7.4 Neoplasia, Oncogenes, Tumor Suppressors & Cutaneous Tumors

7.4 Neoplasia, Oncogenes, Tumor Suppressors & Cutaneous Tumors

Independent study guide by OpenExamPrep.

Core Examination Pearl: Board examinations heavily test the distinguishing features of benign versus malignant neoplasms, the molecular genetics of TP53 and RB checkpoints, the superior prognostic value of TNM staging over histological grading, the clinical and histopathologic presentation of Acral Lentiginous Melanoma (Hutchinson's sign, Breslow depth, non-UV etiology), the malignant transformation of chronic wounds/osteomyelitis into Marjolin's ulcer (Squamous Cell Carcinoma), and the classic radiographic/cytogenetic features of Osteosarcoma versus Ewing Sarcoma.

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1. Benign vs. Malignant Neoplasia & Metastasizing

A neoplasm ('new growth') is an abnormal mass of tissue whose growth exceeds and is uncoordinated with that of normal tissues, persisting in the same excessive manner even after cessation of the inciting stimulus. All tumors consist of two basic components: the parenchyma (proliferating neoplastic cells determining biological nature) and the stroma (supporting host connective tissue, blood vessels, and inflammatory cells).

Nomenclature & High-Yield Exceptions

• Benign Tumors: Typically designated by attaching the suffix -oma to the cell of origin (e.g., adenoma [glandular], fibroma [fibrous], lipoma [adipose], chondroma [cartilage], osteoma [bone]).
• Malignant Tumors:
  • Carcinomas: Malignant neoplasms of epithelial origin (e.g., adenocarcinoma, squamous cell carcinoma).
  • Sarcomas: Malignant neoplasms arising from mesenchymal connective tissues (e.g., osteosarcoma, chondrosarcoma, liposarcoma, leiomyosarcoma).
  • High-Yield Board Exceptions (Sound Benign, but are ALWAYS Malignant!):
    • Melanoma: Highly aggressive malignancy of melanocytes.
    • Lymphoma: Malignant proliferation of lymphoid cells.
    • Seminoma: Malignant germ cell tumor of the testis.
    • Hepatoma (Hepatocellular Carcinoma): Malignant tumor of hepatocytes.
    • Mesothelioma: Highly lethal malignancy of pleural/peritoneal mesothelial lining.

+-----------------------------------------------------------------------------------------+
|                        BENIGN vs. MALIGNANT TUMOR CHARACTERISTICS                       |
+-----------------------+-----------------------------+-----------------------------------+
| Characteristic        | Benign Neoplasms            | Malignant Neoplasms               |
+-----------------------+-----------------------------+-----------------------------------+
| Differentiation       | **Well-differentiated**;    | Ranges from well-differentiated   |
|                       | closely resembles parent    | to poorly differentiated or       |
|                       | tissue structure & function | **anaplastic** (dedifferentiated) |
| Nuclear Morphology    | Normal size, uniform shape, | **Pleomorphism**, hyperchromatic, |
|                       | normal N:C ratio (1:4–1:6)  | **high N:C ratio** (1:1), nucleoli|
| Mitotic Figures       | Rare, normal bipolar        | Frequent, atypical, bizarre       |
|                       | mitotic spindles            | multipolar spindles (tri/tetrad)  |
| Rate of Growth        | Slow, progressive expansion;| Rapid, erratic; can outgrow       |
|                       | may arrest or regress       | vascular supply causing necrosis  |
| Local Invasiveness    | **Non-invasive**; cohesive, | **Invasive & Infiltrative**;      |
|                       | circumscribed, encapsulated | breaches basement membrane        |
| Distant Metastasis    | **Strictly ABSENT**         | **FREQUENT** (definitive hallmark |
|                       | (never metastasizes)        | of malignancy)                    |
+-----------------------+-----------------------------+-----------------------------------+

Anaplasia: The Hallmarks of Malignancy

Anaplasia refers to the complete lack of cellular differentiation, representing the morphological hallmark of extreme malignant transformation:

1. Pleomorphism: Marked variation in cell size and cellular shape. Cells may be miniature or gigantic.
2. Abnormal Nuclear Morphology:
   • High Nuclear-to-Cytoplasmic (N:C) Ratio: Approaching 1:1 (normal resting cells maintain an N:C ratio of approximately 1:4 to 1:6).
   • Nuclear Hyperchromasia: Nuclei are dark, dense, and deeply basophilic due to excessive, coarse chromatin aggregates.
   • Prominent Nucleoli: Greatly enlarged, multiple nucleoli reflecting intense ribosome synthesis.
3. Atypical Mitoses: Frequent mitotic figures featuring bizarre, abnormal spindle shapes (tripolar, tetrapolar, or multipolar mitotic figures).
4. Loss of Polarity: Disorganization of normal architectural tissue orientation. Epithelial cells lose sheet-like architecture and grow in disordered, haphazard masses.
5. Tumor Giant Cells: Bizarre multinucleated or single massive monstrous cells containing polymorphic nuclear lobes.

Pathways of Metastatic Dissemination

Metastasis—the spread of a tumor to sites that are physically discontinuous with the primary lesion—is the absolute, unequivocal hallmark of malignancy (a benign tumor never metastasizes):

1. Lymphatic Spread:
   • The primary and classic route of initial dissemination for carcinomas (epithelial malignancies).
   • Tumor cells enter thin-walled afferent lymphatic channels and travel to the sentinel lymph node (the first regional lymph node receiving drainage from the primary tumor bed).
   • Podiatric Lymphatic Drainage Pattern: Cutaneous and subcutaneous lesions on the medial plantar foot and medial leg drain via superficial lymphatics alongside the great saphenous vein directly to the superficial inguinal lymph nodes. Lesions on the lateral plantar foot, lateral heel, and posterolateral leg drain via lymphatics traveling alongside the small saphenous vein to the popliteal lymph nodes before ascending to the deep inguinal nodes.
2. Hematogenous Spread:
   • The preferred and classic route of dissemination for sarcomas (mesenchymal malignancies), though carcinomas frequently utilize this route late in their course.
   • Veins are penetrated far more readily than thick-walled elastic arteries. Embolized tumor cells follow venous blood flow, lodging in the first vascular capillary bed they encounter.
   • Dominant Secondary Sites: The Lungs (receiving systemic venous drainage from the entire body, including the lower extremities) and the Liver (receiving portal venous drainage from the gastrointestinal tract).
   • Carcinoma Exceptions (Spread Hematogenously Early): Renal Cell Carcinoma (invades renal vein to IVC), Hepatocellular Carcinoma (invades portal vein), Follicular Thyroid Carcinoma, and Choriocarcinoma.
3. Seeding of Body Cavities & Surfaces:
   • Malignant cells penetrate into a natural open anatomical space (peritoneal, pleural, pericardial, subarachnoid, or joint cavities).
   • Classic example: Ovarian carcinoma seeding the peritoneal surface, or gastric adenocarcinoma seeding bilaterally to the ovaries (Krukenberg tumor, characterized by mucin-producing signet-ring cells).

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2. Molecular Oncology: Oncogenes vs. Tumor Suppressor Genes

Carcinogenesis is a multistep process driven by the sequential accumulation of non-lethal genetic and epigenetic alterations targeting two primary regulatory classes of genes:

+-----------------------------------------------------------------------------------------+
|                        ONCOGENES vs. TUMOR SUPPRESSOR GENES                             |
+-----------------------+-----------------------------+-----------------------------------+
| Parameter             | Proto-Oncogenes / Oncogenes | Tumor Suppressor Genes            |
+-----------------------+-----------------------------+-----------------------------------+
| Normal Function       | Promote cell growth,        | Inhibit cell proliferation, repair|
|                       | proliferation, and survival | DNA damage, induce apoptosis      |
| Mutation Type         | **Gain-of-Function**        | **Loss-of-Function**              |
|                       | (constitutive activation)   | (inactivation / deletion)         |
| Alleles Required      | **One allele** (Dominant at | **Both alleles** (Recessive at    |
|                       | cellular level)             | cellular level; 'Two-Hit')        |
| Mode of Origin        | Point mutation, gene        | Point mutation, deletion,         |
|                       | amplification, translocation| promoter hypermethylation         |
| Classic Examples      | **RAS**, **BRAF**, **MYC**, | **TP53**, **RB**, **APC**,        |
|                       | **HER2/neu**, **RET**       | **BRCA1/2**, **WT1**, **PTEN**    |
+-----------------------+-----------------------------+-----------------------------------+

1. Proto-Oncogenes & Oncogenic Activation

• RAS (KRAS, NRAS, HRAS):
  • Encodes a small, membrane-associated G-protein (GTPase) acting as an essential molecular switch downstream of Receptor Tyrosine Kinases (RTKs).
  • Mechanism: In the inactive resting state, RAS binds GDP. When stimulated by growth factor binding, RAS exchanges GDP for GTP, adopting an active conformation that stimulates downstream MAPK/ERK and PI3K/AKT proliferative signaling cascades.
  • GTPase-Activating Proteins (GAPs): Normally accelerate the intrinsic GTPase activity of RAS by >1,000-fold, hydrolyzing GTP back to GDP and turning RAS 'off'.
  • Oncogenic Mutation: Point mutations (most commonly at codons 12, 13, or 61) trap RAS permanently in the active GTP-bound state, rendering it resistant to GAP-mediated GTP hydrolysis. Mutated in approximately 30% of all human cancers.
• BRAF:
  • A serine/threonine protein kinase situated directly downstream of RAS in the MAPK signaling cascade.
  • Board Pearl: A specific point mutation, BRAF V600E (valine substituted by glutamic acid at codon 600), results in constitutive, growth factor-independent kinase activation. Found in >50% of cutaneous melanomas and papillary thyroid carcinomas. Targeted by selective BRAF inhibitors (e.g., vemurafenib, dabrafenib).
• c-MYC: Transcription factor promoting S-phase entry. Burkitt Lymphoma: reciprocal translocation t(8;14), placing the c-MYC proto-oncogene on chromosome 8 adjacent to the highly active Immunoglobulin heavy chain (IgH) enhancer locus on chromosome 14.

2. Tumor Suppressor Genes & Knudson's Two-Hit Hypothesis

Knudson's Two-Hit Hypothesis states that the development of cancer requires the functional inactivation of both alleles of a tumor suppressor gene:

• In familial (hereditary) cancer syndromes, an individual inherits one defective germline allele ('first hit') in all somatic cells. Cancer develops when a somatic mutation inactivates the remaining normal allele ('second hit') in a susceptible tissue.
• In sporadic cancers, both normal alleles must be independently inactivated by two distinct somatic mutational events within the same individual cell lineage.

High-Yield Tumor Suppressors: TP53 & RB

1. TP53 ('The Guardian of the Genome'):
   • Located on chromosome 17p; encodes the transcription factor p53. Inactivated in >50% of all human malignancies.
   • Mechanism: In unstressed cells, p53 has a short half-life, continually targeted for proteasomal degradation by the E3 ubiquitin ligase MDM2.
   • Response to DNA Damage: Atmospheric UV radiation, ionizing radiation, or chemical carcinogens induce ATM/ATR kinase phosphorylation of p53, displacing MDM2 and stabilizing p53.
   • Downstream Actions:
     1. G1/S Cell Cycle Arrest: p53 transactivates the CDKN1A gene, producing p21. p21 is a Cyclin-Dependent Kinase Inhibitor (CDKI) that binds and inhibits Cyclin D-CDK4/6 and Cyclin E-CDK2 complexes, maintaining the Retinoblastoma protein in an active, hypophosphorylated state and halting the cell cycle at the G1/S checkpoint to permit DNA repair.
     2. DNA Repair: Transactivates GADD45 (Growth Arrest and DNA Damage) repair machinery.
     3. Apoptosis Induction: If DNA damage is beyond repair, p53 upregulates pro-apoptotic BH3-only genes (PUMA, NOXA) and BAX, triggering the intrinsic mitochondrial apoptotic pathway.
   • Germline Mutation: Causes Li-Fraumeni Syndrome (autosomal dominant inheritance of one mutant TP53 allele), predisposing young individuals to a wide spectrum of early-onset malignancies (sarcomas, breast cancer, brain tumors, leukemias, adrenocortical carcinomas).
2. The Retinoblastoma Gene (RB):
   • Located on chromosome 13q14; encodes the Retinoblastoma protein (pRb), the master molecular checkpoint governing the transition from G1 to S phase.
   • Mechanism:
     • In its hypophosphorylated (active) state in quiescent cells, pRb binds tightly to and sequesters the E2F transcription factor family, repressing the transcription of genes required for DNA replication.
     • Growth factor signaling drives synthesis of Cyclin D and CDK4/6, which hyperphosphorylate (inactivate) pRb.
     • Hyperphosphorylated pRb releases E2F. Free E2F translocates into the nucleus and activates transcription of S-phase genes (cyclin E, DNA polymerase, thymidine kinase).
   • Pathology: Biallelic loss of RB eliminates the E2F checkpoint, causing unregulated, continuous entry into the S phase. Associated with childhood familial/sporadic retinoblastoma and a markedly elevated risk of adult osteosarcoma.

Grading vs. Staging of Neoplasms

• Histologic Grading: Microscopic evaluation of the degree of differentiation, cytological atypia, and mitotic index of the tumor. Typically categorized from Grade 1 (well-differentiated, low grade) to Grade 4 (undifferentiated / anaplastic, high grade).
• Clinical / Pathological Staging: Quantitative assessment of the anatomical size, local invasion, and distant physical spread of the tumor within the patient's body. Staged using the TNM System:
  • T (Primary Tumor): Size and depth of local invasion (T0 to T4; Tis = carcinoma in situ).
  • N (Regional Lymph Nodes): Number, size, and location of regional nodal metastases (N0 to N3).
  • M (Distant Metastasis): Presence or absence of distant hematogenous metastases (M0 or M1).

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3. Cutaneous & Podiatric Neoplasms

Skin malignancies frequently manifest on the foot and lower extremity, where delayed recognition due to dependent location, footwear friction, or misdiagnosis as benign dermatoses (warts, ulcers, hematomas) leads to advanced presentation.

+-----------------------------------------------------------------------------------------+
|                        CUTANEOUS NEOPLASMS OF THE FOOT & ANKLE                          |
+-----------------------+-----------------------------+-----------------------------------+
| Neoplasm              | Clinical Presentation       | Histopathology & Board Pearls     |
+-----------------------+-----------------------------+-----------------------------------+
| **Basal Cell**        | Pearly papule with rolled   | Nests of basaloid cells with      |
| **Carcinoma (BCC)**   | borders, telangiectasias;   | **peripheral palisading**; rare on|
|                       | non-healing central ulcer   | foot; PTCH1/Hedgehog mutations    |
+-----------------------+-----------------------------+-----------------------------------+
| **Squamous Cell**     | Hyperkeratotic, scaling,    | **Keratin pearls**, intracellular |
| **Carcinoma (SCC)**   | ulcerated nodule or plaque; | bridges (desmosomes); actinic     |
|                       | indurated base              | keratosis precursor               |
| • **Marjolin Ulcer**  | Aggressive SCC arising in   | Arises in chronic osteomyelitis   |
|                       | **chronic non-healing wound**| sinuses or burn scars; highly met|
+-----------------------+-----------------------------+-----------------------------------+
| **Malignant**         | Pigmented lesion fulfilling | Proliferation of atypical melanoc;| 
| **Melanoma**          | ABCDE criteria              | **Breslow depth** = key prognosis |
| • **Acral Lentiginous**| Soles, palms, subungual;    | **Not related to UV radiation**;  |
|   **Melanoma (ALM)**  | Hutchinson sign on nail fold| dominant melanoma in dark skin    |
+-----------------------+-----------------------------+-----------------------------------+
| **Kaposi Sarcoma**    | Multiple purple/violaceous  | Spindle cells forming **slit-like |
|                       | vascular macules or nodules | vascular spaces**; extravasated   |
|                       | on lower extremities        | RBCs; caused by **HHV-8**         |
+-----------------------+-----------------------------+-----------------------------------+

1. Basal Cell Carcinoma (BCC)

• Epidemiology: The most common human cancer overall. Occurs predominantly on chronic sun-exposed areas (face, head, neck); relatively rare on the lower extremity and foot (<2% of cases).
• Clinical Presentation: Smooth, pearly, translucent papule or nodule with fine branching telangiectasias (spider veins) and rolled, firm borders. Can develop central ulceration ('rodent ulcer').
• Histology: Islands and nests of uniform, darkly basophilic cells resembling the basal layer of epidermis, exhibiting pathognomonic peripheral palisading of outer nuclei and artificial clefting / retraction artifact from the surrounding fibrous stroma.
• Prognosis: Locally invasive and destructive, but metastasis is extraordinarily rare (<0.01%).

2. Squamous Cell Carcinoma (SCC) & Marjolin Ulcer

• Precursor Lesion: Actinic Keratosis (rough, erythematous, sandpaper-like hyperkeratotic papules on sun-damaged skin showing atypical basal keratinocytes; high rate of spontaneous regression, but ~1% per year transform into invasive SCC).
• Clinical Presentation: Firm, indurated, erythematous, scaling plaque or hyperkeratotic nodule that may ulcerate and bleed easily.
• Histopathology: Atypical keratinocytes invading the dermis, characterized by abundant eosinophilic cytoplasm, intercellular bridges (desmosomes), and keratin pearls (concentric laminated whorls of bright pink keratinized cells).
• High-Yield Podiatric Entity: Marjolin Ulcer:
  • An aggressive, highly malignant Squamous Cell Carcinoma that develops within sites of chronic, long-standing, non-healing wounds, burn scars, chronic venous stasis ulcers, or draining sinus tracts of chronic osteomyelitis on the lower extremity.
  • Latency: Typically emerges after a latent interval of 10 to 30 years of chronic smoldering inflammation.
  • Clinical Clues: A chronic neuropathic or venous ulcer that suddenly undergoes rapid enlargement, develops rolled, everted, indurated borders, exhibits excessive foul-smelling vegetative granulation tissue, or begins bleeding profusely.
  • Prognosis: Significantly more aggressive than conventional sun-induced cutaneous SCC, with a high rate of regional lymph node metastasis (>30–40%), often requiring wide surgical margin excision or major limb amputation.

3. Malignant Melanoma & Acral Lentiginous Melanoma (ALM)

Malignant melanoma arises from the neoplastic transformation of melanocytes residing in the basal layer of the epidermis. It accounts for the vast majority of skin cancer deaths.

• The Clinical ABCDE Criteria:

  • A - Asymmetry: One half of the pigmented lesion does not match the other half.
  • B - Border Irregularity: Notched, scalloped, ragged, or poorly defined margins.
  • C - Color Variegation: Multiple shades of tan, dark brown, jet black, mixed with red, white (areas of regression), or blue.
  • D - Diameter: Lesion diameter >6 mm (size of a pencil eraser; note: melanomas can be smaller).
  • E - Evolution: Any change in size, shape, color, elevation, or new symptoms (itching, bleeding, ulceration).

• Breslow Depth / Thickness:

  • The single most important prognostic factor for localized primary cutaneous melanoma.
  • Measured with an ocular micrometer from the top of the epidermal stratum granulosum (or ulcer base) vertically down to the deepest invading tumor cell in the dermis or subcutaneous fat.
  • Correlates directly with regional lymph node metastasis, distant dissemination, and 5-year survival rates (e.g., <0.8 mm carries excellent prognosis; >4.0 mm carries high metastatic mortality).

• Acral Lentiginous Melanoma (ALM - Top Podiatric Focus):

  • Anatomical Distribution: Localized strictly to the non-hair-bearing glabrous skin of the palms, soles (plantar foot), and subungual nail apparatus (nail matrix/bed).
  • Etiology: Completely unrelated to ultraviolet (UV) radiation or sun exposure!
  • Epidemiology: While ALM accounts for only ~5% of all melanomas in Caucasian populations, it is the most common melanoma subtype diagnosed in dark-skinned individuals, representing >60% to 70% of all melanomas in African American, Asian, and Hispanic patients.
  • Subungual Melanoma & Hutchinson's Sign:
    • Arises from the nail matrix, presenting initially as a dark brown or black longitudinal band running down the nail plate (longitudinal melanonychia).
    • As the lesion invades, pigment extends beyond the nail plate onto the adjacent periungual skin—the proximal nail fold, lateral nail fold, or hyponychium.
    • The presence of periungual pigment extension is known as a positive Hutchinson's sign, an ominous clinical sign pathognomonic for invasive subungual malignant melanoma that requires immediate full-thickness matrix/bed biopsy.

4. Kaposi Sarcoma (KS)

• Etiology: A vascular endothelial malignancy driven by Human Herpesvirus 8 (HHV-8 / KSHV).
• Histopathology: Neoplastic proliferation of endothelial cells that become elongated and spindle-shaped, forming jagged, slit-like vascular channels containing extravasated red blood cells, accompanied by dense hemosiderin pigment and an inflammatory infiltrate.
• Clinical Variants:
  • Classic (Mediterranean): Elderly men of Mediterranean or Eastern European Jewish descent; slow-growing, red-purple-brown macules/plaques on the distal lower extremities; indolent.
  • Epidemic (AIDS-Associated): AIDS-defining illness (CD4 <200 cells/μL); widespread, rapidly progressive violaceous cutaneous lesions on the lower extremities, face, oral cavity, and GI tract.
  • Endemic (African): Aggressive variant in HIV-negative children and young men in sub-Saharan Africa.
  • Iatrogenic (Transplant-Associated): Develops following solid organ transplantation under high-dose immunosuppression; often regresses upon reduction of immunosuppressive drugs.

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4. Musculoskeletal & Soft Tissue Tumors of the Lower Extremity

1. Plantar Fibromatosis (Ledderhose Disease)

• Pathology: A benign, locally aggressive, nodular fibroblastic and myofibroblastic proliferative disorder of the deep plantar aponeurosis.
• Clinical Presentation: Firm, non-mobile, slow-growing, solitary or multiple subcutaneous nodules embedded within the medial-central band of the plantar fascia. Often painful with direct ambulation or footwear pressure.
• Systemic Associations: Belongs to the superficial fibromatoses; associated with palmar fibromatosis (Dupuytren's contracture of the hand) and penile fibromatosis (Peyronie's disease).

2. Ganglion Cyst

• Pathology: The most common benign soft tissue 'tumor' of the foot and ankle. A non-neoplastic mucinous pseudocyst arising from cystic myxoid degeneration of a joint capsule (e.g., subtalar, ankle, Chopart joint) or tendon sheath (extensor digitorum longus, peroneals).
• Diagnostic Hallmarks:
  • Lacks a true cellular epithelial or synovial lining (hence 'pseudocyst').
  • Filled with thick, gelatinous, viscous clear fluid rich in hyaluronic acid and glucosamines.
  • Transilluminates brightly with a penlight (differentiating it from solid neoplasms like fibromas or synovial sarcomas).

3. Subungual Exostosis vs. Osteochondroma

• Subungual Exostosis: A benign, reactive osteocartilaginous bone outgrowth arising from the dorsal or dorsomedial aspect of the distal phalanx of a digit (most commonly the hallux). Clinically elevates the nail plate, causing severe subungual pain, onycholysis, and secondary paronychia. Radiographs demonstrate trabecular bone in continuity with the distal phalanx capped by fibrocartilage.
• Osteochondroma: The most common benign bone tumor overall. A lateral bony outgrowth (sessile or pedunculated) arising from the metaphysis of long bones (distal femur, proximal tibia), characterized by a hyaline cartilage cap and direct continuity of the lesion's medullary cavity with the native bone marrow space.

4. Malignant Bone Tumors: Osteosarcoma vs. Ewing Sarcoma

+-----------------------------------------------------------------------------------------+
|                         OSTEOSARCOMA vs. EWING SARCOMA                                  |
+-----------------------+-----------------------------+-----------------------------------+
| Feature               | Osteosarcoma                | Ewing Sarcoma                     |
+-----------------------+-----------------------------+-----------------------------------+
| Peak Incidence Age    | Bimodal: 10–20 years and    | Children & adolescents:           |
|                       | elderly (>65 y, Paget's)    | **10 to 15 years** (<20 y)        |
| Anatomical Location   | **Metaphysis** of long bones| **Diaphysis** (shaft) of long     |
|                       | (around knee: distal femur, | bones (femur, tibia, fibula),     |
|                       | proximal tibia)             | pelvis, and ribs                  |
| Radiographic Features | Bone destruction, lifting   | Destructive lytic lesion with     |
|                       | of periosteum forming       | concentric, laminated, multilayered|
|                       | **Codman triangle**, and    | **'onion-skin'** periosteal reactn|
|                       | radial **'sunburst'** pattern|                                   |
| Histopathology        | Pleomorphic malignant cells | Monomorphic sheets of **small,    |
|                       | actively producing unmineral| **round, blue cells**; glycogen-  |
|                       | ized bone (**osteoid**)     | rich cytoplasm (**PAS positive**) |
| Cytogenetics / Genes  | Inactivation of **RB** and  | Reciprocal translocation:         |
|                       | **TP53** tumor suppressors  | **t(11;22)(q24;q12)** creating    |
|                       |                             | **EWS-FLI1** fusion protein       |
+-----------------------+-----------------------------+-----------------------------------+