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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)](https://image.slidesharecdn.com/kciapmslideseminar2014presentation-140129103200-phpapp02/75/Kciapm-slide-seminar-2014-presentation-193-2048.jpg)
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- 5. Cellular area showing pleomorphism of follicular cells with nuclear enlargement and hyperchromasia, and with nuclear enlargementand hyperchromasia and pale‐staining colloid
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- 8. Differential diagnosis Differential diagnosis • • • • • • • • • • • • Follicular neoplasm with hurthle cell change Flli 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. 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.
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- 11. DIAGNOSIS • • • • • DYSHORMONOGENETIC GOITRE DYSHORMONOGENETIC GOITRE Hypercellular nodules with presence of cells arranged in cords, microfollicular trabecular di d i flli 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. 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. 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
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- 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 sectionshowed a grey‐white mass 16 x 10 x 8 cm Areas of hemorrhage and cystic spaces
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- 20. Focal clusters of foamy macrophages seen in this section Focal clusters offoamy macrophages seen in this section
- 23. 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
- 24. 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 resemblesordinary 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
- 25. DIAGNOSIS Solid variant of invasive papillary carcinoma S lid i tfi 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.
- 26. SOLID VARIANT OF INVASIVE PAPILLARY CARCINOMA • A diti 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
- 27. SOLID VARIANT OF INVASIVE PAPILLARY CARCINOMA • Mi Microscopically these tumours show multiple nodules, i llth 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
- 28. References References • Tavassoli FA, DevileeP. 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.
- 29. CASE 3 CASE 3 21/F, TOTAL THYROIDECTOMY SPECIMEN 21/F, TOTALTHYROIDECTOMY SPECIMEN
- 30. GROSS Total Thyroidectomy specimen measuring 7 x 6 x 3.5 cm Total Thyroidectomy specimenmeasuring 7 x 6 x 3 5 cm Enlarged right lobe
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- 33. Cribriform areas under higher magnification Cribriform areas underhigher magnification
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- 35. Focal areas showing squamoid nodules without evidence of keratinization Focal areas showingsquamoid nodules without evidence of keratinization
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- 37. Differential diagnosis Differential diagnosis • • • • • • • • Mixed medullary and papillary carcinoma Morular cribriform variant of papillary carcinoma pp 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
- 38. DIAGNOSIS OFFERED DIAGNOSIS OFFERED DIAGNOSIS OFFERED DIAGNOSIS OFFERED Papillary cell carcinoma Tall cell variant llll 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
- 39. DIAGNOSIS Papillary Thyroid carcinoma (PTC) Cribriform morular Papillary Thyroidcarcinoma (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.
- 40. 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)
- 41. REFERENCES • Harach HR, Williams GT, Williams ED. Familial adenomatous polyposis associated with thyroid adenomatous polyposisassociated 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.
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- 43. 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
- 44. LAB INVESTIGATIONS Bronchoscopy Bronchial wash –AFB and cytology CT scan RML biopsy
- 45. Bronchoscopy -mass occluding right middle lobe bronchus Bronchial wash – AFB – negative Cytology – negative for atypical cells
- 46. 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.
- 47. 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.
- 50. PER‐ PER‐OPERATIVE Right posterolateralthoracotomy, 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.
- 51. HISTOPATHOLOGY Gross – rightmiddle 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
- 56. Microscopy Tumor composed of squmaous cells, intermediate cells and mucin secreting cells. All lymph nodes exhibit reactive changes changes.
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- 61. DIFFERENTIALS • • • • • • • • • • Large cell undifferntiatedcarcinoma 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
- 62. Impression – low grade salivary epithelial neoplasm, ? Low grade mucoepidermoid carcinoma , ? Pleomorphic adenoma.
- 63. 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
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- 67. Final diagnosis Final diagnosis • Mucoepidermoidcarcinoma of the lung – Low g grade
- 68. DISCUSSION Rare primar tumorof 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 • • • •
- 69. REFERENCES • Respiratory MedicineCase 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
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- 71. CLINICAL PRESENTATION Male 25years 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.
- 72. PER OPERATIVE Persistant mullerianduct syndrome with left sided large testicular tumor and right sided small testicular tumor
- 73. 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.
- 77. 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
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- 83. DIFFERENTIALS • • • • • • • Leydig L di cellh 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
- 84. 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
- 85. DISCUSSION • • • • • • Rare form ofmale 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
- 86. Case 6 CLINICAL DETAILS •Male patient aged 37 years • Fracture of L5 vertebra • Blocks for opinion
- 92. Microscopy • Tumor cellsare 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
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- 94. Differential diagnosis • • • • • • • • • • • Hemangioendothelioma He angioendothelioa 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
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- 99. • Primary /metastatic • No clinical evidence of primary sweating, palpitations, • No history of sweating palpitations hypertension
- 100. • Primary paragangliomasof 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
- 101. 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
- 102. 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
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- 104. CLINICAL DETAILS • Femalepatient aged 56 y p g years • ? Ovarian mass • Blocks for opinion p
- 110. MICROSCOPY • • • • • • • • • Tumor with spindlecells Hyalinized and oedematous stroma Bizarre hyperchromatic nuclei Clumped chromatin Prominent nucleoli Multinucleated forms No necrosis Occasional mitosis (0-1/10HPF) Ovarian stroma not identified
- 111. Differential diagnosis • • • • • • • • Embryonal carcinoma Eb l i Sarcomatous variant of yolk sac tumor y Sarcomatoid transformation of stromal tumor Fibrosarcoma Poorly differentiated ovarian carcinoma Angiosarcoma Nodular fascitis Leiomyosarcoma
- 112. • • • • • • • • Atypical bizarre cellularleiomyoma 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
- 113. Signed out report •Smooth muscle origin • Benign nature Symplastic leiomyoma
- 114. GROSS 1. Specimen ofuterus 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
- 121.
- 122. • 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
- 124. 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
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- 132. Differential diagnosis Differential diagnosis • • • • • • • • • Lipoid variant of invasive urothelial carcinoma Liid 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
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- 137. Final diagnosis Final diagnosis • Malignant melanoma –? Primary y – ? Metastatic
- 138. Discussion Discussion • Primary melanoma of bladder is very rare • 19odd cases reported in literature 19 odd cases reported in literature • Mostly metastatic from the skin or urethra
- 139. Criteria for primary melanoma of bladder • Ainsworth criteria i h ii • 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
- 140. 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.
- 141. Case 9 Case 9 • Skin biopsy in a male patient •Age not known Age not known
- 145. Differential diagnosis Differential diagnosis • • • • • • • • • Cutaneous mastocytosis C t tt i Dermal nevus Glomus tumor Leukaemic infiltration Cutaneous plasmacytoma Lymphomatoid papillomatosis, DLE ??? Urticaria pigmentosa pg Metastatic cutaneous deposit‐ Adenocarcinoma
- 147.
- 148. Cutaneous mastocytosis • 80% of cases are urticariapigmentosa % 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
- 149. Clinical symptoms Clinical symptoms • Release of histamines and leucotrienes –Pruritis – Itching – Flushes – Syncope
- 150. WHO classification of mastocytosis WHO classification ofmastocytosis • 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
- 151. Case 10 Case 10 • 34 yr old male •Azoospermia for evaluation. for evaluation. • Left and right testicular biopsy was done
- 156.
- 157. Differential Diagnosis Differential Diagnosis Sertoli lld 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 • • • • •
- 158. Final diagnosis Final diagnosis • Hamartomatousnodule in probable Androgen y y insensitivity syndrome
- 159. 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
- 160. Statistics • Affects 1in 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
- 161. 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 ddi 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.
- 162. References References • 1991;10(2):126‐44. • Theandrogen 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
- 163. • • • • • • • Forty‐three patients with the androgen insensitivity syndrome (AIS), ages Forty three patientswith 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
- 164. References • Arch Pathol Lab Med‐Vol 123, March 1999 • Ackerman’s Surgical Pathology, Male Ackerman s Surgical Pathology, Male reproductive system , Pg 1438‐ 1439
- 165. 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
- 166.
- 167. Immunofluorescence • One core with 6 glomeruli, all of which are g g gg q pp negative for IgG, IgA, IgM, C3C, C1q, kappa and lambda.
- 172. Differential diagnosis Differential diagnosis • Ct 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
- 173. Final diagnosis Final diagnosis • Chronic tubulointerstitialnephritis secondary y p gy g to crystalluria morphology favoring Oxaluria.
- 174. 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
- 175. Primary hyperoxaluria Type I mutation of AGXT gene on chromosome 2 that codes for alanine glyoxylate aminotransferase alanine glyoxylate aminotransferase Type II mutation ofGRHPR gene on chromosome 9 that codes Type II mutation of GRHPR gene on chromosome 9 that codes for glyoxylate reductase and hydroxypyruvate reductase.
- 178. 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
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- 185. 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
- 186. Diagnoses….. Diagnoses • • • • • • • • Embryonal rhabdomyosarcoma ‐ 2 b lh bd Olfactory neuroblastoma‐ 2 y Ganglioglioma ‐2 Astrocytoma ‐2 Astrocytoma 2 Carcinosarcoma ‐1 Rhinoscleroma ‐1 Melanoma 1 Melanoma ‐1 Ganglioneuroblastoma‐ 1
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- 189. So….. So • • • • Poorly circumscribed, submucosal lesion in sinus Poorly circumscribedsubmucosal 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
- 190. Peripheral neuroblastic tumors Not so grey…. • • • • Classification……. Cl ifi i Staging…… Risk stratification…… Closely related to the molecular/genetic Closelyrelated 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…)
- 191. Q1: Where do they come from? Q1: Where dothey come from? Neural crest = sympathetic nervous system Neuroblasts, Ganglion cells, Schwann cells Satellite cell Ganglion cell Nerve roots Neck to pelvis……
- 192. Differentiate from ..for confusion/clarity • Peripheral i hl 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
- 193. How do they look? International Neuroblastoma P thl 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)
- 194. Neuroblastoma (poor diff), Neuroblastoma (differ), Neuroblastoma (undiff), Ganglioneuroblastoma: intermixed) it 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
- 195. How do they behave? stratification…. How do theybehave? 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
- 196. How do they behave? stratification How do theybehave? 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
- 198. 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
- 199. 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 blti chemo with SCR •External radiotherapy •MIBG…..
- 200. Bottom line…. Bottom line • Our case –Ganglioneuroblastoma, intermixed g , – MKI: ? – Favourable histology Favourable histology
- 201. The Wrong Right Iscreened 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
- 202. My battered egoappeased 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
- 203.