Soft Tissue Pathology

Key questions

1. Q1What counts as "soft tissue"?

   Non-epithelial tissue outside bone, brain and organs: fibrous tissue, fat, smooth and skeletal muscle, peripheral nerve and its sheaths, and blood/lymphatic vessels.
2. Q2How common are soft tissue tumors, and which are most common?

   The great majority are benign (lipoma is the most common soft tissue tumor). Sarcomas (malignant mesenchymal tumors) are rare — that rarity makes them hard to recognize and easy to mistreat.
3. Q3Why are they hard to diagnose?

   Hundreds of entities, most made of look-alike spindle cells (elongated cells, longer than wide — the hallmark cell; scan at low power to see the growth pattern, then look for secondary features such as inflammation, hyalinization or necrosis); classification (WHO) now combines morphology, immunohistochemistry and molecular testing.
4. Q4What causes most soft tissue tumors?

   Unknown for most. Some benign lesions follow trauma or foreign material (nodular fasciitis may follow trauma).
5. Q5What are the risk factors for sarcoma?

   Prior radiation (latency ~5–10 years), chemicals (vinyl chloride and thorium dioxide → angiosarcoma of the liver; herbicides; alkylating chemotherapy), viruses (HHV-8 → Kaposi; EBV → smooth muscle tumors in immunosuppressed), chronic lymphedema (angiosarcoma) and familial syndromes (NF1 → MPNST; Gardner/FAP → desmoid; Li-Fraumeni; hereditary retinoblastoma).
6. Q6What do sarcoma karyotypes look like?

   Simple karyotype (~20%): one recurrent translocation, monomorphic cells, younger patients (e.g., synovial sarcoma, myxoid liposarcoma, alveolar rhabdomyosarcoma, Ewing). Complex karyotype (~80%): many gains/losses, genomic instability, pleomorphic tumors in older patients.
7. Q7Where do sarcomas arise?

   Mostly deep tissues: extremities (especially the thigh), retroperitoneum and abdomen, trunk, genitourinary tract, head and neck.

Key questions

1. Q8What history matters?

   Age, duration, rate of growth (sudden enlargement), pain or neurologic symptoms, history of trauma, prior radiation, lymphedema and family syndromes.
2. Q9Which features raise concern for sarcoma?

   Size >5 cm, deep location (below the fascia), rapid or recent growth, firm/fixed mass, older patient, retroperitoneal site. (A fatty mass in the retroperitoneum is a liposarcoma, not a lipoma, until proven otherwise.)
3. Q10What does imaging do?

   CT/MRI localizes and characterizes (fat, myxoid, mineralization, necrosis, vascularity), guides biopsy and plans definitive surgery; many deep tumors are only found on imaging.
4. Q11Which biopsy is preferred?

   Percutaneous core needle biopsy (or open incisional biopsy when more tissue is needed). FNA yields individual cells rather than a tissue core, so it is less informative for a first diagnosis. Excisional biopsy is reserved for very small lesions or a known lipoma.
5. Q12Why avoid "shelling out" a possible sarcoma?

   Excisional biopsy or enucleation contaminates tissue planes, leaves tumor behind, and makes later limb-sparing wide excision harder — "unnecessary complications."
6. Q13What ancillary tests help?

   Immunohistochemistry for lineage (desmin/myogenin for muscle, S-100/SOX10 for nerve sheath, CD31/ERG for vessels, keratin/EMA and TLE1 for synovial sarcoma, CD99 for Ewing, MDM2 for liposarcoma) and cytogenetics/molecular tests for signature translocations.
7. Q14Who should manage these patients?

   An experienced multidisciplinary team — surgeon, radiologist, pathologist, oncologist — because the tumors are rare and errors are costly.

Key questions

1. Q15What is the most important prognostic factor for a sarcoma?

   Histologic grade (incorporated into TNM staging) — along with size, depth and margins.
2. Q16How are sarcomas graded?

   By necrosis, cellularity, pleomorphism and mitotic count (atypical mitoses point to high grade). Low grade = bland, few mitoses; high grade = pleomorphic, mitotically active, necrotic.
3. Q17Which sarcomas have an inherent grade?

   Many: well-differentiated liposarcoma is grade 1 by definition; rhabdomyosarcoma, Ewing sarcoma and (by convention) synovial sarcoma are high grade.
4. Q18What is the surgical principle?

   Wide excision with a cuff of normal tissue around the tumor (limb-sparing when possible) — never "shell out" along the pseudocapsule. Radiation adds local control; chemotherapy is standard for metastatic (stage IV) disease, adjuvant use is controversial.
5. Q19How do sarcomas spread?

   Hematogenously — most often to the lungs, then bone. Lymph node spread is unusual.
6. Q20Which sarcomas break the rule and go to lymph nodes?

   Rhabdomyosarcoma, clear cell sarcoma, synovial sarcoma, epithelioid sarcoma (and angiosarcoma).

Key questions

1. Q21What is nodular fasciitis?

   A benign, self-limited reactive (pseudosarcomatous) proliferation of fibroblasts/myofibroblasts, often after trauma. Rapidly growing, small (1–3 cm), sometimes tender nodule in the subcutis — most often the forearm — of young adults (20–40).
2. Q22How is nodular fasciitis recognized under the microscope?

   Plump, uniform (myo)fibroblasts in a loose "tissue culture–like," feathery pattern with microcystic spaces, extravasated red cells and scattered lymphocytes; mitoses may be frequent but are not atypical. It carries t(17;22) MYH9-USP6. Often mistaken for sarcoma and sent for second opinion; does not recur after excision.
3. Q23What are fibromatoses?

   Benign but infiltrative fibroblastic proliferations of adults with a tendency to recur and never metastasize: firm, poorly circumscribed masses of bland fibroblasts in long sweeping fascicles with abundant collagen that infiltrate surrounding muscle.
4. Q24What are the superficial fibromatoses?

   Small, slow, arising from fascia/aponeuroses: palmar (Dupuytren — flexion contracture of the 4th/5th fingers), plantar (Ledderhose — non–weight-bearing sole) and penile (Peyronie — plaque on dorsal/lateral shaft → curvature).
5. Q25What are the deep fibromatoses (desmoid tumors)?

   Large, faster-growing, infiltrative: extra-abdominal (shoulder, chest wall, pelvis, thigh of adolescents/young adults), abdominal wall (pregnant or postpartum women, often within a year of childbirth) and intra-abdominal (mesentery/pelvis — associated with FAP/Gardner). Locally aggressive, recur, do not metastasize; mutations in β-catenin (CTNNB1) or APC.
6. Q26What is Gardner syndrome?

   An autosomal dominant FAP variant (APC mutation): colorectal adenomatous polyps with near-certain colon cancer, plus osteomas (skull/jaw), soft tissue tumors (fibromas, lipomas, desmoids), epidermal cysts, dental abnormalities (unerupted/supernumerary teeth) and congenital hypertrophy of the retinal pigment epithelium (bilateral pigmented fundus lesions). Loss of APC → β-catenin accumulates → uncontrolled proliferation.
7. Q27What is a lipoma?

   The most common soft tissue tumor: benign, encapsulated, soft, mobile, slowly growing subcutaneous mass of mature fat (back, shoulder, neck, proximal extremities), usually adults 40–60. Simple excision cures it; it does not recur.
8. Q28Which lipoma variants should you know?

   Angiolipoma (fat + small capillaries with fibrin thrombi; young adults, forearm; often multiple and painful), chondroid lipoma (cartilage-like matrix; rare, women) and spindle cell/pleomorphic lipoma (spindle cells and "floret" giant cells; posterior neck/shoulder of older men).
9. Q29What is liposarcoma and how is it diagnosed?

   The most common adult sarcoma: a malignant fatty tumor of deep tissues (thigh, retroperitoneum), never arising from a lipoma. The key cell is the lipoblast — a primitive fat cell with bubbly, vacuolated cytoplasm scalloping a compressed nucleus.
10. Q30What are the liposarcoma types?

    Well-differentiated (looks like fat with fibrous bands and atypical stromal cells; MDM2 amplification; recurs, especially retroperitoneal) ↔ dedifferentiated (high grade, aggressive). Myxoid ↔ round cell (t(12;16) FUS-DDIT3; 30–40s, thigh; gelatinous myxoid matrix, lipoblasts, delicate "chicken-wire" capillaries; the more round cells, the worse the prognosis; tends to metastasize to other soft tissue sites). Pleomorphic (rare, high grade).
11. Q31How does round cell liposarcoma differ grossly from myxoid?

    Round cell is solid and opaque on cut section; myxoid is gelatinous.

Key questions

1. Q32What is rhabdomyosarcoma?

   The most common soft tissue sarcoma of childhood: a malignant tumor showing skeletal muscle differentiation, often in sites with little skeletal muscle (head and neck, genitourinary tract). Desmin and myogenin/MyoD1 positive; rhabdomyoblasts may show cross-striations. High grade by definition.
2. Q33What is embryonal rhabdomyosarcoma?

   The most common subtype (~50%), children under 10: head and neck (orbit, nasopharynx) and genitourinary tract; resembles stages of developing skeletal muscle, from small round blue cells to strap cells.
3. Q34What is the botryoid variant?

   An embryonal subtype arising beneath the mucosa of hollow organs (vagina of young girls, urinary bladder): grape-like polypoid mass; defined by a cambium layer — a dense subepithelial band of tumor cells separated from intact surface epithelium by a loose zone.
4. Q35What is alveolar rhabdomyosarcoma?

   ~20%; adolescents and young adults (10–25); deep soft tissue of the extremities and head and neck; discohesive tumor cells clustered around fibrous septa, mimicking lung alveoli; t(2;13) PAX3-FOXO1 or t(1;13) PAX7-FOXO1.
5. Q36What is pleomorphic rhabdomyosarcoma?

   Rare adult form (men >60), deep thigh; large, bizarre eosinophilic cells. Spindle cell type occurs at any age and site.
6. Q37What is a hemangioma?

   A benign tumor of endothelial cells, most common in infancy/childhood, usually head and neck and superficial (can occur in the liver). Classified by vessel caliber.
7. Q38Capillary vs cavernous hemangioma?

   Capillary (including infantile "strawberry" hemangioma): red, raised, appears soon after birth, grows then usually regresses; small, plump endothelial cells with inconspicuous lumens. Cavernous: less common, larger, deeper, poorly circumscribed, bluish; large dilated blood-filled channels with flat endothelium; does not regress; large lesions can trap platelets (consumptive thrombocytopenia).
8. Q39What is angiosarcoma?

   An aggressive malignant tumor of blood or lymphatic endothelium: atypical endothelial cells forming irregular, anastomosing vascular channels; as grade rises the lumens become poorly formed and atypia increases. CD31/ERG positive.
9. Q40What are the clinical settings of angiosarcoma?

   1) Primary cutaneous — elderly, scalp/face, bruise-like indurated patches. 2) Lymphedema-associated — chronic lymphedema after mastectomy/axillary dissection (Stewart-Treves): red-brown nodules that ulcerate and bleed, or skin discoloration. 3) Post-radiation — breast, usually within ~5 years. 4) Deep soft tissue — any age; 1/3 with predisposing conditions. 5) Parenchymal organs — liver (vinyl chloride, arsenic, Thorotrast), bone.

Key questions

1. Q41What is a schwannoma?

   A benign, encapsulated nerve sheath tumor made entirely of Schwann cells, growing eccentrically on the side of the nerve (the nerve can be spared at surgery). S-100 positive.
2. Q42What does a schwannoma look like?

   Alternating cellular Antoni A areas (spindle cells with nuclear palisading — Verocay bodies) and loose, myxoid Antoni B areas; hyalinized vessels. Usually solitary and sporadic; vestibular (acoustic) schwannomas at the cerebellopontine angle; bilateral = NF2.
3. Q43What is a neurofibroma?

   A benign, unencapsulated tumor of mixed cells — Schwann cells, fibroblasts and perineurial cells — that grows through the nerve and incorporates axons, in a loose myxoid/collagenous ("shredded carrot") stroma.
4. Q44What forms do neurofibromas take?

   Localized cutaneous (soft, solitary, common, often sporadic), localized intraneural (fusiform nerve enlargement with residual axons), diffuse, and plexiform (many fascicles of a large nerve expanded — "bag of worms"). Plexiform neurofibromas are essentially diagnostic of NF1 and can become malignant (MPNST); diffuse neurofibromas are sometimes NF1-associated.
5. Q45What is NF1?

   Autosomal dominant (1 in ~2,500–3,000), 17q11.2, neurofibromin — a GTPase-activating protein that turns off RAS; loss → RAS stuck "on." Variable expressivity, complete penetrance.
6. Q46What are the features of NF1?

   Café-au-lait macules, axillary/inguinal freckling (by age 3–5), neurofibromas (cutaneous and plexiform), Lisch nodules (iris melanocytic hamartomas, highly specific), optic pathway glioma, skeletal dysplasia (tibial bowing, sphenoid wing dysplasia), scoliosis; learning disabilities/ADHD in ~50%; ~10% lifetime risk of MPNST; also pheochromocytoma, GIST, glomus tumor, arterial stenoses.
7. Q47What is NF2?

   Autosomal dominant, much rarer (1 in ~35,000), chromosome 22, merlin (schwannomin) — a cytoskeletal/Hippo-pathway protein needed for contact inhibition. Hallmark: bilateral vestibular (acoustic) schwannomas; also meningiomas, ependymomas, cutaneous schwannomas and juvenile posterior subcapsular cataracts.
8. Q48What is synovial sarcoma?

   A sarcoma of uncertain histogenesis — despite the name it does not arise from synovium. Young adults (15–40), deep soft tissue near large joints (especially around the knee). Biphasic (epithelial glands + spindle cells) or monophasic spindle; calcifications common. Keratin/EMA and TLE1 positive; t(X;18) SS18-SSX in >90%. High grade; can spread to lymph nodes and lungs.