describes various clear cell lesions of head and neck region, its classification, origin, their immunohistochemistry profiles, various clear cell types, physiological and pathological clear cells, their causes.with histopathological images.

1. CLEAR CELL LESIONS OF HEAD &
NECK
SHANTI SUDHA SAHU
SCB DENTAL COLLEGE, CUTTACK

2. CONTENTS:
• Introduction
• Physiological
• Pathological
• Classification
• Clear cell Odontogenic lesion
• Clear cell salivary gland lesions
• Metastatic clear cell lesions

3. Introduction
• A clear cell is epithelial or mesenchymal cell composed of pale
or clear cytoplasm with distinct nucleus.
• Associated with both physiological and pathological
conditions.
• Physiological clear cells like remnants of dental lamina
sometimes give rise pathological conditions like odontogenic
cyst

4. Defined as:
“A cell, especially a neoplastic ,finely vacuolated with
central dark nuclei, containing abundant glycogen or other
material that is not stained by haematoxylin or eosin, so
that the cytoplasm appears clear histologically”

5. Types Of Clear Cells:
• 1. Physiologic Clear Cells
• 2. Pathologic Clear Cells

6. PhysiologicClear Cells
Non keratinocytes
1. Pigment producing cells
(melanocytes)
2. Langerhans cells
3. Merkel cells

7. Pathologic Clear Cells
• Clear cells represent a minor element in otherwise typical
tumours
• Clear cells may be observed in almost any benign or malignant
tumour of epithelial, mesenchymal, melanocytic or
hematopoietic derivation.
• Salivary gland, odontogenic neoplasms, and metastatic clear
cell tumours( in head & neck)

8. Varying Modes Of Clear Cell Presentation In
Clear Cell Lesions
 Neoplastic proliferation of diverse lineage may manifest a virtually identical
clear cell appearance, regardless of whether they are benign or malignant in
nature.
 Tumour progression can lead to extensive clear cell changes, perhaps as a
secondary phenomenon or as a result of clonal evaluation.
 Identification of origin and differentiation of tumour becomes increasingly
difficult in cases where clear cell changes have noticed in primary neoplasms
e.g. clear cell variant of renal cell carcinomas metastasizing to oral cavity and
other organs of body

9. scarcity of organelles in cells of salivary ducts which give them an
empty appearance;
Intracellular accumulation of various substances such as glycogen
in myoepithelial cells, accumulation of mucin in mucous cells,
lipids in sebaceous cells, tonofilaments in epidermoid clear cells,
immature zymogen granules in clear acinar cells

10. An artefact during fixation - cellular material disappears from the cell
and Improper Cellular Preservation.
In routine histological sectioning, lipid is lost − xylene (processing)
→ cells appears clear
Artifactual changes (that may cause clear cell changes in the first place)
may diminish or abrogate the immunoreactivity sought in
immunohistological assessments. This effect is potentially irremediable,
even after so-called “antigen-retrieval” methods have been applied to
the tissues in question. Limiting the applicability of immuno-
histochemistry staining.
Electron microscopic examination of deparafinized section can often
have clear cell artifact as well.

11. CLASSIFICATION:
Clear cells can be broadly classified as physiological and
pathological. Pathological can be seen in various tumours
while as physiological can be either epithelial or
mesenchymal in origin and include both odontogenic and non
odontogenic tumors.

12. Classification of physiological clear cells
a. Odontogenic:
Rests of malassez
Rests of serres
b. Non odontogenic:
Lower level epithelial clear cells-
Melanocytes, Merkels Cells.
Higher level epithelial clear cells-
Langerhans cells.
Salivary gland- mucous acinar
cells
• Adipocyte
1. Epithelial: 2. Mesenchymal:

13. Classification of pathological clear cells
i. Clear cell odontogenic
lesions:
1) Odontogenic cyst
a) Gingival cyst of adult.
b) Lateral periodontal cyst
c) Clear cell calcifying odontogenic
cyst.
2) Odontogenic tumors
a) Clear cell odontogenic carcinoma
b) Clear cell odontogenic ghost cell
tumor
c) Clear cell calcifying epithelial
odontogenic tumor.
ii. Clear cell salivary gland
tumors
a) Clear cell myoepithelial
carcinoma
b) Clear cell oncocytoma
c) Clear cell mucoepidermoid
carcinoma
d) Clear cell acinic cell carcinoma
e) Clear cell epithelial-
myoepithelial carcinoma
f) Hyalinizing clear cell
carcinoma.

14. iv. Clear cell keratinocytic tumors
a) Clear cell variant of squamous cell
carcinoma
b) Clear cell variant of basal cell
carcinoma
iii. Clear cell metastatic tumor include
carcinoma arising from
a) Kidney
b) Liver
c) Thyroid
d) Prostate
e) Large bowel
v. Clear cell melanocytic tumor
a) Balloon cell nevus
b) Balloon cell melanonoma
vi. Clear cell bone and cartilaginous
tumors
a) Clear cell chondrosarcoma
b) Clear cell osteosarcoma
vii. Adipocytic tumors
a) Lipoma
b) Liposarcoma
viii. Clear cell arising from skin adnexa
a) Trichilemmoma
b) Clear cell acanthoma
c) Sebaceous adenoma carcinoma
d) Syringomas
e) Eccrine spiradenoma
f) Clear cell hidradenoma
ix. Miscellaneous clear cell conditions
a) Storage diseases--- Hurlers syndrome
b) Viral lesions -----koilocytes
c) Alveolar soft part sarcoma
d) Paraganglioma
e) Hybernoma(adipose tissue)

15. II) Functional Classification:
Lesions In Which Clear Cells Are The Predominant Histologic Finding And Form The Basis
For Their Recognition
1) Salivary gland tumors
Benign
 Clear cell myoepithelial carcinoma
 Clear cell oncocytoma
Malignant
 Clear cell mucoepidermoid carcinoma
 Clear cell acinic cell carcinoma
 Clear cell epithelial-myoepithelial
carcinoma
 Hyalinising clear cell carcinoma
2) Non odontogenic non salivary
gland tumors
Benign
 Clear cell melanocytic tumor
 Leukoedema
 White sponge nevus
 Fordyces granules
Malignant
 Clear cell variant of squamous cell
carcinoma
 Clear cell variant of basal cell
carcinoma
 Clear cell variant of malignant
melanoma

16. 3) Tumors and cysts of Odontogenic
Epithelial origin
 Clear cell variant of calcifying
epithelial odontogenictumor
 Clear cell odontogenic carcinoma
 Clear cell ameloblastoma
4)Tumors of connective tissue origin
Benign
 Lipoma
 Hibernoma
 Xanthoma
 Juvenile xanthogranuloma
 Verruciform xanthoma
Malignant
 liposarcoma
 Clear cell chrondrosarcoma
 Clear cell osteosarcoma
 Clear cell leiomyosarcoma
 Clear cell sarcoma
5) Metastatic tumors
 Renal cell carcinoma
 Liver
 Thyroid
 Prostrate
6) Infections
 Herpes
Lesions Containing Clear Cells:
 Gingival cyst of adult
 Lateral periodontal cyst
 Clear cell calcifying odontogenic

17. 1) Odontogenic cyst
a) Gingival cyst of adult.
b) Lateral periodontal cyst
c) Clear cell calcifying odontogenic cyst.
2) Odontogenic tumors
a) Clear cell odontogenic carcinoma
b) Clear cell odontogenic ghost cell tumor
c) Clear cell calcifying epithelial odontogenic tumor.
Clear Cell Odontogenic Lesions:

18. Clear Cell Odontogenic Lesions:
Odontogenic lesions with significant clear cell component
are exceedingly uncommon. In these lesions clear cell
component may be evident as glycogen rich plaques,
pseudo glandular clusters and sheets.
Presence of clear cells in the odontogenic tumours should
not be considered surprising because of their origin from
the dental lamina that has clear cell components.

19. OdontogenicCyst:
Clear cells are frequently observed in the epithelial lining
of inflammatory odontogenic cysts

20. Gingival Cyst Of Adult:
• Developmental odontogenic cyst of the gingival soft tissue
• Occurring in either the free or attached gingiva
• Arising from cystic transformation of dental lamina or the ‘glands’ or
rests of serres, lining of embryonic epithelium of cuboidal cells
• Extraosseous counterpart of LPC
• Age – >40 , Site – mandibular bicuspid & cuspid area.
• Small, well-circumscribed, painless swelling of the gingiva, seldom
measures over 1 cm in diameter

21. Histopathologically

22. Lateral Periodontal Cyst:
• slow growing, non expansile ,
• developmental origin arising from cystic degeneration of clear
cells of the dental lamina.
• Lateral root surface of an erupted tooth (mandibular bicuspid
area)
• AGE = 22–85 years.
• M>F
• Site = 67% Mandibular bicuspid/cuspid/incisor area,
33% maxillary lateral incisor area

23. Histopathology

24. CLEAR CELL CALCIFYING ODONTOGENIC CYST
• A benign odontogenic cyst that represents approximately 2%
of all benign odontogenic lesions .
• Occurs centrally or peripherally
• Wide age range; 2nd to the eight decades
• No sex prevalence; maxilla = mandible.
• Known predilection for anterior jaw involvement .

25. • Variations within the highly-differentiated epithelium have been
Described
• The clear cell change in COC is exceptionally rare and bears
resemblance to clear cell changes in CEOT.
• The clear cells form clusters and are arranged in an organoid
pattern and surrounded by a collagenous background.
• The recognition of clear cell changes in both CEOT and COC is
expediently important to exclude the possibility of metastatic clear
cell carcinoma of renal origin & others.

26. o lining of odontogenic epithelium that is 6-8 cells thick.
o basal layer - ameloblast-like
o typical microscopic characteristic - ghost cells.
HISTOPATHOLOGY:

28. 2) Odontogenic Tumors
a) Clear cell odontogenic carcinoma
b) Clear cell odontogenic ghost cell tumor
c) Clear cell calcifying epithelial odontogenic tumor.

29. CLEAR CELLODONTOGENIC CARCINOMA:
• In 1985 Hansen et al., reported a locally aggressive odontogenic
neoplasm and named it as a Clear cell odontogenic tumour
• Previously called clear cell ameloblastoma
• In the WHO classification of odontogenic tumors given in 1992,
clear cell odontogenic tumor (CCOT) was classified as a benign
but locally invasive tumor. However, high rate of recurrence, local
and distant metastasis and tumor related deaths have lead to its
reclassification as clear cell odontogenic carcinoma (CCOC).
• Histopathology: exhibit three histological patterns:
 Monophasic
 Biphasic
 Ameloblastomatous.

30. • The monophasic variant is represented by islands that show only the
clear cell phenotype.
• Biphasic tumor (most common) characterized by oval and linear nests
of large clear cells intermixed with smaller islands of polygonal cells
with eosinophilic cytoplasm.
• The ameloblastomatous (least common) which is comprised of clear
cell nests with a tendency for ameloblastomatous palisading at the
periphery.
 Most cells do not contain organelles with the exception of few that
demonstrated glycogen (which explains the PAS positivity)
Positive = diastase degradable PAS, Cytokeratin AE1/AE3, EMA,
Negative = S100, SOX10, HMB45, SMA, Mucicarmine, Alcian blue, Congo red
> 80% cases show EWSR1-ATF1 translocations

31. Biphasic tumour pattern

32. CCOC showing palisading of ameloblast like
cells.
CCOC showing polygonal cells
monophasic

33. Clear Cell Odontogenic Ghost Cell Tumor
• Ghost cell odontogenic carcinoma is a malignant odontogenic epithelial
tumour with features of calcifying cystic odontogenic tumour and/or
dentinogenic ghost cell tumour.
• male: female=2:1 ; age range of 13-72 years (peak : fourth decade)
• maxilla : mandible (2:1), either at anterior or posterior area,
• swelling, often with paraesthesia
• poorly demarcated, osteolytic radiolucency with some radiopaque material.
• Large lesions in the maxilla often destroy the sinus wall, grow into the nasal and
orbital cavities,

34. HISTOPATHOLOGY
 Malignant component consists of rounded epithelial islands in a
fibrous stroma
 Epithelial cells are either small, rounded with dark nuclei or larger with
vesicular nuclei.
 Many mitoses are seen.
 Ghost cells are found in varying numbers either isolated or in clusters.
 Dysplastic dentin may be present
 Two distinct forms.
I. Malignant epithelial component is physically separated from the
classical benign lesion, which is either cystic or solid.
II. Admixture of the malignant epithelial component with typical benign
features
 PCNA labelling index

37. CalcifyingEpithelial Odontogenic Tumour(CEOT)/ Pindborg
Tumour:
• It was first described in 1959 by Pindborg. It accounts for less than
1% of all odontogenic tumors.
• first case of CCCEOT reported by Abrams and Howell (1967)
• Males = Females, Wide age range, AV age = 4th /5th decades of
life
• Intraosseous location >>> peripheral lesion.
• May also occur in pericororonal Location.
• clear cell variant is well recognized in both central and peripheral
locations.

38. Histopathology, (CCCEOT) shows sheets or strands of clear cells are
present which are almost entirely composed of polyhedral epithelial cells
with clear vacuolated cytoplasm in bland fibrous stroma.
•Frequent homogenous masses that sometimes called as liesegang ring
within tumor sheets are present.
• Amorphous eosinophilic areas of amyloid were noted in the connective
tissue.
•These tumour variants demonstrate a rather consistent "biphasic"
histologic pattern with areas diagnostic of the tumour entity in question
and other areas with conspicuous clear-cell component.
 PAS positive granules are seen within the clear cells.
 All epithelial cells (including the clear cells) react positively with
cytokeratin Cocktail (but not with other cytokeratins), fibronectin, and
collagen IV.

39. CCCEOT showing clear cells (clear cells with hyper chromatic, centrally placed nuclei).

41. CLASSIFICATION OF CLEAR CELL TUMORS OF SALIVARY
GLANDS
Benign myoepithelioma, oncocytoma, oncocytic hyperplasia
Malignant a) Carcinoma not usually characterized by clear cells but
with clear cell predominant areas (e,g, Mucoep. &
acinic cell carcinoma)
b) Carcinoma usually characterized by clear cells
i. Dimorphic : Epithelial myoepithelial carcinoma
ii. Monomorphic: clear cell carcinoma
myoepithelial carcinoma

42. ii) Clear Cell Salivary GlandTumors:
• Studies have shown that the clear cell appearance is the light
microscopic manifestation of the three basic factors.
 First, clear cells may contain large amount of intracellular non
staining compounds (glycogen, mucin, lipid).
 Second, they may have a sparcity of cell organelles.
 Third, the cells may appear clear because of post removal or
fixation artifact.
Clear cells may predominate or be only a component of major and
minor salivary gland tumor

43. Clear Cell Myoepithelioma
Modified Myoepithelial cells constitute a significant component of
numerous salivary gland neoplasms.
• Both the benign myoepithelialiomas (and myoepithelial carcinoma)
are made exclusively of myoepithelial cells, with histologic variation.
•Myoepitheliomas represent 1.5 % of all salivary gland tumors;
M = F, develop at any site; parotid > hard and soft palates.

44. • Asymptomatic mass that slowly enlarges over a course of months
or years.
• 1 to 5 cms in greatest dimensions, well demarcated (smooth,
sometimes bosselated external appearance)
• Generally encapsulated except for palatal myoepitheliomas
• Microscopically, primarily spindle-shaped cells, occasionally
plasmacytoid cells, or a combination of these two cell types
constitutes these tumours, stellate and clear cell variants as rare.
• Immunohistochemical:
+ve = cytokeratin, S-100 and muscle-specific actin (MSA)
–ve = desmin and EMA

46. Clear Cell Variant Of Oncocytoma
• Clear cell oncocytoma is a variant of oncocytoma described for the first time
by ELLIS G L in 1988.
• Comprise approximately 1% of all salivary gland tumors (parotid gland)
• Mean age: 85 ; no sex predilection.
• Clear-cell Oncocytoma of the salivary gland is a benign tumor with excellent
prognosis as compared to other salivary tumors with exclusively or
predominantly clear cell features which are at least low-grade malignant
tumors

47. HISTOPATHOLOGY:
• Most of the tumor cells are completely clear, where as others
had variable amount of eosinophilic granular cytoplasm at the
periphery of the cells.
• It has been shown that the clear cell change is due to
combination of fixation artefact and intracytoplasmic glycogen
accumulation.
Oncocytomas/ Clear cell
variant;
PTAH +, CK +.
S-100 protein & MSA negative.

48. Clear cell variant of oncocytoma

50. Oncocytosis (Nodular Oncocytic Hyperplasia)
• Benign condition
• Oncocytosis refers to both the proliferation and the accumulation of
oncocytes within salivary gland tissue.
• it is considered to be a metaplastic process rather than a neoplastic one.
Microscopically:
• Reveals focal nodular collections of oncocytes within the salivary gland
tissue.
• On occasion, these cells may have a clear cytoplasm from the
accumulation of glycogen
• The multifocal nature of the proliferation may be confused with that of a
metastatic tumor, especially when the oncocytes are clear in appearance.

51. Oncocytosis. Multifocal collections of clear
oncocytes (arrows) in the parotid gland.

52. ClearCell VariantOf SalivaryGlandTumours

53. Mucoepidermoid Carcinoma (Clear Cell Variant)
• In 1945 Waldron and Mustoe demonstrated clear cells in
Mucoepidermoid carcinoma
• Mucoepidermoid carcinoma is the most common malignant salivary
gland tumors with > 50% of cases involve the major salivary glands
with the balance involving the minor salivary glands of the palate,
buccal mucosa, retromolar trigone, and lips.
• Microscopically, three distinct cell types are recognized; the
epidermoid, mucous and intermediate cells.
• The mucous cells are the neoplastic cells of mucoepidermoid
carcinoma.

54. • The clear cells are common; comprise approximately 10% of tumor
population but may occasionally form a large portion of the tumor cell
population.
• The clear cells appear to be modified epidermoid and intermediate cells.
• The transition between the epidermoid and clear cells is often seen.
• The clear cells in mucoepidermoid carcinoma stain positively with PAS
with and without digestion with diastase confirming its glycogen content.
• Special staining for mucicarmine or Alcian blue can readily identify the
mucous cell population;

56. Mucoepidermoid carcinoma, mucin positive

57. Acinic Cell carcinoma (Clear Cell Variant)
• Parotid gland (83%) >>submandibular gland(4%) >intraoral minor salivary
glands.
• The tumors may be infiltrative or well circumscribed, demonstrate variable
growth patterns (vacuolated and clear cell patterns)
• Clear cells are generally found in approximately 6% of acinic cell
carcinomas but may comprise a major population of tumor cells in about
1% of neoplasms.
• Microscopically:
Thin encapsulated, serous acinar cell, intercalated duct like cells,
fibrovascular collagenous CT.

59. • The identification of PAS positive diastase resistant; zymogen
cytoplasmic granules is diagnostic.
• The clear cells do not contain glycogen and the clearing is probably
attributed to fixation artifact or reduction in the number of
organelles or may reflect transformation of neoplastic acinar cells
• Immunohistochemistry;
+ staining for anti-S-100 protein, cytokeratin, Vimentin, transferrin,
alpha 1- antitrypsin, CEA, GFAP and amylase

60. Epithelial Myoepithelial Carcinoma
• Epithelial myoepithelial carcinoma was first described by Donath et al., in
1972 and because of the presence of the clear cell component initially
epithelial myoepithelial carcinoma was described as glycogen-rich or clear
cell adenoma.
• origin from intercalated duct.
• uncommon salivary gland tumor which comprises about 1% of all salivary
gland tumors.
• Primarily involve the major salivary glands / parotid, only 10-15% involving
the minor salivary glands.
• Adults, average age is in the 7th decades of life. M = F

61. Histopathologically:
• Duct like structures of solid, cystic, spindle, tubular, organoid
nodular, papillary, or cribriform proliferation of cells,
characteristically arranged in a biphasic pattern:
A. Ductal, cuboidal, intercalated duct like eosinophilic cells
typically arranged around a lumen.
B. Larger polygonal cells exhibiting clear cytoplasm/myoepithelial
differentiation peripherally.

64. Immunohistochemical stains can further delineate the
biphasic pattern:
• The inner intercalated duct like cells stain positively with Cytokeratin
and EMA (epithelial membrane antigen)
• The outer clear myoepithelial cells stain positively with anti-S-100
protein and GFAP/ (SMA +).
• PAS special stain confirms the glycogen content within the clear cells.
• The PAS stain can further highlight a well formed basement
membrane that separates the cells, while mucicarmine stain is
negative.

65. HYALINIZING CLEAR CELL CARCINOMA (HCCC)
• Milchgrub et al., designated the monophasic variant composed
solely of clear cells as hyalinizing clear cell carcinoma
• minor salivary glands of the palate, buccal mucosa, tongue, floor of
mouth retromolar pad and tonsillar areas.
• no sex predilection; involve adults in the 6th - 7th decades
• Microscopically, the HCCC shows clear cells, arranged in
anastomosing thick trabeculae, cords, nests, or solid sheets
surrounded by hyalinized bands with foci of myxohyaline stroma.
• They show infiltrative borders with minimal nuclear pleomorphism
and a very low mitotic index

66. Nests of clear cells surrounded by hyalinized band

67. IMMUNOHISTOCHEMISTRY STAINING
• Variable results; most tumors are focally immunoreactive for
cytokeratin, but reactivity to S- 100 protein, glial fibrillary
acidic protein(GFAP) and vimentin may be seen.
• Ultrastructural studies favor ductal differentiation but do not
demonstrate myoepithelial differentiation

68. CLEAR CELL MYOEPITHELIAL CARCINOMA (CCMC)
Tumours arising from myoepithelial cells lacking ductal differentiation and
exhibiting both epithelial and smooth muscle cell characteristics
Malignant counterparts mostly occur in the salivary glands.
• Most common sites - parotid gland as well as the nasopharynx, paranasal
sinus and nasal cavity of head-neck region
• comprised exclusively of myoepithelial cells that may be arranged in
various patterns.
• CCMC comprises about 16% of all myoepithelial carcinomas.

70. IMMUNOHISTOCHEMISTRY
• Positively with anti S-100 protein, vimentin, high molecular
weight cytokeratin, muscle specific actin (MSA) and alpha
smooth muscle actin (SMA).
• Calponin is the most sensitive and specific marker to identify
myoepithelial differentiation in myoepithelial carcinoma and
thought to be superior to MSA and SMA in delineating the
myoepithelial cells

71. iii) Clear Cell Metastatic Tumors:
• very rare and represent approximately 1% of all oral
neoplasms.
• Carcinomas from kidney, liver, bowel, prostrate and
thyroid are known to have potential for clear cell
differentiation and are able to metastasize to maxillofacial
area.
• Renal cell carcinoma (RCC) is most frequently
metastasizing tumor.
prognosis of patients with metastatic carcinoma is poor.

72. Renal Cell Carcinoma (RCC)
• Paul Grawitz in 1883 described clear cells in Renal Cell
Carcinoma
• also known as renal cell cancer or renal cell adenocarcinoma.
• most common type of kidney cancer

73. • Among all salivary tumors with clear cell features, clear cell carcinoma
is probably the most difficult to differentiate from metastatic renal cell
carcinoma
• The 3rd most common metastatic lesion to the head and neck after
breast and lungs.
• Metastasis represents the initial presenting symptoms of the tumor in
8% of these tumors.
• RCC most commonly metastasizes to the nose/paranasal sinuses,
larynx, parotid gland, temporal bone, thyroid gland and jaws
(mandibular involvement 4-5 times more frequent than the maxilla).
• Metastasis to the oral soft tissues is also rarely seen

74. Renal Cell Carcinoma with cells having clear cytoplasm,
typically arranged in nests and nuclear atypia

75. Clear Cell Carcinoma Vs Metastatic Renal Cell Carcinoma; Points To
Consider:
• Glycogen positivity can be demonstrated in both tumors.
• Positive immunohistochemistry staining for RCC antigen & others.
• The identification of intracytoplasmic lipid on frozen sections favors a diagnosis
of renal cell carcinoma.
• The presence of heterogeneous highly vascularized tumor with lots of sinusoidal
spaces favors a diagnosis of renal cell carcinoma.
100% + for - CK-LMW/ 8.18, Vimentin and RCC
90 % + for - CD10
+ for EMA may be focal)
+ for CK-AE1/AE3 (few cases may be neg)
+ or negative for S-100 *

76. • The presence of haemorrhage and hemosiderin, coupled with
pronounced pleomorphism and cytological atypia should favour
metastatic renal cell carcinoma.
• The identification of a clinically and radiographically detectable
renal mass accompanied by hematuria and flank pain would
further prompt confirmation of the presence of renal cell
carcinoma

77. Immuno-histochemical Profiling Of Various Clear Cell
Lesions

78. Thank You