Ординатура / Офтальмология / Английские материалы / Ocular Pathology_6th edition_Yanoff, Sassani_2009

The group of tumors includes keloids, desmoids, fibromatoses of palmar and plantar fascias and of sternomastoid muscle, radiation fibromatosis, and congenital progressive polyfibromatosis.

b.It may recur after excision and is frequently mistaken for fibrosarcoma.

c.Histologically, it is composed of fibrous tissue interlacing with numerous mature capillaries.

A rare tumor in infants contains both fibroblastic and smooth-muscle elements and is called infantile myofibromatosis.

D.Fibrous–histiocytic–neoplastic

1.Fibrous histiocytoma (FH)† (xanthoma; Fig. 14.24)

Xanthoma consists of an intracellular accumulation of fat, as opposed to a lipogranuloma, which is composed of an extracellular accumulation of fat.

a.FH is the most common primary mesenchymal orbital tumor of adults.

In the past, FH has been misdiagnosed as hemangiopericytoma, sclerosing hemangioma, dermatofibrosarcoma protuberans (DFSP), and even neurofibroma. When associated with multinucleated giant cells and lipid-filled histiocytes, FH has been misdiagnosed as synovial giant cell tumor and villonodular synovitis.

b.FH may involve ocular structures such as orbit (most commonly), lids, conjunctiva, and corneoscleral limbus.

c.Although its cell of origin has been thought to be the histiocyte or the fibroblast, it is most probably a primitive mesenchymal cell that shows divergent lines of di erentiation, expressing fibroblastic, histiocytic, and even myofibroblastic phenotypes.

d.A variant of FH that forms no fibers at all and is entirely composed of histiocytes is called a histiocytoma.

e.FH has a malignant potential.

Malignant FH (MFH), is considered to be a sarcoma having an undifferentiated mesenchymal cell origin

A

C

that differentiates along a broad fibroblastic and histiocytic (fibrohistiocytic) spectrum and usually has a predominant “fibroblastic” component.

f.Histologically, FH shows a characteristic, diphasic pattern with mainly “storiform” (matted) areas composed of fibrous spindle cells along with scattered areas showing single or grouped foamy histiocytes.

1). FH can be richly vascularized and then easily confused with hemangiopericytoma.

2). MFH shows a mixture of storiform and pleomorphic features.

MFH may be difficult to differentiate from other pleomorphic soft-tissue tumors such as pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, malignant schwannoma, leiomyosarcoma, and epithelioid sarcoma—a very rare orbital malignancy presumably of tendon sheath origin, having both epithelial and mesenchymal features. KP-1 (CD68), a recently described monoclonal antibody to a cytoplasmic epitope present on tissue histiocytes and macrophages, may have specific marker properties to help identify MFH. Vimentin also is usually positive. Finally, molecular assays for spe-

h

f

B

Fig. 14.24 Fibrous histiocytoma. A, This is the fourth recurrence of an orbital tumor that had first been excised 10 years previously. The histology of the primary lesion and of the four recurrences appears identical. B, A histologic section shows the diphasic pattern consisting of a histiocytic component (h) (mainly on far left) and a fibrous component

(f). C, Increased magnification shows that the fibrous component forms a storiform or matted pattern. Controversy exists as to whether the tumor arises from histiocytes or fibroblasts (most of the evidence points toward a primitive mesenchymal cell origin). (Case reported by Jones WD III et al.: Br J Plast Surg 32:46, 1979. Copyright 1979 with permission from Elsevier.)

cific gene fusion provide a genetic approach to the differential diagnosis of soft-tissue sarcomas.

2.Atypical fibroxanthoma (AFX)‡

a.AFX usually occurs in the sun-damaged skin of the head and neck in the elderly.

b.Histologically, spindle cells and pleomorphic polyhedral cells occur with many giant cells and mitotic figures.

1). Despite its anaplastic appearance, AFX is regarded as a low-grade malignant tumor, usually acts benign, but rarely may metastasize.

2). Immunohistochemically,AFX and Dermatofibrosarcoma (DFSP) (see later) stain nearly identically: negative for cytokeratin, desmin, S-100 protein, and melanoma antibodies

HMB-45 and HMB-50; strongly positive for vimentin and NKI/C3, and variable positivity for muscle-specific actin (HHF-35).

Although AFX and DFSP can be confused with spindle cell, squamous cell carcinoma and desmoplastic malignant melanoma, the absence of cytokeratin, HMB-45, and HMB-50 staining easily distinguishes AFX and DFSP from the others.

3.Dermatofibrosarcoma (DFSP)‡

a.DFSP usually occurs in young or middle-aged persons as large cutaneous nodules.

b.Histologically, DFSP is composed of relatively uniform spindle cells with a conspicuous storiform pattern (similar to FH except for the lack of a histiocytic component).

1). DFSP is regarded as a low-grade malignant tumor, usually acts benign, but extremely rarely may metastasize.

2). Immunohistochemically, DFSP and AFX (see earlier) stain nearly identically.

4.Fibroma‡ and fibrosarcoma‡

a.True orbital fibroma is rare.

An even rarer tumor is the elastofibroma, which consists of a fibrous proliferation of abundant elastinophilic polymorphic structures.

Histologically, orbital fibroma is composed of scattered spindle-shaped cells, sometimes showing a herringbone pattern, but lacking atypia and mitotic figures.

b.Fibrosarcoma (Fig. 14.25) is a very rare, slowgrowing, orbital tumor.

Histologically, fibrosarcoma is composed of interlacing bundles of spindle-shaped cells forming a herringbone pattern, often with atypical cells and mitotic figures.

5.Solitary fibrous tumor‡

a.Solitary fibrous tumor is a rare tumor of mesenchymal origin that most often involves the pleura; rarely, the orbit is involved.

The tumor may arise from mesenchymal cells that show fibroblastic differentiation.

b.Although usually benign, it can recur locally and rarely metastasizes.

c.Histologically,usually strong CD34and vimen- tin-positive spindle cells with elongated, wavy nuclei and inconspicuous nucleoli in hypocellular collagen-rich areas form a characteristic “patternless pattern.”

Solitary fibrous tumor resembles giant cell angiofibroma but lacks multinucleated giant cells and pseudovascular spaces

6.Fibrous hamartoma of infancy‡

a.Benign solitary tumor (0.5 to 4.0 cm) present at birth or at a very young age

b.Male to female ratio 2 :1

c.Growth slows with age without malignant transformation

d.Histologically it consists of well-defined bundles of dense fibrocollagenous tissue, immature and primitive mesenchyme arranged in nests, concentric whorls or bands, and mature adipose tissue intimately admixed with the other components.

7.Giant cell angiofibroma‡

a.Giant cell angiofibroma, probably a benign tumor, occurs mainly in men from the third to the eighth decades.

b.Although most occur in the orbit, they can also occur in the lids and, rarely, conjunctiva.

c.Histologically the tumors are richly vascularized and contain a patternless proliferation of spindle

cells, numerous multinucleated giant cells, and some pseudovascular spaces, all embedded in variably collagenized stroma.

1). Myxoid stromal deposition may be present.

2). The spindle cells and multinucleated giant cells stain intensely positive with CD34 and vimentin.

Solitary fibrous tumor, which resembles giant cell angiofibroma, lacks multinucleated giant cells and pseudovascular spaces. Stains for KP1 (CD68) are negative, unlike in FH, where they are positive.

E.Muscle

1.Leiomyoma‡ and leiomyosarcoma‡ are very rare orbital tumors.

An even rarer tumor, composed of myofibroblasts surrounding a hemangiopericytoma-like stroma, is infantile myofibromatosis.

Histologically, leiomyoma (Fig. 14.26) consists of interlacing fascicles of smooth-muscle cells.

1). Immunohistochemistry shows strong positivity for the sensitive marker muscle-specific actin and focal positivity for desmin.

2). Electron microscopy shows the characteristic

findings for smooth muscle, namely cytoplasmic filaments associated with dense bodies, plasmalemmal densities, and pinocytotic vesicles, and investing thin basement membrane.

3). Leiomyosarcoma, in addition, shows atypical nuclei and mitotic figures.

2.Mesectodermal leiomyoma‡ (see p. 350 in Chapter

9) and leiomyosarcoma‡ are very rare orbital tumors whose origin seems to be from tissue derived from neural crest.

Histologically, mesectodermal leiomyoma resembles ganglionic, astrocytic, and peripheral nerve tumors.

Electron microscopy, however, demonstrates the smooth-muscle origin of the tumor.

Mesectodermal leiomyoma also occurs in the ciliary body. The tumor has some similarities to a malignant schwannoma or rhabdomyosarcoma by light microscopy. Electron microscopy aids in identifying the smooth-muscle nature of the tumor. Finally, molecular assays for specific gene fusion provide a genetic approach to the differential diagnosis of soft-tissue sarcomas.

3.Malignant rhabdoid tumor‡

a.Malignant rhabdoid tumor is a rare, highly aggressive renal tumor of infants.

1). The tumor rarely involves extrarenal sites in children and adults, and even more rarely involves the orbit.

2). Although its name, malignant rhabdoid tumor, implies a muscle origin, more likely the tumor arises from epithelium.

b.Histologically, the tumor is composed of dyscohesive, globoid, and eosinophilic cells, often containing cytoplasmic inclusions.

1). Immunohistochemically, the inclusions consist of whorls of vimentin-positive (intermediate) filaments, and the cells express epithelial membrane antigen and cytokeratin positivity (evidence of epithelial origin).

2). Electron microscopy shows intercellular junctions and interrupted segments of thin basement membrane material, further evidence of epithelial origin.

4.Rhabdomyoma‡ is a very rare, benign orbital tumor.

Histologically, well-di erentiated rhabdomyoblasts are present.

5.Rhabdomyosarcoma†

a.Rhabdomyosarcoma is the most common malignant mesenchymal orbital neoplasm, and is the most common primary malignant orbital tumor in children.

b.Although found in many parts of the body, rhabdomyosarcoma has a predilection for the orbit.

It can rarely occur in the eyelid, conjunctiva, and uveal tract.

c.The average age of onset is approximately 6 years, with most children younger than 10 years of age; it is extremely rare after 25 years of age.

d.The tumor is characterized clinically by a very rapid onset, often simulating an orbital cellulitis.

e.Three types exist: embryonal, di erentiated, and alveolar.

f.Embryonal type (Fig. 14.27)—most common type.

An undifferentiated tumor that resembles rhabdomyosarcoma, but without demonstrable rhabdomyoblasts, should be classified as embryonal sarcoma. Many of the metastases, however, show rhabdomyoblasts with cross-striations; then the classification embryonal rhabdomyosarcoma (or alveolar rhabdomyosarcoma, according to pattern) is appropriate.

1). When it arises in the submucosa of the conjunctiva, it is identical to the vaginal submucosal tumor of infancy, sarcoma botryoides.

2). Histologically, it is composed of malignant embryonal cells, rhabdomyoblasts, in a loose syncytial arrangement of fascicles of spindle cells running in a haphazard arrangement, usually showing frequent mitotic figures. a). The cells are round, oval, elongate, or stel-

late, with nuclei rich in chromatin and cytoplasm rich in glycogen.

b). A ribbon of eosinophilic cytoplasm may be seen around the nucleus.

Usually, only undifferentiated embryonal cells with large hyperchromic nuclei and a scant amount of cytoplasm are present. In some areas, however, cells with a ribbon of pink cytoplasm can be seen. Cross-striations are most likely to be found in these latter areas.

c). Cross-striations may sometimes be present in the metastases even though they were not found in the primary tumor.

d). Immunohistochemistry shows positivity for vimentin, myosin, myoglobin, musclespecific actin, and desmin.

Insulin-like growth factor-2, which acts as an autocrine growth and motility factor, may be operating in rhabdomyosarcomas. The expres-

sion of the myogenic determination gene MyoD, a member of the helix–loop–helix family of transcription factors, is the most sensitive marker for rhabdomyosarcoma. Rhabdomyosarcomas seem to be deficient in a factor required for MyoD activity.

e). Electron microscopy shows, in better-dif- ferentiated tumors, the characteristic findings for striated muscle (formed sarcomeres containing interdigitated thick myosin and thin actin filaments outlined by transverse Z-bands), but in primitive cases may show only focal myofilamentary di erentiation.

g.Di erentiated type

1). The di erentiated form of rhabdomyosarcoma is the least common type, but seems to have the best prognosis.

2). Cross-striations are easily found in the differentiated type.

The adult pleomorphic form of rhabdomyosarcoma rarely, if ever, involves the orbit.

h.Alveolar type (Fig. 14.28)

1). The alveolar form of rhabdomyosarcoma seems to have the worst prognosis.

a). The diagnosis of alveolar rhabdomyosarcoma depends heavily on the presence of rearrangement of the FKHR (forkhead) gene located on chromosome 13q14.

b). The tumor is characterized by a tumorspecific translocation, t(2;13)(q35;q14) and t(1;3)(p36;q14)

c). Molecular confirmation of alveolar rhabdomyosarcoma is important in the treatment of this tumor

2). The individual cell type is similar to that seen in the embryonal type, but the tumor has a distinct alveolar pattern.

3). Some rhabdomyoblastic cell processes fuse to form the walls of the alveoli, whereas other rhabdomyoblasts lie free in the alveolar lumen.

4). It is the most di cult tumor in which to find cross-striations.

Molecular assays for specific gene fusion provide a genetic approach to the differential diagnosis of soft-tissue sarcomas.

I. Prognosis

1). If the tumor is confined to the orbit, the survival rate is 90% with a combination of chemotherapy and radiation.

2). If there is bone destruction and extension beyond the orbit exist, the survival rate decreases to 65%.

3). Most deaths occur within the first 3 years, so that a 5-year cure probably is a valid one.

4). DNA content is an important variable in predicting prognosis. DNA hyperdiploid and tetradiploid rhabdomyosarcomas have a favorable prognosis, whereas DNA diploid and polyploid tumors have a poor prognosis.

F.Cartilage—chondroma‡ and chondrosarcoma‡

1.Chondroma and chondrosarcoma are extremely rare orbital tumors.

2.Chondrosarcoma may be congenital or may arise primarily without antecedent cause, but most frequently it follows radiation for retinoblastoma or pre-existing Paget’s disease.

Enchondroma, a tumor that originates from misplaced islands of cartilage in the intramedullary canal of bone, is extremely rare.

G.Bone

Nonneoplastic and neoplastic diseases of bone usually cause exophthalmos by decreasing orbital volume.

a.Aneurysmal bone cyst‡

b.Fibrous dysplasia† (Fig. 14.29)

c.Giant cell tumor‡

d.Giant cell reparative granuloma‡

e.Juvenile fibromatosis‡ (psammomatoid ossifying fibroma)

f.Cholesterol granuloma‡ and cholesteatoma‡

(see p. 534 in this chapter)

g.Leontiasis ossea‡

h.Osteitis fibrosa cystica (brown tumor)†

i.Osteopetrosis‡

j.Paget’s disease†

k.Osteoma‡, osteoblastoma‡, and osteogenic sarcoma (osteosarcoma)‡

l.Benign osteoblastoma‡

1). All are extremely rare orbital tumors.

Osteomas may occur in Gardner’s syndrome, an autosomal-dominant disorder characterized by

intestinal polyposis, various skin and soft-tissue tumors, retinal pigment epithelial hypertrophy, and osteomas.

2). Osteogenic sarcoma (osteosarcoma)‡ may rarely be primary, may be associated with Paget’s disease of bone, or may follow radiation for retinoblastomas.

m. Ameloblastoma‡ IV. Neural tumors

A.Amputation neuroma‡

1.An amputation neuroma is rare in the orbit.

2.Histologically, it is composed of a haphazard entanglement of regenerated nerve fibers from the cut end of the peripheral ciliary nerve(s).

B.Neurofibromas† (see Figs 2.3 to 2.5)

C.Neurilemmoma (schwannoma†; Figs 14.30 and 14.31)

1.A neurilemmoma is a rare orbital tumor composed of neoplastic Schwann cells.

Even more rarely, the tumor may occur in the uveal tract or in the conjunctiva.

2.Histologically, nuclei of spindle-shaped Schwann cells show a tendency toward palisading.

a.When the texture is compact and composed of interwoven bundles of long bipolar spindle cells, often with ribbons of palisading cells alternating with relatively acellular areas, the Antoni type A pattern is present.

1). Areas of the tumor may mimic tactile corpuscles and are called Verocay bodies.

2). The tumor may have a haphazard arrangement, a loose texture, and mucinous and microcystoid areas of necrosis; this type of degenerative pattern is called the Antoni type B pattern.

b.The tumor is usually encapsulated in the perineurium of the originating nerve.

c.Immunohistochemistry shows positivity for human nerve growth factor (NGF), laminin, the major glycoprotein of basement membranes,

HMB-45, and S-100 protein.

Immunohistochemistry may be quite helpful in differentiating the very rare melanotic neurilemmoma from a malignant melanoma, especially if the former arises in the choroid. A rare histologic variant of neurilemoma, called ancient schwannoma, shows distinctive areas of hypercellularity and hyperchromic nuclei suggesting fibrosarcoma, as well as hypocellular areas containing considerable fibrosis; the clinical course, however, tends to be benign.

d.Electron microscopy may show Luse bodies (see Fig. 14.31C; i.e., aggregates of long-spaced collagen).

3.Malignant peripheral nerve sheath tumor (malignant schwannoma, malignant neurilemmoma, neurofibrosarcoma, perineural fibrosarcoma, neurogenic sarcoma)‡ is extremely rare, but when present is associated with neurofibromatosis in 50% of cases.

S-100 protein and NGF positivity and electron microscopic evidence of basement membrane mate-

rial and mesaxon or pseudomesaxon formation help to identify these often poorly di erentiated tumors.

Mutations in the p53 tumor suppressor gene, located on the short arm of chromosome 17 at position 17p13.1, represent the most frequent genetic alteration detected in human solid malignancies. In approximately half of all cancer cases, p53 is inactivated by mutations and other genomic alterations, and in many of the remaining cases, p53 is functionally inactivated by the binding of the cellular

MDM2 oncoprotein, a cellular inhibitor of the p53 tumor suppressor. The p53 gene encodes a 53-kD nucleophosphoprotein that binds DNA and negatively regulates cell division, preventing progression from G1 to S phase. Approximately 25% of adult sarcomas of different types are associated with p53 abnormalities. It also appears to be a marker of tumor progression (i.e., a direct correlation seems to exist between mutations at the p53 locus and increasing histologic grade). This correlation may be especially applicable to malignant peripheral nerve sheath tumors.

4.Juvenile pilocytic astrocytoma (glioma) of optic nerve† (see pp. 514–518 in Chapter 13)

D.Peripheral primitive neuroectodermal tumors (PNETs‡; Fig. 14.32)

1.PNETs are a group of soft-tissue tumors of presumed neural crest origin arising outside the central and sympathetic nervous system.

Fig. 14.31 Neurilemmoma. A, A 61-year-old patient had decreased vision in the right eye for 8 months. The computed tomography scan shows a right orbital mass. B, Histologic section was characteristic of neurilemmoma and, as seen in this figure, is positive for S-100 protein. C, Electron microscopy shows a Luse body (i.e., an aggregate of longspaced collagen), often found in neurilemmomas. (Case presented by Dr. HE Grossniklaus to the meeting of the Verhoeff Society, 1994.)

a.PNETs include adult neuroblastoma, neuroepithelioma, primitive neuroectodermal tumor of bone, and malignant small cell tumors of the thoracopulmonary region (Askin’s tumor).

b.All share in a chromosomal aberration translocation (11;22)(q24]2).

Ewing’s sarcoma also has the same genetic abnormality and may represent the opposite end of the same spectrum. However, despite their genetic and antigenic similarity, most authors recognize PNET and extraosseous Ewing’s sarcoma as separate entities, a distinction based primarily on the more neural differentiation of PNET and its graver prognosis.

c.Histologically, scattered nests of small tumor cells containing an even chromatin pattern, similar to Ewing’s sarcoma cells, are set in a highly desmoplastic stroma.

Ewing’s sarcoma stains positively for periodic acid– Schiff (PAS) stain, vimentin, and especially terminal deoxynucleotidyl transferase and MIC-2 (CD99), a cell surface glycoprotein encoded by genes on chromosomes X and Y. The histologic differentiation includes other small cell tumors such as lymphomas, rhabdo-