Desmoid tumor differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2]

Overview

Extra-abdominal desmoid tumor must be differentiated from fibrosarcoma, low-grade fibromyxoid sarcoma and Gardner fibroma. Intra-abdominal desmoid tumor must be differentiated from gastrointestinal stromal tumor (GIST), benign fibrous tumor/solitary fibrous tumor (SFT), inflammatory myofibroblastic tumor (IMT), sclerosing mesenteritis and retroperitoneal fibrosis. Furthermore, generally all desmoid tumors must be differentiated from acute hematoma, lymphoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma, neurofibroma, nodular fasciitis, hypertrophic scars, keloids and primitive neuroectodermal tumor.

Differentiating Desmoid tumor from other Diseases

• Extra-abdominal fibromatosis/desmoid tumor must be differentiated from:
  • Fibrosarcoma/fibroblastic sarcoma
  • Low-grade fibromyxoid sarcoma
  • Gardner fibroma
• Intra-abdominal fibromatosis must be differentiated from:
  • Gastrointestinal stromal tumor (GIST)
  • Benign fibrous tumor/Solitary fibrous tumor (SFT)
  • Inflammatory myofibroblastic tumor (IMT)
  • Sclerosing mesenteritis
  • Retroperitoneal fibrosis due to:
    • Idiopathic [Ormond's disease]
    • Secondary to certain drugs
    • Underlying malignancy such as lymphoma
• Furthermore, generally all desmoid tumorss must be differentiated from:
  • Acute hematoma
  • Lymphoma
  • Rhabdomyosarcoma
  • Liposarcoma
  • Leiomyosarcoma
  • Neurofibroma
  • Nodular fasciitis
  • Hypertrophic scars
  • Keloids
  • Primitive neuroectodermal tumor

Differentiating desmoid tumor from other diseases

Disease entity	Etiology (Genetic or others)	Histopathological findings	Immunohistochemical staining	Benign/Malignant	Risk factors	Common site of involvement	Clinical manifestations	Other associated features
Desmoid tumor	Sporadic desmoids are associated with following mutations: Wnt/beta-catenin signaling pathway Mutations in CTNNB1 (Beta-catenin gene) (85%) APC gene mutations (10-15%) Familial desmoids/Hereditary desmoid disease is associated with: Mutation in second copy of APC gene Pediatric desmoids have following additional mutations involving: AKT1 E17K (31%) BRAF V600E (19%) TP53 R273H (9%)	Histologically, desmoid tumors consist of: Linearly arranged elongated fibroblasts and myofibroblasts Characterized by elongated, tapered cytoplasm; elongated, vesicular, typical-appearing nuclei; and multiple small nucleoli Surrounded and separated from each other by collagen	Positive for: Nuclear beta-catenin (90%) Vimentin Alpha smooth muscle actin Muscle actin Negative for: Desmin Cytokeratins S-100 c-KIT	Benign High local aggressive infiltration High local recurrence	Familial adenomatous polyposis (FAP) Gardner syndrome (inherited desmoids) Turcot syndrome Specific location of APC (adenomatous polyposis coli) gene mutation i.e. 3' end of the APC gene, specifically between codons 1445 and 1580 Family history of desmoid tumor Family history of colon cancer/FAP Estrogen therapy Oral contraceptive pills Pregnancy History of antecedent surgical/accidental trauma at the tumor site (30%) History of breast cancer History of repeated irradiation to a certain body part Female gender Sex hormones/androgens	Abdominal wall (intra-abdominal desmoids) Extra-abdominal desmoids may involve: Shoulder girdle Upper arms Upper legs Hip/buttock region Trunk Head Neck Breast (history of breast cancer/breast surgery Intra-abdominal desmoids may involve: Mesentery Retroperitoneum Bowel	Asymptomatic Painless/painful lump in affected area Pain or soreness caused by compressed nerves or muscles Limping or other difficulty using the legs, feet, arms or hands Decreased movement or range of motion Nausea Vomiting Breast mass (in case of breast desmoids) Loss of sleep Anxiety Abdominal mass/pain Constipation Bloating Intestinal rupture Rectal bleeding Compression of kidneys, ureters, mesenteric vessels and vena cava	Desmoids may be associated with following: Other sporadic tumors such as: Dupuytren's contracture Plantar fibrosis Peyronie's disease Carpal tunnel syndrome Infantile fibrosarcoma Fibrous dysplasia Trisomy 8 Trisomy 20
Fibrosarcoma/Fibroblastic sarcoma	Unknown precise cause Genetics may play a role	Tumor cells resemble mature fibroblasts (spindle-shaped), secreting collagen, with rare mitoses Spliting and merging cells arranged in short fascicles giving "fish bone" appearnace Immature blood vessels (lacking endothelial cells) favor the bloodstream metastasizing "Herringbone" pattern of cell arrangement	Strongly positive for: Vimentin Negative for: Desmin Smooth muscle actin HHF-35 Osteocalcin CD-68 LCA s100 HMB-45 CD-31 CD-34 Cytokeratin Epithelial membrane antigen CD-99	Malignant (with metastatic potential)	Familial adenomatous polyposis Li-Fraumeni syndrome Neurofibromatosis type 1 Nevoid basal cell carcinoma syndrome Retinoblastoma Tuberous sclerosis Werner syndrome Giant cell tumor Enchondroma Fibrous dysplasia Bizarre parosteal osteochondromatous proliferation Chronic osteomyelitis Paget's disease Radiation therapy Surgically treated fracture Bone infarction Exposure to certain chemicals, such as thorium dioxide, vinyl chloride, or arsenic Lymphedema, a swelling in the arms and legs	Primary bone malignancy involving end of long bones: Upper end of tibia Lower end of femur	Localized Pain Swelling Loss of range of motion Pain with weight-bearing Night pain Pathologic fracture of affected bone	Moth-eaten appearance on Xray
Low-grade fibromyxoid sarcoma	Translocation: t(7;18;16) or t(7;16) (q34:p11) Fusion gene: FUS/CREB3 L2 (76%-96%) FUS/CREB3 L1 (4%-6%)	Low to moderate cellularity Regular medium sized nuclei Loosely arranged fascicles of bland spindle cells (whorling pattern) Loose myxoid stroma No cellular atypia Hypocellular/myxoid areas in nodules merging with collagenised areas	Positive for: MUC4 (highly specific and sensitive) Vimentin Occasionally positive for: Desmin SMA EMA CD34 Negative for: Keratin Actin S100 Epithelial membrane antigen CD31 CD68 Cytokeratin (AE1/AE3) Leu-7 Neuron-specific enolase	Benign (histological appearance) High metastasizing potential/local aggressive infiltration High local recurrence	_	Majority occurring in subfascial location and rarely involving subcutis or dermis in following sites: Lower extremities Trunk Groin Upper extremities Thorax Buttocks Abdominal wall Maxillofacial region (rarely)	Painless, slow-growing well-circumscribed mass Average size-5cm (ranges from 1-20cm)	_
Benign fibrous tumor/Solitary fibrous tumor (SFT)	Intra-chromosomal inversion at: Chromosome 12q13 leading to formation of NAB2–STAT6 chimeric fusion gene (highly variable breakpoints) TERT promoter mutations responsible for: High aggressive potential Metastatic potential	Fibroblast-like tumor cells arranged in a “patternless” pattern Collagenous stroma with staghorn, hyalinized blood vessels Increased mitotic activity Hypercellularity Nuclear atypia Pleomorphism Lipomatous, myxoid, or dedifferentiated variants	Positive for: CD34 Vimentin CD99 (013) Bcl-2 In few cases, positive for: Focal keratin reactivity Focal desmin reactivity Negative for: CD31 Cytokeratin Glial fibrillary acidic protein Smooth muscle actin S-100 protein Epithelial membrane antigen	Metastasis(10%-20%) Recurrence (10%-20%)	_	Any anatomic site Serosal membranes such as: Pleura (most common site) Dura of the meninges Peritoneum (or peritoneal cavity) Thoracic cavity (mediastinum, lung parenchyma) Intra-abdominal SFTs involve: Retroperitoneal soft tissue (most common) Liver Diaphragm Pelvis visceras (bladder, prostate, seminal vesicle, kidney) Head and neck sites include: sinonasal tract oral cavity orbit buccal mucosa tongue lower lip Extremities Skin (dermis) Bone	Asymptomatic Pulmonary symptoms (cough, shortness of breath, chest pain, hemoptysis, obstructive pneumonitis because of airway obstruction) Intra-abdominal symptoms (pain,weight loss, dysuria, urinary retention, hydronephrosis, nocturia, constipation, incontinence, vomiting) Paresthesias Symptoms due to nerve impingement Meningeal symptoms Hypoglycemia (due to paraneoplastic syndromes) Symptoms due to hypertrophic pulmonary osteoarthropathy include: Clubbing of the fingers Periostitis Synovial effusions	Paraneoplastic syndromes associated with SFTs include: Doege-Potter syndrome (Refractory hypoglycemia due to IGF2, associated with large peritoneal/pleural tumors) Hypertrophic pulmonary osteoarthropathy (HPO)/Pierre-Marie-Bamberger syndrome( in pleuropulmonary SFTs, secretes hyaluronic acid, cytokines)
Gardner fibroma/Gardner-associated fibroma (GAF)	APC gene mutation	Thick haphazardly arranged collagen bundles (greater abundance of collagen) Few interspersed spindle cells of fibroblast type (less cellularity)	Positive for: Nuclear Beta-catenin (highly positive) CD34 Cyclin-D1 C-myc	Benign	Gardner-type familial adenomatous polyposis Germline mutations in APC gene Inherited desmoids Gardner syndrome The presence of nuchal-type fibroma may indicate Gardner Fibroma, when seen in children	Any part of body: Back (most common) Paraspinal region (most common) Chest wall Abdomen Head Neck Arms Legs	Firm rubbery mass (not a well-circumscribed) Size from 1-10 cm Signs and symptoms due to associated FAP or Gardner syndrome	Precursor lesion for desmoid (50% cases) with a more cellular appearance Precursor lesion for colonic adenomas in asymptomatic FAP patients
Gastrointestinal stromal tumor (GIST)	Activating mutation of: C-KIT ( tyrosine kinase growth factor receptor) gene (Exon 9,13 & 17) Platelet-derived growth factor receptor alpha (PDGFRA on chromosome 4q11-12) gene (Exon 18) BRAF kinase (rare) Protein kinase C (rare) Pediatric GISTs (SDH-deficient) have mutations of one of the: SDH (succinate dehydrogenase)gene subunits GIST as a part of Carney triad has following mutation: Hypermethylation of the SDHC promoter causing epigenetic inactivation of the SDHC gene Wild-type GISTs have following three molecular subtypes: DHX mutations (66%) SDHC promoter hypermethylation (22%) SDH competent (12%) which can further be broken into: NF1 mutations BRAF V600E mutations Other rare mutations or fusions No identified abnormality	GIST cells basically arise from interstitial cells of Cajal (ICCs) and appear as follows on histology: Spindle cells (60%-80%): Fascicular or whorled like appearance Multiple compact cells with minimal stroma Eosinophilic, basophilic or amphophilic cytoplasm Epithelioid cells (20%-30%) Clearly defined with an abundant amphophiliccytoplasm Pleomorphic/mixed cells (occasionally, 10%) Both spindle or epitheloid cells	Positive for: CD117 (overexpression of the receptor tyrosine kinase KIT is the most prominent diagnostic test) CD34 DOG-1 PKC-theta (protein kinase C theta) Consistently negative for: Beta-catenin	Malignant potential (esophageal and colonal GIST) Metastasis (to liver, lungs, bones, subcutis, spleen)	Age group of 50-80years Primary familial GIST syndrome Neurofibromatosis type 1 (NF1) Carney-Stratakis syndrome (dyad of GISTs and paragangliomas) Carney triad (GIST, paraganglioma, and pulmonary chondromas) Urticaria pigmentosa	Can involve any part of GIT: Stomach (most common) Duodenum Omentum Mesentery Esophagus Colon Peritoneum	Depending on tumor size and localization in GIT: Pain Nausea Vomiting Bleeding Obstruction Anemia Melena Abdominal distension Abdominal perforation Peritonitis Volvulus Intussusception Surgical complications associated with resection include: Atelectasis Pneumonia Urinary tract infection Abscess formation Small-bowel obstruction Deep venous thrombosis
Inflammatory myofibroblastic tumor (IMT)	Unknown underlying etiology, may be due to inflammatory reaction to: Infection Underlying low grade malignancy Mutations such as: ALK (anaplastic lymphoma kinase) gene mutations in the tyrosine kinase locus at band 2p23	Spindle to stellate-shaped cells Spindle cells arranged in short fascicles with a focal storiform (whorled or cartwheel-like) architecture Spindle cells show features of fibroblasts and myofibroblasts Variably dense, chronic, mixed polymorphic infiltrate of mononuclear inflammatory (plasma cells and lymphocytes, histiocytes, neutrophils, and occasional eosinophils) Histiocytes have multinucleated forms with finely vacuolated cytoplasmic lipid droplets Plasma cells with cytoplasmic Russell bodies (globular cytoplasmic inclusions of immunoglobulin) and polyclonal pattern of light chain expression Absent hyperchromasia and atypical mitoses	Positive for: IG+ (plasma cells) IL-1 IL-6 Smooth muscle actin Desmin Calponin Activin-like kinase 1 Negative for: Beta-catenin	Metastatic	Multiorgan disease in association with chronic persistent Eikenella corrodens infection Epstein Barr virus infection Human herpes virus (HHV)-8 infection (Kaposi's sarcoma, multicentric Castleman's disease)	Lungs Gastrointestinal system Pelvic region Bladder Uterus Retroperitoneum Skin Bone (femur, temporal bone, jaw bone) CNS Soft tissues Larynx Heart (right ventricle is most commonly involved) Pancreas (rarely)	Asymptomatic (70%) Painless asymptomatic mass/lump/swelling Pulmonary IMT presents as: Chest pain Cough Dyspnea Hemoptysis (recurrent) Fever Fatigue Weight loss Appetite loss Bone IMT presents with: Mild bone pain Easy fractures Headache Dizziness Numbness at tumor site Bone marrow involvement in some cases Heart IMT presents with: Chest pain Difficulty breathing Palpitations Fainting Obstruction of blood flow in the heart (large tumors) Bladder IMT presents with: Painless hematuria Chronic pelvic pain Difficulty in urinating Presence of burning sensation CNS IMT presents with: Presence of solitary or multiple tumors at various locations in the brain Recurrent headaches Headache Nausea and vomiting Blurred vision Double vision Drooping of the eyelid Dizziness Back pain (if spine involved) Seizures	Also known as: Pseudo-inflammatory tumors Inflammatory pseudotumor Plasma cell granuloma Inflammatory pseudotumor Fibrous histiocytoma Fibroxanthoma Xanthogranuloma Inflammatory pseudosarcoma Atypical fibromyxoid tumor Atypical myfibroblastic tumor
Sclerosing mesenteritis	Unknown exact etiology: Encompasses a spectrum of idiopathic primary inflammatory and fibrotic processes affecting mesentery	Varying components of: Inflammation, fibrosis, and fat necrosis Adipocyte necrosis (mesenteric lipodystrophy) Chronic inflammatory state (mesenteric panniculitis) Fibrosis (sclerosing mesenteritis)	_	Non-neoplastic inflammatory and fibrotic disease	Abdominal surgery/trauma: Cholecystectomy Appendectomy Hysterectomy Colectomy Pneumatic jackhammer Occult ileal perforation Autoimmunity: Riedel thyroiditis Primary sclerosing cholangitis Retroperitoneal fibrosis Orbital pseudotumor Autoimmune hemolytic anemia Minimal change nephropathy Systemic lupus erythematosus Relapsing polychondritis Multifocal fibrosclerosis Limited systemic sclerosis Celiac-associated T-cell lymphoma Paraneoplastic syndrome: Non-Hodgkin lymphoma(most common) Breast cancer Carcinoid Melanoma Squamous carcinoma and adenocarcinoma of the lung Renal carcinoma Multiple myeloma Hepatocellular carcinoma Prostate adenocarcinoma Ovarian carcinoma Endometrial carcinoma Cervical carcinoma Angiosarcoma Gastrointestinal adenocarcinomas Ischemia and infection history: Typhoid fever Dysentery Tuberculosis Syphilis Malaria Influenza Rheumatic fever	Mesentery	Asymptomatic Abdominal pain Nausea and vomiting Altered bowel habits (Constipation or diarrhea) Weight loss Fever Malaise Abdominal tenderness Abdominal distension Peritoneal inflammation and ascites (usually chylous) Pleural effusion Protein-losing enteropathy (Fever, edema) Biliary obstruction (hemolytic anemia, jaundice) Bowel obstruction Obstructive uropathy/renal failure Chylous ascites Chronic mesenteric ischemia Anemia Hypoalbuminemia Mesenteric vascular occlusion (both arterial and venous)	Nomenclature used in the medical literature for idiopathic primary inflammatory and fibrotic processes of the mesentery is as follows: Mesenteric lipodystrophy (predominant fat necrosis predominance) Mesenteric fibrosis Mesenteric panniculitis Mesenteric lipodystrophy Retractile mesenteritis Mesenteric Weber-Christian disease Xanthogranulomatous mesenteritis Mesenteric lipogranuloma Liposclerotic mesenteritis Inflammatory pseudotumor Isolated lipodystrophy Retroperitoneal xanthogranuloma
Retroperitoneal fibrosis	Idiopathic (70%) [Ormond's disease] is an immune-mediated disease caused by: Other autoimmune diseases Immunoglobulin G4-related disease (IgG4-RD) Chronic periaortitis Allele HLA‑DRB1*03, D32 polymorphism of the gene encoding CCR5 (chemokine receptor) TTCCAT haplotype of the gene encoding CCL11/eotaxin‑1 (drives the recruitment of eosinophils) Secondary to: Certain drugs Underlying malignancy such as lymphoma	Fibro-inflammatory disease histologically hallmarked by fibrous tissue and chronic inflammation: Fibrous tissue composed of extracellular matrix containing type I collagen fibers organized in thick irregular bundles, often encircling small retroperitoneal vessels Fibroblasts: Show signs of activation and transition into myofibroblasts (α‑smooth muscle actin expression) Are major source of collagen production Rarely show mitoses, undergo clonal proliferation Inflammatory infiltrate consists of numerous lymphocytes, plasma cells, and macrophages Inflammatory cells maybe: Interspersed within the collagen bundles (“diffuse” pattern) or Organized in nodular aggregates, usually around small vessels, having a B cell core surrounded by CD4+ T cells When IgG4+/total IgG+ plasma cell ratio is >40%, RPF is classified as “IgG4-related” if other features such as storiform fibrosis, eosinophil infiltration, and obliterative phlebitis are also present	Tryptase positive (mast cells)	Benign immune mediated inflammatory process	Idiopathic [Ormond's disease] Secondary to certain drugs (ergot-derivatives, methysergide, bromocriptine, beta blockers, methyldopa, hydralazine, analgesics) Biological agents (etanercept, infliximab) Underlying malignancy (carcinoid, Hodgkin and non-Hodgkin lymphoma, sarcomas, colorectal, breast, prostate and bladder carcinoma) Infections (tuberculosis, histoplasmosis, actinomycosis) Radiation therapy for testicular seminoma, colon and pancreatic cancer Retroperitoneal hemorrhage Surgery (lymphadenectomy, colectomy, aortic aneurysmectomy) Secondary (AA) amyloidosis Trauma Barium enema Mesenteric panniculitis Different forms of histiocytosis particularly Erdheim-Chester disease Exposure to asbestos Tobacco smoke exposure	Thoracic aorta Mesenteric arteries Renal arteries and veins Epiaortic arteries Ureters Abdominal organs Pancreas Salivary glands Lymph nodes Pituitary gland	Pain in the lower back, abdomen, or flank (most common presentation, bilateral or unilateral flank pain that radiates to the inguinal region, or acute onset pain similar to renal colic) Abdominal aortic aneurysms Malaise Anorexia Weight loss Fever Nausea and vomiting Testicular pain Constipation Venous compression (inferior vena cava) leading to: Lower limb edema (lymphatic compression) Inferior vena cava syndrome Deep vein thrombosis Pulmonary embolism Arterial stenosis (rare) causing: Upper-leg claudication Mesenteric ischemia (mesenteric arteries compression) Thoracic aorta and/or the epi-aortic arteries' compression Recurrent laryngeal nerve paralysis causing hoarsness and dry cough Acute kidney injury (AKI) (due to bilateral encasement of ureteral and renal involvement in peri-iliac retroperitoneal fibrosis) Renal atrophy (due to previous transient unilateral obstruction or renal artery stenosis) Obstructive uropathy Gross hematuria Urinary symptomes (urinary urgency,frequency, and dysuria) Hypertension (due to renal artery impingement) Obstruction of the inferior vena cava and/or iliac veins Thrombophlebitis Deep vein thrombosis Varicocele Hydrocele	Retroperitoneal fibrosis is also known as: Ormond's disease Periureteritis fibrosa Periureteritis plastica Chronic periureteritis Sclerosing retroperitoneal granuloma Fibrous retroperitonitis
Lymphoma	Diffuse large B cell lymphoma (DLBCL): Rare MALT1 rearrangements, trisomy 18 in some, possible NFκB activation in minority Extranodal marginal B cell lymphoma arising from mucosal associated lymphoid tissue (MALT lymphoma): Clonal rearrangements of immunoglobulin genes Often trisomy of 3, 12, 18 Usually negative for characteristic MALT1 rearrangements t(11;18)(q21;q21) and t(14;18)(q32;q21) Follicular lymphoma: Presence of t(14;18)(q32;q21) translocation has not been systematically assessed in primary breast follicular lymphoma Burkitt lymphoma: t(8;14)(q24;q32) c-Myc and IgH translocation is most frequent t(2;8)(p12;q24) IgΚ and c-Myc t(8;22)(q24;q11) c-Myc and Igλ	Diffuse large B cell lymphoma (DLBCL): Diffuse infiltration by large lymphoid cells, centroblastic > immunoblastic, activated B cell type > germinal center type Extranodal marginal B cell lymphoma: Vaguely nodular growth pattern, neoplastic cells occupy the marginal zone surrounding the B cell follicle mantle zone but can have diffuse growth pattern if follicles infiltrated / replaced Marginal zone B cells, variable plasma cells, reactive follicles (±) Monocytoid-like cells Plasmacytic differentiation Low mitotic rate Follicular lymphoma: Follicular and diffuse architectural patterns Monotonous population of small cleaved cells (centrocytes) Variable numbers of centroblasts (large noncleaved cells) Associated sclerosis can cause single file infiltration pattern Burkitt lymphoma: Sheets of uniform medium sized lymphocytes with round nuclei, multiple basophilic nucleoli, course chromatin, scant to moderate basophilic cytoplasm, minimal intervening stroma High mitotic rate Tingible body macrophages containing apoptotic debris produce a "starry sky" appearance Mantle cell lymphoma: Small to medium sized, slightly irregular cells with scant cytoplasm Classic Hodgkin lymphoma: Reed-Sternberg cells and variants in a reactive background Nodular lymphocyte predominant Hodgkin lymphoma: Vague nodules of small B cells and interspersed large tumor cells (LP cells) with thin nuclear membranes, fine chromatin and variable nucleoli MALT lymphoma: Infiltration of thyroid epithelium creates lymphoepithelial lesions (lymphocytes "stuff" glandular lumina) May have background lymphocytic thyroiditis	Positive for: Diffuse large B cell lymphoma (DLBCL): CD45, CD20, CD79a, PAX5, BCL2, Ki67 (high) Activated B cell type (CD10-, BCL6- or CD10-, BCL6+, MUM1 / IRF+) is more common Germinal center type (CD10+, BCL6+ or CD10-, BCL6+, MUM1 / IRF-) Surface Ig+ CD43± Extranodal marginal B cell lymphoma arising from mucosal associated lymphoid tissue (MALT lymphoma): Surface and cytoplasmic Ig+ (IgM > IgG or IgA) CD45, CD20, CD79a, PAX5, variable CD43, variable BCL2, Ki67 (low) Variable monotypic cytoplasmic immunoglobulin seen in cases with plasmacytic differentiation CD21 and CD23 highlight expanded / disrupted follicular dendritic meshworks CD43± Follicular lymphoma: Surface Ig+ CD45, CD20, CD79a, CD10, BCL6, BCL2 CD21 and CD23 highlight follicular dendritic cell meshworks Burkitt lymphoma: Surface IgM+ CD45, CD20, CD79a, PAX5, CD10, BCL6, Ki67 (~100%) Mantle cell lymphoma: Surface IgMD+, CD20+, CD5+, CD10-, CD43+, cyclin D1+ Classic Hodgkin lymphoma: R-S cells: CD30+, CD15±, PAX5+ Nodular lymphocyte predominant Hodgkin lymphoma: LP cells: CD45+, CD20+ Thyroid MALT lymphoma: CD20 Keratin Thyroglobulin CD45 Anaplastic large T cell lymphoma: CD3, CD10, CD30, CD43, CD99, TdT PreT lymphoblastic lymphoma: CD3, CD10, CD99, TdT Negative for: Diffuse large B cell lymphoma (DLBCL): EBER Extranodal marginal B cell lymphoma, MALT type: CD5, CD10, CD23, BCL6, cyclin D1 Follicular lymphoma: CD5, CD23, cyclin D1 Burkitt lymphoma: CD5, CD23, TdT, BCL2 Mantle cell lymphoma: CD10- Classic Hodgkin lymphoma: R-S cells: ALK-, CD45-, CD3- Nodular lymphocyte predominant Hodgkin lymphoma: LP cells: CD15-, CD30- Anaplastic large T cell lymphoma: ALK1, bcl6 PreT lymphoblastic lymphoma: bcl6-	Malignant	MALT lymphoma (Extranodal marginal B cell lymphoma may arise from it) Underlying autoimmune disease EBV (endemic and sporadic Burkitt lymphoma) HIV (immunodeficiency associated Burkitt lymphoma) HHV8 Chronic hepatitis C infection Transplants Chemotherapy	Anywhere in body Lymph nodes Esophagus Bladder Bone Oral cavity Thyroid gland	Painless palpable mass, with or without ipsilateral lymphadenopathy Fever Night sweats Weight loss Neck mass Dysphagia Odynophagia Chest / abdominal pain Weight loss Hemorrhage Vocal cord paralysis / hoarseness Stricture / obstruction Perforation with esophagomediastinal or esophagotracheobronchial fistula or mediastinitis Vocal cord paralysis Cold nodule	WHO classification of lymphoma: Hodgkin lymphomas arise from precursor B cells (Reed-Sternberg cells) Classic Hodgkin lymphoma (CHL) - 95% is further subclassified as: Nodular sclerosis Lymphocyte rich Mixed cellularity Lymphocyte depleted Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) - 5% Non-Hodgkin lymphomas arise from monoclonal expansion of malignant B or T cells B cell lymphomas B cell acute lymphoblastic lymphoma (ALL) Chronic lymphocytic lymphoma / small lymphocytic leukemia (CLL / SLL) Mantle cell lymphoma Follicular lymphoma Marginal zone B cell lymphoma Extranodal MALT type Hairy cell leukemia Plasmacytoma / plasma cell myeloma Diffuse large B cell lymphoma (DLBCL) Burkitt lymphoma T / NK cell lymphomas T cell acute lymphoblastic lymphoma (ALL) T cell CLL Mycosis fungoides / Sézary syndrome Peripheral T cell lymphoma Angioimmunoblastic T cell lymphoma Enteropathy associated intestinal T cell lymphoma Hepatosplenic T cell lymphoma Anaplastic large cell lymphoma (ALCL) Extranodal NK / T cell lymphoma, nasal type
Rhabdomyosarcoma (RMS)	MyoD1 and PIK3CA mutation (sclerosing and spindle cell RMS) Most common translocation is t(2;13)(q35;q14), causingPAX3'FOXO1 gene fusion (alveolar RMS) t(1;13)(p36;q14), causingPAX7'FOXO1 gene fusion Embryonal RMS is associated with: Loss of heterozygosity (LOH) at 11p15 locus (site of IGF-2 gene) Other genes at 11p15.5 locus: H19 CDKN1C HOTS Other mutations include pRb, TP53, GLI, CDKN2A, CDKN2B, RAS, FGFR4, PIK3CA, CTNNB1 [beta-catenin] and NF1 genes VGLL2andNCOA2rearrangements Gene fusions include VGLL2-CITED2, VGLL2-NC0A2, TEAD1-NCOA2, PAX3-NCOA2, PAX3-NCOA2, and SRF-NCOA2. Further gene mutations include: RAS RB1 PTCH MDM2 CDK4 MYCN Basic helix-loop-helix [bHLH]	Histologic classification: Embryonal RMS comprises of: Rhabdomyoblasts arranged in sheets and large nests, with infrequent intermixed fusiform cells Myofilaments with cross-striations Botryoid (sarcoma botryoides) and spindle cell (leiomyomatous) RMS: "Grape-like" gross appearance of the tumor Polypoid mass grows beneath an epithelial surface, with dense subepithelial aggregates of rhabdomyoblasts (the so-called "cambrium" layer) Sclerosing and spindle cell RMS Alveolar RMS comprises of: Fibrovascular septae lined with densely packed ovoid to round tumor cells separated by pseudo-alveolar spaces (vaguely resemble pulmonary alveoli) "Loosely adherent" rhabdomyoblasts shed into these pseudo-alveolar spaces Anaplastic RMS comprises of: Large hyperchromatic nuclei with atypical bizarre mitotic figures Nuclear size is threefold larger than that of adjacent "typical" tumor cells	Positive for: Actin Myosin Desmin Myoglobin Z-band protein Myogenic differentiation 1 (MyoD1) Maybe positive for: Cytokeratin Synaptophysin Neuron-specific enolase S-100 protein	Malignant soft tissue tumor Metastatic	In utero radiation exposure Accelerated in utero growth Low socioeconomic status Antibiotics receival soon after birth Recreational drugs usage during pregnancy Neurofibromatosis Li-Fraumeni syndrome Beckwith-Wiedemann syndrome Costello syndrome	Head and neck (orbit, parameningeal sites including middle ear, nasal cavity, paranasal sinuses, nasopharynx, infratemporal fossa, scalp, parotid gland, oral cavity, pharynx, thyroid and parathyroid glands) Genitourinary tract (bladder, prostate, or the male or female genital tracts) Sarcoma botryoides (urinary bladder wall, vagina, nasopharynx) Extremity Trunk Chest wall Perineal-perianal region Biliary tract Liver Brain Trachea Heart Breast Ovary	Proptosis Ophthalmoplegia Nasal, aural, or sinus obstruction with or without a mucopurulent or sanguineous discharge Localized, painless enlarging mass Hematuria Large pelvic mass Urinary obstruction Urinary frequency Constipation Mucosanguineous vaginal discharge Polypoid mass protruding from vagina Scrotal or inguinal enlargement (paratesticular tumors)	Histology of RMS similar to that of other childhood small round blue cell tumors involving bone and soft tissue such as: Lymphoma Small cell osteosarcoma Mesenchymal chondrosarcoma Ewing sarcoma family of tumors (EFT)
Liposarcoma	Atypical lipomatous tumor/well differentiated liposarcoma and dedifferentiated liposarcoma are associated with: Presence of a large/giant marker chromosome and/or ring chromosomes at 12q13-15 region Amplification of this chromosome region rich in protooncogenes, including CHOP, CDK4, MDM2, HMGI-C, GLI, SAS, OS1, HMGA2 and OS9 Myxoid liposarcoma is associated with: t(12:16)(q13;p11) - CHOP(DDIT3) / FUS or t(12;22)(q13;q22) - CHOP(DDIT3) / EWS Pleomorphic liposarcoma is associated with: Complex karyotypic aberrations	Well-differentiated liposarcoma: Sclerosing liposarcoma (distinctive stromal cells distributed across the tissue, associated with lipoblasts filled with multiple vacuoles, and collagenous background of fibrillary appearance) Adipocytic liposarcoma (adipocytes with different cell sizes, hyperchromasia, and nuclear atypia. Fibrous septa containing hyperchromatic stromal cellssurrounding adipocytes) Inflammatory liposarcoma (heavy chronic inflammatory infiltrate composed of different lympho-plasmacytic aggregates) Spindle cell lipocarcinoma (proliferation of neural-like spindle cells organized in a fibrous structure containing lipoblasts) De-differentiated liposarcoma: Myxoid liposarcoma ( non-homogenous appearance with cystic and solid components) Round Cell liposarcoma ( small, round, or spindle cells with sparse eosinophilic and granular cytoplasm and large nuclei,scattered lipoblasts and areas of necrosis) Pleiomorphic liposarcoma (pleomorphic cells with enlarged round to bizarre nuclei)	Atypical lipomatous tumor/well differentiated liposarcoma is positive for: MDM2 CDK4 p16 S100 (stains adipocytes and lipoblasts)	Round cell liposarcoma metstasizes to retroperitoneum, pleural cavity, soft tissue, or pelvis and lungs (poor prognosis)	Chemical carcinogens Phenoxyacetic herbicides Chlorophenols Dioxin contaminations Arsenic Thorium dioxide (Thorotrast) Radiation (dose of 50 GY) Immunodeficiency (regional acquired immunodeficiency) Genetic susceptibility Li-Fraumeni syndrome Neurofibromatosis (NF1; von Recklinghausen disease) Gardner syndrome (Familial adenomatous polyposis) Retinoblastoma Werner syndrome Nevoid basal cell carcinoma (Gorlin syndrome) Viral infections	Retroperitoneum Esophagus Bowel Mediastinum	Retroperitoneal liposarcoma maybe asymptomatic or causes: Weight loss Abdominal pain Oliguria renal failure (due to ureters or kidneys' compression) Palpable abdominal mass Abdominal tenderness Abdominal distention Esophageal liposarcoma may cause: Dysphagia Vomiting Cough Gastrointestinal bleeding Hoarseness Bowel liposarcoma may cause: Gastrointestinal bleeding Mediastinal liposarcoma may cause: Dyspnea Cough Chest pain Weight loss	_
Leiomyosarcoma	Loss of normal chromosome 1q (hereditary leiomyomatosis) Renal cell cancer (HLRCC) gene mutation	Prominent cellular atypia Nuclear atypia, including nuclear pleomorphism, hyperchromatism, irregularity in nuclear membranes, high nuclear size, and prominent nucleoli Abundant mitoses, mitotic index higher than10 or more per 10 high-power fields Areas of coagulative necrosis (tumor cell necrosis), always accompanied by cytologic atypia and brisk mitotic activity	Positive for: HHF35 (90%) Alpha-smooth muscle actin (90%) Vimentin Desmin (75%) H-caldesmon PTAH (stains myofibrils) Keratin (30%) ER (usually in uterine and female retroperitoneal tumors) S100 (occasionally weak staining) EMA (may be focal) CD34 Negative for: CD117	Malignant Metastatic to lungs, liver, blood vessels, or any other soft tissue in the body	Immundeficiency (HIV) Digoxin exposure Human herpes virus type-8 (HHV-8) Epstein barr virus Long term tamoxifen use History of pelvic radiations Hereditary breast carcinoma with BRCA1 mutation Hereditary nonpolyposis colorectal carcinoma with MSH2 mutation Li-Fraumeni syndrome Malignant melanoma Retinoblastoma	Uterus Abdomen Esophagus Rectum Skin / subcutis Retroperitoneum Extremities Large vessels (inferior vena cava, saphenous vein, femoral vein, pulmonary artery, femoral artery) Superficial or deep soft tissues Bone Breast Colon Epididymis Mediastinum Lungs	Asymptomatic (uterine leiomyosarcoma may be associated with: Irregular vaginal bleeding (intermenstrual or postmenopausal) New lump or a mass protruding into vagina or growing mass in abdomen or pelvis Abdominal pain Abdominal distension Pelvic pain Urinary symptoms Esophageal leiomyosarcoma may cause: Dysphagia Hematemesis rectal leiomyosarcoma may cause: Black, tarry stools Rectal bleeding	_
Neurofibroma	Can be sporadic or as a part of Neurofibromatosis 1 and 2 NF1 gene located at chromosomal region 17q11.2, codes for neurofibromin Functional part of neurofibromin GAP (or GTPase-activating protein) accelerates the conversion of the active GTP-bound RAS to its inactive GDP-bound form Loss of RAS control leads to increased activity of other signaling pathways including RAF, ERK1/2, PI3K, PAK, MAPK, SCF/c-kit and mTOR-S6 kinase	Made of nerve fibers, schwann cells (cells that cover the nerve fibers), blood vessels, inflammatory white blood cells (mast cells), and connective tissue (fibroblasts and loose material called extra cellular matrix) Spindle cells with wavy nuclei without pleomorphism Intermixed with wire-like collagen Moderate increase of cellularity vis-a-vis normal dermis Mast cells	Positive for: S100 CD34 (focal) Factor XIIIa (focal) Negative for: EMA (except in plexiform neurofibromas)	Cutaneous neurofibromas are always benign Diffuse neurofibromas can become malignant	Neurofibromatosis 1 Neurofibromatosis 2 (multiple neurofibromas, meningiomas of the brain or spinal cord, and ependymomas of the spinal cord)	Anywhere in body Scalp (diffuse neurofibroma)	Soft masses/bumps on or under skin (internal or superficial) Transient itching (mast cells release histamine) Transient pain Numbness and tingling in the affected area Severe bleeding (sign of tumor growth) Physical disfiguration Cognitive disability Stinging Neurological deficits Changes in movement (clumsiness in the hands, trouble walking Changes in bowel or bladder function (a sense of urgency when urinating, bowel or bladder incontinence) Scoliosis (an abnormal curvature of the spine, if the tumor creates muscular imbalance or erodes bones of the spine)	Types of neurofibromas in NF1: Diffuse neurofibromas Cutaneous or Dermal neurofibromas Intramuscular neurofibromas Plexiform neurofibromas Intraneural
Nodular fasciitis	Balanced translocation t(17;22)(p13;q13) resulting in MYH9-USP6 gene fusion	Histologically vast array of patterns Fibroblasts, spindle-shaped cells found in connective tissue Myofibroblasts, large cells with an appearance between fibroblasts and smooth muscle tissue Sub-membranous "tram track" pattern characteristic of myofibroblasts on immunostaining Short C or S-shaped fascicles or cartwheel formations Feathery appearance cells, with holes or tears in the tissue Visible chromosomes in cells during cell division Fine, pale, and even-looking chromatin Inflammation, accelerated mitotic index with normal mitoses Non-pleomorphic cells with high rate of mitosis Essentially spindle cell proliferation Stroma is rich in collagen and/or myxoid ground substance	Positive for: Smooth muscle actin Muscle specific actin Vimentin Calponin CD68 Negative for: S100 Desmin Keratin CD34 Caldesmon ALK p53	Benign	Reparative process secondary to trauma	Anywhere in body Arms (34%) Flexor forearm (27%) Head and neck region (24%) Trunk (chest, back) (21%) Thigh (17%) Legs (14%) Upper arm (12%) Hands (rarely) Bladder Breast Cervix Intra-articular Prostate Vagina Vulva	Solitary firm non-painful mass Oval or round in shape with irregular margins Tender (maybe)	Also known as: Nodular pseudosarcomatous fasciits Subcutaneous pseudosarcomatous fibromatosis Pseudosarcomatous fasciitis
Hypertrophic scars	Overexpression of growth factors such as: TGF-beta VEGF CTGF Decreased production of matrix metalloproteinases Increased numbers of PDGF receptors on fibroblasts Over-activation of signals for insulin-like growth factor-1 Decreased fibroblast apoptosis rate Increased expression of thymic stromal lymphopoietin Increased fibrocyte activation via stromal cell-derived factor-1 Genes in four susceptibility loci on chromosomes 1q41, 3q22.3-23, and 15q21.3	Excess collagen formation with varying numbers of fibroblasts and myofibroblasts Collagen fibers are arranged in a wavy pattern predominantly oriented parallel to the epithelial surface Nodular structures containing myofibroblasts and vertically aligned vessels	_	Benign	Frequent complication of burn injuries Piercings Cuts Surgical wounds Lacerations Adverse wound healing factors at the injury site such as: Infection (acne, folliculitis, chicken pox, and vaccinations) Excessive tension	Milder than keloids Don’t grow beyond the boundaries of the original skin injury	Cosmetic disfigurement Pruritis Pain Functional impairment (from contracture or mechanical irritation) Loss of temperature regulation Dry skin Neuropathic pain	Hypertrophic scars can be classified as: Mature scar Immature scar Linear, hypertrophic scar (surgical/traumatic) Widespread, hypertrophied scar (burn)
Keloids	Epigenetic alteration in fibroblast DNA and acetylation of histone proteins Overexpression of growth factors such as: TGF-beta VEGF CTGF Decreased production of matrix metalloproteinases Increased numbers of PDGF receptors on fibroblasts Over-activation of signals for insulin-like growth factor-1 Decreased fibroblast apoptosis rate Increased expression of thymic stromal lymphopoietin Increased fibrocyte activation via stromal cell-derived factor-1 Genes in following susceptibility loci on chromosomes: 1q41 3q22.3-23 15q21.3 2q23 7p11 10q23.31 In Japanese population, 4 SNP loci (rs873549, rs1511412, rs940187, and rs8032158) in 3 chromosomal regions (1q41, 3q22.3–23, and 15q21.3) exhibit significant associations with keloids	Hyalinized collagen bundles Excess collagen formation with varying numbers of fibroblasts and myofibroblasts Hypocellular zones of fibrous tissue containing thickened, glassy, eosinophilic collagen bundles	_	Benign	Minor injuries Insect bites Pimples Earlobe piercings Adverse wound healing factors at the injury site such as: Infection Inflammation Excessive tension Excessive motion (such as in injuries over a joint), Wound left to heal without stitches Keloids may be associated with rare inherited syndromes such as: Rubinstein-Taybi syndrome Goeminne syndrome	Any part of body having injury Upper chest Shoulders Upper back Head and neck (especially on ears)	Cosmetic disfigurement Raised, reddish nodules Skin pigmentation Itchiness Redness Unusual sensations Pain Functional impairment	Keloid is Greek for "crab claw" Extend beyond the borders of the original wound Regress spontaneously Recur after excision Darkly pigmented people/African-American, Asians (Han Chinese, Japanese) are more prone to form keloids Keloids can be prevented by using: Pressure dressing Silicone gel pad Paper tape over the injury site for 23-24hours per day Keloids can be classified as: Minor keloid Major keloid
Primitive neuroectodermal tumor (PNET)	EWS / FLI1 fusion product by RT-PCR due to t(11;22)(q24/q22;q12) (90%) p53 tumor suppressor gene mutations	Small blue cell tumor Round hyperchromatic cells Abundant mitotic figures Homer Wright rosettes Fibrosis Neurosecretory granules on electron microscopy	Positive for: CD99 FLI1 PAS+ diastase sensitive (glycogen) Vimentin Neuron specific enolase Negative for: Cytokeratin (usually) Desmin WT1 GFAP PAX2	Malignant neural crest tumor Highly aggressive (rapid death within 1 year) Metastases to lung, pleura, bone and liver	Gorlin syndrome Turcot syndrome Coffin-Siris syndrome Cowden syndrome Gardner syndrome Li-Fraumeni syndrome Rubinstein-Taybi syndrome	CNS PNET: Intracranial (cerebral hemisphere) Peripheral PNET: kidneys	Asymptomatic for years Morning headache Restlessness Recurrent vomiting Diplopia Frequent falls Positional dizziness Increased intracranial pressure Cranial nerve palsy Seizures Papilledema Strabismus Nystagmus Ataxia Motor weakness Facial sensory loss Third, fourth, and sixth cranial nerve palsies Abdominal/flank pain Hematuria	Also known as: CNS PNET Askin tumor Peripheral neuroepithelioma Ependymoblastoma WHO classified PNET into 3 subtypes: Central primitive neuroectodermal tumors (PNETs) Neuroblastomas Peripheral primitive neuroectodermal tumors (pPNETs) Peripheral PNET (pPNET) is now thought to be virtually identical to Ewing sarcoma