A Potpourri of Head and Neck Pathology
Moderators: Dr. Leon Barnes and Dr. Antonio Cardesa
Section 2 -
Intraoperative Consultation in Mucosal Lesions of the Upper Aerodigestive Tract (UADT)
Bruce M. Wenig
Continuum Hospitals of New York
Indications for intraoperative consultation (IOC) in mucosal (squamous cell) lesions of the UADT
include: 1) render a histologic diagnosis (e.g., carcinoma/dysplasia) when definitive therapeutic
intervention is planned immediately; 2) assessment of the adequacy of resection (i.e., surgical resection
margins); 3) preliminary assessment of the nature of a planned procedure based on the extent and
distribution of the neoplasm (e.g., subtotal versus total laryngectomy); 4) adequacy for diagnostic
purposes; 5) determination for special handling (e.g., immuno-hisotochemistry, flow cytometry,
microbiologic cultures, other); 6) determination of neurotropism, lymph-vascular space invasion (LVI) or
bone involvement that may necessitate resection of the involved bone (e.g., mandibulectomy); 7) if lymph
nodes are excised then a frozen section may be requested to exclude the presence of metastatic disease
and the need for a neck dissection.
The surgeon expects the pathologist: 1) to establish the diagnosis of carcinoma/dysplasia and
differentiate it from look-alike lesions; 2) confirm presence of absence of lesional tissue at the
margins of resection; 3) when applicable, identify the presence of osseous involvement; 4) when
applicable, identify the presence of nodal metastasis.
Specimen Handling and Orientation
The evaluation of surgical margins of resection for the presence or absence of lesional tissue falls
under the purview of the surgical pathologists. However, how the specimen is removed and the orientation
of the specimen is the responsibility of the surgeon. Once removed and properly oriented, the specimen
becomes the responsibility of the surgical pathologist. There is no standard method
by which surgeons remove tissue and thereby request intraoperative consultation of the surgical resection
margins. Some approaches include: excision of the entire lesion, designation of specific margins
and tissue selection by the pathologist for frozen section; submission of biopsies from areas of clinical
concern following the main resection and these biopsies are entirely submitted for frozen section. There
are some centers in which all of the circumferential resection margins are submitted for frozen section
irrespective of the number of frozen sections that may be required to completely evaluate the
circumferential margins. In other centers, a limited number of frozen sections (e.g., up to four –
anterior, posterior, medial and lateral) are submitted as determined by the pathologist.
Right Angle (Perpendicular) versus Parallel (En-Face) Sections
Right angle sections: Advantages - technically easier to obtain full
thickness sections; distance of the lesion to the resection margin can be viewed and measured. Disadvantages - allows for evaluation of a relatively small area of the
Parallel sections: Advantages - allows for evaluation of a larger area of
the lesion/margin to include an entire margin if necessary. Disadvantages -
if the surgical margin is uninvolved the distance of the lesion to the resection margin cannot be
viewed and/or measured; due to retraction from the underlying connective tissues the superficial layers
(i.e., mucosa and submucosa) may not be optimally seen. Note: If parallel
sections are made, the recommendation is to embed the tissue with the true surgical margin deepest in the
Surgical Resection Margins
Arguably, the most common request of the pathologist by the head and neck surgeon at the time of IOC
is the assessment of the surgical margins. Successful local control of a malignant tumor depends on
complete surgical excision of all the disease. The presence of gross residual cancer results in local
persistence of disease and increased morbidity and mortality. Factors that impact on the assessment of
the surgical margins include the type of surgical specimen, proper orientation of the specimen, proper
sectioning of the specimen and obviously the correct interpretation of the histopathologic changes. Even
in the best situations an intraoperative report of negative margins may be followed a few days later by a
permanent section diagnosis of positive margins. The use of IOC will also allow the surgeon to extend
the surgical resection without loss of orientation of the operative field, a potential problem when
additional surgery is required in a second operation. Further, carcinoma remnants that have
not been completely removed in the initial operation often are difficult to identify macroscopically,
making their removal in a second operation more difficult.
Errors in interpretation and in sampling accounted for discrepancies. Insufficient leveling of the
frozen block may resulted in discrepancies. In examining mucosal margins for dysplasia/SCC, the frozen
section tissue should be completely sampled by examining several levels at the time of frozen section.
While the frozen section diagnosis of surgical margins are extremely accurate they are not entirely
reliable in eliminating positive margins in the final diagnostic report.
Definition of a "Positive" Margin
Specimens in which no tumor or dysplasia is present at the surgical margins of resection, are
considered as completely excised. "At the margin of resection" means that the neoplastic cells are seen
in contact with or lie within millimeters of inked margin. In this situation, the specimen is considered
incompletely excised, requiring a wider excision. Batsakis made a number of cogent recommendations
including: 1) the sole reliance of margins as assessed on the resected specimen should be discouraged
and, when feasible, the intraoperative evaluation of tissue surrounding the specimen should be made and
have that regarded as the "true margin"; 2) the histologic definition of what constitutes a "positive"
should be uniformly accepted and applied. There is discrepancy in the literature as to what constitutes
a positive or negative resection margin. While some authors only include invasive carcinoma at the
margin as positive excluding carcinoma in situ, dysplasia and gross residual disease, most pathologists
would agree with the classification of positive margins, as defined by Loree and Strong: lesional tissue
within 0.5 mm of the surgical margin (so-called close margins) with the exception of laryngeal lesions.
Suffice to say that the evaluation of dysplasia under optimal circumstances can be subjective let
alone at the time of frozen section where tissue distortion and artifact create additional diagnostic
difficulties potentially resulting in misdiagnoses, including overdiagnosis and underdiagnosis. The
diagnosis of severe dysplasia has equal biologic significance with carcinoma in situ and microinvasive
carcinoma. A diagnosis of mild dysplasia is of questionable significance as the progression of low-grade
dysplasia to higher grade epithelial lesions is so low as to make this diagnosis of little clinical
significance, and often of minimal concern to the head and neck surgeon. However, the progression of
moderate dysplasia to a higher grade lesion is nearly similar to that of severe dysplasia, so that a
frozen section diagnosis of moderate dysplasia results in a therapeutic approach similar to that of
Adequacy of Resection Margins
The presence of lesional tissue within 5mm of the inked surgical margin irrespective of whether it is
invasive carcinoma or carcinoma in situ/severe dysplasia places a patient at a nearly equal risk for
local recurrence. These margins are associated with approximately 80% incidence of recurrent disease, so
that failure of local control is not inevitable with such positive margins. The absence of positive
margins does not guarantee local control of disease nor is it a reliable guide to the biologic behavior
of a tumor. The question of how wide a tumor should be excised is the responsibility of the surgeon.
However, for some specimens such as the laryngeal SCC, free margins up to 5 mm may be sufficient while a
similar tumor at another extralaryngeal site, such as the oral cavity and pharynx (oro-, hypopharynx)
wider margins (1.0 cm) are optimal.
Factors Impacting of Margin Status and Prognosis
The variability in "positive surgical margins" is dependent on multiple factors, not the least
important of which may be the definition of what constitutes a positive margin. The factors that may
impact on whether a margin is positive or negative, and in prognosis (control of disease) include:
clinical stage; tumor size; pattern of invasion; adjuvant therapy; histopathologic evaluation; site
dependency; soft tissue margins.
Brandwein-Gentsler et al suggest that resection margin status alone is not an independent predictor of
local recurrence nor should resection margin status alone be used as the sole variable in deciding
whether adjunctive radiation therapy is required; rather the need to give adjunctive radiation is
suggested to be based histologic assessement that results in stratification of patients into low-risk,
intermediate-risk and high-risk categories that define recommendations for adjuvant radiotherapy (Table 1).
Table 1. Risk Assessment for Oral Squamous Cell Carcinoma
** = sum of all points; LR = Local recurrence; RT = Radiotherapy.
|Histologic Variable ||0 ||1 ||3|
|Perineural invasion ||None ||Small nerves ||Large nerves|
|Lymphocytic response ||Continuous band ||Large patches ||Little to none|
|Worst pattern of invasion at interface ||1, 2 or 3 ||4 ||5|
| || || |
|Risk Score*||Risk for LR ||Overall Survival Probability ||Adjuvant Treatment with RT|
|0 ||Low ||Good ||No benefit|
|1 or 2 ||Intermediate ||Intermediate ||No benefit|
|3 - 9 ||High ||Poor ||Beneficial regardless of 5 mm margins|
Tissue Shrinkage and Surgical Margins
Disparate surgical margin lengths of resected specimens between the in vivo measurements by the
surgeon and the in vitro measurements by the pathologist have been reported for head and neck resection
specimens. A mean tissue shrinkage of 31 to 46% may occur from the initial in-situ measurement by the
surgeon to the final microscopic assessment of oral cavity and lingual surface mucosal margins by the
Histologic Prognostic Indicators
Among the histologic findings that may impact on the prognosis in head and neck squamous cell
carcinoma include: 1) status of the surgical resection margins, 2) tumor size, thickness and location of
the lesion; 3) pattern of invasion; 4) involvement of lymph-vascular spaces, 5) invasion of soft tissue
structures including nerves, bone and cartilage, 6) nodal metatsasis with or without extranodal extension
of tumor; 7) distant metastasis; 8) host response; 9) neovascularization, and 10) presence of multiple
Pitfalls in the Intraoperative Assessment of Squamous Cell Carcinoma/Dysplasia
On frozen section consultations of mucosal surface lesions, potential diagnostic pitfalls may include:
reactive epithelial changes, postirradiation changes and Juxtaoral Organ of Chievitz.
Contraindications for the utilization of IOC on mucosal lesions include: 1) when the frozen section
diagnosis will not have any impact on surgery or no immediate decision; 2) if the tissue specimen is
small and additional sampling is not planned; 3) for heavily calcified or ossified tissue; 4) for certain
lesions such as small cutaneous melanocytic lesions and lymphoproliferative lesions requiring special
handling or extensive histologic evaluation for diagnosis.
Intraoperative "Rapid" Immunohistochemical Assessment
Intraoperative immunohistochemical assessment consisting of touch smear cytologic preparations and
cytokeratin staining in 20 minutes from the time of tissue sampling. Limited studies to date on gastric
mucosal margins in patients undergoing gastrectomy for gastric (non-signet ring cell) carcinomas show
accurate and rapid assessment of tumor margins. To date, such analyses have not been published relative
to mucosal margins of the UADT.
Molecular Biology in the Assessment of Surgical Margins ("Molecular Margins")
To date, there have been limited use of molecular biologic markers in assessing histopathologic
negative surgical margins and negative lymph nodes for patients with HNSCC. The presence of p53
mutations in surgical margins and in lymph nodes negative for tumor by light microscopic examination
portended a substantially higher risk of local recurrent disease than those patients without p53
mutations in their surgical specimens. Molecular biologic studies may augment conventional light
microscopy in identifying cancer at surgical margins and in lymph nodes, and also may improve the
prediction of local tumor recurrence.
In general, the accuracy of frozen section diagnosis in head and neck surgery is high, and when
deferred diagnoses are excluded, the reported accuracy ranges from 97 to 99%. Potential discrepancies in
the frozen section-to-permanent section diagnosis may include: sampling errors;
interpretative errors; technical errors; communication errors.
The frozen section diagnosis of lymph nodes is considered to be extremely accurate with an an accuracy
rate of 98.9 percent, excluding deferred diagnoses, with a 0.1 percent false-positive rate and a 1
percent false negative rate. It should be noted that the lymph nodes represents the most frequently
deferred specimen in frozen section diagnosis, especially in the diagnosis of a lymphoma. In general,
the diagnosis of a carcinoma in a lymph node is not problematic at frozen section. Lymph node frozen
section has also been utilized for accurate staging of the head and neck cancer patient.
Sentinel Lymph Nodes in Head and Neck Squamous Cell Carcinoma
There is increasing literature documenting the efficacy of sentinel lymph node evaluation patients
clinically staged as N0 necks with diagnostic accuracy of over 90% and with few reported false negatives
The application of sentinel lymph node biopsy to HNSCC has not as yet reached the level of standard of
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