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Protocol for the Examination of Specimens From Patients With Retinoblastoma.

A Basis for Checklists

This protocol is intended to assist pathologists in providing clinically useful and relevant information as a result of the examination of surgical specimens. Use of this protocol is intended to be entirely voluntary. If equally valid protocols or similar documents are applicable, the pathologist is, of course, free to follow those authorities. Indeed, the ultimate judgment regarding the propriety of any specific procedure must be made by the physician in light of the individual circumstances presented by a specific patient or specimen.

It should be understood that adherence to this protocol will not guarantee a successful result. Nevertheless, pathologists are urged to familiarize themselves with the document. Should a physician choose to deviate from the protocol based on the circumstances of a particular patient or specimen, the physician is advised to make a contemporaneous written notation of the reason for the procedure followed.

The College recognizes that this document may be used by hospitals, attorneys, managed care organizations, insurance carriers, and other payers. However, the document was developed solely as a tool to assist pathologists in the diagnostic process by providing information that reflects the state of relevant medical knowledge at the time the protocol was first published. It was not developed for credentialing, litigation, or reimbursement purposes. The College cautions that any uses of the protocol for these purposes involve considerations that are beyond the scope of this document.

PROTOCOL FOR THE EXAMINATION OF SPECIMENS FROM PATIENTS WITH RETINOBLASTOMA
I. Cytologic Material (note A)
 A. Clinical information
 1. Patient identification
 a. Name
 b. Identification number
 c. Age (birth date)
 d. Gender
 2. Responsible physician(s)
 3. Date of procedure
 4. Clinical information
 a. Relevant history
 (1) Clinical findings
 (2) Status of other eye
 (3) Previous treatment
 (4) Family history
 b. Relevant findings (eg, laboratory and radiologic
 studies)
 c. Clinical diagnosis
 d. Procedure (eg, anterior chamber paracentesis)
 e. Operative findings
 f. Anatomic site of specimen (right or left
 eye; part of eye sampled)
 B. Macroscopic examination
 1. Specimen
 a. Fixed/unfixed (specify fixative) (note B)
 b. Number of slides received
 c. Quantity and appearance of fluid specimen
 d. Other (eg, tissue received for cytologic
 preparation)
 e. Results of intraprocedural consultation
 2. Material submitted for microscopic evaluation
 (eg, smear, cytocentrifuge, filter preparation)
 3. Special studies (specify) (eg, cytochemistry,
 immunocytochemistry, DNA analysis [specify
 type], morphometry, cytogenetics) (note C)
 C. Microscopic examination
 1. Adequacy of specimen for evaluation (indicate
 if unsatisfactory or limited for evaluation,
 specify reason)
 2. Tumor
 a. Histologic type, if possible (note D)
 b. Degree of differentiation, if possible (note D)
 c. Other features
 (1) Necrosis
 (2) Calcification
 (3) Apoptosis
 (4) Other
 3. Additional pathologic findings, if present
 a. Inflammatory cells
 b. Other(s)
 4. Results/status of special studies (specify)
 5. Comments
 a. Correlation with intraprocedural consultation
 b. Correlation with other specimens, as appropriate
 c. Correlation with clinical information, as
 appropriate
II. Biopsy (note A)
 A. Clinical information
 1. Patient identification
 a. Name
 b. Identification number
 c. Age (birth date)

 d. Gender
 2. Responsible physician(s)
 3. Date of procedure
 4. Clinical information
 a. Relevant history
 (1) Clinical findings
 (2) Status of other eye
 (3) Previous treatment
 (4) Family history
 b. Relevant findings (eg, laboratory and radiologic
 studies)
 c. Clinical diagnosis
 d. Procedure (eg, anterior chamber biopsy)
 e. Operative findings
 f. Anatomic site of specimen (right or left
 eye; part of eye sampled)
 B. Macroscopic examination
 1. Specimen
 a. Fixed/unfixed (specify fixative) (note B)
 b. Number of pieces
 c. Largest dimension of each piece
 d. Results of intraoperative consultation
 2. Tumor, if discernible
 a. Descriptive features
 3. Tissue submitted for microscopic evaluation
 a. Submit all (after selection of fragments for
 special studies, if performed)
 b. Frozen section fragment(s), if applicable
 4. Special studies (specify) (eg, histochemistry,
 immunohistochemistry, DNA analysis [specify
 type], electron microscopy, morphometry,
 cytogenetics) (note C)
 C. Microscopic examination
 1. Tumor
 a. Histologic type, if possible (note D)
 b. Histologic grade, if possible (notes D and E)
 c. Other features
 (1) Necrosis
 (2) Calcification
 (3) Apoptosis
 (4) Involvement of intraocular structures
 (if able to determine)
 (5) Other
 2. Additional pathologic findings, if present
 a. Inflammatory cells
 b. Other(s)
 3. Results/status of special studies (specify)
 4. Comments
 a. Correlation with intraprocedural consultation
 b. Correlation with other specimens, as appropriate
 c. Correlation with clinical information, as
 appropriate
III. Resection (Globe)
 A. Clinical information
 1. Patient identification
 a. Name
 b. Identification number
 c. Age (Birth date)
 d. Gender
 2. Responsible physician(s)
 3. Date of procedure
 4. Clinical information
 a. Relevant history
 (1) Clinical findings
 (2) Status of other eye
 (3) Previous treatment
 (4) Family history
 b. Relevant findings (eg, laboratory and radiologic
 studies)
 c. Clinical diagnosis
 d. Procedure (eg, enucleation)
 e. Operative findings
 f. Anatomic site(s) (left/right eye)
 g. Results of intraoperative consultation
 B. Macroscopic examination
 1. Specimen
 a. Fixed/unfixed (specify fixative) (notes B
 and C)
 b. External aspect
 c. Orientation of globe (based on identification
 of extraocular muscle insertions and
 other landmarks) (note F)
 d. Dimensions
 (1) Anteroposterior, horizontal, vertical dimensions
 of globe
 (2) Length and diameter of optic nerve
 (3) Corneal horizontal and vertical diameter
 (4) Diameter of pupil , if visible
 e. Transillumination (helpful to identify location
 of tumor and measure basal dimension
 prior to sectioning globe)
 (1) Quality of transillumination (eg, transilluminates
 light well/poorly)
 (2) Transillumination defects
 i. Location (eg, inferotemporal quadrant
 of globe posterior to equator)
 ii. Size (2 dimensions)
 iii. Trace outline with marking implement
 f. Sectioning of specimen (globe) (surgical
 end of optic nerve cross-sectioned, inked/
 marked to maintain orientation, and submitted
 separately) (notes C and G)
 2. Tumor(s), if discernible
 a. Location
 b. Color
 c. Consistency
 d. Shape
 e. Size
 (1) Base at cut edge (ie, portion of tumor
 closest to sclera)
 (2) Height at cut edge
 (3) Maximal tumor height
 f. Distance of anterior margin of tumor base
 from limbus at cut edge
 g. Distance of posterior margin of tumor base
 from optic disc
 h. Extrascleral extension, if present
 (1) Location
 (2) Extent (2 dimensions)
 i. Structures involved and extent (eg, extent
 of retinal involvement, optic nerve involvement,
 macroscopic involvement of vitreous)
 3. Other (uninvolved) ocular tissues
 a. Cornea (clear/cloudy/opaque)
 b. Anterior chamber (deep/shallow/flat)
 c. Angle (open/narrow/closed)
 d. Iris (abnormal blood vessels/color)
 e. Ciliary body
 f. Lens (cataractous/clear)
 g. Vitreous (color/consistency/hemorrhage)
 h. Retina (detachment, total or partial; hemorrhage)
 i. Choroid
 j. Sclera (thinning/defects)
 k. Optic disc/nerve (pallor; increased cupdisc
 ratio)
 4. Section(s) submitted for microscopic evaluation
 (note H)
 a. Tumor (multiple)
 b. Optic nerve
 c. Frozen section fragment(s), if applicable
 5. Special studies (specify) (eg, histochemistry,
 immunohistochemistry, DNA analysis [specify
 type], electron microscopy, morphometry,
 cytogenetic) (note C)
 C. Microscopic evaluation
 1. Tumor
 a. Histologic features (note D)
 b. Degree of differentiation (note E)
 c. Growth pattern (notes E and I)
 (1) Endophytic
 (2) Exophytic
 (3) Mixed endophytic-exophytic
 (4) Diffuse infiltrating
 d. Location (eg, within retina, subretinal
 space, surface of retina, retinal periphery,
 macula, relation to equator of globe)
 e. Size (note E)
 f. Involvement of other structures (notes E
 and J)
 (1) Choroid
 (2) Ciliary body
 (3) Iris
 (4) Vitreous
 (5) Angle
 (6) Sclera
 g. Extent of growth (notes E and J)
 (1) Anterior extent of tumor (eg, peripheral
 retina, anterior chamber)
 (2) Posterior extent of tumor (eg, posterior
 to equator, to edge of optic disc, optic
 nerve anterior to lamina cribrosa, optic
 nerve posterior to lamina cribrosa, to
 cut edge of optic nerve)
 h. Additional features of prognostic significance
 (eg, basophilic staining of tumor vessels)
 (note E)
 2. Additional pathologic findings, if present
 a. Evidence of previous excision or treatment
 b. Cancer-related lesions
 (1) Neovascularization of iris
 (2) Iris bombe with angle occlusion
 (3) Peripheral anterior synechiae
 (4) Intraocular hemorrhage
 (5) Other(s)
 c. Non-cancer-related lesions
 (1) Congenital angle anomaly
 (2) Corneal anomalies
 (3) Cataract
 (4) Other(s)
 3. Margins
 a. Optic nerve (notes E and J)
 (1) No tumor present
 (2) Tumor present
 4. Results/status of special studies (specify)
 5. Comments
 a. Correlation with intraoperative consultation
 b. Correlation with other specimens, as appropriate
 c. Correlation with clinical information, as
 appropriate (note J)


EXPLANATORY NOTES

A: Cytology/Biopsy.--Cytologic and biopsy specimens are rarely obtained from eyes with suspected retinoblastoma owing to the potential risk of tumor seeding. An anterior chamber paracentesis may be performed if indicated by clinical findings and is not associated with risk of tumor seeding.[1,2]

B: Fixation.--The minimum recommended fixation time for whole globes with intraocular tumors is 48 hours. The globe should be fixed in an adequate volume of fixative; a 10:1 ratio of fixative volume to specimen volume is recommended. Incisions or windows in the globe are not necessary for adequate penetration of fixative and are not recommended. Injection of fixative into the globe is also not recommended.

C: Additional Studies.--Genetic studies may be requested on neoplastic tissue, and specimens should be harvested prior to fixation.[3] The surgical margin of the optic nerve should be obtained prior to opening the globe (note G). Once tissue is harvested for genetic studies, the globe can be fixed prior to completing macroscopic examination. The appropriate materials/medium required by the laboratory performing genetic testing should be obtained prior to the procedure.

D: Histologic Features.--Typical histologic features include cells with large basophilic nuclei and scant cytoplasm. Mitoses are generally frequent. Calcification and necrosis are common, with sleeves of viable cells typically surrounding blood vessels (pseudorosettes). Apoptotic cells may be seen. The extent of differentiation may be judged based on the presence and type of rosettes. Homer Wright rosettes similar to those seen in neuroblastoma or medulloblastoma may be seen and are not a sign of significant differentiation. Flexner-Wintersteiner rosettes are evidence of higher differentiation. Fleurettes are considered the most differentiated form of rosette found in the tumor. A benign variant of retinoblastoma termed retinocytoma or retinoma has been described. This tumor consists entirely of benign, well-differentiated cells often with associated calcification. The cells have smaller, less hyperchromatic nuclei and abundant cytoplasm. Necrosis is typically absent and mitotic figures are rare.[4-9] Retinoblastomas may arise in multicentric foci.

E: Histologic Features of Prognostic Significance.--Histologic features with prognostic significance for survival include the following: invasion of optic nerve, particularly if tumor is present at the surgical margin (most important feature); invasion of sclera; invasion of choroid; tumor size; basophilic staining of tumor vessels; seeding of vitreous; degree of differentiation; involvement of anterior segment; and growth pattern.[10-16] This list should not be confused with the Reese-Ellsworth classification, which is intended as a predictor for visual outcome, not survival.[17]

F: Orientation of Globe.--The orientation of a globe may be determined by identifying extraocular muscle insertions, optic nerve, and other landmarks as illustrated in Figure 1. The terms temporal and nasal are generally used in place of lateral and medial with reference to ocular anatomy. G: Sectioning the Globe.--The globe is generally sectioned in the horizontal or vertical plane with care to include the pupil and optic nerve in the cassette to be submitted for microscopic examination. If the mass cannot be included with horizontal or vertical sectioning, the globe is sectioned obliquely to include tumor, pupil, and optic nerve (Figure 2). The surgical margin of the optic nerve should be sectioned and submitted prior to sectioning the globe to ensure that intraocular malignant cells do not contaminate this important surgical margin.[3] Retinoblastoma is an extremely friable tumor.

[ILLUSTRATIONS OMITTED]

H: Sections Submitted for Microscopic Examination.--Multiple sections should be examined with special attention to sections containing optic nerve and tumor. The nerve should be sectioned along the various levels to determine tumor extension.

I: Growth Pattern.--Endophytic growth pattern indicates growth from the inner retinal surface into the vitreous cavity. Exophytic tumors grow primarily from the outer surface of the retina into the subretinal space toward the choroid. Mixed growth pattern exhibits features of both endophytic and exophytic growth. Diffuse infiltrating tumors grow laterally within the retina without significant thickening.

J: TNM Stage Groupings.--The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) TNM staging system for retinoblastoma is shown below.[18]

CLINICAL TNM CLASSIFICATIONS

Tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor(s) limited to [is less than or equal to] 25%
 of the retina
T2 Tumor(s) involve(s) [is greater than] 25%
 but [is less than or equal to] 50% of the retina
T3 Tumor(s) involve(s) [is greater than] 50% of the retina
 and/or invade(s) beyond the retina, but remain(s)
 intraocular
 T3a Tumor(s) involve(s) [is greater than] 50% of the retina
 and/or tumor cells in the vitreous
 T3b Tumor(s) involve(s) the optic disc
 T3b Tumor(s) involve(s) anterior chamber and/or uvea
T4 Tumor with extraocular invasion
 T4a Tumor invades retrobulbar optic nerve
 T4b Extraocular extension other than invasion of
 the optic nerve


Note.--The following suffixes may be added to the appropriate T categories: "m" indicates multiple tumors (eg, T2 [m2]); "f" indicates cases with a known family history; and "d" indicates diffuse retinal involvement without the formation of discrete masses.

Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis


Regional lymph node involvement is rare, and direct extension into the central nervous system is more common.[18]

Distant Metastasis (M)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis


PATHOLOGIC TNM CLASSIFICATIONS
Tumor (pT)

TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor(s) limited to [is less than or equal to]
 25% of the retina
T2 Tumor(s) involve(s) [is greater than] 25% but
 [is less than or equal to] 50% of the retina
T3 Tumor(s) involve(s) [is greater than] 50%
 of the retina and/or invade(s) beyond the
 retina, but remain(s) intraocular
 T3a Tumor(s) involve(s) [is greater than] 50%
 of the retina and/or tumor cells in the vitreous
 T3b Tumor(s) involve(s) the optic nerve as far as
 the lamina cribrosa
 T3b Tumor(s) involve(s) anterior chamber and/or
 invasion with thickening of the uvea and/or
 intrascleral invasion
T4 Tumor with extraocular invasion
 T4a Intraneural tumor beyond the lamina cribrosa
 but not at the line of resection
 T4b Tumor at the line of resection or other extraocular
 extension


Note.--The following suffixes may be added to the appropriate T categories: "m" indicates multiple tumors (eg, T2 [m2]); "f" indicates cases with a known family history; and "d" indicates diffuse retinal involvement without the formation of discrete masses.

Regional Lymph Nodes (pN)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis


Distant Metastasis (pM)
MX Presence of distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis


TNM Stage Groupings
Stage IA T1 N0 M0
Stage IB T2 N0 M0
Stage IIA T3a N0 M0
Stage IIB T3b N0 M0
Stage IIC T3c N0 M0
Stage IIIA T4a N0 M0
Stage IIIB T4b N0 M0
Stage IV Any T N1 M0
 Any T Any N M1


References

[1.] Karcioglu ZA, Gordon RA, Karcioglu GL. Tumor seeding in ocular fine needle aspiration biopsy. Ophthalmology. 1985;92:1763-1767.

[2.] Stevenson KE, Hungerford J, Garner A. Local extraocular extension of retinoblastoma following intraocular surgery. Br J Ophthalmol. 1989;73:739-742.

[3.] Shields JA, Shields CL, DePotter P. Enucleation technique for children with retinoblastoma. J Pediatr Ophthalmol Strabismus. 1992;29:213-215.

[4.] Zimmerman LE. Retinoblastoma and retinocytoma. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1986:1292-1351.

[5.] Tso MOM, Fine BS, Zimmerman LE. The Flexner-Wintersteiner rosettes in retinoblastoma. Arch Pathol. 1969;88:665-671.

[6.] Tso MOM, Fine BS, Zimmerman LE. The nature of retinoblastoma, I: photoreceptor differentiation: a clinical and histologic study. Am J Ophthalmol. 1970; 69:339-350.

[7.] Tso MOM, Fine BS, Zimmerman LE. The nature of retinoblastoma, Il: photoreceptor differentiation: an electron microscopic study. Am J Ophthalmol. 1970; 69:350-359.

[8.] Margo C, Hidayat A, Kopelman J, Zimmerman LE. Retinocytoma: a benign variant of retinoblastoma. Arch Ophthalmol. 1983;101:1519-1531.

[9.] Gallie BL, Ellsworth RM, Abramson DH, Phillips RA. Retinoma: spontaneous regression of retinoblastoma or benign manifestation of the mutation? Br J Cancer. 1982;45:513-521.

[10.] Redler LD, Ellsworth RM. Prognostic importance of choroidal invasion in retinoblastoma. Arch Ophthalmol. 1973;90:294-296.

[11.] Kopelman JE, McLean IW. Multivariate analysis of clinical and histological risk factors for metastasis in retinoblastoma [abstract]. Invest Ophthalmol Vis Sci. 1983;24(ARVO suppl):50.

[12.] Kopelman JE, McLean IW. Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. Ophthalmology. 1987;94:371-377.

[13.] Haik BG, Dunleavy SA, Cooke C, et al. Retinoblastoma with anterior chamber extension. Ophthalmology. 1987;94:367-370.

[14.] Magramm I, Abramson DH, Ellsworth RM. Optic nerve involvement in retinoblastoma. Ophthalmology. 1989;96:217-222.

[15.] Shields CL, Shields JA, Baez KA, Cater J, DePotter PV. Choroidal invasion of retinoblastoma: metastatic potential and clinical risk factors. Br J Ophthalmol. 1993;77:544-548.

[16.] Shields CL, Shields JA, Baez K, Cater JR, DePotter P. Optic nerve invasion of retinoblastoma: metastatic potential and clinical risk factors. Cancer. 1994;73: 692-698.

[17.] Reese AB, Ellsworth RM. The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol Otolaryngol. 1963;67:164-172.

[18.] Fleming ID, Cooper JS, Henson DE, et al, eds. AJCC Manual for Staging of Cancer. 5th ed. Philadelphia, Pa: Lippincott Raven; 1997.

Bibliography

Albert DM. Principles of pathology. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. Vol 4. Philadelphia, Pa: WB Saunders Co; 1994:2101-2126.

Albert DM, Dryja TP. The eye. In: Cotran RS, Kumar V, Robbins SL, eds. Pathologic Basis of Disease. 6th ed. Philadelphia, Pa: WB Saunders Co; 1998.

Sahel JA, Brini A, Albert DM. Pathology of the retina and vitreous. In: Albert DM, Jakobiec FA, eds. Principles and Practice of Ophthalmology. Vol 4. Philadelphia, Pa: WB Saunders Co; 1994:2239-2280.

Yanoff MF, Fine BS. Ocular Pathology: A Text and Atlas. 3rd ed. Philadelphia, Pa: JB Lippincott Co; 1989;684-694.

Zimmerman LE. Retinoblastoma and retinocytoma. In: Spencer WH, ed. Ophthalmic Pathology: An Atlas and Textbook 3rd ed. Philadelphia, Pa: WB Saunders Co; 1986:1292-1351.

Accepted for publication May 10, 2001.

From the Department of Ophthalmology, University of Wisconsin Hospital, Madison, Wis (Dr Albert); and the Departments of Ophthalmology and Pathology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pa (Dr Syed).

This protocol was developed by the Cancer Committee of the College of American Pathologists and submitted for editorial review and publication. It represents the views of the Cancer Committee and is not the official policy of the College of American Pathologists.

Reprints: See Archives of Pathology & Laboratory Medicine Web site at www.cap.org.
COPYRIGHT 2001 College of American Pathologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2001 Gale, Cengage Learning. All rights reserved.

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Author:Albert, Daniel; Syed, Nasreen
Publication:Archives of Pathology & Laboratory Medicine
Geographic Code:1USA
Date:Sep 1, 2001
Words:3149
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