lesions like squamous papilloma, verrucous hyperplasia, or carcinoma  Distinguished from other intraoral minor salivary gland tumors because it is exophytic and not a smooth, mucosa- covered mass.  Treatment is surgical excision

56. INVERTED DUCTAL PAPILLOMA  Originates from the excretory ducts of the minor salivary glands  different entity from the inverted oral papilloma  M=F  Lesions are raised but not ulcerated  Treatment is surgical excision

57. HEMANGIOMAS  Most common tumors of infancy  10% of all births  Rapid growth phase -1 to 6 months  Involution phase-1 to 12 years.  Hemangiogenesis :somatic mutation in one or more components of critical vascular growth-regulatory pathways (VEGFpathway)

58. HEMANGIOMAS  Both hemangiomas and placental microvessels shows immunoreactivity for Erythrocyte-type glucose transporter GLUT1 Lewis Y antigen Merosin  INFERENCE:placenta as a potential site of origin of hemangiomas.

59. TREATMENT  Steroids -2 to 4 mg/kg per day.  Response to steroids is usually immediate and often dramatic.  Unfortunately, the response rate to steroids is only 40% to 60%.  In such patients, interferon is an option.

60. MUCOEPIDERMOID CARCINOMA  Most common salivary gland malignancy  5-9% of salivary neoplasms  Parotid 45-70% of cases  Palate 18%  3 rd -8 th decades, peak in 5 th decade  F>M

61. MUCOEPIDERMOID CARCINOMA  Presentation Low-grade: slow growing, painless mass High-grade: rapidly enlarging, +/- pain **Minor salivary glands: may be mistaken for benign or inflammatory process Hemangioma Papilloma

62. MUCOEPIDERMOID CARCINOMA  Gross pathology Well-circumscribed to partially encapsulated to unencapsulated Solid tumor with cystic spaces

63. MUCOEPIDERMOID CARCINOMA  Histology—Low-grade Mucus cell > epidermoid cells Prominent cysts Mature cellular elements

64. MUCOEPIDERMOID CARCINOMA  Histology— Intermediate- grade Mucus = epidermoid Fewer and smaller cysts Increasing pleomorphism and mitotic figures

65. MUCOEPIDERMOID CARCINOMA  Histology—High- grade Epidermoid > mucus Solid tumor cell proliferation Mistaken for SCCA Mucin staining

66. MUCOEPIDERMOID CARCINOMA  Features of high grade mucoepidermoid CA: 1.Four or more mitotic figures per 10 high power fields 2. Neural invasion 3. Necrosis 4. Intracystic component <20% 5. Cellular anaplasia

67. MUCOEPIDERMOID CARCINOMA  Treatment Influenced by site, stage, grade Stage I & II Wide local excision Stage III & IV Radical excision +/- neck dissection +/- postoperative radiation therapy postoperative irradiation for patients with positive margins, nodal metastasis, and high-grade malignancies.

68. ADENOID CYSTIC CARCINOMA  Overall 2 nd most common malignancy  Most common in submandibular, sublingual and minor salivary glands  Perineural invasion(typical)  Hard palate-mc site  M = F  5 th decade  Presentation Asymptomatic enlarging mass Pain, paresthesias, facial weakness/paralysis

69. ADENOID CYSTIC CARCINOMA  Gross pathology Well-circumscribed Solid, rarely with cystic spaces infiltrative

70. ADENOID CYSTIC CARCINOMA  Histology— cribriform pattern Most common Good prognosis

71.  Histology—tubular pattern Layered cells forming duct- like structures Basophilic mucinous substance Intermediate prognosis ADENOID CYSTIC CARCINOMA  Histology—solid pattern Solid nests of cells without cystic or tubular spaces poorer prognosis

72. ADENOID CYSTIC CARCINOMA Eibling and others found that involvement of nerves with diameters >3 mm correlated with recurrent disease. Exhibits a neurotropic spread, recurrences at the skull base after surgical and radiation treatment. cervical metastases rare Distant metastasis: lung

73. ADENOID CYSTIC CARCINOMA  Treatment Complete local excision Tendency for perineural invasion: facial nerve sacrifice Postoperative RT  Prognosis Local recurrence: 42% Indolent course: 5-year survival 75%, 20-year survival 13%

74. RECENT EVIDENCE  Epidermal growth factor receptor (EGFR) +vity in 85% tumor  EFGR antagonists can be used in case of pts with distant metastasis.  VANDETANIB is a small molecule inhibitor of VEGFR-2 and EFGR tyrosine kinase activity.  Its antitumor efficacy in vitro and in mouse model has already been proved.

75. ACINIC CELL CARCINOMA  2 nd most common parotid malignancy  5 th decade  F>M  Bilateral parotid disease in 3%  Presentation Solitary, slow-growing, often painless mass

76. ACINIC CELL CARCINOMA  Histologic subtypes  solid (38%)  microcystic (33%)  papillary cystic (25%)  follicular (4%),

77. ACINIC CELL CARCINOMA  Primary treatment is complete surgical resection with neck dissection  Postoperative radiation:Not routinely advocated for low- grade malignancies but may be used for advanced or high- grade tumors.  Prognosis 5-year survival: 82% 10-year survival: 68% 25-year survival: 50%

78. SQUAMOUS CELL CARCINOMA  0.3-1.5%of salivary gland neoplasms  7 th -8 th decades  M:F = 2:1  MUST RULE OUT: High-grade mucoepidermoid carcinoma Metastatic SCCA from skin(scalp),aerodigestive tract,ear canal  Gross pathology Unencapsulated Ulcerated fixed

79. SQUAMOUS CELL CARCINOMA  Treatment Radical excision Neck dissection Postoperative RT  Prognosis 5-year survival: 24% 10-year survival: 18%

80. MALIGNANT MIXED TUMORS  Carcinoma ex-pleomorphic adenoma Carcinoma developing in the epithelial component of preexisting pleomorphic adenoma  Carcinosarcoma True malignant mixed tumor—carcinomatous and sarcomatous components  Metastatic mixed tumor Metastatic deposits of otherwise typical pleomorphic adenoma  sixth decade  5% to 12% of salivary gland malignancies

81. CARCINOMA EX- PLEOMORPHIC ADENOMA  Malignant degeneration can occur in 3% to 7% of pleomorphic adenomas.  6 th -8 th decades  Parotid > submandibular > palate  Risk of malignant degeneration 1.5% in first 5 years 9.5% after 15 years  Presentation Longstanding painless mass that undergoes sudden enlargement

82. CARCINOMA EX-PLEOMORPHIC ADENOMA  Gross pathology Poorly circumscribed Infiltrative Hemorrhage and necrosis

83. CT-SCAN CARCINOMA EX-PLEOMORPHIC ADENOMA

84. CARCINOMA EX- PLEOMORPHIC ADENOMA  Treatment Radical excision Neck dissection (25% with lymph node involvement at presentation) Postoperative XRT  Prognosis Dependent upon stage and histology

85. ADENOCARCINOMA  Rare  5 th to 8 th decades  F > M  Parotid and minor salivary glands  Presentation: Enlarging mass 25% with pain or facial weakness

86. ADENOCARCINOMA  Histology Heterogeneity Presence of glandular structures and absence of epidermoid component Variants are Mucinous adenocarcinoma (low grade) Papillary cystadenocarcinoma(low grade) Trabecular adenocarcinoma Clear cell adenocarcinoma Sebacous adenocarcinoma

87. ADENOCARCINOMA  Histlogical Grade based upon: Mitotic rate Cellular pleomorphism, Stromal invasion  Salivary duct variant –worst prognosis  Treatment Complete local excision Neck dissection Postoperative XRT

88. POLYMORPHOUS LOW- GRADE ADENOCARCINOMA  2 nd most common malignancy in minor salivary glands  Palate>lip>buccal mucosa  7 th decade  F > M  Painless, submucosal mass  Histology Isomorphic cells, indistinct borders, uniform nuclei Peripheral “Indian-file” pattern  Treatment conservative excision

89. LYMPHOMA  1.7% of all salivary neoplasms.  parotid >submandibular >minor salivary glands.  B-cell lymphpma> T-cell, mucosa-associated lymphoid tissue (MALT)> Hodgkin's lymphomas  Sjögren's disease -40 times greater risk primary lymphoma  prognosis of primary lymphoma is better than systemic lymphomas  Treatment:Chemotherapy except MALTOMA(surgery)

90. METASTATIC CANCER  Skin of H/N region>Lung >Kidney >Breast >Nasopharynx >Colorectal >Thyroid

91. PROGNOSTIC FACTORS IN SALIVARY GLANDS MALIGNANCY  Tumor histology  Histological grade  Anatomic site of origin  Clinical stage  Age  Facial nerve paralysis  Experience of the surgeons

92. STAGING

94. PRINCIPLES OF MANAGEMENT OF BENIGN SALIVARY GLAND NEOPLASMS  Small adenomas in the tail of the parotid gland only dissection of the lower division of the facial nerve with removal of the tumor and the surrounding parotid tissue  Larger tumors of the superficial lobe -complete superficial parotidectomy.  Deep lobe tumors -total parotidectomy with facial nerve preservation.  Parapharyngeal tumors -cervical-parotid approach and with or without a mandibulotomy.

95.  The skin incision is placed in a preauricular crease and extends superiorly to the level of the root of the helix. The incision extends inferiorly around the lobule of ear over the mastoid tip. It gently curves down along the sternocleidomastoid muscle and then slightly forward in a natural skin crease in the upper neck.  The preauricular portion of the incision passes on or just inside the tragal margin. The incision is then carried below the lobule of the ear, turns posteriorly over the mastoid, and is then extended within the hairline INCISIONS modified Blair's incision Modified "facelift" incision for parotidectomy

96. TYPES OF SURGERY IN MALIGNANT PAROTID TUMOR  Superfical parotidectomy  Total conservation parotidectomy  Total radical parotidectomy  Extended Radical parotidectomy

97. TOTAL CONSERVATION PAROTIDECTOMY  INDICATION:  Benign neoplasm of deep lobe.  Recurrent pleomorphic adenoma.  Certain malignant tumors Facial nerve is preserved.

98.  Total conservation parotidectomy +Sacrifice of facial nerve. TOTAL RADICAL PAROTIDECTOMY

99. SURAL NERVE GRAFT

100. EXTENDED RADICAL PAROTIDECTOMY  Radical parotidectomy +removal of adjacent structures like ascending ramus of mandible,zygomatic arch,temporalis muscle,sternomastoid muscle(anterior part),EAM and mastoid process.  Radical neck dissection is usually performed along with this procedure.  Larger defect is closed with PMMF.

101. NECK DISSECTION  Elective neck dissection for N0 neck indicated in high grade mucoepidermoid carcinoma,SCC and adenocarcinoma of parotid.  MND type-1 usually performed.

102. PORT AND SURVIVAL