Soft Tissue - Spindle Cell Tumours

Question 1

Locations of specific tumours

Answer 1

Fingers and Toes
* Glomus tumour
* Inclusion body fibromatosis

Genitals
* Rhabdomyosarcomas

GIT
* GIST
* Inflammatory myofibroblastic tumor

Head and Neck
* Alveolar soft part sarcoma
* Rhabdomyosarcomas
* Granular cell tumour

Retroperitoneum
* Dedifferentiated liposarcoma

Back
* Elastofibroma
* Spindle cell lipoma/Pleomorphic lipoma

Acral/Distal Extremities
* Calcifying aponeurotic fibromas
* Clear cell sarcomas

Question 2

Ages

Answer 2

< 10 years - Rimn’
* Rhabdomyosarcoma
* Infantile fibrosarcoma
* Malignant rhabdoid tumour
* Neuroblastoma

Between 11 and 40 years - As Emcee
* Alveolar soft part sarcoma
* Synovial sarcoma
* Epithelioid sarcoma
* Malignant peripheral nerve sheath tumour
* Clear cell sarcoma
* Epithelioid hemangioendothelioma
* Extraskeletal Ewing sarcoma

All other types >40 years

Question 3

Painful Lesions

Answer 3

BLEND AN EGG
* Blue rubber bleb
* Leiomyoma
* Eccrine spiradenoma
* Neuroma
* Dermatofibroma
* Angiolipoma
* Neurilemmoma
* Endometriosis
* Granular cell tumour
* Glomus tumour

Question 4

Spindle cell pattern

Answer 4

• Pseudosarcomas (fasciitis, ossicans)
• Fibromatosis + desmoid type
• Solitary fibrous tumour (SFT)
• Elastofibroma
• Neurofibroma
• Schwannoma
• Malignant peripheral nerve sheath tumor (MPNST)
• Synovial Sarcoma
• Dermatofibroma
• Dermatofibrosarcoma protuberans (DFSP)
• Cutaneous leiomyoma
• Kaposi sarcoma
• Angio sarcoma

Question 5

Pseudosarcoma

Answer 5

• Reactive pseudosarcomatous proliferations
• Non-neoplastic
• Develop in response to trauma, or idiopathic
• Clinically ALARMING –> rapid growth

Types:
* Nodular fasciitis
* Proliferative fasciitis
* Proliferative myositis
* Myositis ossificans
* Ischaemic fasciitis

Question 6

Nodular fasciitis

Answer 6

• Neoplasm of fibroblastic / myofibroblastic derivation
• Typically benign and self limited
• Virtually all cases contain recurrent gene fusions
• Wide range of age involvement and anatomic distribution

Clinical:
* Generally small (< 3 cm) but may be much larger
* Rapid growth may be clinically concerning for malignancy
* Mass may be tender, mildly painful or asymptomatic
* Tumors arise throughout the body; common locations include the extremities, head and neck and trunk
* May arise at unusual locations, such as intravascular, intra-articular, intraparotid, cranial and placental
* Most common site is Volar (palm side) of forearm

Micro:
* Variable cellularity
* Extracellular matrix ranges from myxoid to collagenous
* Older lesions may be more collagenous
* Areas of cystic degeneration may be identified
* Spindle stellate cells with a loose fascicular to storiform pattern (so called tissue culture-like and feathery growth)
* Bland ovoid nucle

Molecular:
* MYH9::USP6 is the most common fusion product
* Many other USP6 partners have been identified in nodular fasciitis and related entities
* USP6 rearrangement can be established by FISH, PCR or next generation sequencing techniques

IHC:
Positive:
Smooth muscle actin
Muscle specific actin
Calponin

Negative:
Desmin
Caldesmon

Question 7

Proliferative fasciitis

Answer 7

• Myofibroblastic / fibroblastic proliferation with scattered ganglion-like cells
• Variable collagenous to myxoid stroma
• Subcutaneous / fascial involvement
• Rare, much less common than nodular fasciitis
• Occurs predominantly in middle aged adults (mean age: 51 years)
• Rare subtype of proliferative fasciitis has been described in children
• Equally distributed in both sexes

Clinical:
* Subcutaneous by definition (whereas proliferative myositis is intramuscular)
* Usually located between the subcutis and underlying muscle, in the region of the superficial fascia
* Majority (74%) originate in the extremities
* Most commonly involves the forearm, followed by lower extremity and trunk
* May also arise in dermis

Micro:
* Plump myofibroblastic / fibroblastic spindle cells
* Large ganglion-like cells with round nuclei, prominent nucleoli and abundant amphophilic cytoplasm
* Density of ganglion-like cells (modified fibroblasts) varies
* Mitotic figures are found in both spindle and ganglion-like cells and may be numerous
* No atypical mitotic figures
* Loose tissue culture, myxoid to collagenous stroma
* Older lesions may have abundant hyalinized collagen
* Extravasated red blood cells and stromal lymphocytes are common
* Borders of lesion are typically infiltrative or ill defined

Molecular:
* Adult tumors have shown FOS gene rearrangements, including FOS::VIM fusion

IHC:
* Vimentin
* Spindle cells usually express SMA and MSA, which may be weak and focal in ganglion-like cells

Question 8

Proliferative myositis

Answer 8

• Infiltrative poorly demarcated intramuscular mass resembling nodular fasciitis but…
• With large basophilic cells resembling ganglion cells
• Histologically almost identical to proliferative fasciitis except located in muscle
• Muscles of trunk, shoulder, chest or thigh

Macro:
* Poorly circumscribed, scar-like induration of muscle
* Usually 3 - 4 cm
* Can occur under fascia, decreases the central portion of muscle in a wedge fashion

IHC:
Vimentin
Smooth muscle actin
Muscle specific actin

Question 9

Ischemic fasciitis

Answer 9

• Painless pseudosarcomatous fibroblastic proliferation in soft tissue
• Overlying bony prominences subject to intermittent pressure-induced ischemia
• Occurs primarily in immobilized and physically impaired patients (i.e., wheelchair bound, bedridden), with mean age of presentation 70 - 90 years
• Also occurs in younger patients not debilitated or patients with physical disabilities
• Patients present with painless mass slowly growing over 3 weeks to 6 months

Micro:
* Zonal pattern
* **Central fibrinoid necrosis **with uneven borders staining deep red / violet
* **prominent myxoid areas **surrounded by ectatic, thin walled vessels and proliferating fibroblasts
* Endothelial cells may be atypical
* Fibroblasts have degenerative features with abundant, eosinophilic to amphophilic cytoplasm, enlarged nuclei with smudged chromatin and prominent nucleoli (resembling ganglion-like cells in proliferative fasciitis)
* Variable mitotic activity, but no atypical mitotic figures
* Fibrin thrombi are common within peripheral vessels, which may show fibrinoid necrosis and recanalization but no true vasculitis
* May have multivacuolated macrophages in myxoid zones mimicking lipoblasts

IHC:
Vimentin,
Actin (focal)
CD68 (focal)
variable CD34 in enlarged fibroblasts

Question 10

Myositis ossificans

Answer 10

• MISNOMER –> muscle may not be involved
• Benign, reactive, ossifying soft tissue mass lesion, associated with trauma and characterized by zonal pattern
• Usually physically active young males (second and third decade) with rapid growth of mass
• 60 - 75% have history of trauma in prior 4 - 6 weeks
• May also occur after elective surgery, severe burns, neurological injury
• Benign process with excellent prognosis
• Does not recur if completely excised

Micro:
* May be mistaken for osteosarcoma (reverse of MO)
* Zonal pattern –> inner zone, intermediate zone and peripheral zone

Inner central zone:
* Fibroblastic / myofibroblastic proliferation
* Richly vascular
* Rich in inflammatory cells and resembles nodular fasciitis
* Some multinucleated giant cells may also be seen
* Cells show mild degree of pleomorphism and brisk mitosis

Intermediate zone:
* Mixture of fibroblasts and osteoblasts
* Erratic osteoid separated by small sized vessels
* Scattered chondrocytes may be appreciated

Peripheral zone:
* Osteoid undergoes calcification
* Lamellar bone formation
* Islands of mature or immature cartilage may be present
* Extreme periphery / margin shows mature bone with osteoblastic rimming and little to no pleomorphism
* Lesion is separated from the normal tissue by a zone of loose, myxoid fibrous tissue

Question 11

Fibromatosis

Answer 11

Juvenile:
* Congenital generalised fibromatosis
* Aponeurotic fibroma
* Infantile digital fibromatosis
* Aggressive infantile fibromatosis
* Fibromatosis colli
* Dermatofibrosis lenticularis (Buschke-Ollendorf syndrome)

Adult:

Superficial (fascial) fibromatoses:
* Palmar (Dupuytren contracture) fibromatosis
* Plantar (Ledderhose disease) fibromatosis
* Pachydermodactyly
* Penile (Peyronie disease) fibromatosis
* Knuckle pads
* Dermatofibroma
* Nodular fasciitis
* Elastofibroma
* Fibrous papule of the face

Slow growing tumour
Small size
Arise from fascia or aponeurosis
Less aggressive

Deep (musculoapopneurotic) fibromatoses:
Desmoid tumours
* Extra-abdominal fibromatosis
* Abdominal fibromatosis
* Intra-abdominal fibromatosis

Rapidly growing pseudotumour
Usually, reach a large size
Often involve deeper structures (muscle of trunk and extremities

Question 12

Desmoid Type Fibromatosis

Answer 12

• Locally aggressive fibroblastic / myofibroblastic tumor arising in deep soft tissues with no metastatic potential
• Benign tumor with infiltrative borders and a propensity for local recurrence
• May be associated with familial adenomatous polyposis (Gardner syndrome)
• Local recurrence in 20 - 30%
• Margin status shown to predict local recurrence in primary tumors but was not significant in recurrent presentations

Micro:
* Typically poorly defined borders
* Long sweeping fascicles with elongated, slender, spindled cells of uniform appearance and pale cytoplasm set in a collagenous stroma
* No nuclear hyperchromasia, minimal cytologic atypia and variable mitotic rate (typically low but may be focally increased)
* Thin walled and prominent blood vessels with perivascular edema
* Vascular microhemorrhages may be seen

Molecular:
* CTNNB1 mutations reported in ~90% of cases, usually in exon 3; most common mutations are T41A, S45F and S45P
* FAP patients have germline mutations in APC leading to deregulation of the Wnt / beta catenin pathway

IHC:
* Variable positivity for SMA and MSA; rarely focal desmin
* Beta catenin (70 - 98%; higher in mesenteric / FAP associated tumors)
* Cyclin D1 (71 - 75%)
* Calretinin (75%)

Question 13

Solitary fibrous tumor

Answer 13

• Fibroblastic tumor characterized
• Haphazardly arranged spindled to ovoid cells
• Prominent staghorn vasculature
• Paraneoplastic syndrome (Doege-Potter syndrome) extremely rare; due to IGF2 production by tumor

Three tier prognostic criteria (Demicco):
* Size
* Mitosis
* Necrosis

Malignant criteria:
* Nuclear atypia
* >4 mitoses/10 HPF
* Necrosis
* Infiltrative margin

Molecular:
* NAB2-STAT6 gene fusion

IHC:
* CD34: diffuse to focal but nonspecific, present in 85 - 95% of cases
* STAT6 (nuclear): highly sensitive and specific marker (close to 100%)
* May have focal EMA (30%) and actin (20%)
* BCL2 (30%) and CD99 (70%): nonspecific and not diagnostically useful

Question 14

Elastofibroma

Answer 14

• Benign, ill defined proliferation of fibroelastic tissue with excessive abnormal degenerated elastic fibers
• Mostly asymptomatic mass at infrascapular region, incidentally found on radiological examination for other causes
• Well circumscribed lesion
• Mature fat, fibrous tissue and characteristic abnormal eosinophilic looking elastic fibers
• Surgical excision is curative, required mostly in symptomatic cases, with very rare local recurrence
• Arises almost exclusively in the elderly, with peak incidence between the seventh and eighth decades of life
• F > M

IHC:
* Elastic (Verhoeff van Gieson): intense black staining of abnormal elastic fibers
* Alcian blue: stains mucopolysaccharide component of stromal connective tissue
* CD34: membranous positivity in a patchy manner seen in the fibroblasts

Question 15

Neurofibromatosis type 1

Answer 15

• Also called von Recklinghausen disease, NF1
• Defect in neurofibromin gene at 17q11.2
• 50% from autosomal dominant inheritance
• 50% are new mutations
• Adrenomedullin (ADM) is serum biomarker of NF1

Diagnostic features
Two or more of the following:
* Multiple neurofibromas (plexiform, solitary); plexiform are relatively specific
* ≥ 6 cafe au lait spots over nerve trunks, ≥ 1.5 cm
* Freckling in axilla or inguinal region
* Lisch nodules (pigmented iris hamartomas, 94% by age 6)
* 2 - 4x increased risk of other tumors (childhood CML, ganglioneuroma, meningioma, pheochromocytoma, rhabdomyosarcoma); 5 - 13% develop MPNST; also acoustic neuroma (schwannoma), astrocytoma, gastric carcinoid, GIST, glomus tumor, lipoma, optic nerve glioma, Wilm tumor
* Nontumors: congenital malformations, fibrosing alveolitis, megacolon, skeletal lesions (30% have spinal deformities, bone cysts)
* First degree relative with NF!

Question 16

Neurofibromatosis type 2

Answer 16

• Also known as NF2, acoustic neurofibromatosis
• Autosomal dominant, incidence of 1 per 40,000
• Mutation in merlin gene at 22q12
• Nonsense mutations usually more severe than missense mutations
• cafe au lait spots but no Lisch nodules

Diagnostic features
* Bilateral vestibular schwannomas
* First degree relative with NF2 + Unilat vestibular schwannoma, or two of the followng –> meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular cataracts
* Unilat schwannoma + meningioma, schwannoma, glioma, neurofibroma or posterior subcapsular cataracts
* Multiple Meningiomas + unilat schwannoma or two of the followng –> meningioma, glioma, neurofibroma, posterior subcapsular cataracts

Question 17

Neurofibroma

Answer 17

• Benign peripheral nerve sheath tumor with classic identifiable features
• Presence of a neuronal component comprising transformed Schwann cells and a nonneoplastic fibrous component that includes fibroblasts
• Sporadic (localized variant) –> Occurs in individuals who do not have neurofibromatosis type 1
• Cutaneous and subcutaneous –> Almost all patients with neurofibromatosis type 1
• Inherited (diffuse and plexiform variants) –> Close associations with neurofibromatosis type 1

Pacinian:
* Rare neurofibroma with proliferation of structures resembling Pacinian (Vater-Pacini) corpuscles
* It is a skin mechanoreceptor responsible for sensitivity to pain and pressure

Pigmented:
* Rare tumor of scattered melanin laden cells and benign neural cells
1 - 5% of neurofibromas

Macro:
* Painless
* slowly growing
* solitary
* skin colored
* soft, flaccid, rubbery to firm papule or nodule with a smooth surface
* measuring up to 2 cm
* Lesion invaginates with pressure

Micro:
* Proliferation of all elements of peripheral nerves
* Schwann cells with wire-like collagen fibrils (wavy serpentine nuclei and pointed ends)
* Stromal mucosubstances
* Mast cells
* Wagner-Meissner corpuscles
* Pacinian corpuscles, axons (highlight with silver or acetylcholinesterase stain, NSE, neurofilament),
* Fibroblasts
* Collagen
* Usually lacks capsule

Molecular:
* Biallelic inactivation of the tumor suppressor gene neurofibromatosis type 1 which is located on 17q11.2

IHC:
* S100 shows strong positivity
* CD34 shows fingerprints-like positivity
* SOX10 shows strong positivity
* factor XIIIa is useful to differentiate neurofibroma from neurotized neavi
* calretinin shows focal positivity
* EMA shows weak positivity
* podoplanin shows weak positivity
* neurofilaments stains entrapped axons
* collagen type IV shows strong positivity, low Ki67

Question 18

Schwannoma

Answer 18

• Benign nerve sheath tumor arising from differentiated Schwann cells
• Encapsulated, well circumscribed
• Most cases have a zonal pattern composed:
• Cellular areas (Antoni A) with nuclear palisading (Verocay bodies) and a hypocellular component (Antoni B)
• 90% are sporadic
• 3% with neurofibromatosis type 2,
• 2% with schwannomatosis,
• 5% with meningiomatosis with or without neurofibromatosis type 2

Micro:
* Biphasic: compact hypercellular Antoni A areas and myxoid hypocellular Antoni B areas (may be absent in small tumors)
* Nuclear palisading around fibrillary process (Verocay bodies) is often seen in cellular areas
* Cells are narrow, elongated and wavy with tapered ends interspersed with collagen fibers
* Tumor cells have ill defined cytoplasm, dense chromatin
* May have degenerative nuclear atypia, cystic degeneration and hemorrhage (ancient change)
* Blood vessels may have thickened hyalinized walls and thrombi

Molecular:
* May occur spontaneously
* Can occur in familial tumor syndromes, such as neurofibromatosis type 2 (NF2)
* Schwannomatosis
* Carney complex
* Loss of function of the tumor suppressor gene merlin (schwannomin)
* Direct genetic change involving the NF2 gene on chromosome 22 or secondarily to merlin inactivation

IHC:
* S100 (strong and diffuse staining)
* Calretinin
* CD56
* SOX10
* podoplanin
* Weak, variable CD34
* Other stains include laminin, type IV collagen, vimentin, CD68

Question 19

Malignant peripheral nerve sheath tumor (MPNST)

Answer 19

• Malignant neoplasm arising from peripheral nerve
• May arise:
• From a preexisting nerve sheath tumor in neurofibromatosis type 1 (NF1) (40-50%)
• Sporadic (50%)
• In the setting of prior radiation therapy (10%)

Micro:
* Low power: marbled appearance due to alternating hypocellular and hypercellular areas with perivascular accentuation
* Uniform spindle cells with hyperchromatic, thin, wavy, or focally buckled nuclei
* Can have foci of myxoid stroma and hyalinization
* Epithelioid morphology can be present
* Precursor lesion, such as neurofibroma, may be identifiable
* Nuclear palisading is uncommon

Molecular:
* Inactivating mutations in CDKN2A / CDKN2B and PRC2
* Germline NF1 mutations in the setting of NF1
* Point mutations in BRAF V600 in a subset of cases

IHC:
* S100 and SOX10 are usually patchy or focal and only seen in up to 50% of cases
* Loss of nuclear H3k27me3 in high grade sporadic and radiation associated tumours

Variants:
Epithelioid MPNST
* Rare subtype, usually not associated with NF1
* Rare cases may arise in epithelioid Schwannoma
* Typically have diffuse and strong expression of S100 and SOX10
* Distinct molecular features from conventional MPNSTs and harbor SMARCB1 gene inactivation and INI1 loss in up to 40 - 67% of cases

MPNST with heterologous rhabdomyoblastic differentiation (Malignant Triton tumor)
* Has been associated with adverse clinical behavior

Question 20

What is the difference between neurofibroma, schwannoma and MPNST

Answer 20

Neurofibromas, schwannomas, and malignant peripheral nerve sheath tumors (MPNSTs) are all types of nerve sheath tumors, but they differ in their biology, behavior, and clinical implications. Here’s a breakdown of the key differences:

1. Neurofibroma
Origin: Neurofibromas arise from multiple cell types within the peripheral nerve sheath, including Schwann cells, fibroblasts, and perineural cells.

Benign nature: They are typically benign and slow-growing.
Appearance: These tumors can be cutaneous (under the skin), subcutaneous, or involve deeper tissues, and are often soft, mobile, and sometimes tender.

Genetic association: Neurofibromas are strongly associated with Neurofibromatosis type 1 (NF1), a genetic disorder that leads to the formation of multiple neurofibromas across the body.
Clinical features: In NF1, individuals often have multiple neurofibromas that can appear anywhere on the body. They can cause symptoms like pain, compression of nearby structures, and cosmetic concerns, but they are generally not malignant.

2. Schwannoma (also called Neurilemoma)
Origin: Schwannomas arise from Schwann cells, which are responsible for the myelin sheath surrounding peripheral nerves.

Benign nature: Like neurofibromas, schwannomas are typically benign and slow-growing.

Appearance: Schwannomas are usually well-circumscribed, firm, and encapsulated. They can cause nerve compression or pain depending on their location.

Genetic association: Schwannomas are associated with Neurofibromatosis type 2 (NF2), where individuals may develop multiple schwannomas, particularly affecting cranial and spinal nerves, such as the vestibular nerve (leading to vestibular schwannomas).

Clinical features: Schwannomas often present as a solitary mass and can cause symptoms due to nerve compression, such as pain, numbness, or weakness.

3. Malignant Peripheral Nerve Sheath Tumor (MPNST)
Origin: MPNSTs arise from the nerve sheath and are thought to develop from neurofibromas or schwannomas that have undergone malignant transformation.

Malignant nature: MPNSTs are malignant tumors and are considered a high-grade sarcoma. They have the potential for local invasion and distant metastasis.

Appearance: These tumors are often poorly defined, infiltrative, and tend to grow rapidly compared to benign tumors. They can be painful and cause neurological deficits depending on their location.

Genetic association: MPNSTs are commonly associated with NF1, with individuals having a higher risk of developing malignant transformation of pre-existing neurofibromas. They can also occur sporadically without an underlying genetic condition.

Clinical features: MPNSTs present as large, often rapidly growing masses. They may cause significant pain, motor weakness, sensory loss, and other neurological symptoms due to compression of adjacent nerves. MPNSTs are more aggressive and have a worse prognosis than benign nerve sheath tumors.

Question 21

Synovial sarcoma

Answer 21

• Malignant soft tissue tumor of uncertain histogenesis with variable epithelial differentiation
• Can occur in or around any tissue in the body
• Usually –> aggressive, deep seated mass presenting around large joints (80% in knee and ankle) in young adults
• Multiple morphologies

Micro:
General:
* 2 main subtypes: biphasic and monophasic spindle cell
* Rarer subtypes: poorly differentiated (round cell), monophasic epithelial, calcifying / ossifying and myxoid

Biphasic:
Architecture:
* 2 components: spindle cells and gland-like epithelial structures
* Glandular lumina contain mucin

Cytologic features:
* Epithelial component has moderate, distinct amphophilic cytoplasm with round to ovoid nuclei
* Rarely, squamous metaplasia can occur

Monophasic:
Architecture:
* Infiltrative borders
* Hypercellular fascicular architecture with little intervening stroma
* Can rarely show hyalinization or myxoid change
* Ill defined nuclear palisading may be seen

Cytologic features:
* Monotonous cells with scant amphophilic cytoplasm, ovoid to spindled vesicular nuclei with evenly dispersed chromatin and inconspicuous nucleoli
* Nuclei often close enough to overlap with adjacent nuclei

Poorly differentiated:
* Highly cellular round cells with hyperchromatic nuclei and frequent mitotic activity and necrosis

Additional features:
* Characteristically features focal staghorn (or hemangiopericytic), branching vascular pattern, reminiscent of solitary fibrous tumor
* Mast cells are common
* Focal calcification can be seen in 33% of cases

Prognostic factors:

Poor prognostic factors:

• SS18-SSX1 translocation
• Monophasic and poorly differentiated subtypes
• Male gender
• Older age at diagnosis
• Size ≥ 5 cm
• Nonextremity location
• Deep seated tumors
• Higher percentage of tumor necrosis
• Mitotic activity ≥ 10/high power field or higher Ki67 activity
• Tumor grade based on Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC)
• Immunohistochemical expression of CXCR4 and IGF1R
• Positive surgical margins
• H3K27me3 and VEGF expression associated with histologic grade, distant metastasis and stage

Better prognosis:

• Age <25 years
• Heavy calcification
• Rarer superficial cases present in the skin of the hands and feet as smaller tumour

Molecular:
Has a characteristic chromosomal translocation t(X;18)(p11;q11) involving genes SS18 and either SSX1, SSX2 or SSX4

IHC:
TLE1
BCL2
CD99
CD56
SYT
CKs and EMA –> variable positivities
Beta Catenin, CD57, calretinin, S100 –> may be positive

Question 22

Dermatofibroma

Answer 22

• Dermatofibromas (also known as fibrous histiocytomas) are a spectrum of benign dermal based lesions with fibroblastic and histiocytic differentiation
• There is debate as to whether dermatofibroma is a reactive or neoplastic process
• Benign dermal based, nodular proliferation of fibroblasts and histiocytes
• Collagen trapping at periphery and follicular induction commonly seen
• IHC is nonspecific for dermatofibroma

Clinical:
* Painless
* 5 mm - 2 cm
* Variable color: skin colored to brown to purple
* Variable shape: plaques, nodules or polyps
* Covered by intact skin
* Suspected by pinching the nodule between the fingers and observing that the tumor is fixed within the dermis
* Pinch sign: overlying skin dimples on pinching the lesion

Micro:
* Symmetric and predominantly dermal based
* Relatively circumscribed but have irregular and unencapsulated borders
* Patterns range from diffuse to reticular to hemangioma-like to keloid-like
* Made up of spindled fibroblasts or histiocytes
* Spindled cells: thin, elongated nuclei with pointed ends and eosinophilic cytoplasm
* Histiocytic cells: epithelioid shaped cells with abundant pale cytoplasm
May see varying amounts of inflammatory cells
* Some areas densely cellular, while others are sclerotic and hypocellular
* Early lesions: more cellular
* Later lesions: more sclerotic
* Cytologic atypia and pleomorphism are variable
* Mitotic activity is variable
* Touton giant cells and ringed lipidized siderophages may be present
* Collagen trapping at periphery
* Spheres of eosinophilic collagen (collagen balls) surrounded by the fibroblast proliferation
* Grenz zone (sparing of the superficial papillary dermis) commonly seen

IHC:
* Nonspecific for dermatofibroma
* Factor XIIIa, CD163, CD10 –> maybe positive

Question 23

Dermatofibrosarcoma protuberans (DFSP)

Answer 23

• Locally aggressive, superficial mesenchymal neoplasm with fibroblastic differentiation
• Fibrosarcomatous transformation imparts an increased risk of recurrence and metastasis
• Tumors are generally presumed to occur sporadically
• a nodular lesion on the mid-back—is characteristic of DFSP

Micro:
* Generally centered within the dermis or subcutis and characterized by spindle cells with a storiform to whorled pattern
* Cytoplasm is generally abundant and eosinophilic
* Nuclei are monomorphic and ovoid to elongated with variable mitotic activity
* Tumors infiltrate and expand fibrous septa; interdigitation among lobules of fat yields a honeycomb pattern
* Adnexal structures are typically spared
* Stroma may be collagenous, myxoid or microcystic

Multiple variants exist:
* Giant cells
* Melanin pigmentation (Bednar tumor)
* Myoid differentiation
* Myxoid stroma
* Pseudocystic change
* So called sarcomatous transformation (mimics undifferentiated pleomorphic sarcoma)
* Fibrosarcomatous transformation denotes those with cellular spindle cell fascicles or a herringbone pattern –> increased risk of recurrence and mets, usually following multiple local recurrences

Molecular:
* t(17;22)(q22;q13)
* Most common fusion is COL1A1::PDGFB

IHC:
* CD34: may be diminished / absent with fibrosarcomatous transformation
* Vimentin
* p53: with fibrosarcomatous transformation
* Fontana-Masson (Bednar tumor)

Question 24

Cutaneous leiomyoma

Answer 24

• Cutaneous leiomyomas are benign tumors originating from:
• Arrector pili (piloleiomyoma) –> Cutaneous piloleiomyomas can be sporadic or inherited in association with multiple cutaneous and uterine leiomyomatosis (also known as Reed syndrome or hereditary leiomyomatosis and renal cell cancer)
• Vascular (angioleiomyoma)
• Periareolar and genital smooth muscle cells (genital leiomyoma)

Clinical features:
* Cutaneous leiomyomas can be solitary or multiple
* When multiple, they may be clustered or linear in distribution
* They present as skin colored or red-brown, firm papules and nodules
* Pain and cold sensitivity are common complaints
* Genital leiomyomas may be pedunculated and are less likely to be painful compared to other subtypes

Micro:
* Smooth muscle cells have elongated, thin nuclei with blunt ends; they are often described as cigar shaped with pink, eosinophilic cytoplasm
* Perinuclear vacuoles made of glycogen may be seen
* Well circumscribed tumor consisting of fascicles and interlacing smooth muscle bundles
* Piloleiomyomas are nonencapsulated while angioleiomyomas can be encapsulated
* Angioleiomyomas have prominent vessels described as slit-like or round; smooth muscle layers surrounding the vessels interlace with surrounding smooth muscle fascicles
* Overlying epidermal changes such as acanthosis and hyperkeratosis can be seen
* Cytologic atypia is usually absent and mitotic activity is negligible

IHC:
Smooth muscle actin
Desmin
Muscle specific actin (MSA)
h-caldesmon
Variable cytokeratin
Variable EMA

Question 25

Kaposi sarcoma

Answer 25

• Vascular neoplasm caused by human herpesvirus 8 (HHV8)
• Tends to be indolent but may be locally aggressive

Epidemiology
Depends on the clinical variant of Kaposi sarcoma (4 subtypes)

**Classic / sporadic **
* Middle aged to elderly; M > F
* Ethnic groups from regions with high prevalence of HHV8 (Middle East, Eastern Europe and the Mediterranean) are at increased risk
* Usually few lesions limited to the lower limbs
* Visceral and mucosal involvement is uncommon
* Indolent

Endemic (African)
* Male adults and children of both sexes
* Not related to HIV
* Mirrors HHV8 seropositivity
* Most commonly in sub-Saharan Africa
* Children develop visceral involvement including the lymph nodes
* Skin involvement is not typical in children
* Adults can present with lower limb lymphedema
* Visceral involvement may occur in some adult patients
* Fatal

**Iatrogenic (transplant related) **
* M > F
* Patients > 50 years
* Solid organ transplant patients
* Risk correlates with the level of immunosuppression; hence, the risk is higher in multiorgan transplants and with greater HLA mismatching
* Typically affects the lower limbs
* Mucosal and visceral involvement is relatively common
* Indolent

**Epidemic (HIV / AIDS associated) **
* Patients infected with HIV
* Risk increases with declining CD4 cell counts and is reduced with the early use of combined antiretroviral therapy (cART)
* Most aggressive, but can be indolent
* May regress with HIV treatment

Clinical:
Progressive, enlarging red to violaceous skin lesions

Patch stage
* Red or purple macules or patches

Plaque stage
* Thickened red, purple or brown plaques

Tumor stage
* Nodule formation

• Skin lesions may be painful with associated lymphedema and secondary infection
• All clinical subtypes of Kaposi sarcoma may show these stages
• Multiple different stages may be present simultaneously

Micro:

Patch stage
* Dilated vascular channels dissecting through dermal collagen
* Promontory sign: tumor vascular channels surround and entrap native vessels (classic but uncommon feature)
* May be very subtle in early lesions

Plaque stage
* More extensive, compressed, slit-like vascular channels infiltrating deeper dermis
* Infiltrative proliferation of spindled endothelial cells (may resemble fibroblasts)
* Spindle cells infiltrating and destroying eccrine coils is very characteristic

Tumor (nodular) stage
* Discrete nodules composed of intersecting fascicles of uniform spindle cells
* Intervening blood filled spaces between spindle cells
* Slit-like spaces (longitudinal section)
* Sieve-like spaces (cross section)
* Intracytoplasmic hyaline globules may be seen

IHC
* HHV8 (also referred to as LANA1) nuclear staining in virtually 100% of cases
* ERG
* CD34
* CD31
* D2-40
* Hyaline globules are PAS positive, diastase resistant

Question 26

Angiosarcoma

Answer 26

• Angiosarcoma is a malignant neoplasm showing morphological or immunophenotypic evidence of endothelial differentiation
• Most common sites of angiosarcoma are skin of the head and neck (about 60% of cases); can also present within the soft tissues, visceral organs, bone and retroperitoneum
• Other classics are –> in chronic lymphoedema, post radiation in breast Ca.

Micro:
* Wide morphologic appearance, ranging from lesions that are cytologically bland and vasoformative, to solid sheets of highly pleomorphic cells without definitive vasoformation
* Numerous irregularly shaped anastomosing vascular channels lined by atypical endothelial cells
* Highly infiltrative architecture and poor demarcation
* Multilayering of endothelial cells, nuclear atypia, increased mitoses, necrosis
* Tumor cells are typically plump, pleomorphic and mitotically active
* They can be spindle shaped, polygonal, epithelioid and primitive round cells, forming papillae or solid nests within vascular lumina

Molecular:
* Upregulation of vascular specific receptor tyrosine kinases, including TIE1, KDR, TEK and FLT
* Upregulation of these genes and overexpression of VEGFR can cause endothelial cell expansion, angiogenesis and also vascular leaks
* KDR mutations are seen in primary breast angiosarcoma regardless of exposure to radiation
* c-MYC amplification is seen in radiation induced and lymphedema associated angiosarcoma
* FLT4 amplification has been detected in 25% of secondary angiosarcomas

IHC:
* Angiosarcoma expresses endothelial cell markers, including CD31, CD34, ERG, FLI1, VEGF and factor VIII
* Cytokeratin, EMA and CD30 may be expressed in a subset of epithelioid angiosarcoma