PATHOLOGY - AIM4PG

Chediak Hegashi Syndrome -AR -Defect in innate immunity -Due to mutation in CHS 1 gene encoding LYST protein leading to defective fusion of phagosome and lysosome. -Defect in formation of phagolysosome results in infections Features- -Fever -Leucocyte abnormalities- neutropenia, degranulation defect, and delayed phagocytosis -Recurrent infections with staph aureus -periodontal disease , gingivitis -Melanocyte abnormalities- oculocutaneous albinism -photophobia -Peripheral neuropathy, parkinsonism cerebellar ataxia mental retardation -Nystagmus -Thrombocytopenia -Accelerated phase or hemophagocytic lymphohistiocytosis (HLH)- Precipitated by viral infections like EBV, mostly in childhood, is characterised by pancytopenia, high grade fever, lymphadenopathy, hepatosplenomegaly has poor prognosis. Requires bone marrow transplant Diagnosis PBS- Giant primary granules in neutrophils and other granulocytes Increased BT Definite diagnosis- molecular genetic testing of CHS1 . By- Dr Gudly For daily notes join www.aim4pg.com/study-group

BRAF V600 mutation seen in "Her MAN CLaP" Her- Hairy cell leukaemia M- Melanoma A- Astrocytoma N- Nevi benign C- Colon cancer L- Langerhans cell histiocytosis P- Papillary Carcinoma Thyroid By Dr Gudly www.aim4pg team

Hemochromatosis (Bronze Diabetes) • Autosomal recessive. • Males > females (slow progression in females due to loss of iron during menstruation) • Presents > 40yrs when total body iron > 20 g; Mechanisms of liver injury (1) lipid peroxidation via free radicals , (2) activation of hepatic stellate cells leading to cirrhosis, (3) predisposition to hepatocellular cancer (the risk of HCC is 200 times more) I. Hereditary Hemochromatosis • Mutation in HFE gene( chromosome 6), • Others- mutations involving transferrin receptor 2 (TfR2), HAMP coding for hepcidin , hemojuvelin II. Secondary Hemochromatosis • Parenteral iron overload due to multiple tranfusions in thalassemia major • X linked Sideroblastic anemia • Chronic Hemolytic Anemias (sickle cell disease) • Increased intake in diet • Chronic liver disease- Hep C, ALD, NASH, Porphyria cutanea tarda • Myelodysplastic syndrome- erythroid progenitors release Erythroferrone that suppresses hepcidin production, • African iron overload (Bantu siderosis) Pathogenesis • Mutation in HFE gene is most common • C282Y mutation (cysteine to tyrosine substitution at 282 position) causes decreased hepcidin synthesis leading to uncontrolled absorption of Iron • H63D mutation- histidine to aspartic acid at 63 position C/F Deposition of Iron as hemosiderin in various organs • Liver- hepatomegaly that later progresses to cirrhosis, • Pancreas- diabetes mellitus, • Myocardium- dilated cardiomyopathy > restrictive, arrhythmias, sick sinus syndrome • Pituitary- hypogonadotropic hypogonadism • Joints- calcium pyrophosphate deposition especially in metacarpophalangeal joints- squared off bone ends and hook like osteophytes • Skin- bronze hyperpigmentation Diagnosis • iron profiles- increase ferritin, increase iron, decrease TIBC, increased transferrin saturation (cutoff- 45%) • confirmed by DNA sequencing • Perl’s Prussian blue stain- hemosiderin deposition in hepatocytes (periportal zone 1) sparing the Kupffer cells By Dr Gudly www.aim4pg team

Prussian blue staining in hemochromatosis

Retinoblastoma • most common primary intraocular malignancy in children (mostly below 5 years) • Cottage cheese appearance • Can be endophytic- grows into vitreous, exophytic- into choroid, or diffuse • retinocytoma or retinoma— possibly a premalignant lesion Pathogenesis- • Familial - AD inheritance - due to germline mutation of one RB allele(13q). Retinoblastoma arises when second hit occurs by somatic mutation leading to a loss of heterozygosity (knudson’s two hit hypothesis) -Usually bilateral. -trilateral retinoblastoma - If associated with pinealoblastoma - can be associated with secondary malignancies like Osteosarcoma • sporadic - both alleles are lost by acquired somatic mutations. Histopath- • small round blue cell tumor • small blue cells arranged in rosettes- Flexner-Wintersteiner rosettes (true rosette)- indicates well differentiated • Fleurettes (indicates greater photo receptor differentiation) • Focal zones of dystrophic calcification seen in areas of necrosis. • C/F- Leucocoria, squint, glaucoma, retinal detachment -Tumor cells can appear in the -Ant Chamber- Pseudo Hypopyon • Investigation- CT scan shows intra tumoral calcification, USG MRI Aqueous humor has high LDH Definite- Biopsy after enucleation • Metastasis- typically occurs through the optic nerve into CSF, hematogenous metastases may occur to the bone marrow. By Dr Gudly www.aim4pg team

Flexner-Wintersteiner rosettes in Retinoblastoma

Oligodendroglioma • best prognosis among glial tumors • involving the white matter of cerebral hemispheres Pathogenesis- • mutation in IDH genes • Loss of 1p and 19q- good prognosis, sensitive to chemo • loss of chromosome 9p, leads to deletion of the CDKN2A (TSG)– bad prognosis (progresses to anaplastic oligodendroglioma) Gross- mass with focal haemorrhage and cystic degeneration, intratumoral calcification Histopath- • cells similar to normal oligodendrocytes with nuclei surrounded by a clear halo(vacuolated cytoplasm)- fried egg appearance • anastomosing capillaries resembling “chicken wire” • calcification and perineuronal satellitosis • Glial Fibrillary Acidic Protein(GFAP) positive • Anaplastic oligodendrogliomas (WHO grade III)- features of anaplasia present C/F- • Most commonly present as seizures • Signs of intracranial space occupying lesion (headache, raised ICP, focal neurological deficits) • May sometimes present with hemiparesis, neglect or visual defects depending on the area involved. • Investigation- MRI • Definite diagnosis- Biopsy By Dr Gudly www.aim4pg team

Fried egg appearance in Oligodendroglioma

Endometrial Cancer • Most common invasive cancer of female genital tract • Smoking, exercise, multiparity are protective • Varieties- Adenocarcinoma (endometrioid is most common), Adenocarcinoma with squamous elements, Papillary serous carcinoma , Mucinous adenocarcinoma , Clear cell adenocarcinoma , Secretory carcinoma, Squamous cell carcinoma, Mixed carcinoma • Can be localised(mostly in the fundus) or diffuse • Categories- • Type I (most common type): 55-65yrs -Hyperestrogenic conditions (early menarche/late menopause, nulliparity, infertility , anovulatory cycles,), obesity, DM, HTN, tamoxifen(SERM with weak estrogenic action on endometrium) -Arises from a Hyperplastic Endometrium -Pathogenesis- increased signalling through PI3K/AKT pathway due to mutations in PTEN, PIK3CA, activation of KRAS, loss of function in ARID 1A. -Association- Lynch II syndrome- due to epigenetic silencing of DNA mismatch repair genes. Constitutes of Colorectal Cancer, Breast cancer and endometrial cancer -Histopath- Endometroid Morphology (mimicking proliferative endometrium) Well diff- composed of formed glands Mod diff- ≤ 50% of solid sheets of cells Poor diff- > 50% solid • Type II: 65-75yrs -Develops in an Atrophic endometrium -Serous, Clear cell, Mixed Mullerian tumors -Aggressive extra uterine and lymphatic spread -Metastasis- most common to lungs -Pathogenesis- mutation in TP53, PI3K, PP2A -Histopath- papillary growth pattern with features of anaplasia(high nuclear to cytoplasmic ratio, hyperchromasia, high mitotic index, loss of polarity) and psammoma body • C/F: menometrorrhagia, postmenopausal bleeding, discharge(leukorrhea), bulky tumors can result in pyometra • 1st investigation- TVS for endometrial thickness (postmenopausal cutoff- ≥4mm) • IOC- Endometrial aspiration using Pipelle cannula • Gold standard- Fractional curettage(endocervical curettage followed by endometrial curettage from fundus and lower part of the body of uterus) By Dr Gudly www.aim4pg team

Endometrial Cancer • Most common invasive cancer of female genital tract • Smoking, exercise, multiparity are protective • Varieties- Adenocarcinoma (endometrioid is most common), Adenocarcinoma with squamous elements, Papillary serous carcinoma , Mucinous adenocarcinoma , Clear cell adenocarcinoma , Secretory carcinoma, Squamous cell carcinoma, Mixed carcinoma • Can be localised(mostly in the fundus) or diffuse • Categories- • Type I(most common type): 55-65yrs -Hyperestrogenic conditions (early menarche/late menopause, nulliparity, infertility , anovulatory cycles,), obesity, DM, HTN, tamoxifen(SERM with weak estrogenic action on endometrium) -Arises from a Hyperplastic Endometrium -Pathogenesis- increased signalling through PI3K/AKT pathway due to mutations in PTEN, PIK3CA, activation of KRAS, loss of function in ARID 1A. -Association- Lynch II syndrome- due to epigenetic silencing of DNA mismatch repair genes. Constitutes of Colorectal Cancer, Breast cancer and endometrial cancer -Histopath- Endometroid Morphology (mimicking proliferative endometrium) Well diff- composed of formed glands Mod diff- ≤ 50% of solid sheets of cells Poor diff- > 50% solid • Type II: 65-75yrs -Develops in an Atrophic endometrium -Serous, Clear cell, Mixed Mullerian tumors -Aggressive extra uterine and lymphatic spread -Metastasis- most common to lungs -Pathogenesis- mutation in TP53, PI3K, PP2A -Histopath- papillary growth pattern with features of anaplasia(high nuclear to cytoplasmic ratio, hyperchromasia, high mitotic index, loss of polarity) and psammoma body • C/F: menometrorrhagia, postmenopausal bleeding, discharge(leukorrhea), bulky tumors can result in pyometra • 1st investigation- TVS for endometrial thickness (postmenopausal cutoff- ≥4mm) • IOC- Endometrial aspiration using Pipelle cannula • Gold standard- Fractional curettage(endocervical curettage followed by endometrial curettage from fundus and lower part of the body of uterus)

Endometrial Cancer • Most common invasive cancer of female genital tract • Smoking, exercise, multiparity are protective • Varieties- Adenocarcinoma (endometrioid is most common), Adenocarcinoma with squamous elements, Papillary serous carcinoma , Mucinous adenocarcinoma , Clear cell adenocarcinoma , Secretory carcinoma, Squamous cell carcinoma, Mixed carcinoma • Can be localised(mostly in the fundus) or diffuse • Categories- • Type I(most common type): 55-65yrs -Hyperestrogenic conditions (early menarche/late menopause, nulliparity, infertility , anovulatory cycles,), obesity, DM, HTN, tamoxifen(SERM with weak estrogenic action on endometrium) -Arises from a Hyperplastic Endometrium -Pathogenesis- increased signalling through PI3K/AKT pathway due to mutations in PTEN, PIK3CA, activation of KRAS, loss of function in ARID 1A. -Association- Lynch II syndrome- due to epigenetic silencing of DNA mismatch repair genes. Constitutes of Colorectal Cancer, Breast cancer and endometrial cancer -Histopath- Endometroid Morphology (mimicking proliferative endometrium) Well diff- composed of formed glands Mod diff- ≤ 50% of solid sheets of cells Poor diff- > 50% solid • Type II: 65-75yrs -Develops in an Atrophic endometrium -Serous, Clear cell, Mixed Mullerian tumors -Aggressive extra uterine and lymphatic spread -Metastasis- most common to lungs -Pathogenesis- mutation in TP53, PI3K, PP2A -Histopath- papillary growth pattern with features of anaplasia(high nuclear to cytoplasmic ratio, hyperchromasia, high mitotic index, loss of polarity) and psammoma body • C/F: menometrorrhagia, postmenopausal bleeding, discharge(leukorrhea), bulky tumors can result in pyometra • 1st investigation- TVS for endometrial thickness (postmenopausal cutoff- ≥4mm) • IOC- Endometrial aspiration using Pipelle cannula • Gold standard- Fractional curettage(endocervical curettage followed by endometrial curettage from fundus and lower part of the body of uterus)

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Sideroblastic anemia Sideroblastic anemia is anemia due to defective utilization of iron. It is characterized by the presence of ringed sideroblasts in the bone marrow. The iron is present in the mitochondria. Sideroblastic anemia can be congenital or acquired. There are several forms of congenital sideroblastic anemia: • X-linked sideroblastic anemia due to mutation of 5-aminolevulinic acid synthase gene (ALAS2) or mutation in the ABC7 gene that encodes a half-type ATP-binding cassette transporter. • Autosomal recessive sideroblastic anemia. • Mitochondrial DNA defect (e.g., Pearson syndrome where there occurs sideroblastic anemia, neutropenia, thrombocytopenia, exocrine pancreatic, and hepatic dysfunction). • Wolfram syndrome also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) is also accompanied by sideroblastic or megaloblastic anemia. Patients usually present with diabetes mellitus followed by optic atrophy in the first decade of life followed by cranial diabetes insipidus and sensorineural deafness in the second decade, which later leads to further complications including multiple neurological abnormalities followed by premature death. This syndrome is due to mutation in the WFS1 (Wolfram syndrome 1) gene. Congenital sideroblastic anemia usually exhibits dimorphic red cells (normocytic normochromic and microcytic hypochromic) or microcytic hypochromic red cells. This is in contrast to acquired sideroblastic anemia, which shows normocytic or macrocytic red cells. Acquired sideroblastic anemia may be primary or secondary. Primary acquired sideroblastic anemia is actually myelodysplasia. Secondary acquired sideroblastic anemia is most often due to drugs (e.g., antituberculous drugs), alcohol, and lead poisoning. By Dr Ayan www.aim4pg team

Clear Cell Sarcoma (Malignant Melanoma of Soft Parts) Clinical ♦ Intimately associated with tendons and aponeuroses ♦ Peak age: 20-40 years; slight female predominance ♦ Common sites: distal extremities, especially foot and ankle ♦ Slowly growing, painful mass ♦ Repeated local recurrences due to incomplete excision ♦ 50% develop late metastases to lungs, lymph nodes or bone ♦ Poor long-term prognosis despite adjuvant therapy Microscopic ♦ Usually <5 cm, associated with fascia and tendons ♦ Nests or fascicles of cells separated by fibrous septa ♦ Infiltrate into fibrotendinous tissue, subcutis or deep dermis ♦ Uniform cells with pale eosinophilic to clear cytoplasm ♦ Intracytoplasmic glycogen ♦ Round, polygonal to spindle cells ♦ Vesicular nuclei with prominent nucleoli ♦ Multinucleated giant cells (wreath-like nuclei) ♦ Melanin (variable) ♦ Fibrosis (variable) Immunohistochemistry ♦ S-100+ ♦ HMB 45+ ♦ Neuron specific enolase (NSE)+ Cytogenetics ♦ t(12; 22) (q13; q13) Differential Diagnosis ♦ Cutaneous melanoma: – Junctional activity; irregular growth pattern, more pleomorphism ♦ Fibrosarcoma: – No cellular aggregates, no intracytoplasmic glycogen – S-100-, HMB 45- ♦ MPNST: – Association with peripheral nerve or NF-1 – No glycogen, more hyperchromatic nuclei and more mitoses – HMB 45- ♦ Metastatic renal cell carcinoma: – Less prominent nucleoli, no fusiform appearance – Cytokeratin (low molecular weight) and EMA+ By Dr Ayan www.aim4pg team

Which one of the listed cells is thought to be the source of hepatic stem cells? a. Ito cells b. Limbus cells c. Oval cells d. Paneth cells Ans C Stem cells are unique cells that are characterized by their ability for asymmetric replication, which refers to the fact that one of the products of cell division is capable of self-renewal. Embryonic stem cells are pluripotent, that is, they are capable of forming all the tissues of the body, while adult stem cells are usually only able to differentiate into a particular tissue. Stem cells, which have been identified in many different tissues, are located in special sites called niches. For example, cells located in the canals of Hering of the liver can give rise to precursor cells called oval cells, which are capable of forming hepatocytes and biliary cells. Limbus cells located in the canals of Schlemm are stem cells for the cornea. In contrast to stem cells, Ito cells, which are located in the subendothelial space of Disse, store vitamin A, and Paneth cells, located near the bottom of crypts, provide host defense against microorganisms. By Dr Ayan www.aim4pg team

Genetic Tumor Syndromes Associated With Bone and Soft Tissue Tumors 1.Enchondromatosis (Ollier disease and Maffucci syndrome) 2.Li-Fraumeni syndrome 3. McCune-Albright syndrome 4. Rothmund-Thomson syndrome . 5. Werner syndrome 6. Multiple osteochondromas 7. Neurofibromatosis type 1 By Dr Ayan www.aim4pg team

Cytochemistry in hematology Cytochemistry can be used to study both red blood cells and white blood cells, although the focus is on the latter. The most common staining techniques include: • Myeloperoxidase, an enzyme present most strongly in granulocytes and their precursors, but may also be present in red cells and their precursors. • Sudan black, which stains a component of the granules of granulocytes and monocytes, and so often provides the same information as does myeloperoxidase. • Neutrophil alkaline phosphatase, an enzyme found predominantly in mature neutrophils. • Acid phosphatase, an enzyme found in granulocytes, but which is generally used to define certain lymphocytic leukaemias in peripheral blood. However, in the bone marrow, macrophages and megakaryocytes are strongly positive. The use of acid phosphatase is one of the few methods that can be used to detect platelets. • Periodic acid–Schiff (PAS), a stain used to stain glycogen and related polysaccharides. Although granulocyte precursors stain weakly, if at all, mature neutrophils show intense staining. • The esterases, a family of enzymes that are generally used to investigate different leukaemias. Abnormalities in red cell biology can be investigated using Perls’ stain, which is also known as Prussian blue. This stain detects the presence of iron-containing molecules inside the cell and so, if found in a red blood cell, defines a siderocyte. The same stain when applied to a bone marrow aspi- rate can identify iron within red blood cell precursors such as sideroblasts—these are erythroblasts with inappropriate deposits of iron, and are associated with a particular type of anaemia. By Dr Ayan www.aim4pg team