1. Discuss papillary lesions of breast 2. Prognostic markers of breast cancer 3. Molecular classification of breast tumors 4. Follicular patterned thyroid tumors 5. Paraganglioma 6. Discuss role of IHC in diagnosis of soft tissue tumors 7. Metabolic disorders of bone 8. Medulloblastoma

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Here are comprehensive discussions of all 8 topics, based on Robbins Pathologic Basis of Disease, Robbins Basic Pathology, and surgical textbooks:

1. Papillary Lesions of the Breast

Papillary lesions of the breast form a spectrum from benign to malignant, all characterized by finger-like projections with fibrovascular cores lined by epithelium.

Classification

A. Intraductal Papilloma (Benign)

Solitary (Central) Papilloma: Occurs in large subareolar ducts, typically in women aged 30-50 years. The most common cause of bloody nipple discharge. The lesion is small (~0.5 cm, but can reach 5 cm), tannish, friable, resembling miniature broccoli florets attached to the duct wall by a stalk. Microscopically composed of branching papillae with a central fibrovascular core lined by a superficial epithelial layer (both luminal epithelial cells and myoepithelial cells are present - a key feature distinguishing benign papilloma from papillary carcinoma). Variable fibrosis between epithelial components. Confers a small increased relative risk (2.1x) of breast cancer in either breast.
Peripheral (Multiple) Papillomas / Papillomatosis: Multiple small papillomas in the periphery of the breast (>5 cm from nipple), arising in TDLUs. More common in young women, more often bilateral. Unlike solitary central papillomas, peripheral papillomatosis has a significantly higher upgrading rate to cancer on excision and carries a markedly increased relative risk (3-3.5x) of future breast cancer. These women require high-risk surveillance (clinical breast exam every 6 months, annual mammography, consider annual breast MRI).

B. Atypical Papilloma

An intraductal papilloma with foci of atypical ductal hyperplasia (ADH) or lobular neoplasia. Upgrading rate to cancer at excision is significantly higher than benign papillomas. Surgical excision is required.

C. Papillary DCIS (Ductal Carcinoma In Situ)

Produces true papillae with fibrovascular cores that lack a myoepithelial cell layer - the key distinguishing histological feature from benign papilloma. The malignant epithelium is monotonous. The absence of myoepithelial cells can be confirmed with IHC (p63, calponin, SMA negative at the papillary fronds). Calcifications may be present.

D. Micropapillary DCIS

Produces complex bulbous protrusions without fibrovascular cores - so-called "roman bridges" and "micropapillae." Often multifocal, spans large areas of the ductal system. Higher risk of underestimating extent.

E. Encapsulated Papillary Carcinoma (EPC)

A well-circumscribed mass with fibrous capsule containing papillary structures lined by malignant cells lacking myoepithelial cells at the papillary fronds AND at the capsule. Considered a low-grade, indolent carcinoma. Generally ER+, HER2-negative. Behaves like low-grade in situ disease despite lack of capsular myoepithelial cells.

F. Solid Papillary Carcinoma (SPC)

Composed of solid nodules of neoplastic cells that may contain fibrovascular cores (sometimes only appreciable on careful examination). Cells often have neuroendocrine features. Two types: in situ (circumscribed nodules) and invasive (irregular infiltrating nests of similar morphology).

G. Invasive Papillary Carcinoma

Rare form (~1-2% of breast cancers). Tumor forms papillary structures within the invasive component. Often seen in elderly women; ER-positive and low grade.

Management Approach

Benign papilloma on core biopsy: Surgical excision NOT required if large-bore needle (≤14 gauge) used, lesion solitary and adequately sampled (>50% removed), no atypia, radiologic-pathologic concordance, and lesion ≤10-15 mm. Upgrading rate to cancer is ≤2% under these criteria.
If concurrent ipsilateral breast cancer is present with intraductal papilloma as a second finding, excision is warranted as upstaging rate to cancer >20%.
Peripheral papillomatosis: Always excise; offer high-risk surveillance.

2. Prognostic Markers of Breast Cancer

Prognostic markers predict the natural history of a breast cancer in the absence of systemic therapy. They can be divided into classical clinicopathological factors and molecular/biological markers.

A. Classical Clinicopathological Prognostic Factors

1. Axillary Lymph Node Status

The most important prognostic factor in operable breast cancer. Spread to ipsilateral axillary nodes occurs in 15-30% of patients. Nodal involvement dramatically worsens prognosis. Number of nodes involved matters: N0 (negative) has the best prognosis; N1 (1-3 nodes), N2 (4-9 nodes), N3 (≥10 nodes) progressively worsen.

2. Tumor Size

Larger tumors correlate with worse prognosis. Independent of nodal status. Key TNM thresholds: ≤2 cm (T1), 2-5 cm (T2), >5 cm (T3), chest wall/skin invasion (T4).

3. Histological Grade (Nottingham Grade / Elston-Ellis modification of Scarff-Bloom-Richardson)

Three components scored 1-3:

Tubule formation (>75% = 1, 10-75% = 2, <10% = 3)
Nuclear pleomorphism (small uniform = 1, moderate = 2, marked = 3)
Mitotic count (per 10 HPF, thresholds vary by field diameter)
Total score: Grade 1 (3-5) = well differentiated, Grade 2 (6-7) = moderately differentiated, Grade 3 (8-9) = poorly differentiated. Higher grade = worse prognosis.

4. Histological Type

Low-grade special types (tubular, cribriform, mucinous, medullary) have better prognosis than NOS (no special type) carcinoma.
Invasive lobular carcinoma: similar prognosis to NOS but higher rate of contralateral disease and late recurrence.

5. Lymphovascular Invasion (LVI)

Presence of tumor emboli in peritumoral lymphovascular spaces is an independent adverse prognostic factor, predicts nodal spread and distant metastases.

6. Surgical Margins

Positive or close margins predict local recurrence.

B. Biomarker-Based Prognostic Factors

1. Estrogen Receptor (ER) and Progesterone Receptor (PR)

ER positivity (~70-80% of breast cancers) is associated with better prognosis, slower growth, and sensitivity to endocrine therapy (tamoxifen, aromatase inhibitors, CDK4/6 inhibitors).
PR positivity adds additional prognostic value; ER+/PR+ tumors have the best endocrine therapy response.
Assessed by IHC; ≥1% nuclear staining = positive (ASCO/CAP guideline).

2. HER2 (Human Epidermal Growth Factor Receptor 2)

Overexpressed/amplified in ~15-20% of breast cancers.
Historically associated with poor prognosis but now a predictive marker for trastuzumab (and other HER2-targeted) therapy response.
Assessed by IHC (3+ = positive) or FISH (gene amplification).
HER2-low (IHC 1+ or 2+/FISH non-amplified) is now a targetable category with trastuzumab deruxtecan.

3. Ki-67 (Proliferation Index)

Measures the proportion of cycling tumor cells. Higher Ki-67 = worse prognosis. Used to distinguish Luminal A (Ki-67 <14%) from Luminal B (Ki-67 ≥14%). Threshold varies by laboratory.

4. Triple Negative Status (ER-/PR-/HER2-)

TNBC constitutes ~15-20% of breast cancers. Associated with younger age, African ancestry, BRCA1 mutations, basal-like molecular subtype, aggressive behavior, early visceral metastases, but also higher rates of pathologic complete response (pCR) to neoadjuvant chemotherapy. Historically worst prognosis but immunotherapy (pembrolizumab) has changed the landscape for PD-L1-positive TNBC.

5. Gene Expression Signatures

Used in ER+/HER2- early breast cancer to guide chemotherapy decisions:

Oncotype DX (Recurrence Score, RS): 21-gene assay; predicts 10-year distant recurrence risk. RS 0-17 (low) = endocrine therapy alone; RS 26+ (high) = benefit from chemotherapy. RS 18-25 (intermediate) = chemotherapy benefit in premenopausal women.
MammaPrint (70-gene signature): Classifies into low-risk (endocrine therapy alone) vs. high-risk (benefit from chemotherapy); validated by MINDACT trial.
PAM50 (Prosigna): Provides intrinsic subtype and risk of recurrence score.
EndoPredict, Breast Cancer Index: Used in specific clinical contexts for late recurrence prediction.

6. BRCA1/2 Mutation Status

BRCA1/2 mutations confer lifetime breast cancer risk of ~70%.
BRCA1-associated cancers are typically TNBC/basal-like; BRCA2-associated tend to be luminal.
Therapeutic relevance: PARP inhibitors (olaparib, talazoparib) in HER2-negative metastatic breast cancer with germline BRCA1/2 mutations.

7. PIK3CA Mutation

Present in ~40% of ER+ breast cancers. Targetable with alpelisib (PI3K inhibitor) in ER+/HER2-negative metastatic disease after endocrine therapy failure.

8. Tumor-Infiltrating Lymphocytes (TILs)

Higher stromal TIL levels are associated with improved prognosis and pCR, particularly in TNBC and HER2-positive disease.

9. PD-L1 Expression

Predicts benefit from pembrolizumab in TNBC (combined positive score ≥10 for first-line metastatic, CPS ≥20 for neoadjuvant).

3. Molecular Classification of Breast Tumors

Gene expression profiling using microarray technology (Perou et al., 2000) established intrinsic molecular subtypes that better capture the biological heterogeneity of breast cancer than traditional histological classification.

Six Intrinsic Subtypes (Gene Expression Profiling)

1. Luminal A

Profile: ER+, PR+, HER2-, low Ki-67 (<14%), low proliferation
Equivalent clinical subtype: ER+/HER2-negative with low grade
Frequency: ~40% of all breast cancers; most common subtype
Characteristics: Well to moderately differentiated, slow-growing, predominantly postmenopausal
Prognosis: Best among all subtypes; low rate of distant recurrence
Treatment: Endocrine therapy (tamoxifen, aromatase inhibitors); chemotherapy adds little benefit

2. Luminal B

Profile: ER+, PR+/-, HER2+/-, higher Ki-67 (≥14%), higher proliferation
Two sub-variants: Luminal B HER2- and Luminal B HER2+
Frequency: ~20% of breast cancers
Characteristics: Higher grade than Luminal A, more aggressive behavior
Prognosis: Worse than Luminal A; intermediate overall
Treatment: Endocrine therapy + chemotherapy; HER2+ variant also receives anti-HER2 therapy

3. HER2-Enriched

Profile: ER-, PR-, HER2 amplified/overexpressed, high proliferation
Frequency: ~15% of breast cancers
Characteristics: High grade, high mitotic activity, aggressive
Prognosis: Poor historically; now improved significantly with anti-HER2 therapy
Treatment: Anti-HER2 therapies (trastuzumab, pertuzumab, T-DM1, tucatinib) + chemotherapy; excellent pCR rates

4. Basal-Like

Profile: ER-, PR-, HER2- (triple negative), expresses basal cytokeratins (CK5/6, CK14, CK17), EGFR+, often p53 mutated
Frequency: ~15% of breast cancers; accounts for ~75% of TNBCs
Note: Basal-like ≠ TNBC (overlap is ~80%; ~20% of basal-like tumors are not truly triple negative)
Characteristics: High grade (almost always Grade 3), high proliferation, necrosis, pushing borders, lymphocytic infiltrate, BRCA1 mutations common
Prognosis: Poor; early peak of recurrence within 3-5 years
Treatment: Chemotherapy; platinum agents in BRCA1-mutated; pembrolizumab; PARP inhibitors for germline BRCA mutations

5. Normal-Like

Profile: ER+/-, HER2-, shows gene expression pattern similar to normal breast tissue (high expression of genes related to adipose tissue and basal epithelium)
Frequency: ~5-10%
Prognosis: Intermediate (better than basal-like, similar to Luminal A)
Note: May represent contamination with normal breast tissue rather than a true distinct entity; not consistently reproduced

6. Claudin-Low

Profile: Low expression of claudins (1, 3, 4) and E-cadherin; enriched for epithelial-to-mesenchymal transition (EMT) markers; stem cell-like features; high immune cell infiltration
Frequency: ~10-15% of breast cancers; mostly triple negative
Characteristics: Often Grade 3, medullary-like features, high TILs
Prognosis: Poor
Treatment: Chemotherapy; immunotherapy may benefit given high TILs

Clinical Approximation

Because gene expression profiling is not routine, molecular subtypes are approximated by IHC markers:

Molecular Subtype	ER	PR	HER2	Ki-67
Luminal A	+	+	-	<14%
Luminal B (HER2-)	+	+/-	-	≥14%
Luminal B (HER2+)	+	+/-	+	Any
HER2-Enriched	-	-	+	High
Basal-Like/TNBC	-	-	-	High

4. Follicular-Patterned Thyroid Tumors

Follicular-patterned thyroid tumors comprise a spectrum of lesions that share a follicular growth architecture and must be carefully distinguished from each other.

Classification

A. Follicular Adenoma (FA)

A benign encapsulated follicular cell-derived neoplasm with no capsular or vascular invasion.

Morphology: Encapsulated tumor with a complete fibrous capsule. Architecturally shows variable patterns:

Normofollicular (simple)
Macrofollicular (colloid-rich)
Microfollicular (fetal pattern)
Trabecular/solid (embryonal pattern)

Cytology: Uniform follicular cells with round nuclei, no papillary nuclear features. Colloid may be present.

Variants: Hurthle cell (oncocytic) adenoma - cells with abundant granular eosinophilic cytoplasm due to mitochondrial accumulation; Toxic adenoma (hyperfunctioning); Hyalinizing trabecular adenoma.

IHC: Normal thyroid transcription factor (TTF-1+), thyroglobulin+. No specific markers distinguish FA from well-differentiated follicular carcinoma.

Management: Surgical excision (lobectomy); definitive diagnosis requires complete capsule assessment.

B. Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP)

A low-risk neoplasm (formerly called "non-invasive encapsulated follicular variant of papillary thyroid carcinoma"). Reclassified in 2016 to reflect its indolent behavior.

Criteria for diagnosis:

Encapsulated OR well-circumscribed
Follicular growth pattern (no papillae or psammoma bodies)
Papillary thyroid carcinoma (PTC)-like nuclear features: nuclear enlargement/elongation, irregular nuclear contours, nuclear clearing (ground-glass), intranuclear grooves/pseudoinclusions
No capsular invasion, no vascular invasion, no necrosis, no >3 mitoses per 10 HPF

Molecular: Frequently harbors RAS mutations (particularly NRAS codon 61), similar to follicular adenoma/carcinoma. BRAF V600E mutations are absent (their presence excludes NIFTP).

Clinical: Essentially no risk of metastasis or recurrence after complete excision. Does NOT require radioiodine ablation.

C. Follicular Thyroid Carcinoma (FTC)

The second most common thyroid malignancy (~10-15%). Distinguished from FA only by evidence of capsular and/or vascular invasion on histology - FNA cannot reliably distinguish them.

Types based on invasion:

Minimally invasive FTC: Only focal capsular penetration (capsular invasion without vascular invasion). Excellent prognosis (~97% 10-year survival).
Encapsulated angioinvasive FTC: Capsular invasion + limited vascular invasion (<4 vessels). Intermediate prognosis.
Widely invasive FTC: Extensive invasion through capsule and/or ≥4 vascular invasion foci. Worse prognosis; higher rate of distant metastases.

Morphology: Encapsulated tumor with follicular growth (macro- or microfollicular, solid/trabecular areas). Cells have round nuclei WITHOUT papillary nuclear features. The capsule shows disruption with tumor cell penetration into or through it, or tumor emboli within endothelium-lined vascular spaces (vascular invasion must be unequivocal - within a vessel, with endothelial lining, and/or with attached thrombus).

Molecular genetics: RAS mutations (NRAS, HRAS, KRAS) ~40-50%; PAX8-PPARG rearrangement ~30-40%; PTEN mutations; EIF1AX mutations (mutually exclusive with RAS).

Metastasis: Hematogenous spread (unlike PTC which spreads via lymphatics). Distant metastases to lung, bone (lytic lesions), brain. Lymph node metastases are rare.

IHC: TTF-1+, thyroglobulin+. No specific marker to distinguish FTC from FA except Ki-67 (slightly higher in carcinoma).

Management: Total thyroidectomy + radioiodine ablation (unlike NIFTP).

D. Hurthle Cell (Oncocytic) Carcinoma

Considered a distinct entity (not a variant of FTC). Composed >75% of Hurthle (oncocytic/oxyphilic) cells - large cells with abundant granular eosinophilic cytoplasm due to mitochondrial accumulation.

Features: Encapsulated; requires capsular/vascular invasion for malignancy diagnosis. More aggressive than conventional FTC. Higher rate of lymph node involvement. Less radioiodine-avid (Hurthle cells take up less iodine). More likely to be RAS-wildtype.

E. Invasive Encapsulated Follicular Variant of PTC

Similar to NIFTP but WITH capsular or vascular invasion. Contains PTC-type nuclear features plus invasion. Managed like PTC (more aggressively than NIFTP).

Key Diagnostic Points

Feature	FA	NIFTP	FTC	FV-PTC
PTC nuclear features	No	Yes	No	Yes
Capsular invasion	No	No	Yes	Yes/No
Vascular invasion	No	No	Yes	+/-
RAS mutation	Common	Common	Common	Less common
BRAF V600E	No	No	No	Sometimes

5. Paraganglioma

Paragangliomas (PGLs) are neuroendocrine tumors arising from extra-adrenal paraganglia (autonomic nervous system-associated neuroendocrine cells). Pheochromocytomas (adrenal medullary paragangliomas) are the most common (~80-85% of all cases); extra-adrenal PGLs constitute the remainder.

Classification by Location

1. Paravertebral (Sympathetic) Paragangliomas

Arise from paravertebral paraganglia (e.g., organ of Zuckerkandl at aortic bifurcation, para-aortic, pelvic)
Sympathetic connections; stain positively for chromaffin (chromaffin-positive)
Often functional (produce catecholamines - epinephrine, norepinephrine, dopamine)
Symptoms: paroxysmal hypertension, headache, palpitations, diaphoresis ("spells")
Biochemical markers: elevated urinary/plasma catecholamines and metanephrines

2. Head and Neck (Parasympathetic) Paragangliomas

Arise near great vessels: carotid body, jugulotympanic ganglia, vagal ganglia, aorticopulmonary chain, larynx, orbit
Parasympathetic innervation; usually non-functional (rarely produce catecholamines)
~70% of all extra-adrenal PGLs occur in head and neck
Carotid body tumor is the most common type
Carotid body tumor: grows at bifurcation of common carotid artery, envelopes it ("lyre sign" on angiography)
Incidence is higher in people living at high altitudes (chronic hypoxia stimulates carotid body hyperplasia)

Morphology (Histology)

Gross: Red-pink to brown, well-circumscribed, usually ≤6 cm
Classic pattern: Zellballen - nests of round to oval chief cells with abundant clear or granular eosinophilic cytoplasm and uniform round-ovoid vesicular nuclei, surrounded by delicate vascular fibrous septae
Chief cells: Neuroectodermal origin; stain positively for chromogranin, synaptophysin, INSM1, CD56 (neuroendocrine markers)
Sustentacular cells: Peripheral spindle-shaped stromal/supporting cells surrounding the zellballen; positive for S-100 protein
Electron microscopy: Well-demarcated neuroendocrine granules (dense-core granules) in paravertebral tumors; fewer in non-functioning parasympathetic tumors
Little pleomorphism; scant mitoses - histological benignity does NOT reliably predict behavior

Molecular Genetics / Hereditary Syndromes

Loss-of-function mutations in succinate dehydrogenase (SDH) subunit genes are the most common genetic alterations in both hereditary and sporadic PGLs:

SDHA, SDHB, SDHC, SDHD, SDHAF2 mutations = Hereditary Paraganglioma Syndromes (PGL1-5)
- SDHD mutations (PGL1): Head and neck PGLs, paternal imprinting
- SDHB mutations (PGL4): Extra-adrenal sympathetic PGLs; highest risk of malignancy (~30%)
- SDHC mutations (PGL3): Head and neck PGLs
MEN2 (RET mutations): Pheochromocytomas, usually bilateral adrenal
VHL (von Hippel-Lindau): Pheochromocytomas, often bilateral; clear cell morphology
NF1 (neurofibromatosis type 1): Pheochromocytomas
~30% of head and neck PGLs have germline mutations
SDH mutations cause metabolic dysregulation (disrupted oxidative phosphorylation; "pseudo-hypoxia")

Clinical Features

Rare, slow-growing, painless masses; 5th-6th decades of life
Often solitary and sporadic; may be familial
May be multicentric (simultaneous carotid body + vagal PGL = ~10%)
Malignancy criteria: Presence of metastases (regional nodes or distant sites) is the ONLY reliable criterion for malignancy; histological features are unreliable (no mitoses/pleomorphism rule)
Carotid body tumors frequently recur after incomplete resection; may metastasize despite benign appearance
SDHB-mutated PGLs have highest malignant potential
Management: Surgical resection (primary treatment); pre-operative alpha-blockade for functional tumors; MIBG scintigraphy for staging; [177Lu-DOTATATE for metastatic SDH-mutated PGL

6. Role of IHC in Diagnosis of Soft Tissue Tumors

Immunohistochemistry (IHC) plays a pivotal role in the classification of soft tissue tumors (STTs) because morphological features alone often overlap between different tumor types, and accurate diagnosis has major implications for treatment (especially targeted therapies).

Principles of IHC in Soft Tissue Tumors

Why IHC is Needed

Many STTs are composed of undifferentiated spindle cells, epithelioid cells, or round cells that are morphologically indistinguishable
STTs can mimic carcinoma, lymphoma, and melanoma (and vice versa)
IHC confirms lineage of differentiation (smooth muscle, skeletal muscle, nerve sheath, endothelium, epithelial, etc.)
Some markers are diagnostically specific (e.g., TFE3 translocation-associated protein in alveolar soft part sarcoma)
Guides targeted therapy selection

Panel-Based Approach

IHC is performed as panels rather than single markers:

1. Fibroblastic/Myofibroblastic Tumors

Vimentin: Pan-mesenchymal; present in virtually all STTs (non-specific but confirms mesenchymal lineage)
SMA (Smooth Muscle Actin, alpha-SMA): Myofibroblastic tumors (nodular fasciitis, fibromatosis, myofibroblastoma); also smooth muscle
Beta-catenin (nuclear): Desmoid fibromatosis - nuclear positivity due to CTNNB1 mutation (highly specific; cytoplasmic staining is non-specific)
STAT6 (nuclear): Solitary fibrous tumor (SFT) - highly sensitive and specific; reflects NAB2-STAT6 fusion
CD34: SFT, dermatofibrosarcoma protuberans (DFSP); also endothelial

2. Smooth Muscle Tumors

Desmin: Strong and diffuse positivity in leiomyoma/leiomyosarcoma
SMA: Strong positivity
Caldesmon: Highly specific for smooth muscle differentiation (distinguishes leiomyosarcoma from other sarcomas)
Calponin: Smooth muscle and myoepithelial cells

3. Skeletal Muscle Tumors (Rhabdomyosarcoma)

Desmin: Sensitive but not specific
MyoD1: Nuclear positivity - highly specific for skeletal muscle differentiation; positive in rhabdomyosarcoma (embryonal, alveolar, pleomorphic)
Myogenin: Nuclear positivity; alveolar RMS shows strong/diffuse staining; embryonal RMS shows focal/weak
Myosin (fast): Positive in RMS

4. Vascular Tumors

CD31: Most sensitive and specific marker for endothelial differentiation (hemangioma, angiosarcoma)
CD34: Endothelial marker (less specific than CD31); also positive in SFT, DFSP
ERG: Nuclear; highly sensitive endothelial marker; also expressed in prostate cancer
FLI1: Endothelial (and Ewing sarcoma)
D2-40 (podoplanin): Lymphatic endothelium (Kaposi sarcoma, lymphangiosarcoma)

5. Peripheral Nerve Sheath Tumors

S-100: Sensitive marker for schwannoma (strong, diffuse) and neurofibroma; also positive in melanoma, chondrosarcoma, fat cells
SOX10: More specific than S-100 for neural/melanocytic differentiation
CD34: Neurofibroma (intraneural fibroblasts)
H3K27me3 (loss): Loss of nuclear H3K27 trimethylation in malignant peripheral nerve sheath tumor (MPNST) due to loss of PRC2 complex (EED, SUZ12 mutations); distinguishes MPNST from its benign counterparts

6. Adipocytic Tumors

MDM2 (amplification): Well-differentiated liposarcoma (WDLS) / Dedifferentiated liposarcoma (DDLS): MDM2 gene amplification (12q14-15) detected by FISH; IHC shows nuclear MDM2 positivity as a screening tool - highly sensitive for WDLS/DDLS
CDK4: Also amplified/overexpressed in WDLS/DDLS alongside MDM2
S-100: Lipoblasts are S-100 positive; useful in myxoid liposarcoma

7. Gastrointestinal Stromal Tumors (GIST)

CD117 (c-KIT): Positive in ~95% of GISTs (cytoplasmic, membranous, or dot-like perinuclear); most sensitive marker
DOG1 (ANO1): Highly specific for GIST; positive in ~95% including most KIT-negative GISTs
CD34: ~70% of GISTs
SDHA/SDHB: Loss of SDHB staining indicates SDH-deficient GIST (pediatric/young adult; associated with Carney triad, Carney-Stratakis syndrome; KIT/PDGFRA wildtype; responds poorly to imatinib)

8. Synovial Sarcoma

TLE1 (nuclear): Strong nuclear staining; highly sensitive marker for synovial sarcoma (reflects SS18-SSX fusion)
EMA and AE1/AE3 (cytokeratin): Focal epithelial differentiation, especially in biphasic synovial sarcoma
CD99: Variable; non-specific
Confirm with FISH for SS18 (SYT) gene rearrangement

9. Ewing Sarcoma / PNET

CD99 (MIC2): Strong, diffuse membranous staining - highly sensitive (~95%), but not specific
FLI1: Nuclear; ~70%
NKX2.2: Sensitive for Ewing sarcoma (reflects EWSR1-FLI1 or EWSR1-ERG fusion)
Vimentin: Positive
Confirm with FISH/RT-PCR for EWSR1 rearrangement (EWSR1-FLI1 in ~85%, EWSR1-ERG in ~10%)

10. Alveolar Soft Part Sarcoma (ASPS)

TFE3 (nuclear, IHC): Positive due to ASPSCR1-TFE3 fusion; sensitive and specific
PAS-positive, diastase-resistant crystals (crystalline material in tumor cells)
Confirm with TFE3 FISH

11. Epithelioid Sarcoma

Cytokeratin (AE1/AE3, MNF116): Positive (can mimic carcinoma or granulomatous disease)
EMA: Positive
INI1 (SMARCB1) loss: Nuclear loss of INI1 is pathognomonic in epithelioid sarcoma, especially proximal type; also lost in rhabdoid tumors and some MPNST
CD34: Positive in ~50% of proximal-type epithelioid sarcoma

12. Clear Cell Sarcoma (Melanoma of Soft Parts)

S-100: Positive
HMB-45: Positive (unlike true melanoma arising at same site)
MelanA: Positive
Confirm with EWSR1-ATF1 or EWSR1-CREB1 fusion

Approach to "Small Round Blue Cell Tumors" (SRBCT)

Differential includes Ewing sarcoma, alveolar RMS, DSRCT, neuroblastoma, lymphoma, Wilms tumor:

Tumor	CD99	Desmin	MyoD1/Myogenin	NSE	LCA	WT1
Ewing sarcoma	+++	-	-	-	-	-
Alveolar RMS	+/-	+	+	-	-	-
DSRCT	-	+	-	-	-	+
Neuroblastoma	-	-	-	+	-	-
Lymphoma	-	-	-	-	+	-

7. Metabolic Disorders of Bone

Metabolic bone diseases are conditions characterized by abnormal bone mass, composition, or mineral homeostasis, usually due to systemic biochemical or endocrine disturbances.

A. Osteoporosis

Definition: A skeletal disorder characterized by compromised bone strength predisposing to increased fracture risk. Operationally defined as bone mineral density (BMD) T-score ≤ -2.5 SD below young adult mean (DXA scan).

Types:

Primary (Type I / Postmenopausal): Estrogen deficiency accelerates osteoclastic bone resorption; mainly affects trabecular bone; wrist and vertebral fractures predominate. Affects women within 10-15 years of menopause.
Primary (Type II / Senile): Age-related; affects both trabecular and cortical bone; hip fractures predominate. Affects both sexes >70 years.
Secondary: Glucocorticoid excess (most common cause of secondary osteoporosis), hyperthyroidism, hyperparathyroidism, hypogonadism, malabsorption, malignancy, medications (aromatase inhibitors, anticonvulsants, PPIs)

Pathogenesis: Imbalance between osteoblast (bone formation) and osteoclast (bone resorption) activity. Key pathways:

Loss of estrogen reduces OPG (osteoprotegerin) production, increasing RANK-L activity, driving osteoclastogenesis
Reduced calcium absorption (aging, vitamin D deficiency) stimulates PTH, which accelerates bone resorption
Reduced physical activity decreases bone formation

Morphology: Thin, porous cortex; enlarged marrow spaces; thinned, perforated, and disconnected trabeculae (microarchitectural deterioration). Bone composition is qualitatively normal (unlike osteomalacia).

Lab: Serum calcium, phosphate, and ALP are typically normal. Bone turnover markers (CTX, NTX, P1NP) may be elevated.

Treatment: Bisphosphonates (alendronate, risedronate, zoledronate); denosumab (anti-RANKL); teriparatide/abaloparatide (anabolic); romosozumab (sclerostin inhibitor).

B. Rickets (Children) and Osteomalacia (Adults)

Definition: Defective mineralization of newly formed osteoid matrix. In growing children, the growth plate cartilage also fails to mineralize = rickets.

Causes:

Vitamin D deficiency (nutritional deficiency, malabsorption, lack of sunlight)
Vitamin D-dependent rickets Type I (1-alpha-hydroxylase deficiency) and Type II (VDR mutation)
X-linked hypophosphatemia (PHEX mutation; phosphate-wasting)
Tumor-induced osteomalacia (FGF-23-secreting tumors)
Renal tubular acidosis
Chronic liver/renal disease (impaired vitamin D activation)

Pathogenesis: Deficiency of 1,25-(OH)2-D3 (calcitriol) leads to:

Decreased intestinal calcium absorption
Secondary hyperparathyroidism (PTH rises to maintain serum calcium)
Increased phosphate excretion
Failure of osteoid mineralization

Morphology: Wide osteoid seams (thick layer of unmineralized matrix at bone surfaces); decreased calcification front; in rickets: wide, disorganized growth plates with irregular columns of proliferating cartilage cells failing to mineralize; "cupping" and "fraying" of growth plates.

Clinical (Rickets):

Delayed fontanelle closure; craniotabes (soft skull)
Frontal bossing; rachitic rosary (costochondral junction swelling)
Harrison's sulcus (horizontal groove on lower thorax)
Bowed legs (genu varum); wrist widening
Hypotonia, delayed dentition

Lab:

Low serum calcium and phosphate
Markedly elevated ALP (osteoblast activity)
Elevated PTH
Low 25-OH-D3 (nutritional) or low 1,25-(OH)2-D3
Low/normal phosphate (FGF-23-related causes: low phosphate specifically)

C. Hyperparathyroidism (Osteitis Fibrosa Cystica)

Definition: Excess PTH causes increased osteoclastic activity. When severe/prolonged = osteitis fibrosa cystica (von Recklinghausen disease of bone - not to be confused with NF1).

Primary HPT: Parathyroid adenoma (80%), hyperplasia (15%), carcinoma (<5%). May be part of MEN1 or MEN2A.

Pathogenesis: Excess PTH activates osteoclasts via RANK-L upregulation; also increases renal calcium reabsorption and promotes vitamin D activation (1,25-OH2D3 synthesis).

Morphology:

Subperiosteal bone resorption (most characteristic): radial aspect of middle phalanges on X-ray
Brown tumors: Focal collections of osteoclasts (giant cells) surrounded by reactive fibrous stroma; may appear as cystic lytic lesions on X-ray. Not true tumors but hemorrhagic and fibrous lesions; called "brown" due to hemosiderin deposition. Key differential: giant cell tumor of bone (which Brown tumors can mimic)
"Salt and pepper skull" on X-ray (granular decalcification)
Generalized osteoporosis of the skeleton
Osteitis fibrosa cystica: Combination of the above findings; now rare due to early detection

Lab: Elevated PTH, elevated calcium, low phosphate, elevated ALP, elevated urinary cAMP.

D. Renal Osteodystrophy

A complex of bone abnormalities in chronic kidney disease (CKD) due to:

Decreased renal activation of vitamin D → low 1,25-(OH)2D3 → secondary hyperparathyroidism
Phosphate retention (reduced excretion) → hyperphosphatemia → further stimulates PTH
Metabolic acidosis → buffering by bone mineral
Adynamic bone disease (oversuppression of PTH with calcium/vitamin D)
Dialysis-associated amyloidosis (β2-microglobulin amyloid in joints)

Morphology: Mixed pattern - osteomalacia, secondary HPT changes (osteitis fibrosa), adynamic bone disease. Often "mixed uremic osteodystrophy."

E. Paget Disease of Bone (Osteitis Deformans)

Epidemiology: Predominantly affects men >55 years; common in Northwest Europe, North America, Australia; rare in Asia/Africa.

Pathogenesis: Paramyxovirus (measles/respiratory syncytial virus) implicated as trigger in genetically predisposed individuals. SQSTM1 (p62) mutations in 10-20% of familial cases. Characterized by dysregulated osteoclast activity.

Three Phases:

Osteolytic (Hot) Phase: Osteoclasts markedly enlarged with up to 100 nuclei (normal: 3-5 nuclei); intense bone resorption; "blade of grass" or "flame-shaped" lytic lesion on X-ray in long bones
Mixed Phase: Osteoclastic resorption accompanied by osteoblastic activity; bone is rapidly laid down but disorganized
Sclerotic (Burnt-Out) Phase: Osteoclast activity diminishes; osteoblasts produce coarse, thick trabeculae in a disorganized pattern

Morphology: Mosaic/jigsaw pattern of lamellar bone - cement lines create a "mosaic" or "crazy paving" appearance (pathognomonic). Bone is thickened, weak, and prone to fracture.

Clinical:

Often asymptomatic (found incidentally on X-ray or elevated ALP)
Bone pain, deformity, fractures
Skull involvement: frontal bossing, hearing loss (cranial nerve compression), platybasia
Bowing of long bones (tibia - "saber shin")
Spinal cord compression
High-output cardiac failure (extensive vascular bone)
Malignant transformation to osteosarcoma (~1% of Paget patients; very aggressive)

Lab: Markedly elevated ALP (bone-specific); serum calcium and phosphate normal (elevated calcium in immobilized patients); elevated urinary hydroxyproline.

8. Medulloblastoma

Medulloblastoma is the most common malignant primary brain tumor of childhood (~20% of all pediatric brain tumors). It is a WHO Grade 4 embryonal tumor arising exclusively in the cerebellum.

Epidemiology

Peak incidence: 5-9 years (children); second smaller peak in adults (3rd-4th decade)
Male > female (1.5-2:1)
Constitutes ~1% of all intracranial tumors but 15-20% of childhood brain tumors
Associated with Gorlin syndrome (PTCH1 mutations, nevoid basal cell carcinoma syndrome) - SHH pathway medulloblastoma
Associated with Turcot syndrome (APC/MLH1 mutations) - WNT-activated medulloblastoma

Location and Gross Pathology

Children: Midline cerebellar (vermis) location; arises from the roof of the 4th ventricle
Adults: More often lateral cerebellar hemispheres
Gross: Well-circumscribed, gray, friable mass; may extend to cerebellar surface and involve leptomeninges
Often causes obstructive hydrocephalus (4th ventricle obstruction)

Histology

Classic medulloblastoma is one of the "small round blue cell" (SRBC) tumors of childhood.

Microscopy:

Densely cellular sheets of monomorphic cells
Small cells with scant cytoplasm and hyperchromatic nuclei
Abundant mitoses
Homer Wright (neuroblastic) rosettes: Tumor cells surrounding a central zone of neuropil (pink, delicate neuronal processes); indicates neuronal differentiation
May show seeding of CSF ("drop metastases" along spinal cord and cranial leptomeninges)

Immunohistochemistry:

Neuronal markers: synaptophysin, MAP2, NeuN (nearly always expressed)
Glial markers (GFAP): expressed in rare cases
Ki-67: Very high proliferation index

Molecular Classification (WHO 2021 - Four Principal Groups)

Group 1: WNT-Activated Medulloblastoma

Genetics: Activating mutations in CTNNB1 (beta-catenin); also APC mutations (Turcot syndrome)
IHC: Nuclear beta-catenin accumulation; DKK1 expression
Histology: Classic histology; large cell/anaplastic variants very rare
Demographics: Children >3 years and adults; equal sex ratio
Location: Often involves brainstem/dorsal midline
Prognosis: EXCELLENT - ~95-100% overall survival at 5 years with standard therapy
Note: Despite being WHO Grade 4, WNT-activated MB has essentially curable disease

Group 2: SHH-Activated (Sonic Hedgehog)

Genetics: Mutations activating SHH pathway - PTCH1 (most common in infants and adults), SMO, SUFU, GLI2, MYCN amplification
IHC: GLI1, SFRP1 overexpression; GAB1+
Histology: Often desmoplastic/nodular (infants) or classic; large cell/anaplastic variants occur
Demographics: Bimodal - infants (<3 years) and adults; rare in children 3-17 years
Location: Cerebellar hemispheres (desmoplastic variant)
Prognosis: Variable; TP53-mutated SHH-MB (often in children 7-17 years) has very poor prognosis; TP53-wildtype has intermediate prognosis

Group 3: Non-WNT/Non-SHH, Group 3

Genetics: Heterogeneous; SMARCA4 mutations; MYC amplification; GFI1/GFI1B activation; isochromosome 17q
IHC: No specific defining marker
Histology: Classic or large cell/anaplastic; large cell/anaplastic variant especially common and most aggressive
Demographics: Predominantly young children (<10 years); male predominance
Location: Midline vermis
Prognosis: Poor; MYC-amplified tumors particularly aggressive (~<50% 5-year survival)

Group 4: Non-WNT/Non-SHH, Group 4

Genetics: Most common group (~35%); isochromosome 17q; CDK6 amplification; PRDM6 activation; Tandem duplication of SNCAIP
Histology: Classic or desmoplastic; large cell/anaplastic uncommon
Demographics: Children and adults; male predominance (3:1)
Location: Midline vermis
Prognosis: Intermediate; better than Group 3

Clinical Presentation

Cerebellar signs: truncal ataxia, gait disturbance (midline lesion), appendicular ataxia (lateral lesion)
Raised ICP: headache (worse in morning), vomiting, papilledema - due to 4th ventricle obstruction
Diplopia (6th nerve palsy from raised ICP)
Neck stiffness (if leptomeningeal involvement)
"Drop metastases": back pain, lower limb weakness (spinal seeding)
Neuroimaging (MRI): enhancing midline cerebellar mass; restriction on DWI (hypercellular); leptomeningeal enhancement indicates seeding

Treatment

Surgery: Maximum safe surgical resection - extent of resection is a prognostic factor
Radiotherapy: Craniospinal irradiation (CSI) + posterior fossa boost - medulloblastoma is exquisitely radiosensitive; CSI prevents leptomeningeal relapse. Not used in children <3 years (severe neurocognitive sequelae)
Chemotherapy: Platinum-based (cisplatin/carboplatin), vincristine, lomustine/cyclophosphamide
Targeted therapy: SMO inhibitors (vismodegib, sonidegib) for SHH-pathway MB (especially adults with PTCH1 mutations)
Overall 5-year survival: ~75% with combined modality therapy; WNT-activated ~95-100%; SHH-TP53 mutated and Group 3 MYC-amplified ~<50%

Risk Stratification

Standard risk: Age ≥3 years, total/near-total resection (<1.5 cm2 residual), no metastases (M0), non-anaplastic histology
High risk: Age <3 years, significant residual (>1.5 cm2), metastases (M1-M4), large cell/anaplastic histology, or MYC amplification

Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease (9780443264528); Robbins & Kumar Basic Pathology (9780323790185); Mulholland and Greenfield's Surgery (9781975143169); Fischer's Mastery of Surgery (9781975176433); Bradley and Daroff's Neurology in Clinical Practice (9780323642613)

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