Changes in the 7th edition of the AJCC TNM classification and recommendations for pathologic analysis of lacrimal gland tumors.
Abstract: * In our recent work to update the American Joint Committee on Cancer's AJCC Cancer Staging Manual, we brought the staging system in line with that of salivary gland malignancies to better describe the range of these tumors. In addition, we have suggested that information be collected on biomarkers and clinical and histologic data points. This revised staging, along with careful histologic analysis and patient follow-up, may provide information that helps develop more targeted management for these lesions.

(Arch Pathol Lab Med. 2009;133:1268-1271)
Article Type: Report
Subject: Tumor staging (Methods)
Tumor staging (Standards)
Lacrimal organs (Medical examination)
Eye cancer (Development and progression)
Genetic markers (Identification and classification)
Authors: Rootman, Jack
White, Valerie A.
Pub Date: 08/01/2009
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 College of American Pathologists ISSN: 1543-2165
Issue: Date: August, 2009 Source Volume: 133 Source Issue: 8
Topic: Event Code: 350 Product standards, safety, & recalls
Geographic: Geographic Scope: Canada Geographic Code: 1CANA Canada
Accession Number: 230247115
Full Text: The multi-institutional study coordinated by the University of British Columbia (Vancouver, Canada), and published in the special issue of the Archives of Ophthalmology, (1) emphasizes the lack of consistent data collection, both clinical and pathologic, for complete description and documentation of lacrimal epithelial tumors.

Because of insufficient information in updating to the 7th edition of the TNM classification system for lacrimal gland tumors, we chose to bring the classification in line with that of the more numerous salivary gland malignancies (Table 1). (2) The TNM classification for salivary gland tumors shows good separation in outcome from T1 to T4. (3) Consequently, we have adjusted the sizes for lacrimal gland tumors to reflect those in the salivary glands for T1 to T3 (Figures 1 through 3). In addition, we have increased the number of histologic categories from 10 to 17 and divided them into low and high grade, on the basis of the World Health Organization classification of salivary gland tumors, as essentially all of these tumors have been described in the lacrimal gland, even if only in single case reports (Table 2). (4,5) We have requested that the classification NOT be used for malignancies of the lacrimal sac and drainage apparatus, as tumors of this site have a much different clinical course and pathologic spectrum. Finally, we have divided T4 into 3 categories to provide for greater distinction between periosteal and bony involvement and have created a category of unresectable disease (Figure 4).

Recently, Ahmad et al (6) have provided preliminary evidence that the American Joint Committee on Cancer (AJCC) classification does correlate with outcome in adenoid cystic carcinoma (ACC) of the lacrimal gland.

A new feature of the 7th edition of the AJCC Cancer Staging Manual (2) will be the ability to collect data on biomarkers and additional data points in an attempt to extend the classification system beyond solely an anatomic-based one. There is little evidence for the application of biomarkers in salivary or lacrimal tumors, so we have chosen to request data on proliferative index and nuclear staining for the tumor suppressor gene NM23, as these have shown some evidence of prognostic value in limited studies. (7,8) Regarding additional data points, we have separated that information into clinical and histologic. Clinical data points include information about the type of surgery performed and whether preoperative or postoperative chemotherapy and/or postoperative radiotherapy were given. This is in an attempt to determine the most appropriate method of treatment for high-stage tumors as radical exenteration may not be the treatment of choice. Pathologic data points include the largest diameter of the tumor, presence of basaloid morphology in adenoid cystic carcinomas, presence of perineural invasion, and extent of invasion beyond the capsule in carcinomas ex pleomorphic adenoma.

Clinical staging should include a complete history (with emphasis on duration of symptoms, change in tempo of symptoms, and pain or dysesthesia) and physical examination (including globe displacement or distortion, palpation, and sensory and motor examination). Both computed tomographic imaging, which is better for bone, and magnetic resonance imaging, which is better for soft tissue, of the orbit should be performed to provide critical diagnostic and staging data. Orbital imaging should evaluate size, shape, extent, and invasion of adjacent structures including bone, marrow spaces, skull base, and periorbital areas. To stage the extent of disease, evaluation of the cervical lymph nodes, lungs, and bone should be included.

Ever since Godtfredsen (9) first differentiated benign from malignant lacrimal tumors more than 50 years ago, we have continually improved our ability to distinguish varieties of these tumors, which may have differing biologic behavior that need to be incorporated into the pathologic analysis. Benign pleomorphic adenomas can harbor areas of cellular atypia without implying malignancy or can show anaplasia, necrosis, and increased mitotic activity indicating frank carcinoma. This appears to be more likely in tumors with myoepithelial cell predominance or with significant hyalinization. (1) Therefore, pleomorphic adenomas showing these features should be well sampled. If an area of carcinoma ex pleomorphic adenoma (CEPA) is discovered, it is crucial to determine whether it extends beyond the limits of the capsule. Noninvasive CEPA and pleomorphic adenoma with atypia are unlikely to cause future morbidity if excised without breach of the capsule. In contrast, invasive CEPA carries a prognosis as grim as that of primary carcinoma when it has extended significantly beyond the capsule. (1,4)





Thorough histologic examination of ACC is similarly important and estimation of the proportions of tubular, cribriform, and solid components throughout has prognostic significance, with the presence of any solid component and absence of any cribriform areas portending the worst prognosis. (4,5) Involvement of the margins as well as perineural invasion should also be explicitly stated. Furthermore, ACC may rarely harbor areas of dedifferentiation, which may denote more aggressive potential. (10)

The pathologist must consider rare entities such as basal cell adenocarcinoma and polymorphous low-grade adenocarcinoma when considering a diagnosis of lacrimal carcinoma, since each of these is associated with a considerably better prognosis than ACC. Additional case reports or series, particularly multi-institutional prospective studies with agreed-upon criterion and staging of unusual lacrimal gland tumors, will allow for further evaluation of the management of these more rare entities.

The full extent of a lacrimal gland malignancy may be underestimated in a typical excisional biopsy by lateral orbitotomy. As the lacrimal gland is adjacent to other crucial structures, wide tissue margins are rarely obtained. Questions of perineural extension and local bone invasion often go unanswered. Careful intraoperative inspection of adjacent orbital bone with biopsy or removal of any suspicious areas is warranted. Pathologic specimens should be closely examined for perineural and vascular invasion. Any and all bone removed should be examined pathologically for accurate staging purposes.

In view of the above, the specimen should be handled in a particular fashion. It should be oriented, marked, and analyzed in terms of its position in the orbit and its adjacencies in order for step sectioning to allow for a 3-dimensional analysis of the tumor itself and adjacent tissues. The tumor should be sampled to evaluate histologic type, grade, size, presence of preexisting pleomorphic adenoma, and surgical margins (including the periosteum). Perineural spread, most characteristic of ACC, can result in a clinical underestimation of the true anatomic extent of the disease.

When handling exenteration specimens for lacrimal gland neoplasms, we recommend that the specimen be handled en bloc. The superior and inferior orbital margins should be inked with different colors. The specimen should be sectioned parasagitally in from 5 to 7 slices from 0.5 to 1 cm in thickness. As the superotemporal and posterior orbital margins are of most interest, the temporal slice can be further sectioned horizontally to obtain a complete perpendicular view of the margin, rather than an en face view. (11) If adjacent bone is obtained with en bloc excision because of sufficient spread, it should be oriented in a standardized manner and fully examined pathologically for evidence of involvement. Esmaeli (12) has recently shown that bone was involved in 50% of her series of adenoid cystic carcinomas. If bone is still attached to the specimen and is difficult to remove, the entire specimen can be decalcified in 10% formic acid without loss of cellular detail on histologic examination, although this process can take 2 to 3 weeks for sufficient decalcification to occur for optimal sectioning.

As both benign and malignant lacrimal tumors can recur decades after initial excision and some of the benign tumors can undergo malignant transformation, it is imperative to establish lifelong follow-up for these patients. Hopefully, careful histologic analysis, use of the 7th edition of the AJCC Cancer Staging Manual, and long-term follow-up will allow us to develop more specific and rational management of these difficult tumors and enable us to decrease the sometimes dismal morbidity and mortality of lacrimal epithelial tumors.

We would like to acknowledge Bita Esmaeli, MD, James C. Fleming, MD, Zeynel A. Karcioglu, MD, David Tse, MD, and Christian Wittekind, MD, for reviewing the changes for the 7th edition of the AJCC Cancer Staging Manual

We would also like to acknowledge Jack Rootman, MD, and Ms. Wilma Chang for creating the illustrations.


(1.) Weis E, Rootman J, Joly TJ, et al. Epithelial lacrimal gland tumors: pathologic classification and current understanding. Arch Ophthalmol. 2009. In press.

(2.) Edge SE, Byrd DR, Carducci MA, Compton CA, eds. AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2009.

(3.) Major salivary glands. In: Greene FL, Page DL, Fleming ID, etal, eds. American Joint Commission on Cancer Staging Manual. 6th ed. New York, NY: Springer; 2002:69-76.

(4.) Salivary glands. In: Barnes L, Eveson, JW, Reichart P, Sidransky D, eds. Pathology and Genetics of Head and Neck Tumours. Lyon, France: IARC Press; 2005. World Health Organization Classification of Tumours; vol 9.

(5.) Font RL, Croxatto JO, Rao NA. Tumors of the lacrimal gland. In: Silverberg SG, Sobin LH, eds. Tumors of the Eye and Ocular Adnexa. Washington, DC: Armed Forces Institute of Pathology; 2006:223-246. Atlas of Tumor Pathology; 4th series, fascicle 5.

(6.) Ahmad SM, Esmaeli B, Williams M, et al. Can American Joint Commission on Cancer (AJCC) staging of lacrimal gland adenoid cystic carcinoma help predict outcome? Ophthalmology. 2009. In press.

(7.) Luukkaa H, Klemi P, Leivo I, Vahlberg T, Grenman R. Prognostic significance of Ki-67 and p53 as tumor markers in salivary gland malignancies in Finland: an evaluation of 212 cases. Acta Oncol. 2006;45(6):669-675.

(8.) Cheuk W, Chan JKC. Advances in salivary gland pathology. Histopathology. 2007;51(1):1-20.

(9.) Godtfredsen E. Pathology of mucous and salivary gland tumors in the lacrimal gland and the relation to extra orbital mucous and salivary gland tumours. Br J Ophthalmol. 1948;32(3):171-179.

(10.) Seethala RR, Hunt JL, Baloch ZW, Li Volsi VA, Barnes EL. Adenoid cystic carcinoma with high-grade transformation. Am J Surg Pathol. 2007;31(11):1683 1694.

(11.) Ford AL, Mudhar HS, Farr R, Parsons MA. The ophthalmic pathology cutup--part 1: the enucleation and exenteration specimen. Curr Diagn Pathol. 2005; 11(4):2 84-290.

(12.) Esmaeli B. Histologic status of the bony walls of the lacrimal gland fossa in adenoid cystic carcinoma of the lacrimal gland. Paper presented at: Annual Meeting of the American Association of Ophthalmic Pathologists; November 7, 2008; Atlanta, GA.

Jack Rootman, MD; Valerie A. White, MD, MHSc

Accepted for publication March 26, 2009.

From the Departments of Pathology and Laboratory Medicine and Ophthalmology and Visual Sciences, University of British Columbia and Vancouver General Hospital, Vancouver, British Columbia, Canada.

The authors have no relevant financial interest in the products or companies described in his article.

Reprints: Jack Rootman, MD, Department of Ophthalmology and Visual Sciences, University of British Columbia, 2550 Willow Street, Vancouver, BCV5Z3N9, Canada (e-mail:
Table 1. Definition of TNM (a)

                               Primary tumor (T)

TX       Primary tumor cannot be assessed
T0       No evidence of primary tumor
T1       Tumor 2 cm or smaller in greatest dimension, with or
         without extraglandular extension into the orbital soft
T2       Tumor larger than 2 cm but not larger than 4 cm in
         greatest dimension (b)
T3       Tumor larger than 4 cm in greatest dimension (b)
T4       Tumor invades periosteum or orbital bone or adjacent
T4 (a)   Tumor invades periosteum
T4 (b)   Tumor invades orbital bone
T4 (c)   Tumor invades adjacent structures (brain, sinus,
         pterygoid fossa, temporal fossa)

                           Regional lymph nodes (N)

NX       Regional lymph nodes cannot be assessed
N0       No regional lymph node metastasis
N1       Regional lymph node metastasis

                            Distant metastasis (M)

MX       Distant metastasis cannot be assessed
M0       No distant metastasis
M1       Distant metastasis

(a) Used with the permission of the American Joint Committee on Cancer
(AJCC), Chicago, Illinois. The original source for this material is the
AJCC Cancer Staging Manual, Seventh Edition (2009) published by
Springer Science and Business Media LLC,

(b) Because the maximum size of the lacrimal gland is 2 cm, T2 and
greater tumors will usually extend into the orbital soft tissue.

Table 2.   Histopathologic Type (a)

Major malignant primary epithelial tumors

  Low grade
    Carcinoma ex pleomorphic adenoma
    Polymorphous low-grade carcinoma
    Mucoepidermoid carcinoma, grades 1 and 2
    Epithelial-myoepithelial carcinoma
    Cystadenocarcinoma and papillary cystadenocarcinoma
    Acinic cell carcinoma
    Basal cell adenocarcinoma
    Mucinous adenocarcinoma

  High grade
    Carcinoma ex pleomorphic adenoma (malignant mixed
      tumor) that includes adenocarcinoma and adenoid cystic
      carcinoma arising in a pleomorphic adenoma
    Adenoid cystic carcinoma, not otherwise specified
    Adenocarcinoma, not otherwise specified
    Mucoepidermoid carcinoma, grade 3
    Ductal adenocarcinoma
    Squamous cell carcinoma
    Sebaceous adenocarcinoma
    Myoepithelial carcinoma
    Lymphoepithelial carcinoma

Other rare and unclassifiable carcinomas

(a) Used with the permission of the American Joint Committee
on Cancer (AJCC), Chicago, Illinois. The original source for
this material is the AJCC Cancer Staging Manual, Seventh
Edition (2009) published by Springer Science and Business
Media LLC,
Gale Copyright: Copyright 2009 Gale, Cengage Learning. All rights reserved.