Moran CORE

Orbit Histopathology

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Orbit Bone Structure:

There are 7 bones that form the orbit. These are:

1. sphenoid
2. frontal
3. zygomatic
4. ethmoid
5. lacrimal
6. maxilla
7. palatine

The orbit is a pear shape, with the optic nerve at the stem, and holds approximately 30 cc volume. The entrance to the globe anteriorly is approximately 35 mm high and 45 mm wide. The depth from orbital rim to the orbital apex measures 40-45 mm in adults. The maximum width is 1 cm behind the anterior orbital margin. The orbital cavity contains the globe, nerves, vessels, lacrimal gland, extraocular muscles, tendons, the trochlea, as well as fat and other connective tissue. An increase in the volume of the extraocular structures within the orbit can cause proptosis, which is protrusion of the globe and/or displacement (deviation) of the globe from its normal position.

    

Sagittal section of the globe with surrounding orbital tissues

    

Axial cut of the orbit, both eyes

    

Axial CT of the right and left orbit

The orbital margin is the anterior opening of the globe and has a quadrilateral spine formed by several of the bones that make up the orbit. The roof of the orbit is formed by the orbital plate of the frontal bone and the lesser wing of the sphenoid.  The fossa of the lacrimal gland lies anterolaterally, behind the zygomatic process of the frontal bone.

 

The orbit is divided into three areas:

• Intraconal: the space inside the muscles cone and intramuscular septae
• Extraconal: the space outside the muscle cone to the periosteum
• Subperiosteal: a potential space, located just deep to the periosteum

Lacrimal gland

    

Normal lacrimal gland tissue with cuboidal epithelium lining acini

The lacrimal gland lies in the anterior, superior, temporal quadrant of the orbit.

• The lacrimal gland has orbital and palpebral lobes and these are divided by aponeurosis of levator palpebrae superioris
• The lacrimal gland is composed of eccrine glandular tissue, which forms acini of cuboidal epithelium with cytoplasmic secretory granules
• The lacrimal ducts are within the stroma and are lined by the cuboidal epithelium surrounded by flat, spindle-shaped myoepithelial cells

Tumors of the Lacrimal Gland

Lacrimal gland neoplasia

• The epithelial lacrimal gland tumors are categorized by the WHO epithelial salivary gland classification. The most common types are pleomorphic adenoma (benign-mixed tumor), adenocarcinoma and adenoid cystic carcinoma.

Lacrimal gland lymphoma

    

External photograph of both eyes, with some increased swelling of the right superotemporal orbit with erythema.

    

Coronal CT of both orbits, displaying diffuse fullness of both orbits, rather than a discrete mass.

    

Low magnification view of lymphoma, showing a tight conglomeration of lymphocytes.

    

Immunoperoxidase staining of lymphoma

• Lymphomas tend to spread out around the globe/orbital structures like a pancake.

Nick’s tips:

Contrary to prior knowledge, studies have shown now that 80% of the tumors of the lacrimal gland are lymphoid in nature. By contrast, when the tumor is epithelial-derived, it is more likely to be benign-mixed tumor.

With benign-mixed tumor (pleomorphic adenoma), the key is to remove the tumor completely, because recurrence may develop into malignant-mixed tumor

Pleomorphic Adenoma (Benign mixed tumor)

    

External photograph of both eyes, with subtle fullness of the temporal aspect of the left upper lid

    

CT of the orbit showing a coin lesion near the left lacrimal gland, suspicious for pleomorphic adenoma

    

Low magnification view of benign-mixed tumor

    

Higher magnification view of benign-mixed tumor

    

Low magnification view of malignant mixed tumor

    

Higher magnification view of malignant mixed tumor

Pleomorphic adenoma is the most common epithelial-derived tumor of lacrimal gland

• Pseudoencapsulated “Coin lesion”
• Characterized by a slow expansion that may displace lacrimal fossa bone, and may cause periosteum to lay down thin new bone, without erosion of nearby orbital bone
• Usually painless
• Men are more affected than women, with mean age of 35 years
• Microscopically, a pseudocapsule is seen that has a histologic mix of epithelial + stromal components
  • Nests or tubules lined by bilayer of epithelial cells
  • Stroma may have cartilage or bone
• Tumor is usually positive for multiple tests including keratin, epithelial membrane antigen, actin, myosin, fibronectin, S-100
• Treatment is complete excision with clean margins. Incomplete removal may lead to recurrence and it is very difficult to remove if repeat surgery is needed
  • Recurrent cases may transform into malignant mixed tumor, adenocarcinoma and adenoid cystic carcinoma
  • For this reason, excisional biopsy is not recommended

 

Adenoid cystic carcinoma

    

External photograph showing proptosis and inferior displacement due to fullness of left temporal upper-lid

    

CT scan of orbit with lesion in superotemporal portion of the left orbit

    

Adenoid cystic carcinoma, cribriform pattern eroding into bone

    

Higher magnification view of adenoid cystic carcinoma

    

Basaloid variety of adenoid cystic carcinoma

Can develop in a pleomorphic adenoma or may arise from lacrimal gland.

• More common in women than men
• Median age at presentation: 40 years
• Cells appear benign but behave aggressively
• Lacks a capsule and erodes bone (in contrast to pleomorphic adenoma)
• It also invades orbital nerves, causing patients to present with pain
• Appears grayish, white, firm nodule
• There are several patterns seen on histology

1. 1. Cribriform (“Swiss cheese”), most common
   2. Comedocarcinoma
   3. Sclerosing
   4. Tubular
   5. Basaloid (solid) (5-year survival is 20%)

 

• Expression of p53 is poor prognostic indicator
• Treatment is either exenteration, or intra-arterial chemotherapy

Nick’s tips:

These tumors are disarmingly benign, and do not appear to show signs of malignancy on histopathologic examination, but can indeed be malignant. These can metastasize, and the basaloid variety is the most severe type of adenoid cystic carcinoma.

Nonspecific orbital inflammation:

(orbital pseudotumor, or idiopathic orbital inflammatory syndrome)

     

External photograph of child displaying erythematous lid and swelling of left eye

     

Low magnification view of orbital inflammatory syndrome

     

Higher magnification view of orbital inflammatory syndrome

     

Orbital inflammatory syndrome with diffuse infiltration

    

Sclerosing pseudotumor, which represents a progression of orbital inflammatory syndrome

 

•  Appears similar to neoplasm/cellulitis, but no recognizable cause
•  Patients have abrupt onset of pain
•  Represents 5% of orbital lesions, affecting both children and adults
•  When extraocular muscles are involved, it is called orbital myositis
•  When lacrimal gland is involved, it is called dacryoadenitis
•  In early phase, acute inflammation common to muscles and fat, and fat necrosis results
•  Polymorphous inflammatory response including eosinophils, neutrophils, plasma cells, lymphocytes, and macrophages
•  In late phase, fibrosis occurs which may encase muscles and optic nerve, may also have lymphoid follicles with germinal centers
•  CD20 and CD25 receptors have been identified
• IgG4 is marker of sclerosing variant

Treatment: Prompt treatment steroids will produce a prompt response.  The late phase is refractory to treatment.

Nick’s tips:

Inflammatory conditions can be distinguished from proliferative lesions by special stains which will stain for clonality of lymphoproliferative lesions (lymphoma).

Cysts of the Orbit

Cysts may be congenital or acquired. There are several different categories

• Cysts of surface epithelium
• Teratomatous cysts
• Neural cysts
• Secondary cysts (mucoceles)
• Inflammatory cysts (parasitic)
• Noncystic lesions with a cystic component

Dermoid Cyst

    

Dermoid cyst, gross specimen

    

Cross sectional view of dermoid cyst and contents

    

Dermoid with hair follicles and dermal appendages

Embryonic epithelial nests entrapped in embryogenesis

• Most present in children as a mass in superotemporal area
• May have dumbbell shape with protrusion through frontozygomatic suture
• Rupture causes granulomatous inflammation
• Cysts contain Keratin, hair, adnexal structures
• Rarely contain respiratory or conjunctival epithelium

Nick’s tips:

During removal, it is recommended to remove the lesion whole, because keratin that spills from the lesion can cause additional inflammation. These can also spontaneously rupture, causing inflammation.

Inflammation:

Inflammation can be idiopathic or from a systemic inflammatory disease, infection, or foreign body.

Thyroid Associated Orbitopathy:

    

External photograph of patient with thyroid associated orbitopathy

    

CT scan displaying enlargement of extraocular muscles

    

Autopsy photo of thyroid ophthalmopathy sparing the tendon

    

Myxoid degeneration of thyroid eye disease

Most common cause of unilateral + bilateral proptosis in adults

• Also called Graves’ disease, thyroid ophthalmopathy, thyroid-associated ophthalmopathy, or Basedow’s disease.
• Thyroid dysfunction causes orbital inflammation of connective tissue, adipogenesis and fibrosis of extraocular muscles
• Orbital fibrocytes are from neural crest and are pluripotent, and these can therefore cause adipogenesis
• Mononuclear inflammatory cell response (monocytes, lymphocytes, plasma cells, mast cells, fibroblasts)
• Fibroblasts make hyaluronan and other glycosaminoglycans
• Most commonly affects inferior + medial rectus
• Tendons spared
• Common signs include lid retraction, scleral show
• In late stages, can create fibrosis with severe extraocular movement restriction, severe eyelid retraction and exposure keratitis

Nick’s tips:

In thyroid ophthalmopathy, the tendon is spared, versus in myositis, the tendon may be affected.

Infections

Bacterial infection

• Most common caused by spread from local sinus infection. Can also be caused from bacteremia through hematogenous spread, skin infection, trauma, and retained surgical material.
• The most common species are H. influenza, Streptococcus species, S. aureus, Clostridium, Bacteroides, Klebsiella, and Proteus
• Tuberculous infection of the orbit is rare and causes necrotizing granulomatous

Fungal

Mucormycosis

    

Mucomycosis on GMS stain

• Seen in patients immunocompromised due to diabetes, or patients who have solid malignant neoplasms, neutropenia due to hematologic neoplasms, burns, and patients taking corticosteroids
• Usually spreads from sinus infection
• Both acute and chronic forms have necrosis that is often granulomatous
• Broad, non-septate hyphae on H&E, PAS, GMS stains
• Fungi can invade vessel walls and cause thrombosing vasculitis
• Diagnosis is by biopsy of necrotic tissue in nasopharynx

Aspergillus

    

Hyphae of Aspergillus

• Immunocompromised or healthy patients
• Often slow progressing, insidious onset
• Septate hyphae w/ 45° angle branches
• Treatment: Surgical debridement and antifungal agents such as Amphotericin B
• Both aspergillosis and mucormycosis are often fatal if they gain access to the brain

Allergic fungal sinusitis

• Noninvasive fungal disease
• IgE-mediated hypersensitivity
• Caused by multiple species
• Extend to the orbit and intracranial area

Parasitic infections

• Rare in the United States
• Echinococcus, Taenia solium, Loa loa infections occur in endemic areas
• Enzyme-linked immunosorbent assay (ELISA) antibodies aid in diagnosis

Degenerations

Amyloid

    

Amyloid deposition on H&E stain

    

Amyloid deposition on Congo Red stain

• Amyloid deposition occurs in the context of systemic amyloidosis.
• May produce ptosis, ophthalmoplegia, diplopia
• May be systemic or local to orbit
• Associated with multiple myeloma, atypical lymphomatous proliferation

 

Lymphoproliferative Lesions

• These are difficult to classify since most systems depend on nodal
  architecture for classification, and the orbit lacks lymph nodes. Therefore, lymphoproliferative lesions can be grouped into categories of reactive lymphoid hyperplasia (RLH), atypical lymphoid hyperplasia (ALH), and ocular adnexal lymphoma (OAL).
• Usually these lesions present with painless, gradual proptosis, which may be bilateral

Lymphoid hyperplasia

• Reactive lymphoid hyperplasia is from well differentiated lymphocytes and other cells such as plasma cells, macrophages, eosinophils
• Follicles form with germinal centers
• These rarely show mitotic activity and have vessels with endothelial hyperplasia
• RLH and ALH are one end of a spectrum of lymphoproliferative lesions, versus malignant lymphoma

Orbital Lymphoma

    

External photograph patient with lymphoma, showing fullness of the orbit

    

CT of patient with lymphoma

    

Diffuse sheet of lymphocytes, indicative of lymphoma

    

Lymphoma, which has been stained with immunoperoxidase for B cells

• May be part of a systemic lymphoma or may be from primary in the orbit
  • Secondary orbit involvement in lymphoma is 1-2%
• MALT (mucosa-associated lymphoid tissue) is the most common lymphoma seen in the orbit. This tumor is low grade with an excellent prognosis.
• Follicular, large B-cell, and mantle cell lymphoma occur at lower incidence. Most of these are non-Hodgkin. These are one half of the malignant tumors of orbit and adnexa.
  • Contain B-cells positive for CD19 and CD20
• T-Cell lymphomas are rare, but more aggressive
  • Contain T-cells positive for CD3, CD4, CD8

Nick’s Tips: Lymphoma is on one end of the spectrum of inflammatory/ lymphoproliferative disorders, and on the other is idiopathic orbital inflammatory syndrome/pseudotumor. Atypical lymphoid hyperplasia is somewhere in the middle.

Neoplasia

• Neoplasms may be primary or secondary
• Secondary tumors are more common, from local invasion or metastatic disease
• In children, 90% of orbital tumors are benign
• Rhabdomyosarcoma represents 3% of all orbital masses and is the most common malignant tumor in children
• The orbit can also be involved in retinoblastoma, neuroblastoma, and leukemia/lymphoma

Vascular Tumors

Lymphangioma

    

CT of the orbits with a heterogenous extraconal lesion causing explosive proptosis of the right orbit

    

Large lymphatic-like space created by lymphangioma

    

Lymphoid tissue interspersed with staghorn spaces which are filled with blood

    

Higher magnification of smaller staghorn spaces filled with blood

• Benign orbital lymphatic malformations, (formerly known as lymphangiomas) occur in children
• Display fluctuating proptosis, larger during periods of illness, especially upper respiratory illnesses
• Tumor is not encapsulated, diffuse, infiltrating to surrounding tissue
• Tumor has vascular spaces and lymphoid aggregates (similar to Peyer’s patches) within fibrous space

Nick’s tips:

Proptosis may increase suddenly when the child is sick or when there is spontaneous bleeding into a cyst. These lesions are often called chocolate cysts, due to bleeding in larger cystic areas of the lymphangioma. When they are drained, the blood cells may appear chocolate colored. It can be difficult to remove the entire lymphangioma.

Hemangioma

    

Choroidal folds seen on retinoscopy, potentially due to hyperopia or an intraconal lesion such as a cavernous hemangioma

    

MRI of orbits with lesion arising from the intraconal space of the right eye

    

Gross specimen of cavernous hemangioma

    

Low magnification view of cavernous hemangioma

    

Higher magnification view of cavernous hemangioma, showing separation of RBCs and serum in the cavernous spaces (Indicates low flow)

Cavernous hemangioma in adults

• Vague symptoms like soreness
• These have a pseudocapsule and are often found in the muscle cone
• Slow growing
• Distinguished by cavernous spaces with thick, fibrous walls
• Patients may present with choroidal folds

Capillary hemangiomas in children lack a capsule and are more cellular

• May involve the skin as have capillary-sized vessels

Nick’s tips:  Cavernous hemangioma usually occurs in people in their 20s-30s and is unilateral.

Solitary fibrous tumors

Hemangiopericytomas

    

External photograph with proptosis due to fullness of orbit of the right eye in patient with hemangiopericytoma

    

Hemangiopericytoma showing dense cellular pattern with staghorn lesion

    

Hemangiopericytoma with irregular staghorn spaces surrounding by proliferating cells

    

Staghorn spaces with vascular channels and proliferating stroma/pericytes in hemangiopericytoma

    

Hemangiopericytoma displaying nuclear pleomorphism and clumped chromatin

    

Nucleoli, clumped chromatin, and pleomorphism indicating malignant hemangiopericytoma

    

Reticulin stain of hemangiopericytoma which is useful to distinguish the collagen reticular network, which is created by the pericyte

Fibrous histiocytoma

    

Fibrous histiocytoma with Touton giant cell

Solitary fibrous tumors include hemangiopericytoma, fibrous histiocytoma, and giant cell angiofibromas of the orbit.

• Histopathologic features of various tumors overlap
  • Staghorn vascular pattern (classically seen in hemangiopericytoma)
  • Spindle-shaped, plump cells that look like histiocytes (classically seen in fibrous histiocytoma)
  • Multinucleate floret-type giant cells and angioectatic spaces (classically seen in giant cell angiofibroma)
  • These features overlap, with 87% of fibrous tumors showing staghorn pattern. Other shared features included mild hemorrhage, osteoclast type cells, myxoid changes, and mineralization
• Patients present with proptosis, pain, diplopia and decreased vision
• Hemangiopericytoma often occurs in adults usually in 5^th decade of life
• Fibrous histiocytoma is the most common mesenchymal tumor of the orbit
• Tumors range in spectrum from benign to intermediate to malignant
• Most tumors are benign but may have atypia, increased mitotic activity
• Unfortunately, the histology does not determine potential for metastasis
  • Ki-67 and/or p53 may diagnose borderline or low-grade malignant

Nick’s tips:

Sometimes benign appearing lesions can behave aggressively, and the aggressive appearing lesions can behave benignly. It is important to remove these lesions completely if possible as they can return and undergo malignant transformation.

Rhabdomyosarcoma

    

Proptosis of the right eye

    

CT scan displaying large diffuse lesion obliterating contents of the right orbit

    

Embryonal type of Rhabdomyosarcoma, spindle and round shaped nuclei with tadpole-like cytoplasm

    

Embryonal type of Rhabdomyosarcoma with tadpole appearing cells

    

Tadpole appearing cells with cross striations which are characteristic of embryonal rhabdomyosarcoma

    

Trichrome stain which shows cross-striations of embryonal rhabdomyosarcoma

    

Rhabdomyosarcoma, alveolar variety, with a characteristic septae filled with cells

    

Rhabdomyosarcoma with vimentin staining, which indicates muscle-derived tumor

    

Muscle-specific actin immunoperoxidase stain of rhabdomyosarcoma showing muscle-derived lesion

• Rhabdomyosarcoma is the most common primary malignancy of the orbit in children
• Derived from muscle
• Average age of onset is 7-8 years of age
• Children may present sudden, rapid proptosis, which is an emergency
• Eyelids may be reddish and discolored, no heat or fever (as occurs in cellulitis)
• Orbital rhabdomyosarcoma has a 5-year survival of 90%, which is greater than the systemic form
• There are three main types
  • Embryonal (most common)
  • Alveolar (worst prognosis)
  • Pleomorphic (best prognosis)
• May develop in the conjunctiva as submucosal clusters (botryoid variant)
  • Some cells may have cross striations (60% of embryonal rhabdomyosarcomas)
  • Well-differentiated rhabdomyosarcomas have striations that stain positive for desmin, vimentin, and sometimes myogenin.
  • Electron microscopy may help identify poorly differentiated types.
  • Translocations of FOXO1 is more strongly associated with a worse prognosis than histology alone.

Nerve Tumors

Neurofibroma

    

Low magnification view of plexiform neurofibroma showing bundles of fibroblasts and schwann cells

    

Higher magnification view of plexiform neurofibroma

Neurofibroma is the most common nerve sheath tumor

• Slow growing with endoneural fibroblasts, schwann cells, and axons
• These tumors are circumscribed, but not encapsulated
• Grossly, these tumors have a firm and rubbery consistency, similar to a bag of worms.
• Histologically, these cells have a ribbon arrangement and cords in a matrix of myxoid tissue with collagen that contains axons.
• Neurofibromas are associated with rearrangement of chromosome arm 9p
• Neurofibromas may be isolated
• Plexiform type is usually associated with Neurofibromatosis 1 (von Recklinghausen’s disease)
• The CCN1 gene may be useful for diagnosis and prognosis

Neurilemoma

Also known as schwannoma

• Slow growing and encapsulated tumor
• May be solitary or associated with neurofibromatosis
• Two patterns are common on histology:
  • Antoni A displays spindle cells interlacing cords, whorls, or palisades
  • Antoni B displays stellate cells in mucoid stroma, with thick vessel walls and no axons
• Positive for S-100, vimentin, and CD68

    

Neurilemoma of the optic nerve, shown as an intraconal mass on CT

    

Neurilemoma, Antoni A form, which is a noted by the spindle-shaped cells which line up in a palisading pattern.

  

Neurilemoma, Antoni B form, which has less organized, myxoid appearance

 

Adipose Tumors

    

Low magnification view of lipoma

    

Higher magnification view of lipoma

• Lipomas of the orbit are rare. May show encapsulation and a lobar appearance. These tumors appear similar to normal or prolapsed fat.
• Liposarcomas are extremely rare, malignant tumors, which have varied characteristics, but the most common characteristic is lipoblasts. These tumors tend to recur before metastasis
• Leiomyoma and leiomyosarcoma are rare tumors with smooth muscle differentiation
  • Leiomyoma is a benign tumor that presents with slowly progressive proptosis, typically in patients age 30s to 40s
    • Histology reveals spindle cell tumors and “cigar-shaped” blunt nuclei
    • Cytoplasm stains trichome positive
  • Leiomyosarcoma is a malignant tumor that presents in patients in their 60s
    • Histology shows highly cellular necrosis, pleomorphism, and mitotic figures

Bony Lesions

Fibrous dysplasia

• May be monostotic or polyostotic. In the orbit, this is usually monostatic
• This condition usually presents in the first 30 years of life
• May cross suture lines, involving multiple bones, and this can narrow the orbit or lacrimal structures
• Radiography studies may show ground glass loci with lytic areas. Fluid containing cysts may also appear
• Because bone maturation is arrested, trabeculae may appear woven with fibrous stroma with high vascularization. Additionally, the trabeculae may be C-shaped
• Fibro-osseus dysplasia (Juvenile ossifying fibroma) is a variant of fibrous dysplasia
  • Histologically, this condition shows bony spicules surrounded by osteoblasts
  • At low magnification this may be confused with psammomatous meningioma

Osteoma

    

Low magnification view of osteoma

    

Higher magnification view of osteoma

    

Osteogenic sarcoma

• Osteoma is slow growing and composed of mature bone
• most common location is the frontal sinus
• more common than chondroma

Other bone tumors include osteoblastoma, Ewing sarcoma, giant cell tumor, osteogenic sarcoma, chondroma, chondrosarcoma

Metastatic Tumors:

Secondary tumors may invade via direct extension from surrounding structures of the orbit, such as the sinus, brain, and eye.

• Metastatic tumors may arise from distant origin
• Most common primary tumor to metastasize to the orbit in women is breast and in men is prostate or lung
• Neuroblastoma is the most common primary tumor to metastasize to the orbit in children.

    

Gross photograph of an exenterated eye due to a conjunctival melanoma from the conjunctiva which extended into the orbit. Note the areas of dark tissue consisent with melanoma.

    

Melanocytes cells from a melanoma metastatic to the orbit.

    

Squamous cell carcinoma metastatic to the orbit.

References:

Ahmad, S. M., Esmaeli, B., at el. (2009). American Joint Committee on Cancer classification predicts outcome of patients with lacrimal gland adenoid cystic carcinoma. Ophthalmology, 116(6), 1210-1215.

Hawkins, D. S., Gupta, A. A., & Rudzinski, E. (2014). What’s new in the Biology and treatment of pediatric rhabdomyosarcoma?. Current opinion in pediatrics, 26(1), 50.

Liu, K., DeAngelo, P., Mahmet, K., Phytides, P., Osborne, L., & Pletcher, B. A. (2010). Cytogenetics of neurofibromas: two case reports and literature review. Cancer genetics and cytogenetics, 196(1), 93-95.

Pasmant, E., et al. (2010). Differential Expression of ccn1/cyr61, Ccn3/nov, Ccn4/wisp1, and ccn5/wisp2 in Neurofibromatosis Type 1 Tumorigenesis. Journal of Neuropathology & Experimental Neurology, 69(1), 60-69.

Shan, S. J., & Douglas, R. S. (2014). The pathophysiology of thyroid eye disease. Journal of Neuro-ophthalmology, 34(2), 177-185.

von Holstein, S. L., Coupland, S. E., et al. (2013). Epithelial tumours of the lacrimal gland: a clinical, histopathological, surgical and oncological survey. Acta ophthalmologica, 91(3), 195-206.

Wallace, Z. S., Khosroshahi, A., et al. (2012). IgG4-related systemic disease as a cause of “idiopathic” orbital inflammation, including orbital myositis, and trigeminal nerve involvement. Survey of ophthalmology, 57(1), 26-33.

Weis, E., Rootman, et al. (2009). Epithelial lacrimal gland tumors: pathologic classification and current understanding. Archives of Ophthalmology, 127(8), 1016-1028.