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Giant Cells in Pathology

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Diagram - Types of Giant Cells

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1. Langhans Giant Cell

• Tuberculosis (most classic)
• Leprosy (tuberculoid/borderline)
• Sarcoidosis
• Crohn disease
• Berylliosis
• Syphilis
• Fungal infections (histoplasmosis, coccidioidomycosis)
• Wegener granulomatosis

• Associated with T-cell mediated (type IV hypersensitivity) granulomas
• Found in "tuberculoid granulomas" - compact aggregates of epithelioid histiocytes rimmed by lymphocytes
• NOT exclusive to TB - any caseating or non-caseating granuloma can have them

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2. Foreign Body Giant Cell

• Around exogenous materials: sutures, splinters, talc, silica, silicone, tattoo pigment, aesthetic fillers
• Around endogenous materials: urate crystals (gout), calcium oxalate, cholesterol crystals (cholesteatoma), keratin (ruptured cysts)
• Surgical wounds
• Berylliosis

• Surrounded by histiocytes, lymphocytes, fibroblasts = foreign body granuloma
• Polarization microscopy essential to identify birefringent foreign material within them
• More "reactive" than immunological - appear faster (days to weeks) and with less T-cell involvement
• Can have 50-100+ nuclei

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3. Touton Giant Cell

• Juvenile xanthogranuloma (JXG) - most characteristic
• Xanthoma
• Necrobiotic xanthogranuloma
• Dermatofibroma (occasionally)
• Reticulohistiocytosis
• Xanthomatous conditions generally

• Touton cells are characteristic of JXG but NOT pathognomonic (not specific)
• The peripheral foamy cytoplasm distinguishes them from Langhans or foreign body types
• Reflect lipid engulfment by macrophages

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4. Reed-Sternberg Cell

• Hodgkin lymphoma (classic type: nodular sclerosis, mixed cellularity, lymphocyte-rich, lymphocyte-depleted)
• Infectious mononucleosis (EBV-infected B cells can mimic RS cells)

• Diagnostic RS cell: bilobed/multinucleated, each lobe has a large inclusion-like nucleolus ("owl eye")
• Lacunar variant: folded multilobated nucleus, sits in an open space (artifact of formalin) - seen in nodular sclerosis
• L&H "popcorn" cell: multiple infolded nuclear membranes, small nucleoli - seen in nodular lymphocyte predominant HL; CD20+, CD15-, CD30-
• RS cells are necessary but not sufficient to diagnose HL (must be in appropriate cellular background)
• CD30 is the therapeutic target (brentuximab vedotin)

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5. Osteoclast-type Giant Cell

• Giant cell tumor of bone (GCT) - epiphyses of long bones, 3rd-5th decade
• Aneurysmal bone cyst
• Giant cell reparative granuloma (jaw bones)
• Brown tumor of hyperparathyroidism
• Clear-cell chondrosarcoma (mixed)
• Tenosynovial giant cell tumor (PVNS)
• Paget disease (osteoclastic activity)

• In GCT: monotonous mononuclear stromal cells + macrophages + osteoclast-type giant cells
• GCT is benign but locally aggressive; ~1-2% can metastasize to lung
• RANKL pathway drives formation - denosumab (anti-RANKL) is treatment option for unresectable GCT
• Brown tumors of hyperparathyroidism are histologically indistinguishable from GCT - always check serum calcium and PTH

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6. Warthin-Finkeldey Giant Cell

• Measles (rubeola) - lymph nodes, tonsils, appendix, respiratory mucosa
• Also in HIV lymphadenopathy

• Pathognomonic for measles when seen in lymphoid tissue
• Appear during prodromal/early phase of measles
• Koplik spots (on buccal mucosa) correspond to same virus - Warthin-Finkeldey cells are the histologic counterpart

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7. Tumor Giant Cells (Anaplastic)

• Giant cell carcinoma (e.g., lung, thyroid, pancreas)
• Pleomorphic undifferentiated sarcoma
• Anaplastic large cell lymphoma
• Osteosarcoma

• Not a result of macrophage fusion - these are malignant cells
• Indicate high-grade malignancy with worse prognosis

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8. Syncytiotrophoblast / Placental Giant Cell

• Multinucleated syncytial cells lining chorionic villi
• Physiologic, not pathological
• Can be confused with tumor giant cells if seen in ectopic locations (choriocarcinoma)

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Summary Table

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Key Clinical Pearls

1. Langhans ≠ Langerhans - Langhans = granuloma giant cell; Langerhans = dendritic cell of skin (Birbeck granules, CD1a+, S100+)
2. None of the three main giant cells (Langhans, Foreign Body, Touton) are disease-specific - context and associated findings determine diagnosis
3. Owl-eye nucleolus = Reed-Sternberg cell = Hodgkin lymphoma until proven otherwise
4. Touton cells in the eye (juvenile xanthogranuloma) can cause spontaneous hyphema in infants
5. Brown tumor and Giant Cell Tumor of bone are histologically identical - always check calcium/PTH to exclude hyperparathyroidism before labeling as GCT
6. Denosumab (anti-RANKL monoclonal antibody) targets osteoclastic giant cells in GCT of bone
7. Granulomatous inflammation requires special stains (ZN for TB, PAS/GMS for fungi, polarization for foreign material) before labeling as idiopathic

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• Langhans - horseshoe nuclei at periphery (TB, sarcoidosis)
• Foreign Body - nuclei randomly scattered (implants, sutures)
• Touton - wreath of nuclei + foamy outer rim (JXG)
• Reed-Sternberg - owl-eye bilobed nucleoli (Hodgkin lymphoma)
• Osteoclastic - packed nuclei, massive cell (GCT of bone)
• Warthin-Finkeldey - grape-like nuclear clusters (Measles)
• Tumor/Anaplastic - hyperchromatic pleomorphic nuclei (anaplastic carcinomas)

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Classification of Breast Carcinoma

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I. Broad Classification

BREAST CARCINOMA
├── NON-INVASIVE (In Situ) — 15-20%
│   ├── Ductal Carcinoma In Situ (DCIS)
│   └── Lobular Carcinoma In Situ (LCIS)
│
└── INVASIVE — 80-85%
    ├── No Special Type / NST (formerly IDC-NOS) — ~75%
    └── Special Histologic Types — ~25%

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II. Non-Invasive (In Situ) Carcinomas

A. Ductal Carcinoma In Situ (DCIS)

• Central necrosis calcifies → seen on mammography as pleomorphic linear microcalcifications (especially in comedo type)
• Segmental calcifications on mammogram = DCIS extending along ductal tree from nipple to posterior breast
• Grade and ER status matter more than architecture for prognosis
• Low-grade cribriform DCIS → tends to become low-grade invasive carcinoma
• DCIS can extend through lactiferous ducts to nipple skin → Paget disease of nipple

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B. Lobular Carcinoma In Situ (LCIS)

• Neoplastic cells distend acini of terminal duct-lobular units, preserving cross-sectional architecture
• Cells are small, monomorphic, discohesive - no E-cadherin expression (CDH1 loss)
• No calcifications on mammography - usually incidental
• Considered a risk marker rather than obligate precursor (bilateral risk, both breasts)
• Associated with invasive lobular carcinoma

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III. Invasive Carcinomas

A. Invasive Carcinoma of No Special Type (NST) — 70-80%

• Grade 1 (3-5 points): Well differentiated - tubular/cribriform growth, small uniform nuclei
• Grade 2 (6-7 points): Moderately differentiated
• Grade 3 (8-9 points): Poorly differentiated - solid sheets, enlarged irregular nuclei, necrosis

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B. Special Histologic Subtypes of Invasive Carcinoma

Luminal (ER+/HER2-) Subtypes - generally better prognosis

HER2-enriched Subtypes

Triple Negative (ER-/PR-/HER2-) Subtypes

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IV. Other Breast Malignancies

Paget Disease of the Nipple

• DCIS extends up lactiferous ducts → spreads to nipple epidermis
• Large, pale "Paget cells" (clear cytoplasm, prominent nucleolus) within squamous epithelium of nipple
• Clinically: nipple erythema, eczema-like change, pruritus, crusting, ulceration

• 95% have underlying breast carcinoma

• Not a separate classification - it is a manifestation of DCIS/invasive carcinoma

Inflammatory Breast Carcinoma (Clinical, Not Histologic Type)

• Not a histologic subtype - a clinical presentation
• Dermal lymphovascular plugging by carcinoma cells
• Peau d'orange (skin tethered by Cooper ligaments)
• Diffuse erythema, warmth, swelling - mimics infection (mastitis); no actual inflammation
• Underlying tumor usually high-grade, diffusely infiltrative, no discrete mass
• Worst prognosis among non-metastatic breast cancers

Phyllodes Tumor (<1%)

• Mixed connective tissue + epithelial tumor
• "Leaf-like" architecture (phullon = leaf)
• Benign, borderline, or malignant variants
• Malignant phyllodes = carcinosarcoma-type

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V. Molecular Classification (Gene Expression Profiling)

• "Basal-like" (gene expression) ≠ "Triple negative" (IHC)
• Most basal-like tumors ARE triple negative
• Many triple-negative tumors do NOT have basal-like features
• Some rare TNBCs (adenoid cystic, secretory, low-grade adenosquamous) have favorable prognosis

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VI. Hereditary Breast Cancer Genes

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VII. Staging Overview (TNM)

1. Distant metastases - most important; commonest sites: bone, lung, liver, brain
2. Lymph node status - number of positive nodes; 1-3 vs 4+ nodes
3. Tumor size - strongly correlated with nodal status
4. Histologic grade (Nottingham)
5. ER, PR, HER2 status - both prognostic and predictive
6. Proliferation index (Ki67)
7. Lymphovascular invasion

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Quick Summary Mnemonic

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