GRANULAR CELL

TUMORS

Namrata Sengupta
PG (III)
Guided by Dr. Sachin Sarode
Oral Pathology & Microbiology
Presented on:
 CLASSIFICATION
 ODONTOGENIC TUMOUR
 NON-ODONTOGENIC TUMOUR
 SLIVARY GLAND TUMOUR
 MELANOCYTIC LESIONS
 HISTIOCYTIC LESIONS
 REACTIVE LESIONS
 METASTATIC LESIONS
 MISCELLANEOUS
 ODONTOGENIC
 Granular cell ameloblastoma
 Central and peripheral Granular cell odontogenic tumor/
Granular cell Ameloblastic fibroma/ central granular cell
odontogenic fibroma
 Calcifying epithelial odontogenic tumor
 Granular cell odontogenic cyst (variant of lateral
periodontal cyst)
 NON-
ODONTOGENIC
NON-
ODONTOGENIC

BENIGN MALIGNANT
BENIGN MALIGNANT

8.
2. 6. Granular
4. 5. 7. Perivascula
8.
1. Granular Congenital
2. 3. 6.cell
Granular
Rhabdomy
4. Neurilemm
5. Dermatofib r
Perivascula
cell
1. tumor
Granular epulis of
Congenital Leiomyoma
3. traumatic
cell 7.
oma
Rhabdomy oma
Neurilemm roma epithelioid
r
cell tumor newborn
epulis of Leiomyoma neuroma
traumatic Dermatofib
oma oma cell tumor
epithelioid
newborn neuroma roma
cell tumor
 NON- ODONTOGENIC
NON- ODONTOGENIC

MALIGNANT BENIGN
MALIGNANT BENIGN

2. Malignant 3. 7.
1. Alveolar soft 5. Basal cell
granular cell
2. Malignant Rhabdomyosarc
3. 6. Angiosarcoma Dermatofibrosar
7.
part sarcomasoft
1. Alveolar carcinoma
5. Basal cell
tumor cell
granular oma
Rhabdomyosarc 6. Angiosarcoma coma
Dermatofibrosa
part sarcoma carcinoma
tumor oma coma
 NON-
BENIGN MALIGNANT NON-
NEOPLASTIC
BENIGN MALIGNANT NEOPLASTIC
LESIONS
LESIONS

Acinic cell
Warthin’s tumor
carcinoma Sialadenosis

Mucoepidermoid
Oncocytoma
carcinoma Oncocytosis

Epithelial-
Canalicular
myoepithelial
adenoma
carcinoma

SALIVARY GLAND DISEASES

SALIVARY GLAND DISEASES Oncocytic
carcinoma

Salivary duct
carcinoma
 MELANOCYTIC
MELANOCYTIC
LESIONS
LESIONS

1. Pigmented
1. Pigmented 2. Malignant 4. Melanocytic
basal cell 2. Malignant 3. Naevus 4. macule
Melanocytic
basal cell melanoma 3. Naevus
carcinoma melanoma macule
carcinoma
 HISTIOCYTIC
HISTIOCYTIC
LESIONS
LESIONS

1. Langerhan’s 2. Verruciform 3. 4. Atypical

cell1.histiocytosis
Langerhan’s 2.xanthoma
Verruciform 3.
Xanthogranuloma 4. Atypical
fibroxanthoma
cell histiocytosis xanthoma Xanthogranuloma fibroxanthoma
 REACTIVE LESIONS
REACTIVE LESIONS

1. Gingival hyperplasia 2. Traumatic sites

1. Gingival hyperplasia 2. Traumatic sites
 METASTATIC
METASTATIC
LESIONS
LESIONS

4. Metastatic
1. Granular cell 2. Metastasis 3. Metastatic 4. Metastatic 5. Metastatic
1. Granular cell 2. carcinoma
Metastasis 3. Metastatic oncocytic 5. Metastatic
variant of Renal from malignant oncocytic hepatocellular
variant of Renal from carcinoma malignant carcinoma of hepatocellular
cell carcinoma of breast melanoma carcinoma carcinoma
cell carcinoma of breast melanoma thyroid of carcinoma
thyroid
 MISCELLANEOU
MISCELLANEOU
S
S

1. Fibrous papule 2. Granular cell

1. of
Fibrous papule
the nose 2. Granular
lichen planuscell
of the nose lichen planus
PROPOSED ORIGIN OF GRANULAR
CELLS

 Lysosomes
 Skeletal muscle
 Neural origin
 Macrophages
 Pericytes
 Undifferentiated mesenchymal cells
GRANULAR CELL AMELOBLASTOMA

 Follicular type of SMA shows extensive granular transformation

of central stellate reticulum like cells
 5% of all ameloblastomas
 It is aggressive histologic variant of ameloblastoma and can
show metastatic potential.
 The granular appearance has been described to numerous
lysosomes.
 Size- 1μm in size; giant granules of 30 μm in diameter.
 Ultrastructural features- finger-print-like membranous
structures, myelin figures, small particles, granules, vesicles,
lattice structures and crystalloids.
 This diversity may represent different materials and stages of
digestion of the lysosomal contents.
 Theory-

 Lysosomes represent increased cellular actions of the tumour

ameloblasts to digest unwanted components.
 The myelin figures suggest the presence of phospholipid in the
granules.
 Granular change including aging or degenerating process.
 The ability of lysosomes to digest or dispose these materials
decreases with age and as a result cytoplasm of some tumour
cells become packed with lysosomal granules
 IHC
 Cytokeratin- +VE
 CD68- +VE
 Lysozyme- +VE
 alpha-1-antichymotrypsin- +VE

 These features suggest that the cytoplasmic granularity in GCA might

be caused by increased apoptosis and associated phagocytosis by
neighboring neoplastic cells.
 CENTRAL GRANULAR CELL
ODONTOGENIC TUMOUR
 The central GCOT is a rare benign odontogenic neoplasm that
contains variable amounts of large eosinophilic granular cells
and apparently inactive odontogenic epithelium.
 The average age at presentation was 45.5 years (range, 16–77).
More than half occurred during the sixth to eighth decades of
life.
 In 73.3% of the cases, the central GCOT was found in females.
 Pathogenesis-
 Ageing or degenerative response of fibroblasts.
 Ectomesenchymal influence may be responsible for
proliferation of both gingival epithelium and mesenchymal
cells which are subsequently transformed into granular cells.
 Dalfarno and Donna reported granular cells are of epithelial
origin and the result of processes of an involuted and
dystrophic nature.
 Histopathology-
 Sheets or lobules of round-to-polygonal cells with abundant,
eosinophilic granular cytoplasm with round-to-oval nuclei .
 Scattered among the granular cells are cords and nests of
odontogenic epithelium .
 The epithelial cells often possess clear cytoplasm.
 Thin septae of fibrous connective tissue separate the lobules of
granular cells. The islands of epithelium do not form stellate
reticulum.
 Scattered small cementum-like or dystrophic calcifications were
associated with the granular cells in 50% of the reported cases
Central
Centralgranular
granularodontogenic
odontogenicfibroma.
fibroma.
 IHC
 Vimentin- +ve
 CD68- +ve
 Lysozyme- +ve
 muscle-specific actin- +ve
 alpha-smooth muscle actin- +ve
 Calponin- +ve
 neuron-specific enolase (NSE)- +ve
 CD138- +ve
 bcl-2- +ve
 Special stain

 Size- 20 to 50 μm with abundant eosinophilic granular

cytoplasm and eccentric round to oval nuclei .
 Granular cell cytoplasm is Sudan black B and periodic acid
Schiff (PAS) positive, diastase resistant and negative for
mucicarmine stain.
 Electron microscopic-
 Granular cells contain numerous lysosome-like granules, with
little cytoplasmic organelles and markedly indented nuclei.
 Granules are electron-dense and amorphous, aggregates of fine
granular particles, vesicular granules, granules with myeline-
like structure and granules with mixed appearance of them
 CEOT
 1% of all benign odontogenic tumors.
 It characteristically contains calcified masses and homogenous
acellular material within the tumor epithelium and stroma.
 Most polyhedral granular cells in CEOT are PAS negative;
however few cells contain PAS positive granular material which
can be removed by reaction with diastase.
 Cytoplasmic density appears to be due to polyribosomes,
secondary lysosomal bodies of the autophagic variety.
 Other morphological variants of lysosomes are myelin figures,
and multivesicular bodies
 GRANULAR CELL TUMOR

 Termed as tumour of Abrikosoff, granular cell myoblastoma,

granular cell neurofibroma or granular cell schwannoma.
 Common site- Tongue.
 Origin- mesenchymal cells, neural crest cells, histiocytes or
schwann cells
Pseudoepitheliomatous
hyperplasia

Granular cells
 IHC

 HISTIOCYTIC ORIGIN-
 α-1 antichymotrypsin
 α-1 anti-trypsin
 SCHWANN CELLS ORIGIN-
 S-100
 Vimentin
 Glycoprotein or leu-7
 Neurofilament
 Neurotubules
 NEURAL CREST ORIGIN (melanoma and nevomelanocytic
nevi)-
 NK1/C3 (CD 63)

 Granular cells can occur as a degenerative, reactive or

hamartomatous phenomenon
 PRIMITIVE POLYPOID GRANULAR
CELL TUMOUR (PPGCT)

 Non-neural GCT of the oral cavity.

 It show expansile growth, cellular atypia, mitotic activity
 Histopathology and IHC
 Granular cell changes have been reported in sites of previous
surgical trauma and shows features of both GCT and traumatic
neuroma.
 The granular change inside the nerve and the cytoplasmic
granularity is probably derived from lysosomal engulfment
with myelin products
 S100 -ve
CONGENITAL EPULIS OF NEWBORN

 CEN is also called congenital granular cell lesion (CGCL) or

congenital epulis or Neumann’s tumour or congenital gingival
granular cell tumor.

 Origin- Numerous theories have been postulated including

odontogenic, fibroblastic, histiocytic, myogenic and neurogenic.
 IHC

 S100 –ve

 Difference from GCT- 75 kD nerve growth receptor factor, trk

gene product and phosphotyrosine positive cells in CGCL but
their presence in GCT
  Present at birth
 Age 30-60yrs
 Location- gingiva
 Location – lingual dorsum
GRANULAR CELL CONGENITAL EPULIS OF
 Maxilla> mandible
TUMOR
 Sessile lesion NEWBORN
 Pedunculated lesion
 Overlying epithelium
shows
 Overlying epithelium

pseudoepitheliomatous shows atrophic epithelium

hyperplasia
 Vascular component less  Vascular component more

prominent prominent
 S-100 positive  S-100 negative
 GRANULAR CELL
LEIOMYOMA
 It accounts for 0.42% of all soft tissue lesions of the oral cavity
and arise from the smooth muscle of the vasculature.
 H/P- The tumor usually shows large polygonal to fusiform
shaped cells with abundant eosinophilic, granular cytoplasm,
the nuclei are round to ovoid, hyperchromatic with absence of
mitosis
 Granular appearance is thought to be a degenerative change and
it may be due to tissue response to various factors including
neoplasia, degenerative process and reactive process such as
anoxia, sublethal injury of the cells due to excessive
proliferation of surrounding collagenous fibers, abnormal
increase in the lysosomes or lipids, metabolic storage disorders
and defective lysosomes
 IHC and D/D
 α-1 anti-trypsin.
 PAS with diastase resistance
 S100-ve
 Smooth muscle actin+ve
D/D-
 GCT- absence of spindle cell component.
 Granular cell schwannoma- S100+ve and SMA-ve
PERIVASCULAR EPITHELIOID CELL
TUMOR

 These are very rare in oral cavity.

 Usually occur in patients with tuberous sclerosis complex (TSC).
 PEComa without TSC can occur which results from post zygotic
somatic mutations.
 Pathogenesis-
 First hypothesis is that PEComas are derived from
undifferentiated cells of neural crest that can express dual
smooth muscle and melanocytic phenotype.

 Second hypothesis is that these tumors are of myoblastic and

more specifically smooth muscle origin but are molecularly
altered and coexpress melanogenesis and melanocytic markers.
 Histopathology-

 PEComas show large elongated or epithelioid cells with

granular eosinophilic cytoplasm with occasional cytoplasmic
clearing, centrally located nuclei, occasional nuclear
hyperchromatism, limited collagenous component, minute
capillaries and occasional thick walled capillaries
 IHC
Positive for melanocytic and muscle specific markers.
 HMB-45+ve
 Melan-A+ve
 Microphthalmia transcription factor+ve
 S100-ve

Elongated cells-
 SMA+ve
 Desmin +ve
 Muscle specific actin+ve
 GRANUAR CELL BASAL CELL
CARCINOMA

 Basal cell carcinoma (BCC) is a cutaneous tumor which occurs in

a number of histological forms.
 Granular cell BCC was first described by Barr and Graham.
 M>F
 HISTOPATHOLOGY

 GBCC shows well demarcated tumor mass in nodules which

come in contact with basal cell layer of the epidermis and
invade the dermis.
 Tumor cells show pleomorphic lysosome-like granules with
eosinophilic cytoplasm and peripheral palisading arrangement
of the basal cells.
 IHC
 Cytoplasmic granules are PAS positive, 0.1-0.5μ in size.
 S-100-ve
 Epithelial membrane antigen (EMA)-ve
 carcinoembryonic antigen (CEA)-ve
 Keratins+ve
 bcl-2+ve
 The granules are also positive for CD15 and CD68 which
suggests lysosomal nature
 The granular material is also interpreted as dense pinocytotic
granules, collagenase zymogen granules and acid phosphate
positive which develop as a result of degenerative process.
 Certain studies have shown that mitochondrial proliferation is
attributed to a compensatory hypertrophy mechanism operating
at the subcellular level in response to defective mitochondrial
function contributing to its granularity
ALVEOLAR SOFT PART SARCOMA

 Rare neoplasm of unknown histogenesis

 Believed to a variant of rhabdomyosarcoma
 Chromosome rearrangement on 17q25 and Xp11.2
 Slow growing painless mass
 Young adults and children
 Floor of mouth and tongue
 Female: male= 2:1
 Lesional granular cells have distinct borders, abundant
eosinophilic granular cytoplasm resulting in epithelioid
appearance, round, regular eccentrically placed nucleus,
vesicular chromatin, prominent nucleoli with infrequent mitosis
and necrosis
ALVEOLAR SOFT PART
SARCOMA

LARGE POLYGONAL CELLS, ABUNDANT CYTOPLASM

 IHC
 Cytokeratin-VE
 Epithelial membrane antigen (EMA)-VE
 S-100-VE

Neuroendocrine markers such as

 Chromogranin-A -VE
 Synaptophysin-VE
Melanocytic markers such as
 HMB-45 -VE
 melan-A -VE
ULTRASTRUCTURE FINDINGS

 Ultrastructure shows crystalline structures which may be

rhomboid, rod-like or spiked consisting of aggregates of
monocarboxylate transporter protein (MCT1) and its cellular
chaperone CD147
 PARAGANGLIOMA

 Paragangliomas are neuroendocrine tumors arising from extra-

adrenal autonomic ganglia. Head and neck paraganglia occur in
association with the carotid body, the ganglion nodosum of the
vagus nerve, the middle ear (jugulotympanic paraganglia), and
in other rarer sites where paraganglia are known to exist.
 HISTOPATHOLOGY
 The lesions are usually composed of round nests of
uniform polygonal chief cells with extensive granular
eosinophilic cytoplasm.
 The nuclei of these neoplastic cells are large, regular,
centrally located and shows occasional vesiculation with
no mitoses.
 Nests of polygonal chief cells are separated by the
cytoplasmic processes of elongated cells, associated with
fibrovascular stroma.
 There will be no significant gland formation, anaplasia,
necrosis, mitotic activity, or invasion.
 ULTRASTRUCTURAL STUDY

 Numerous 100- to 200-nm, uniform neurosecretory granules.

 Grimelius and chromogranin A stains confirm the

neurosecretory nature of the chief cell granules, and together
with neuron-specific enolase establish that the tumor arises
from a neuroendocrine cell lineage, rather than a modified
muscle cell type
 DERMATOFIBROMA
 Dermatofibroma is a common benign fibrohistiocytic cutaneous
lesion, most common in the extremities, rare in the oral and
perioral region.

 Cellular granularity is a nonspecific phenomenon characterized

by intracytoplasmic accumulation of lysosomes and may cause
diagnostic difficulties. Traumatic factors may be involved in the
pathogenesis of cellular granularity
 RHABDOMYOMA

 Adult rhabdomyomas- middle age and 70% cases in men

 Asymptomatic polypoid mass which displaces normal
structures
 Floor of mouth, soft palate and base of tongue
 Translocation on chromosome 15 and 17
 Fetal rhabdomyoma- young children
 Painless mass within the muscle layer beneath intact skin or
mucosa
 Face and preauricular region
 HISTOPATHOLOGY
 Adult rhabdomyoma- well circumscribed lobules of large,
polygonal cells which have abundant granular eosinophilic
cytoplasm
 Cells appear vacuolated due to accumulation of glycogen
 Peripheral vacuolization- spider web
 Focal cells with cross striations( PTAH)
 Tumor cells seperated by narrow fibrovascular spaces
ROUNDED AND POLYGONAL CELLS WITH FOCAL VACUOLIZATION
 IHC
 Immunoreactive with-
 Myoglobin +ve
 Desmin +ve
 Vimentin +ve
 Cross striations- PTAH stain
 Intracellular lipid- oil red O
PTAH
 RHABDOMYOSARCOMA
 Most common soft tissue sarcoma of children
 Most frequent site- head and neck
 Embryonal- first 10 yrs, subdivided as spindle and
botyroid variant
 Alveolar- 10 to 23 yrs of age
 Pleomorphic- >40 yrs
 Painless, infiltrative mass grows rapidly
 most frequent intra-oral sites- floor of mouth, soft palate,
buccal mucosa, tongue
 HISTOPATHOLOGY
 Embryonal- represents various stages in the embryogenesis of
skeletal muscle
 Small round/oval cells with hyperchromatic nuclei and
indistinct cytoplasm
 Round to ovoid rhabdomyoblasts with distinctly eosinophilic
cytoplasm and fibrillar material
 Sometimes elongated, strap shaped rhabdomyoblasts
 Deletions on 11p15
 Alveolar type- aggregates of poorly differentiated round to oval
cells seperated by fibrous septa
 Central loss of cohesiveness
 Mitoses and giant cells common
 Translocation t(12;13) (q35;q14)
 Juxtapose PAX3 or PAX7 genes on chromosome 1 and 1 resp.
with FKHR gene on chromosome 13 resulting in chimeric fusion
proteins that act as potent transcription factors
 Pleomorphic- loosely arranged and haphazardly oriented cells
of varying morphology
 Deeply eosinophilic cytoplasm
 Positive for desmin and myoglobin
 SPECIAL STAIN

 Trichrome- red rhabdomyoblasts

 PTAH- myofilaments and cross striations- deep purple
 VERRUCIFORM XANTHOMA
 Specific but rare lesion
 edentulous alveolar ridge, Attached gingiva, buccal
mucosa,palate, floor of mouth
 >45yrs , no sex predilection
 Asymptomatic, slightly raised pebbly surface with slightly pale
or red color either sessile or pedunculated
 PATHOGENESIS
 One theory suggests- focal proliferation of langerhans cells and
supported by IHC
 Another theory- local accumulation of lipid that subsequently
becomes ingested by macrophages

 Secretes epithelial growth factors

 Stimulates epithelial hyperplasia

 HISTOPAHOLOGY
 Verrucous surface covered by parakeratin
 Acanthosis with elongation and extension of retepegs into
connective tissue
 Numerous foamy cells within the papilla
 These are macrophages that contain lipid and PAS positive ,
diastase resistant granules
 Evidence to suggest that they may be necrotic epithelial cells
 LCA +VE
 CD 68 +VE
 S100 -VE
 Contents of cells stain with lipid stains and contain antihuman
lysozome antibody.
 PAS positive diastase resistant
 REACTIVE GRANULAR CELLS AT
THE SITES OF TRAUMA
 First described by Hamperl et al.
 Coarsely granular cells, superficially resembling those of
myoblastoma and thought to be histiocytic (reactive).
 These cells are frequently found near smooth muscle in sites of
previous trauma.
 The granules are PAS, acid-phophatase, neutral and acid
mucopolysaccharide positive and contain acid fast,
fluorescent, yellow-brown pigment.
 The granular cells with few cytoplasmic organelles were
felt to be an end stage of the undifferentiated cell
following incorporation of large quantities of cellular
debris.
 The histiocytic cell granules resemble the so called
“Hamazaki-Wesenberg” (H-W) bodies, which also
contain a lipofuscin- or ceroid –like pigment.
 ONCOCYTOMA
 Rare neoplasm (1%)
 Older adults, 8th decade
 Major salivary glands
 Slow growing, painless mass
 Clinically indistinguishable from other benign tumors
 Bilateral tumors- multinodular oncocytic hyperplasia
 PATHOGENESIS
 Schaffer- degenerative phenomenon in salivary gland
parenchyma
 Hamperl- peculiar degeneration that is irreversible with
age
 Metaplastic, hyperplastic or neoplastic process
 Blanck and associates- not a neoplasm but nodular
hyperplasia
 May be an adaptive or compensatory hyperplastic cell
that occurs secondary to undetermined somatic mutation
 HISTOPATHOLOGY
 Large well defined polyhedral or round cell characterised by
brightly eosinophilic cytoplasm with prominent granularity
 Condensed chromatin, irregular nuclear membrane, prominent
nucleoli and numerous mitochondria
 Stains- PTAH, Bensley’s aniline acid fuschin, luxol fast blue
reaction, thionine and cresyl violet
 WARTHINS TUMOUR
 Second most common benign parotid tumor( 5-14%)
 Slow growing, painless, nodular mass
 Firm or fluctuant to palpate
 Usually bilateral
 Occurs in older adults
 Male: female = 10:1
 PATHOGENESIS
 Arise from heterotopic salivary gland tissue found within
parotid lymph nodes.
 Proliferation of salivary gland ductal epithelium that is
associated with secondary formation of lymphoid tissue
 Association between smoking and development of this tumor
 Association with EBV
 HISTOPATHOLOGY
 Mixture of ductal epithelium and lymphoid stroma
 Epithelium is oncocytic in nature forming rows of cells
surrounding cystic spaces
 Cells have abundant finely granular cytoplasm.
 Inner layer- tall columnar cells with centrally placed
hyperchromatic nuclei
 Outer layer-cuboidal/ polygonal cells, vesicular nuclei
 ACINIC CELL CARCINOMA

 Shows serous cell differentiation

 85% in parotid gland
 2nd to 7th decade
 Female predilection
 Slow growing mass and asymptomatic
 HISTOPATHOLOGY
 Well circumscribed /encapsulated, at times infiltrative
 Most characteristic cell- cell with features of serous acinar cell,
with abundant granular basophilic cytoplasm and a round
darkly staining eccentric nucleus
 Various growth patterns-solid, microcystic, papillary-cystic and
follicular
 Cytoplasmic PAS positive diastase resistant granules
 ONCOCYTOSIS
 Oncocytic metaplasia- transformation of ductal and acinar cells
to oncocytes
 Oncocytosis- proliferation and accumulation of oncocytes
within salivary gland tissue
 More frequent in older adults
 Usually proliferation is multifocal and nodular
 HISTOPATHOLGY- Focal nodular collections of oncocytes
 On occasion clear cells due to glycogen