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KCIAPM SLIDE SEMINAR
ANAND DIAGNOSTIC LABORATORY
ANAND DIAGNOSTIC LABORATORY
26/01/2014
CASE 1
35/F, LEFT HEMITHYROIDECTOMY
35/F, LEFT HEMITHYROIDECTOMY
GROSS APPEARANCE
GROSS APPEARANCE

Specimen of one lobe of thyroid measuring 3.5 x 2.0 x 2.5 cm
Cut section of the specime...
MICROSCOPIC 
MICROSCOPIC

Hypercellular nodules
Cellular area showing pleomorphism of follicular cells 
with nuclear enlargement and hyperchromasia, and
with nuclear enla...
Cellular areas showing hyperchromatic nuclei
Hyperchromatic enlarged nuclei  found at the edge of hyperplastic nodule 
Differential diagnosis 
Differential diagnosis
•
•
•
•
•
•
•
•
•
•
•
•

Follicular neoplasm with hurthle cell change
F lli...
DIAGNOSIS OFFERED
DIAGNOSIS   OFFERED
Follicular neoplasm with Hurthle 
changes 
Hurthle cell neoplasm / Unknown 
Hurthle ...
Final diagnosis
Final diagnosis
• Dyshormonogenetic goitre
DIAGNOSIS
•
•
•
•
•

DYSHORMONOGENETIC   GOITRE
DYSHORMONOGENETIC GOITRE
Hypercellular nodules  with presence of cells 
ar...
DYSHORMONOGENETIC GOITRE
DYSHORMONOGENETIC GOITRE
• Rare, inherited usually autosomal recessive disorder 
• C i bl k i T3 ...
DYSHORMONOGENETIC GOITRE
DYSHORMONOGENETIC GOITRE
MICROSCOPIC
• Hypercellularity resulting from TSH stimulation of the gla...
CASE 2
40/F, MASTECTOMY SPECIMEN
/,
CLINICAL DIAGNOSIS OF PHYLLODES TUMOR
GROSS

Mastectomy specimen measuring 18 x 12 x 6 cm with
overlying skin measuring 15 x 10 x 2 cm
Cut section showed a grey...
Tumour composed of multiple nodules, each representing a duct filled with 
neoplastic proliferation.
MICROSCOPIC

Tumour arranged in solid nests ,sheets  and cribriform areas. 
Tumour shows pushing margins. Infiltration is ...
Papillary areas with hyperchromatic nuclei and increased N/C ratio
Foci showing lymphovascular emboli 
Foci showing lymphovascular emboli
Focal clusters of foamy macrophages seen in this section
Focal clusters of foamy macrophages seen in this section
Differential diagnosis
Differential diagnosis
• Papillary carcinoma
ill
i
– ? Primary, ? Secondary

•
•
•
•
•
•
•

Papilla...
DIAGNOSIS   OFFERED
Papillary transitional cell carcinoma

Why it is ruled out
NO transitional type of epithelium as 
desc...
DIAGNOSIS
Solid variant of invasive papillary carcinoma
S lid
i t fi
i
ill
i
• Multiple  nodules, each representing a duct...
SOLID VARIANT OF INVASIVE 
PAPILLARY CARCINOMA
• A di ti t li i l tit
A distinct clinical entity . 
• Controversial whethe...
SOLID VARIANT OF INVASIVE 
PAPILLARY CARCINOMA
• Mi
Microscopically these tumours show multiple nodules, 
i ll th
t
h
lti ...
References 
References
• Tavassoli FA, Devilee P. World Health Organization 
Classification of Tumours, Tumours of the Bre...
CASE 3
CASE 3
21/F, TOTAL THYROIDECTOMY SPECIMEN
21/F, TOTAL THYROIDECTOMY SPECIMEN
GROSS

Total Thyroidectomy specimen measuring 7 x 6 x 3.5 cm
Total Thyroidectomy specimen measuring 7 x 6 x 3 5 cm
Enlarge...
GROSS

Cut section of right lobe shows friable pale brown 
tumor measuring 4.5 x 3 x 3 cm
Area showing cribriform pattern with back‐to‐back follicles
g
p
Cribriform areas under higher magnification
Cribriform areas under higher magnification
Complex branching papillary structures lined by cuboidal cells
p
gp p
y
y
Focal areas showing squamoid nodules without evidence of keratinization
Focal areas showing squamoid nodules without evide...
Areas showing lymphovascular emboli
Areas showing lymphovascular emboli
Differential diagnosis
Differential diagnosis
•
•
•
•
•
•
•
•

Mixed medullary and papillary carcinoma
Morular cribriform ...
DIAGNOSIS OFFERED
DIAGNOSIS OFFERED
DIAGNOSIS   OFFERED
DIAGNOSIS OFFERED
Papillary cell carcinoma
Tall cell variant
ll ll...
DIAGNOSIS
Papillary Thyroid carcinoma (PTC) Cribriform morular 
Papillary Thyroid carcinoma (PTC) Cribriform‐morular
varia...
Papillary Thyroid Carcinoma 
Cribriform‐Morular Variant
• PTC (C‐MV) is rare morphologic entity
• First described by Harac...
REFERENCES
• Harach HR, Williams GT, Williams ED. Familial 
adenomatous polyposis associated with thyroid 
adenomatous pol...
CASE 4
CASE 4
CLINICAL PRESENTATION

 Female , 39 years old
 Complaints of  fever and cough since 2 months
 P t hi t
Past history of ...
LAB INVESTIGATIONS
Bronchoscopy
Bronchial wash – AFB and cytology
CT scan
RML biopsy
 Bronchoscopy - mass occluding right middle lobe bronchus
 Bronchial wash – AFB – negative
Cytology – negative for atypi...
 CT scan –
 soft tissue density mass measuring 5.4 x 5.7 x 5.8 cms in the right
middle lobe of lung in the perihilar reg...
 Biopsy –


Gross - grey white tissue fragment measuring 0.2x0.2x0.1 cms.

 Microscopy – small sized bland appearing tu...
PER‐
PER‐OPERATIVE

 Right posterolateral thoracotomy, bilobectomy and lymph
node clearance
 Per operative findings – ha...
HISTOPATHOLOGY
Gross – right middle and lower lobes of lung. Tumor with pushing
margins in the middle lobe with occlusion...
 Microscopy  Tumor composed of squmaous cells, intermediate cells and
mucin secreting cells.
 All lymph nodes exhibit r...
Bronchial lining 
Adenoid cystic –
Adenoid cystic – like areas
Pleomorphic adenoma like areas
Squamous islands
DIFFERENTIALS 
•
•
•
•
•
•
•
•
•
•

Large cell undifferntiated carcinoma
L
ll diff
ti t d
i
Large cell neuroendocrine carc...
 Impression –
 low grade salivary epithelial neoplasm, ? Low grade
mucoepidermoid carcinoma , ? Pleomorphic adenoma.
IMMUNOHISTOCHEMISTRY
 Pan CK – positive in tumor cells
 S-100 – negative in tumor cells
 Vimentin – negative in tumor c...
Pan CK
S 100
VIMENTIN
Final diagnosis 
Final diagnosis
• Mucoepidermoid carcinoma of the lung – Low 
g
grade
DISCUSSION
Rare primar tumor of lung – 0 1 – 0 2 %
primary t mor
l ng 0.1 0.2
Wide age range – mean age 40 years
Slow grow...
REFERENCES
• Respiratory Medicine Case Reports 9
(2013) 18-20
• Arch Pathol Lab Med – Vol 131,
,
September 2007
• The new ...
CASE 5
CASE 5
CLINICAL PRESENTATION
 Male 25 years old
Male,
 Mass per abdomen since 4 months
 Bilateral undescended testes
 Radiolo...
PER OPERATIVE

 Persistant mullerian duct syndrome with left sided large
testicular tumor and right sided small testicula...
HISTOPATHOLOGY
 Gross – specimen altogether weighed 2140 grams and
measured 21 x 17 x 7 cms. Specimen consisted of a larg...
 Microscopy –
 Features of classical seminoma in both nodular masses
masses.
 Adjacent testicular parenchyma from the s...
ITGCN
Leydig cell hyperplasia
Seminoma ‐ classical
Seminoma
Endometrium + smooth muscle
DIFFERENTIALS
•
•
•
•
•
•
•

Leydig
L di cell h
ll hyperplasia with atrophic t b l and germ cell
l i
ith t
hi tubules
d
ll...
 Impression –
 Classical seminoma – bilateral testes
 Intratubular germ cell neoplasia – right testis
 P i t t Mulleri...
DISCUSSION
•
•
•
•
•
•

Rare form of male pseudohermaphroditisim ( 46 XY)
R
f
f
l
d h
h diti i
Persistence of mullerian du...
Case 6
CLINICAL DETAILS

• Male patient aged 37 years
• Fracture of L5 vertebra
• Blocks for opinion
Microscopy
• Tumor cells are polygonal to oval
• Arranged in distinctive organoid pattern
• Separated by fibrocollagenous ...
Initial diagnosis
• Neuroendocrine tumor
Differential diagnosis
•
•
•
•
•
•
•
•
•
•
•

Hemangioendothelioma
He angioendothelio a
PNET of vertebra
Mesenchymal chond...
IHC
COURTESY - NIMHANS
SYNAPTOPHYSIN
CHROMOGRANIN - A
PARAGANGLIOMA
• Primary / metastatic
• No clinical evidence of primary
sweating, palpitations,
• No history of sweating palpitations hyp...
• Primary paragangliomas of craniospinal axis arise in
cauda equina
• Encapsulated intradural masses attached to filum
ter...
Immunohistochemistry
• Chief cells - chromogranin, synaptophysin, neuron
specific enolase, serotonin, neurofilament and ne...
REFERENCES
1. Rosai J. Surgical pathology. 9th ed. 19(2): 2586 to 2587
2. Lmejjati M, Parker F, Lacroix C et al. “Paragang...
CASE 7
CLINICAL DETAILS
• Female patient aged 56 y
p
g
years
• ? Ovarian mass
• Blocks for opinion
p
MICROSCOPY
•
•
•
•
•
•
•
•
•

Tumor with spindle cells
Hyalinized and oedematous stroma
Bizarre hyperchromatic nuclei
Clum...
Differential diagnosis
•
•
•
•
•
•
•
•

Embryonal carcinoma
E b
l
i
Sarcomatous variant of yolk sac tumor
y
Sarcomatoid tr...
•
•
•
•
•
•
•
•

Atypical bizarre cellular leiomyoma
Symplastic leiomyoma
Metastatic krukenberg tumor
Sex cord stromal tum...
Signed out report
• Smooth muscle origin
• Benign nature

Symplastic leiomyoma
GROSS
1. Specimen of uterus cervix 8x3.5x3cm
p
E/S - Uterus – cauterized cavity
y
C/S – Endometrium – atrophic
Cervix – na...
Final diagnosis
Symplastic leiomyoma
• Atypical, bizarre, symplastic or pleomorphic
leiomyomas
• Spontaneously or in patients taking progestin
compounds
• Elec...
REFERENCES

1. Rosai J. Surgical pathology. 9th ed. 19(2):1569-1636
2.
2 Fechner RE. Atypical leiomyomas and synthetic pro...
Case 8
Case 8
56/F, case of intermittent 
painless hematuria.TURBT from 
lateral wall of urinary bladder
l
l ll f i
bl dd
Differential diagnosis
Differential diagnosis
•
•
•
•
•
•
•
•
•

Lipoid variant of invasive urothelial carcinoma
Li id i t...
Thought process
Thought process
• ??? Malignant melanoma
Perl s stain for iron
Perl’s stain for iron
Melanin bleach
Melanin bleach
HMB 45
HMB 45
Final diagnosis
Final diagnosis
• Malignant melanoma
– ? Primary
y
– ? Metastatic
Discussion 
Discussion
• Primary melanoma of bladder is very rare
• 19 odd cases reported in literature
19 odd cases repor...
Criteria for primary melanoma of 
bladder
• Ainsworth criteria
i
h i i
• Careful physical examination including the skin 
...
Treatment and prognosis
Treatment and prognosis
• R di l
Radical resection
ti
• Poor prognosis
• R f
References
•
•
•
•
•
...
Case 9
Case 9
• Skin biopsy in a male patient
• Age not known
Age not known
Differential diagnosis
Differential diagnosis
•
•
•
•
•
•
•
•
•

Cutaneous mastocytosis
C t
t t i
Dermal nevus
Glomus tumo...
Final diagnosis
Final diagnosis
• Cutaneous mastocytosis
Cutaneous mastocytosis
• 80% of cases are urticaria pigmentosa
% f
i i i
• Mast cells
– 8‐15 microns in diameter
– Round o...
Clinical symptoms
Clinical symptoms
• Release of histamines and leucotrienes
– Pruritis
– Itching
– Flushes
– Syncope
WHO classification of mastocytosis
WHO classification of mastocytosis
•

Cutaneous mastocytosis
– Maculopapular CM
– Diffu...
Case 10
Case 10
• 34 yr old male
• Azoospermia for evaluation.
for evaluation.
• Left and right testicular biopsy was done
Gross
• Pale brown tissue bit measuring 
0.6x0.3x0.3cm
Differential Diagnosis
Differential Diagnosis
Sertoli ll d l i t hi t ti
S t li cell nodule in atrophic testis.
Gonadoblas...
Final diagnosis
Final diagnosis
• Hamartomatous nodule in probable Androgen 
y y
insensitivity syndrome
Discussion
• Male AIS is a very rare disorder, affecting 
fewer than 1 in 100,000 births
• Two types‐ complete and incompl...
Statistics
• Affects 1 in 20,400 people
Affects 1 in 20,400 people
– 2/3 of cases inherited from mother
– 1/3 of cases com...
Androgen Receptor Gene
• AIS results from mutations in the androgen 
receptor gene, located on the long arm of the X 
chro...
References 
References
• 1991;10(2):126‐44.
• The androgen insensitivity syndrome
The androgen insensitivity syndrome 
(te...
•
•
•
•
•
•
•

Forty‐three patients with the androgen insensitivity syndrome (AIS), ages 
Forty three patients with the an...
References
• Arch Pathol Lab Med‐ Vol 123, March 1999
• Ackerman’s Surgical Pathology, Male
Ackerman s Surgical Pathology,...
Case 11
Case 11
• 1 yr 4 months female baby presented with 
chronic renal failure and failure to thrive
• Renal biopsy was...
Gross 
Gross
• Single linear grey brown tissue measuring 1.5 
g
cm in length.
Immunofluorescence
• One core with 6 glomeruli, all of which are 
g
g g g
q pp
negative for IgG, IgA, IgM, C3C, C1q, kappa...
Differential diagnosis
Differential diagnosis
• C t lli
Crystalline nephropathy
h
th
• Crystalline nephropathy‐ post chemo...
Final diagnosis
Final diagnosis
• Chronic tubulointerstitial nephritis secondary 
y
p
gy
g
to crystalluria morphology favo...
Hyperoxaluria
• Urinary oxalate excretion that exceeds 40 
i
l
i
h
d 0
mg/day.
• Primary ( rare genetic disease)
• Enteric...
Primary hyperoxaluria
Type I mutation of AGXT gene on chromosome 2 that codes for 
alanine glyoxylate aminotransferase
ala...
References
• Shekarriz B et al ; Hyperoxaluria ,emedicine, 
p
Apr 2010
• Ackerman’s Surgical Pathology, Urinary tract, 
Pg...
Case 12…..
Lesion – below sinus lining…..
Lesion –nodules in a 
p
pink stroma…..
Spindled stroma rich….
Nodules…..
Nodules
Large cells and…
Dirty looking “small cells”….
So…..
So
• Poorly circumscribed, submucosal lesion in 
sinus
• Nodules + spindled stroma
• N d l
Nodules: 
– large cells w...
Diagnoses…..
Diagnoses
•
•
•
•
•
•
•
•

Embryonal rhabdomyosarcoma ‐ 2
b
l h bd
Olfactory neuroblastoma‐ 2
y
Ganglioglioma...
S100

Synatophysin

MIB‐1 (Ki67)
Synaptophysin‐ ganglionic element

S100 = schwannian componet

Small cells – very focal synapto+, high MIB = neuroblastic
So…..
So
•
•
•
•

Poorly circumscribed, submucosal lesion in sinus
Poorly circumscribed submucosal lesion in sinus
Nodules...
Peripheral neuroblastic tumors 
Not so grey….
•
•
•
•

Classification…….
Cl ifi i
Staging……
Risk stratification……
Closely ...
Q1: Where do they come from?
Q1: Where do they come from?
Neural crest = sympathetic nervous system
Neuroblasts, Ganglion ...
Differentiate from ..for 
confusion/clarity
• Peripheral 
i h l
neuroblastic tumors 
(pNTs)
( NT )
• neoplastic cells with...
How do they look? 
International Neuroblastoma P th l
I t
ti
lN
bl t
Pathology Classification 
Cl ifi ti
(INPC ‐ Shimada s...
Neuroblastoma (poor diff),  Neuroblastoma (differ),  Neuroblastoma (undiff), 

Ganglioneuroblastoma: 
intermixed)
i t
i d)...
How do they behave? stratification….
How do they behave? stratification
• Clear stratification – “favourable”/
Clear strat...
How do they behave? stratification
How do they behave? stratification
• I t
International Neuroblastoma Ri k G
ti
lN
bl t
...
Why bother?...treatment
Why bother? treatment
• In European countries , the treatment of 
i
h
f
neuroblastoma patients dep...
Mostly triploid
(FISH)
No structural 
aberrations
•Surgery alone
•Standard 
chemotherapy
h
h

Structural 
aberrations

Two...
Bottom line….
Bottom line
• Our case
– Ganglioneuroblastoma, intermixed
g
,
– MKI: ?
– Favourable histology
Favourable his...
The Wrong Right
I screened the slide back and forth
As I peeked through the microscope
A furious looking cell stared at me...
My battered ego appeased
Out of the hospital stormed an egotist
Ecstatic at being proven a whiz
I deserved to treat myself...
Thank you
Thank you
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
Kciapm slide seminar 2014 presentation
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  1. 1. KCIAPM SLIDE SEMINAR ANAND DIAGNOSTIC LABORATORY ANAND DIAGNOSTIC LABORATORY 26/01/2014
  2. 2. CASE 1 35/F, LEFT HEMITHYROIDECTOMY 35/F, LEFT HEMITHYROIDECTOMY
  3. 3. GROSS APPEARANCE GROSS APPEARANCE Specimen of one lobe of thyroid measuring 3.5 x 2.0 x 2.5 cm Cut section of the specimen showed nodule measuring 3 x 2 cm 
  4. 4. MICROSCOPIC  MICROSCOPIC Hypercellular nodules
  5. 5. Cellular area showing pleomorphism of follicular cells  with nuclear enlargement and hyperchromasia, and with nuclear enlargement and hyperchromasia and pale‐staining colloid
  6. 6. Cellular areas showing hyperchromatic nuclei
  7. 7. Hyperchromatic enlarged nuclei  found at the edge of hyperplastic nodule 
  8. 8. Differential diagnosis  Differential diagnosis • • • • • • • • • • • • Follicular neoplasm with hurthle cell change F lli l l ith h thl ll h Hurthle cell neoplasm of unknown malignant potential Papillary carcinoma (Hurtle/Follicular variant) Nodular hyperplasia Nodular goitre with atypical adenoma Dyshormonogenetic goitre Oncocytic parathyroid adenoma with atypia Nodular goitre with adenomatous hyperplasia and radiation  changes h Follicular adenoma with bizarre nuclei Parathyroid adenoma y MNG with atypical adenoma Hurthlized colloid adenoma with bizarre nuclei
  9. 9. DIAGNOSIS OFFERED DIAGNOSIS   OFFERED Follicular neoplasm with Hurthle  changes  Hurthle cell neoplasm / Unknown  Hurthle cell neoplasm / Unknown malignant potential  Papillary carcinoma (Hurthle /  Papillary carcinoma (Hurthle / Follicular type)  Nodular hyperplasia  Why it is ruled out No neoplasm, multiple  nodules, no capsule No neoplasm, multiple  No neoplasm multiple nodules, no capsule No nuclear features N l f More colloid, should show  focal hyperplasia, no bizarre,  hyperchromatic nuclei.
  10. 10. Final diagnosis Final diagnosis • Dyshormonogenetic goitre
  11. 11. DIAGNOSIS • • • • • DYSHORMONOGENETIC   GOITRE DYSHORMONOGENETIC GOITRE Hypercellular nodules  with presence of cells  arranged in cords, microfollicular trabecular  di d i f lli l t b l pattern. Presence of pale staining colloid Presence of pale staining colloid Nuclear pleomorphism, hyperchromatic and  bizzare nuclei.  bizzare nuclei Presence of pleomorphism at the edge of the  hyperplastic nodules and not in the entire gland. hyperplastic nodules and not in the entire gland Focal areas of fibrosis.
  12. 12. DYSHORMONOGENETIC GOITRE DYSHORMONOGENETIC GOITRE • Rare, inherited usually autosomal recessive disorder  • C i bl k i T3 /T4 th Causing block in T3 /T4 pathway • Defects involve  TSH unresponsiveness TSH unresponsiveness Defective iodine transport Abnormal thyroid peroxidase  y p Formation of abnormal iodoprotein and defective  deiodination of monoiodotyrosine and diiodotyrosine – Abnormal th roglob lin s ntheses and e cretion Abnormal thyroglobulin syntheses and excretion – – – – • Rarely associated with deafness (Pendred’s syndrome)
  13. 13. DYSHORMONOGENETIC GOITRE DYSHORMONOGENETIC GOITRE MICROSCOPIC • Hypercellularity resulting from TSH stimulation of the gland • Cellular nodules of trabeculae, cords, with solid or microfollicular pattern  of epithelial cells with pale colloid.  of epithelial cells with pale colloid • May have papillary foci, marked cellular pleomorphism .  • Presence of pleomorphism at the edge of the hyperplastic nodules and  not in the entire gland. not in the entire gland • Mitosis, bizarre hyperchromatic nuclei are seen. • True invasion is rare. IMMUNOHISTOCHEMISTRY • Thyroglobulin positive • Calcitonin negative Ref :Vittal S, Chandrasekaran M, Bijai Kumar K, et al.Dyshormonogenetic Goitre. JR Coll Surg Edinb;1993;38:205‐207
  14. 14. CASE 2 40/F, MASTECTOMY SPECIMEN /, CLINICAL DIAGNOSIS OF PHYLLODES TUMOR
  15. 15. GROSS Mastectomy specimen measuring 18 x 12 x 6 cm with overlying skin measuring 15 x 10 x 2 cm Cut section showed a grey white mass 16 x 10 x 8 cm  Cut section showed a grey‐white mass 16 x 10 x 8 cm Areas of hemorrhage and cystic spaces 
  16. 16. Tumour composed of multiple nodules, each representing a duct filled with  neoplastic proliferation.
  17. 17. MICROSCOPIC Tumour arranged in solid nests ,sheets  and cribriform areas.  Tumour shows pushing margins. Infiltration is noted in the muscle.
  18. 18. Papillary areas with hyperchromatic nuclei and increased N/C ratio
  19. 19. Foci showing lymphovascular emboli  Foci showing lymphovascular emboli
  20. 20. Focal clusters of foamy macrophages seen in this section Focal clusters of foamy macrophages seen in this section
  21. 21. Differential diagnosis Differential diagnosis • Papillary carcinoma ill i – ? Primary, ? Secondary • • • • • • • Papillary transitional carcinoma p y Papillary carcinoma in situ Micropapillary carcinoma with invasion Invasive papillary carcinoma Invasive papillary carcinoma Adenomyoepithelioma Malignant myoepithelioma Papillary carcinoma with solid and papillary areas
  22. 22. DIAGNOSIS   OFFERED Papillary transitional cell carcinoma Why it is ruled out NO transitional type of epithelium as  described in literature. NO whorling or  streaming pattern. Papillary carcinoma in situ Usually resembles ordinary cribriform DCIS on  Usually resembles ordinary cribriform DCIS on papillary stalks. Myoepithelial cells MAY be  present along stalks.  Micropapillary carcinoma with vascular  invasion Shows  fibrovascular cores. Psammoma bodies not seen. Tubulo‐alveolar pattern NOT  seen. seen Invasive papillary carcinoma Papillary carcinoma of breast tall cell  variant Adenomyoepithelioma/ malignant  myoepithelioma Papillary carcinoma with solid papillary  areas NO “tall cells” seen. Nuclear criteria also not  fulfilled Histology not consistent with diagnosis, 2  types of cells needed types of cells needed
  23. 23. DIAGNOSIS Solid variant of invasive papillary carcinoma S lid i t fi i ill i • Multiple  nodules, each representing a duct filled  with neoplastic proliferation. Cells are ovoid to  with neoplastic proliferation Cells are ovoid to spindle exhibiting solid pattern with  fibrovascular   network. network • Other features observed were  microcystic spaces  and foamy macrophages. and foamy macrophages. • Well defined pushing borders • ER positive PR focally positive P63 negative ER positive, PR focally positive, P63 negative. 
  24. 24. SOLID VARIANT OF INVASIVE  PAPILLARY CARCINOMA • A di ti t li i l tit A distinct clinical entity .  • Controversial whether they could be  considered  low–grade tumours   low grade tumours • Originate from large or dilated ducts • Pi Primary affect older women occasionally seen in  ff ld i ll i women below 50 years of age • 90% il t l d i i th 90% unilateral and arise in the central area of the  t l f th breast • Present with a bloody nipple discharge Present with a bloody nipple discharge • Nodular configuration and well circumscribed 
  25. 25. SOLID VARIANT OF INVASIVE  PAPILLARY CARCINOMA • Mi Microscopically these tumours show multiple nodules,  i ll th t h lti l d l each representing a duct filled with neoplastic  p proliferation. Cells are ovoid to spindle exhibiting solid  p g pattern with  fibrovascular  network. • Other features observed may be organoid pattern,  microcystic spaces and foamy macrophages i ti df h • Well defined pushing borders • Positive for ER and PR Positive for ER and PR • Negative for CK5/6. • Other markers useful in diagnosis include Calponin Other markers useful in diagnosis include Calponin,  P63, Skeletal muscle myosin heavy chain
  26. 26. References  References • Tavassoli FA, Devilee P. World Health Organization  Classification of Tumours, Tumours of the Breast  and Female Genital Organs.2nd edition,Lyon France: IARC Press. • Gallager HS.Pathological types of breast cancer:  their prognosis.Cancer.1984;53:623‐629. their prognosis Cancer 1984;53:623‐629 • Pettinato G, Manivel CJ, Panico L etal.Invasive micropapillary carcinoma of the breast;Am J Clin i ill i f h b Cli Pathol.2004:121(6) 857‐866.
  27. 27. CASE 3 CASE 3 21/F, TOTAL THYROIDECTOMY SPECIMEN 21/F, TOTAL THYROIDECTOMY SPECIMEN
  28. 28. GROSS Total Thyroidectomy specimen measuring 7 x 6 x 3.5 cm Total Thyroidectomy specimen measuring 7 x 6 x 3 5 cm Enlarged right lobe
  29. 29. GROSS Cut section of right lobe shows friable pale brown  tumor measuring 4.5 x 3 x 3 cm
  30. 30. Area showing cribriform pattern with back‐to‐back follicles g p
  31. 31. Cribriform areas under higher magnification Cribriform areas under higher magnification
  32. 32. Complex branching papillary structures lined by cuboidal cells p gp p y y
  33. 33. Focal areas showing squamoid nodules without evidence of keratinization Focal areas showing squamoid nodules without evidence of keratinization
  34. 34. Areas showing lymphovascular emboli Areas showing lymphovascular emboli
  35. 35. Differential diagnosis Differential diagnosis • • • • • • • • Mixed medullary and papillary carcinoma Morular cribriform variant of papillary carcinoma p p y Papillary carcinoma Columnar cell carcinoma C l ll i Tall cell variant of papillary carcinoma Papillary carcinoma follicular variant Diffuse sclerosing Diffuse sclerosing variant Papillary variant of medullary carcinoma
  36. 36. DIAGNOSIS OFFERED DIAGNOSIS OFFERED DIAGNOSIS   OFFERED DIAGNOSIS OFFERED Papillary cell carcinoma Tall cell variant ll ll Diffuse sclerosing variant Papillary variant of medullary carcinoma Papillary thyroid carcinoma‐ Cribriform morular (with foci of  C ib if l ( ith f i f tall cell variant )  Why it is ruled Why it is ruled out Nuclear features of PTC present.  However, doesn't satisfy criteria of 'tall  d ' f f ' ll cells' Lymphocytic infiltrate usually seen along  with other features with prominent  sclerosing areas. Papillae are lined by multiple layers of  p y p y neoplastic cells with small and irregular  nuclei containing condensed chromatin.  Lack typical nuclear features of papillary  Lack typical nuclear features of papillary carcinoma
  37. 37. DIAGNOSIS Papillary Thyroid carcinoma (PTC) Cribriform morular  Papillary Thyroid carcinoma (PTC) Cribriform‐morular variant. • Complex branching papillae lined by cuboidal cells Complex branching papillae, lined by cuboidal cells.  Nuclei are  hyperchromatic, optically clear, with  longitudinal grooves .There is a blending of several  longitudinal grooves There is a blending of several histological patterns . • Cribriform areas with back to back crowding with Cribriform areas with back to back crowding,  with  arches of cells  in the absence of intervening   fibrovascular stroma fibrovascular stroma • Solid areas consisting of morules of squamoid cells that   do not show any keratinization or intercellular bridges.
  38. 38. Papillary Thyroid Carcinoma  Cribriform‐Morular Variant • PTC (C‐MV) is rare morphologic entity • First described by Harach et al in association with FAP ( FAMILIAL  ADENOMATOSIS POLYPOSIS) • Commonly seen in young females usually less than 30 years of  age • Gross well circumscribed, somewhat lobulated mass, ranging  from 1.5‐2 cms in size. Sometimes show multiple satellite  from 1 5 2 cms in size Sometimes show multiple satellite nodules • PTC (C‐MV) carries a better prognosis than other aggressive PTC (C‐MV)  carries a better prognosis than other aggressive  variants of PTC ( tall cell, columnar, diffuse sclerosing and diffuse  yp ) follicular types) 
  39. 39. REFERENCES • Harach HR, Williams GT, Williams ED. Familial  adenomatous polyposis associated with thyroid  adenomatous polyposis associated with thyroid carcinoma: a distinct type of follicular cell  neoplasm. Histopathology.1994;6: 549 561. neoplasm Histopathology 1994;6: 549‐561 • Cameselle‐TeijeiroJ Chan JK Cribriform‐morular Cameselle‐TeijeiroJ, Chan JK. Cribriform‐morular  vriant of papillary carcinoma; a distinctive variant  p presenting the sporadic counterpart of familial  g p p ff adenomatous polyposis associated thyroid  carcinoma? Mod Pathol.1999;4: 400‐411.
  40. 40. CASE 4 CASE 4
  41. 41. CLINICAL PRESENTATION  Female , 39 years old  Complaints of  fever and cough since 2 months  P t hi t Past history of pulmonary tuberculosis 4 years back f l t b l i 4 b k
  42. 42. LAB INVESTIGATIONS Bronchoscopy Bronchial wash – AFB and cytology CT scan RML biopsy
  43. 43.  Bronchoscopy - mass occluding right middle lobe bronchus  Bronchial wash – AFB – negative Cytology – negative for atypical cells
  44. 44.  CT scan –  soft tissue density mass measuring 5.4 x 5.7 x 5.8 cms in the right middle lobe of lung in the perihilar region.  Enlarged pretracheal and subcarinal group of lymph nodes largest measuring 2.1 x 1.3 cms.  Features suggestive of BRONCHOGENIC CARCINOMA with metastasis to pretracheal and subcarinal lymphnodes.
  45. 45.  Biopsy –  Gross - grey white tissue fragment measuring 0.2x0.2x0.1 cms.  Microscopy – small sized bland appearing tumor cells with round to oval nucleus arranged in sheets and separated by hyalinized stroma. y  I Impression – F t i Features favoring a benign neoplasm of salivary f i b i l f li gland type; possibility of myoepithelioma is suggested.
  46. 46. PER‐ PER‐OPERATIVE  Right posterolateral thoracotomy, bilobectomy and lymph node clearance  Per operative findings – hard mass measuring about 6 x 4 cms in right middle lobe. Mutiple subcarinal and paratracheal lymphnodes.
  47. 47. HISTOPATHOLOGY Gross – right middle and lower lobes of lung. Tumor with pushing margins in the middle lobe with occlusion of bronchus. Tumor g 6 x 5 x 4 cms. Yellow white appearance. dissection , largest node 2.5 x 1.0 x 0.5 cms. Lymph node
  48. 48.  Microscopy  Tumor composed of squmaous cells, intermediate cells and mucin secreting cells.  All lymph nodes exhibit reactive changes changes.
  49. 49. Bronchial lining 
  50. 50. Adenoid cystic – Adenoid cystic – like areas
  51. 51. Pleomorphic adenoma like areas
  52. 52. Squamous islands
  53. 53. DIFFERENTIALS  • • • • • • • • • • Large cell undifferntiated carcinoma L ll diff ti t d i Large cell neuroendocrine carcinoma Mucoepidermoid carcinoma Squamous cell carcinoma Lymphoepithelioma like carcinoma Adenoid cystic carcinoma Neuroendocrine tumor Adenosquamous carcinoma Ad i Adenoid cystic variant of diffuse malignant mesotheliomabiphasic type with ? Asbestosis p yp Neuroendocrine carcinoma mixed variant
  54. 54.  Impression –  low grade salivary epithelial neoplasm, ? Low grade mucoepidermoid carcinoma , ? Pleomorphic adenoma.
  55. 55. IMMUNOHISTOCHEMISTRY  Pan CK – positive in tumor cells  S-100 – negative in tumor cells  Vimentin – negative in tumor cells  GFAP ( courtesy NIMHANS ) – negative in tumor cells t ti i t ll
  56. 56. Pan CK
  57. 57. S 100
  58. 58. VIMENTIN
  59. 59. Final diagnosis  Final diagnosis • Mucoepidermoid carcinoma of the lung – Low  g grade
  60. 60. DISCUSSION Rare primar tumor of lung – 0 1 – 0 2 % primary t mor l ng 0.1 0.2 Wide age range – mean age 40 years Slow growing tumor Main bronchus- submucosal glands of the bronchus • Classified under salivary gland neoplasms of the lung • Lobectomy, local resection or endoscopic removal – excellent prognosis • Diff Differential di ti l diagnosis iis adenosquamous and i d d adenocarcinoma of lung • • • •
  61. 61. REFERENCES • Respiratory Medicine Case Reports 9 (2013) 18-20 • Arch Pathol Lab Med – Vol 131, , September 2007 • The new World Health Organization classification of lung tumourE. Brambilla 1 , W.D. Travis 2 , T.V. Colby 3 , B. Corrin 4 and Y. Shimosato 5ERJ  December 1, 2001 vol. 18 no. 6 1059 1068 December 1 2001 vol 18 no 6 1059‐1068
  62. 62. CASE 5 CASE 5
  63. 63. CLINICAL PRESENTATION  Male 25 years old Male,  Mass per abdomen since 4 months  Bilateral undescended testes  Radiological finding – mass in right lumbar region measuring 20 x 20 cms. Extension upto liver superiorly pelvis inferiorly and cms superiorly, crossing midline laterally.
  64. 64. PER OPERATIVE  Persistant mullerian duct syndrome with left sided large testicular tumor and right sided small testicular tumor
  65. 65. HISTOPATHOLOGY  Gross – specimen altogether weighed 2140 grams and measured 21 x 17 x 7 cms. Specimen consisted of a large, solid pale brown tumor mass, spermatic cord, omentum and a smaller tumor mass. Mid segment of spermatic cord showed a g p nodular area measuring 2 cms.
  66. 66.  Microscopy –  Features of classical seminoma in both nodular masses masses.  Adjacent testicular parenchyma from the smaller testicuar mass exhibit features of intratubular germ cell neoplasia.  Nodular area in spermatic cord exhibits endometrial glands , endometrial stroma and smooth muscle.  Omentum exhibiting features of reactive mesothelial hyperplasia. h perplasia
  67. 67. ITGCN
  68. 68. Leydig cell hyperplasia
  69. 69. Seminoma ‐ classical
  70. 70. Seminoma
  71. 71. Endometrium + smooth muscle
  72. 72. DIFFERENTIALS • • • • • • • Leydig L di cell h ll hyperplasia with atrophic t b l and germ cell l i ith t hi tubules d ll tumor- seminoma Persistent mullerian duct syndrome with seminoma and leydig y y g cell hyperplasia Persistent mullerian duct syndrome with cryptorchidism and ITGCN and seminoma Gonadal dysgenesis True hermaphrodite p Anaplastic seminoma Spermatocytic seminoma
  73. 73.  Impression –  Classical seminoma – bilateral testes  Intratubular germ cell neoplasia – right testis  P i t t Mullerian duct syndrome Persistent M ll i d t d
  74. 74. DISCUSSION • • • • • • Rare form of male pseudohermaphroditisim ( 46 XY) R f f l d h h diti i Persistence of mullerian duct structures due to lack of antimullerian hormone X linked or autosomal recessive Phenotypically male Unilateral or bilateral cryptorchidism 15% risk of germ cell neoplasms and ITGCN
  75. 75. Case 6 CLINICAL DETAILS • Male patient aged 37 years • Fracture of L5 vertebra • Blocks for opinion
  76. 76. Microscopy • Tumor cells are polygonal to oval • Arranged in distinctive organoid pattern • Separated by fibrocollagenous stroma and Sepa ated b oco age ous st o a a d surrounded by blood vessels
  77. 77. Initial diagnosis • Neuroendocrine tumor
  78. 78. Differential diagnosis • • • • • • • • • • • Hemangioendothelioma He angioendothelio a PNET of vertebra Mesenchymal chondrosarcoma Angiomatous meningioma Capillary hemangioblastoma p y g Paraganglioma Epithelioid hemangioendothelioma Metastatic RCC Multiple myeloma Metastatic carcinoma carcino a Telangiecatic Osteosarcoma
  79. 79. IHC COURTESY - NIMHANS
  80. 80. SYNAPTOPHYSIN
  81. 81. CHROMOGRANIN - A
  82. 82. PARAGANGLIOMA
  83. 83. • Primary / metastatic • No clinical evidence of primary sweating, palpitations, • No history of sweating palpitations hypertension
  84. 84. • Primary paragangliomas of craniospinal axis arise in cauda equina • Encapsulated intradural masses attached to filum terminale or less commonly the spinal roots • Functionally silent • Erosion into the neighbouring bone • Osseous metastases • Good number of cases of primary paragangliomas of the i l th spinal canal have been published lh b bli h d
  85. 85. Immunohistochemistry • Chief cells - chromogranin, synaptophysin, neuron specific enolase, serotonin, neurofilament and neural ifi l i fil d l cell adhesion molecule • S-100 protein negative
  86. 86. REFERENCES 1. Rosai J. Surgical pathology. 9th ed. 19(2): 2586 to 2587 2. Lmejjati M, Parker F, Lacroix C et al. “Paraganglioma of sacral spine”. Neurosciences 2011;16(3):270-272. ; ( ) 3. Shin JY, lee SM, Hwang MY et al. “ MR findings of spinal paraganglioma:report of 3 cases”. J Korean Med Sci. 2001;16:522 6. cases Sci 2001;16:522-6 4. Moran Ca, Rush W, Mena H. “primary spinal paragangliomas:a clinicopathological and immunohistochemical study of 30 cases . cases” Histopathology. 1997;31(2):167-173
  87. 87. CASE 7
  88. 88. CLINICAL DETAILS • Female patient aged 56 y p g years • ? Ovarian mass • Blocks for opinion p
  89. 89. MICROSCOPY • • • • • • • • • Tumor with spindle cells Hyalinized and oedematous stroma Bizarre hyperchromatic nuclei Clumped chromatin Prominent nucleoli Multinucleated forms No necrosis Occasional mitosis (0-1/10HPF) Ovarian stroma not identified
  90. 90. Differential diagnosis • • • • • • • • Embryonal carcinoma E b l i Sarcomatous variant of yolk sac tumor y Sarcomatoid transformation of stromal tumor Fibrosarcoma Poorly differentiated ovarian carcinoma Angiosarcoma Nodular fascitis Leiomyosarcoma
  91. 91. • • • • • • • • Atypical bizarre cellular leiomyoma Symplastic leiomyoma Metastatic krukenberg tumor Sex cord stromal tumor Sclerosing stromal tumor of ovary Endometrial stromal sarcoma Malignant mixed mullerian tumor Retroperitoneal Kaposi’s sarcoma
  92. 92. Signed out report • Smooth muscle origin • Benign nature Symplastic leiomyoma
  93. 93. GROSS 1. Specimen of uterus cervix 8x3.5x3cm p E/S - Uterus – cauterized cavity y C/S – Endometrium – atrophic Cervix – nabothian cyst y 2. Irregular yellow tissue 4x3x3cm C/S – Whorled appearance Ovary not identified
  94. 94. Final diagnosis Symplastic leiomyoma
  95. 95. • Atypical, bizarre, symplastic or pleomorphic leiomyomas • Spontaneously or in patients taking progestin compounds • Electron microscopy demonstrates actin filaments with associated dense bodies as well as incomplete basal lamina (features characteristic of smooth muscle cells) • Low risk of recurrence
  96. 96. REFERENCES 1. Rosai J. Surgical pathology. 9th ed. 19(2):1569-1636 2. 2 Fechner RE. Atypical leiomyomas and synthetic progestin therapy Am J RE therapy. Clin Pathol. 1968,49:697-703
  97. 97. Case 8 Case 8 56/F, case of intermittent  painless hematuria.TURBT from  lateral wall of urinary bladder l l ll f i bl dd
  98. 98. Differential diagnosis Differential diagnosis • • • • • • • • • Lipoid variant of invasive urothelial carcinoma Li id i t f i i th li l i Transitional cell carcinoma Primary small cell carcinoma Clear cell carcinoma Malignant melanoma High grade urothelial carcinoma Neuroendocrine tumor of bladder Metastatic RCC Pigmented paraganglioma
  99. 99. Thought process Thought process • ??? Malignant melanoma
  100. 100. Perl s stain for iron Perl’s stain for iron
  101. 101. Melanin bleach Melanin bleach
  102. 102. HMB 45 HMB 45
  103. 103. Final diagnosis Final diagnosis • Malignant melanoma – ? Primary y – ? Metastatic
  104. 104. Discussion  Discussion • Primary melanoma of bladder is very rare • 19 odd cases reported in literature 19 odd cases reported in literature • Mostly metastatic from the skin or urethra
  105. 105. Criteria for primary melanoma of  bladder • Ainsworth criteria i h i i • Careful physical examination including the skin  p y g with Wood’s light together with detailed  y history to exclude cutaneous melanoma • Exclusion of visceral melanoma • Pattern of recurrence consistent with primary Pattern of recurrence consistent with primary  melanoma of bladder • Histologically proved primary atypical  melanocytes
  106. 106. Treatment and prognosis Treatment and prognosis • R di l Radical resection ti • Poor prognosis • R f References • • • • • • • Jalal Eddine El Ammari et al, “Primary malignant melanoma of the bladder,” Case reports in  urology,vol.2011 B. S. Stein and A. R. Kendall,  Malignant melanoma of the genitourinary tract, Journal of B S Stein and A R Kendall “Malignant melanoma of the genitourinary tract ” Journal of  Urology, vol. 132, no. 5, pp. 859–868, 1984. View at Scopus A. M. Ainsworth, et al., “Primary malignant melanoma of the urinary bladder,” Cancer, vol.  37, no. 4, pp. 1928–1936, 1976. View at Scopus B. Helpap,  Nonepithelial neoplasms of the urinary bladder, Virchows Archiv, vol. 439, no. 4,  B Helpap “Nonepithelial neoplasms of the urinary bladder ” Virchows Archiv vol 439 no 4 pp. 497–503, 2001. View at Publisher ∙ View at Google Scholar ∙ View at Scopus M. C. Wheelock, “Sarcoma of the urinary bladder,” The Journal of Urology, vol. 48, p. 628,  1942. N. M. Anichkov and A. A. Nikonov,  Primary malignant melanomas of the bladder, The N M Anichkov and A A Nikonov “Primary malignant melanomas of the bladder ” The  Journal of Urology, vol. 128, no. 4, pp. 813–815, 1982. C. T. Su and C. L. Prince, “Melanoma of the bladder,” The Journal of Urology, vol. 87, pp. 365– 367, 1962.
  107. 107. Case 9 Case 9 • Skin biopsy in a male patient • Age not known Age not known
  108. 108. Differential diagnosis Differential diagnosis • • • • • • • • • Cutaneous mastocytosis C t t t i Dermal nevus Glomus tumor Leukaemic infiltration Cutaneous plasmacytoma Lymphomatoid papillomatosis, DLE ??? Urticaria pigmentosa pg Metastatic cutaneous deposit‐ Adenocarcinoma
  109. 109. Final diagnosis Final diagnosis • Cutaneous mastocytosis
  110. 110. Cutaneous mastocytosis • 80% of cases are urticaria pigmentosa % f i i i • Mast cells – 8‐15 microns in diameter – Round or oval or fusiform in shape Round or oval or fusiform in shape – Granular cytoplasm – Granules stain metachromatically with toludene Granules stain metachromatically with toludene blue or giemsa – Granules are modified lysosomes containing Granules are modified lysosomes containing  histamines and leukotrienes
  111. 111. Clinical symptoms Clinical symptoms • Release of histamines and leucotrienes – Pruritis – Itching – Flushes – Syncope
  112. 112. WHO classification of mastocytosis WHO classification of mastocytosis • Cutaneous mastocytosis – Maculopapular CM – Diffuse CM – Mastocytoma of skin of skin • Indolent systemic mastocytosis(SM) – Smoldering SM – Isolated bone marrow mastocytosis Isolated bone marrow mastocytosis • • Systemic mastocytosis with an associated clonal hematological non‐mast  cell lineage disease Aggressive systemic mastocytosis Aggressive systemic mastocytosis – With eosinophilia • Mast cell leukaemia – Aleukaemic MCL • • Mast cell sarcoma Extracutaneous mastocytoma
  113. 113. Case 10 Case 10 • 34 yr old male • Azoospermia for evaluation. for evaluation. • Left and right testicular biopsy was done
  114. 114. Gross • Pale brown tissue bit measuring  0.6x0.3x0.3cm
  115. 115. Differential Diagnosis Differential Diagnosis Sertoli ll d l i t hi t ti S t li cell nodule in atrophic testis. Gonadoblastoma Sex cord stromal tumor with annular tubules . Testicular microlithiasis Complete maturation arrest with corpora  amylacea and microlithiasis. • Partial maturation arrest with testicular  microlithiasis • Parasitic cysts • ITGCN • • • • •
  116. 116. Final diagnosis Final diagnosis • Hamartomatous nodule in probable Androgen  y y insensitivity syndrome
  117. 117. Discussion • Male AIS is a very rare disorder, affecting  fewer than 1 in 100,000 births • Two types‐ complete and incomplete • X li k d X‐ linked male pseudohermaphroditism l d h h di i
  118. 118. Statistics • Affects 1 in 20,400 people Affects 1 in 20,400 people – 2/3 of cases inherited from mother – 1/3 of cases come from a spontaneous mutation in 1/3 of cases come from a spontaneous mutation in  the egg • No effect on life expectancy p y • No racial differences • A genetic condition where affected people have male  g p p chromosomes and male gonads with complete or partial  feminization of the external genitals • An inherited X linked recessive disease with a mutation An inherited X‐linked recessive disease with a mutation  in the Androgen Receptor (AR) gene resulting in: – Functioning Y sex chromosome g – Abnormality on X sex chromosome
  119. 119. Androgen Receptor Gene • AIS results from mutations in the androgen  receptor gene, located on the long arm of the X  chromosome (Xq11‐q12). • The AR gene provides instructions to make the  protein called androgen receptor, which allows  cells to respond to androgens, such as  testosterone, and directs male sexual  d di l l development. • A d Androgens also regulate hair growth and sex drive l l h i h d di • Mutations include complete or partial gene  deletions, point mutations and small insertions or  d l ti i t t ti d ll i ti deletions.
  120. 120. References  References • 1991;10(2):126‐44. • The androgen insensitivity syndrome The androgen insensitivity syndrome  (testicular feminization): a clinicopathologic study of 43 cases. study of 43 cases • Rutgers JL, Scully RE. University of California,  Los Angeles
  121. 121. • • • • • • • Forty‐three patients with the androgen insensitivity syndrome (AIS), ages  Forty three patients with the androgen insensitivity syndrome (AIS) ages 14 to 83 (average 27) years, were studied. Forty patients had complete AIS and three patients had incomplete AIS. Microscopic examination of the testes revealed immature tubules, which  Microscopic examination of the testes revealed immature tubules which contained rare spermatogonia in 28% of the cases. Prominent Leydig cells and a spindle‐cell stroma resembling ovarian  stroma were found in a majority of cases were found in a majority of cases.  The organization of the testicular parenchyma could be classified into one  of four patterns: diffuse tubulostromal, lobular tubulostromal, mixed  , p tubulostromal, or stromal‐predominant. Hamartomas were present in 63% and Sertoli cell adenomas in 23% of the  cases.  g p p p Malignant tumors developed in 9% of the patients and comprised two  seminomas, one intratubular germ cell neoplasm with early stromal invasion, and a malignant sex cord tumor
  122. 122. References • Arch Pathol Lab Med‐ Vol 123, March 1999 • Ackerman’s Surgical Pathology, Male Ackerman s Surgical Pathology, Male  reproductive system , Pg 1438‐ 1439
  123. 123. Case 11 Case 11 • 1 yr 4 months female baby presented with  chronic renal failure and failure to thrive • Renal biopsy was sent for light microscopy and  immunofluorescence. immunofluorescence
  124. 124. Gross  Gross • Single linear grey brown tissue measuring 1.5  g cm in length.
  125. 125. Immunofluorescence • One core with 6 glomeruli, all of which are  g g g g q pp negative for IgG, IgA, IgM, C3C, C1q, kappa  and lambda.
  126. 126. Differential diagnosis Differential diagnosis • C t lli Crystalline nephropathy h th • Crystalline nephropathy‐ post chemotherapy for leukemia /  lymphoma y p • Crystalluria – Urate • Oxalosis • Infantile nephropathic cystinosis • Nephrocalcinosis • T b l i t titi l nephritis associated with tubular necrosis Tubulointerstitial h iti i t d ith t b l i • Nephrocalcinois • Storage disease ? Storage disease ? • Multicystic renal dysplasia • Nephronophthisis p p
  127. 127. Final diagnosis Final diagnosis • Chronic tubulointerstitial nephritis secondary  y p gy g to crystalluria morphology favoring Oxaluria.
  128. 128. Hyperoxaluria • Urinary oxalate excretion that exceeds 40  i l i h d 0 mg/day. • Primary ( rare genetic disease) • Enteric • Dietary  • Idiopathic or mild hyperoxaluria
  129. 129. Primary hyperoxaluria Type I mutation of AGXT gene on chromosome 2 that codes for  alanine glyoxylate aminotransferase alanine glyoxylate aminotransferase Type II mutation of GRHPR gene on chromosome 9 that codes  Type II mutation of GRHPR gene on chromosome 9 that codes for glyoxylate reductase and hydroxypyruvate reductase.
  130. 130. References • Shekarriz B et al ; Hyperoxaluria ,emedicine,  p Apr 2010 • Ackerman’s Surgical Pathology, Urinary tract,  Pg‐ Pg 1231 • Diagnostic pathology kidney disease , Colvin‐ Pg4‐ 106
  131. 131. Case 12…..
  132. 132. Lesion – below sinus lining…..
  133. 133. Lesion –nodules in a  p pink stroma…..
  134. 134. Spindled stroma rich….
  135. 135. Nodules….. Nodules Large cells and…
  136. 136. Dirty looking “small cells”….
  137. 137. So….. So • Poorly circumscribed, submucosal lesion in  sinus • Nodules + spindled stroma • N d l Nodules:  – large cells with prominent nucleoli – Component of dirty looking small cells in  aggregates
  138. 138. Diagnoses….. Diagnoses • • • • • • • • Embryonal rhabdomyosarcoma ‐ 2 b l h bd Olfactory neuroblastoma‐ 2 y Ganglioglioma ‐2 Astrocytoma ‐2 Astrocytoma 2 Carcinosarcoma ‐1 Rhinoscleroma ‐1 Melanoma  1 Melanoma ‐1 Ganglioneuroblastoma‐ 1
  139. 139. S100 Synatophysin MIB‐1 (Ki67)
  140. 140. Synaptophysin‐ ganglionic element S100 = schwannian componet Small cells – very focal synapto+, high MIB = neuroblastic
  141. 141. So….. So • • • • Poorly circumscribed, submucosal lesion in sinus Poorly circumscribed submucosal lesion in sinus Nodules + spindled stroma Stroma: schwannian (S100 pos) Nodules:  Nodules: – large cells with prominent nucleoli: ganglionic (neuronal marker synaptophysin (neuronal marker synaptophysin pos) – Component of dirty looking small cells in aggregates  (neuroblastic: synapto focal pos, high MIB‐1) (neuroblastic: synapto focal pos high MIB 1) Ganglioneuroblastoma
  142. 142. Peripheral neuroblastic tumors  Not so grey…. • • • • Classification……. Cl ifi i Staging…… Risk stratification…… Closely related to the molecular/genetic  Closely related to the molecular/genetic properties of the tumors of individual cases not – tumor margins/necrosis/vascular invasion/  tumor margins/necrosis/vascular invasion/ spread…as in other tumors Players….pathology…..behaviour (pathobiology…)
  143. 143. Q1: Where do they come from? Q1: Where do they come from? Neural crest = sympathetic nervous system Neuroblasts, Ganglion cells, Schwann cells Satellite cell Ganglion cell Nerve roots Neck to pelvis……
  144. 144. Differentiate from ..for  confusion/clarity • Peripheral  i h l neuroblastic tumors  (pNTs) ( NT ) • neoplastic cells with a  neuronal phenotype  l h • of neuronal (neural  crest) cellular origin...  t) ll l i i • deletion of  chromosome 1p and  h 1 d MYCN amplification • pPNET ( i h l PNET (peripheral  primitive  neuroectodermal tumor) • neuronal phenotype but  • of unknown (presumably  f k ( bl non‐neuronal) origin • unique chromosomal  i h l translocation fusing  EWS/ETS
  145. 145. How do they look?  International Neuroblastoma P th l I t ti lN bl t Pathology Classification  Cl ifi ti (INPC ‐ Shimada system) • Four categories are discriminated according to the degree of  differentiation [ganglionic cells 'organoid' maturation with the development  cells,  organoid maturation with the development of a Schwann cell stroma, and co‐existence of clones of  different maturity or of distinct aggressiveness]:  Neuroblastoma (Schwannian stroma‐poor)  (undifferentiated, poorly differentiated, dfferentiating) Ganglioneuroblastoma intermixed  (Schwannian stroma‐rich) Ganglioneuroblastoma nodular  g (composite Schwannian stroma‐rich/and stroma‐poor) Ganglioneuroma (Schwannian stroma‐dominant)  (maturing, mature) (maturing mature)
  146. 146. Neuroblastoma (poor diff),  Neuroblastoma (differ),  Neuroblastoma (undiff),  Ganglioneuroblastoma:  intermixed) i t i d) Ganglioneuroblastoma:  nodular) Ganglioneuroma:  Ganglion cells+ schwann cell) Ganglion cells+ schwann cell) Neuronal markers: Synaptophysin, NSE, MAP2, beta tubulin Neuronal markers: Synaptophysin NSE MAP2 beta tubulin Stroma – S100, GFAP
  147. 147. How do they behave? stratification…. How do they behave? stratification • Clear stratification – “favourable”/ Clear stratification  favourable /  “unfavourable” clinical/biological behaviors:  • Favourable (with/without treatment) Favourable (with/without treatment) – involution,  – spontaneous regression spontaneous regression,  – tumor maturation,  • Unfavorable: OR aggressive progression Unfavorable: OR aggressive progression, • Closely related to the molecular/genetic  properties of the tumors of individual cases not – i f h f i di id l tumor margins/necrosis/vascular invasion/  spread… d
  148. 148. How do they behave? stratification How do they behave? stratification • I t International Neuroblastoma Ri k G ti lN bl t Risk Grouping,  i INRG: Prior to any treatment patients will be put  into a risk category into a risk category • Favourable/unfavourable histology – Age – Mitosis/karryorhhexis index (MKI) • Low: <100/5000 cells / • Intermediate: 100‐200/5000 cells • High: >200/5000  cells – DNA l id (FISH) DNA ploidy – MYCN amplification status
  149. 149. Why bother?...treatment Why bother? treatment • In European countries , the treatment of  i h f neuroblastoma patients depends on  – age at diagnosis (below or over 1 year of age),  – extent of the disease (stage)  g – a genetic parameter, i.e. the amplification of the  MYCN oncogene • In United States and Australia, DNA Index of  the tumour cells and histopathology (INPC)  the tumour cells and histopathology (INPC) are also included in therapy stratification 
  150. 150. Mostly triploid (FISH) No structural  aberrations •Surgery alone •Standard  chemotherapy h h Structural  aberrations Two biological/clinical groups: DNA ploidy Source: Atlas of cytogenetics in Oncology & Hematology •Surgery alone •Mutiagent  chemotherapy •Myeloablative  M l bl ti chemo with SCR •External  radiotherapy •MIBG…..
  151. 151. Bottom line…. Bottom line • Our case – Ganglioneuroblastoma, intermixed g , – MKI: ? – Favourable histology Favourable histology
  152. 152. The Wrong Right I screened the slide back and forth As I peeked through the microscope A furious looking cell stared at me Eureka! I exclaimed with pride and glee p g ‘Carcinoma’ was my undoubted decree My adamant colleague refused to agree He made a mockery of my grey cell ability As he dismissed my verdict with a tinge of hostility ‘Tis just a inflammatory cell, buddy As benign as a dead flea! My expertise doubted, my self‐esteem trampled A severe blow to my medical arrogance I took i up as a challenge k it h ll My insult I needed to avenge How can “I” be proven erroneous? Both of us sought the counsel of Big Boss Whose eyes can swoop on a cell like a hawk I prayed my belligerent colleague be proven wrong p y y g g p g And my joy knew no bounds “It is malignancy” he assertively pronounced
  153. 153. My battered ego appeased Out of the hospital stormed an egotist Ecstatic at being proven a whiz I deserved to treat myself to a drink Three cheers for me –An adept pathologist! On my way I glanced at the lady, frail and old Awaiting her young son’s report with hope I did not to notice her, of course d d o o o ce e , o cou se Coz I wasn’t going to be the one to give her the news That her young son had only a few tomorrows I sat in my car and pondered where to party that evening But something gnawed at my heart; an intense aching Hot Tears poured down my cheeks sans warning Undid the façade I was sporting The wee bit of a human hidden in me startled my being Late into the sleepless night I had a dream Big Boss admonished me, yet on my f d h d face I saw a gleam l A single streak of the whitener fluid he drew To erase my reporting and write one anew Do early morning dreams really come true? Reeta Subramaniam Mani
  154. 154. Thank you Thank you
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