Disorders of Extracellular Matrix and Soft Tissue

Question 1

How does the skeleton look in someone with Osteogenesis imperfecta? Why?

Answer 1

Often a short stature with many fractures, “brittle bone disease” -> due to fractures thru the growth plate.

Lack of Type 1 collagen causes osteopenia.

Question 2

What are the other symptoms of osteogenesis imperfecta other than brittle bones? How is it inherited?

Answer 2

ITE
I = eyes, blue sclerae due to relative translucency
T = Teeth, misshapen and discolored due to abnormal dentin
E = ears, impaired hearing

Usually autosomal dominant, but there are some AR forms

Question 3

What causes Marfan syndrome?

Answer 3

Autosomal dominant disorder of fibrillin-1 gene causing defective sheath around elastin -> chromosome 15

Question 4

What are the skeletal, ocular, and cardiovascular defects in Marfan syndrome?

Answer 4

Skeletal - tall with long extremities, pectus carinatum or excavatum, hypermobile joints, arachnodactyly

Cardiovascular - Mitral valve prolapse with mitral regurgitation, cystic medial degeneration of aorta -> aortic root dilation with regurgitation and aortic dissections

Ocular - Ectopia lentis, especially upwardly and usually temporally

Question 5

What are arthrochalasia and dermatosparaxis a feature of?

Answer 5

Arthrochalasia - joint relaxation / joint laxity

Dermatosparaxis - hyperextensible skin

Both are features of Ehlers-Danlos syndrome, caused by collagen defects

Question 6

What causes hypermobile / classical / vascular type Ehler-Danlos?

Answer 6

Hypermobile - most common type - cause unknown, joint instability only

Classical - defect in type V collagen - joint and skin symptoms

Vascular type - vascular and organ rupture -> due to defective type 3 collagen (Ehlers-Danlos Type IV)

Question 7

What are superficial fibromatoses and who do they tend to occur in?

Answer 7

Poorly-delineated progressive thickenings within the superficial fascia of palms, soles, or penis composed of dense collagen with bundles of fibroblasts / myofibroblasts
-> lead to skin retraction

Question 8

What is the most common superficial fibromatosis and what will the clinical symptom commonly be?

Answer 8

Palmar fibromatoses. This thickening can frequently result in finger contraction, especially the 4th and 5th fingers
= “Dupuytren contracture”

Question 9

How do plantar and penile fibromatoses present?

Answer 9

Plantar - thickened nodules of fibroblasts on plantar fascia of feet

Penile - thickening of tunica albuginea, leading to curvature of the shaft -> Peyronie disease

Question 10

What are desmoid tumors also called and what their pattern of invasion? What age group gets them? Why are they difficult to manage?

Answer 10

Also called deep fibromatoses

They are locally aggressive and infiltrate fibroblastic lesions (more aggressive than superficial), but they are present in the deeper tissues.

Typically happen in adolescents / young adults

They are very difficult to easily excise.

Question 11

Where do deep fibromatoses usually arise, in a broad sense?

Answer 11

Extra-abdominal - typically in large proximal muscle groups, very deep (i.e. thigh)

Abdominal - anterior abdominal wall muscles, associated with pregnancy

Intra-abdominal - often in the mesentery and the pelvis

Question 12

What problems can intraabdominal deep fibromatoses cause and what condition are they associated with?

Answer 12

Can cause twisting and turning of the mesentery with bowel obstruction.

Associated with Gardner syndrome (an FAP variant also associated with osteomas of the face). Can be associated with any APC / B-catenin abnormalities.

Question 13

What is nodular fasciitis and why is it scary?

Answer 13

A clonal proliferation of fibroblasts which enlarges very quickly, but it is benign and often spontaneously regresses. It looks mitotically active and you need to differentiate it from a fibrosarcoma.

Question 14

Who tends to get nodular fasciitis and where does it appear?

Answer 14

Tends to occur in young adults as a rapidly-growing soft tissue mass usually on the extremities.

Question 15

What is myositis ossificans a subtype of and what causes it?

Answer 15

Heterotopic ossification

It is more specifically heterotopic ossification within a muscle

Mesenchymal cells which would normally form granulation tissue after a trauma instead form fully differentiated bone (also mesenchymal origin) even replete with bone marrow, calcifying from periphery to center.

Question 16

How is myositis ossificans usually diagnosed? Is it woven or lamellar bone?

Answer 16

Usually diagnosed by a radiologist. Easy to see the mineralized bone within the soft tissue on X-ray, and then that combined with a history of trauma which induced it will make you suspect it’s just heterotopic bone formation.

It is like normal bone -> first woven then replaced by lamellar

Question 17

Are benign or malignant soft tissue tumors more common? Where do they usually arise?

Answer 17

Benign is more common

Benign - usually superficial (i.e. dermis or subcutaneous tissues)

Malignant - frequently in deep soft tissues of extremities (i.e. thighs) or retroperitoneum

Question 18

What is the most common soft tissue tumor of adults?

Answer 18

Lipoma

-> well-circumscribed subcutaneous mass of normal appearing adipocytes

Question 19

What is a benign fibrous histocytoma?

Answer 19

Also called dermatofibroma

Firm, mobile, well-defined dermal papule of short bundles of histiocyte-like cells swirling.

Question 20

What is the defining clinical characteristic of dermatofibroma and who gets it? What’s the other name for it again?

Answer 20

Benign fibrous histiocytoma - Tends to be on the legs of young to middle-aged women.

Looks a bit like a melanoma, but DIMPLES with lateral compression

Question 21

What are the two broad types of neurofibroma, and who can get them? What cell forms the tumor and does it invade the nerve or not?

Answer 21

1. Cutaneous neurofibroma - can be sporadic, or very many if associated with NF-1
2. Plexiform neurofibroma - only associated with NF-1

These are tumors of diverse cellular origins, and intercalate between fibers of the nerve -> removal will destroy nerve function

Question 22

How are plexiform neurofibromas dealt with and why? Where are they found?

Answer 22

Most often found around major nerve trunk

They are removed because they cause pain, and have a risk of transforming into malignant peripheral nerve sheath tumor. Removal even though this destroys function.

Question 23

What are the two growth patterns within a schwannoma? Does the tumor mass intermingle? What syndrome is it associated with?

Answer 23

Tumor mass is well demarcated and can be easily removed from the nerve (i.e. vestibular schwannoma) Associated with NF-2, loss of merlin.

Two growth patterns characterize it histologically:

Antoni A - Associated with Verocay bodies

Antoni B - Hypocellular regions with myxoid stroma

Question 24

What are Verocay bodies?

Answer 24

Hypercellular regions composed of rows of palsading nuclei separated by bands of pink cytoplasmic processes (two stacks of cells lined up with pink between them)

Question 25

Where do most malignant soft tissue neoplasms arise from and who tends to get them? How do they feel? What are their genomic characteristics?

Answer 25

They arise from pluripotent mesenchymal stem cells

They feel like “fish flesh” / squishy, unlike carcinomas which are more stiff due to desmoplasia, these have no desmoplasia.

They are usually diagnosed in middle aged / older adults, except rhabdomyosarcoma.

Genomic characteristics: most have a complex karyotype and are pleomorphic, suggesting genomic instability.

Question 26

What is the single most common soft tissue malignancy of adults, and what cells are characteristic? Where does it arise?

Answer 26

Liposarcoma - a yellowish mass which contains lipoblasts -> cells composed of tiny vacuoles rather than large fat droplets

Arises where all soft tissues malignancies tend to: retroperitoneum or deep proximal muscles (i.e. thigh)

Question 27

What mutation is commonly associated with some forms of liposarcoma?

Answer 27

amplification of a gene encoding p53 inhibitor -> allows cell to adopt the wild karyotypes we were talking about (DNA damage)

Question 28

What is the most common group of adult soft tissue sarcomas and what does it look like grossly and microscopically?

Answer 28

Undifferentiated pleomorphic sarcoma

Looks underdifferentiated, pleomorphic, and mesenchymal-like

Grossly, it looks malignant with areas of hemorrhage and coagulation necrosis

Question 29

Are leiomyomas and leiomyosarcomas unique to the uterus? What helps guide prognosis of the latter?

Answer 29

No, they too can arise in common spaces for benign or malignant neoplasms, respectively.

Prognosis of leiomyosarcoma, being a sarcoma, is based on number of mitoses per high power field as well as the stage

Question 30

What is the most common childhood malignant soft tissue sarcoma? Where does it usually arise and what is it called if it does?

Answer 30

Rhabdomyosarcoma

Arises as a polypoid, grape-like mass in hollow, mucosa-lined cavities, i.e.:
Nasopharynx
Urinary bladder
Vagina - classic presentation

Called sarcoma botryoides

Oddly enough these are all areas where skeletal muscle is not normally present

Question 31

What will the cells look like in sarcoma botryoides and how can they be identified?

Answer 31

This tumor is specifically an embryonal rhabdomyosarcoma. The cell type is “rhadomyoblast”

Immature skeletal muscle cells with eccentric nulcei. They will have a cross-striation pattern on histology and will stain positive for actin and myosin.

Question 32

What is the type of rhabdomyosarcoma which is not embryonal? What is its growth pattern and where does it grow?

Answer 32

Alveolar rhabdomyosarcoma
-> tumor cells are on fibrous septae. Looks like alveoli

Arises in a location more typical for adult soft tissue malignancies: trunk and deep extremities.

May need to be differentiated from Ewing sarcoma based on absence of Codman’s triangles and onion skinning pattern because it’s invading inward not coming out.

Question 33

What is the cell of derivation of synovial sarcoma and who gets it?

Answer 33

Occurs in young adults (in between children and normal older adults you see for sarcomas)

Cell of differentiation is UNKNOWN -> called synovial because it arises near synovial joints (especially the knee)

Question 34

What is the pattern which synovial sarcoma grows?

Answer 34

Grows as a monophasic or biphasic malignancy. Very aggressive.

1. Tightly packed spindle cells
   +/-
2. Gland-like structures (reminiscent of synoviocytes)

Often with scattered calcifications