The head and neck overlaps many organ systems and it is difficult to precisely divide the area. Many diseases overlap with disorders of the gastrointestinal tract, skin, and lungs. However, there are many syndromes as well as diseases which have peculiar presentations at this site. The pathologist may play an important role intraoperatively by performing frozen sections to determine the adequacy of surgical margins. Because many organs are relatively superficial, the pathologist may be called upon to perform a fine needle aspiration to make a rapid diagnosis of a tumor. Finally, cultures of head and neck specimens may sometimes require specialized media which the alert pathologist will utilize.
Nasopharynx, Nose, and Sinuses (Papillomas, Nasopharyngeal Carcinoma)
Oral Cavity (Tounge, Gums)
CASTLE (Carcinoma with thymus-like differentiation)
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
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PATHOGENESIS CHARACTERIZATION CD9
CD9 expression on lymphatic vessels in head and neck mucosa.
Erovic BM, Neuchrist C, Kandutsch S, Woegerbauer M, Pammer J.
Department of Head and Neck Surgery, University of Vienna Medical School, Vienna, Austria.
Mod Pathol. 2003 Oct;16(10):1028-34 Abstract quote.
CD9, a member of the transmembrane 4 superfamily, is involved in cell adhesion, migration, and tumor metastasis. Little is known about its vascular expression pattern. In this study, we investigated CD9 expression on endothelial cells in the mucosa of the head and neck and compared it with vascular tumors.
Using immunohistochemistry, expression of CD9 was studied in 17 samples of head and neck mucosa and skin (laryngeal mucosa: n = 2, oral: n = 6, and epidermis: n = 9) and a variety of vascular tumors (lymphangiomas: n = 9, juvenile nasopharyngeal angiofibromas: n = 4, hemangiomas: n = 7, angiosarcomas: n = 5, and Kaposi's sarcomas: n = 7) and compared with the expression of CD34 and PAL-E (blood vessel markers) and the lymphatic marker podoplanin. Regular lymphatic endothelium and lymphangiomas were strongly positive for CD9 and podoplanin but were mostly negative for PAL-E and CD34. By contrast, blood vessel endothelium and hemangiomas were strongly positive for PAL-E and CD34 but were mostly negative for CD9 and podoplanin. Weak to moderate CD9 reactivity was also observed on EC of juvenile nasopharyngeal angiofibromas, angiosarcomas, and Kaposi's sarcomas. Expression of CD9 by lymphatic EC was confirmed by reverse-transcriptase PCR and Western blot analyses. CD9 may be useful as a marker for lymphatic EC.
It could promote the adherence of inflammatory and tumor cells to lymphatic EC and participate in the growth and maintenance of the lymphatic capillary net.
Sarcomatoid carcinoma of the head and neck: molecular evidence for evolution and progression from conventional squamous cell carcinomas.
Choi HR, Sturgis EM, Rosenthal DI, Luna MA, Batsakis JG, El-Naggar AK.
Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, 77030, USA.
Am J Surg Pathol. 2003 Sep;27(9):1216-20 Abstract quote.
The underlying events associated with the development of sarcomatoid head and neck squamous carcinoma and the biologic significance remain unknown.
To investigate the genetic events involved in the evolution of this entity, comparative analysis of matched microdissected epithelial and sarcoma-like components from 11 primary sarcomatoid carcinomas was performed using microsatellite markers. Nine markers on chromosomes 4p, 9p, and 17p regions (3 per each chromosomal region) were selected based on their informativeness, small product size, and the high alterations in head and neck squamous carcinomas. In this study, loss of heterozygosity (LOH) in at least one marker in either component was noted in all 11 tumors, and instability was found in 10 instances (six in 3 paired specimens and four in the sarcomatoid area only). Concordant results in both components were found in 58 (79.5%) reactions (37 LOH and 21 retention of heterozygosity), and paradoxical findings were noted in 15 instances (20.5%). The latter included LOHs in only two conventional epithelial components and 13 sarcomatoid components. Both keratin-positive and -negative sarcomatoid tumors had a comparable frequency of LOH.
The most frequently altered markers in both components were D9S168 and D9S171 (75% each) and D4S1587 (66%). The sarcomatoid components manifested distinctly high alterations at marker D17S520 on chromosome 17p. Our study supports: 1) an evolution of sarcomatoid carcinoma from the conventional epithelial-type, 2) a malignant nature of the sarcomatoid component, and 3) that molecular progression is associated with the sarcomatoid transformation.
Allelic loss and tumor pathology in head and neck squamous cell carcinoma.
Rybicki BA, Savera AT, Gomez JA, Patel SC, Ballard NE, Benninger MS, Zarbo RJ, Van Dyke DL.
Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, Michigan 48202, USA.
Mod Pathol. 2003 Oct;16(10):970-9. Abstract quote
Allelic loss is a common occurrence in head and neck tumors and has been shown to be an independent predictor of prognosis; however, the relationship between allelic loss and tumor pathology is not well-known.
We studied 139 patients who were newly diagnosed with squamous cell cancer of the head and neck to determine whether tumor pathology was correlated with allelic loss at one or more of eight different regions on chromosomes 3p, 5q, 8p, 9p, 10p, 18q, and 21q. At each chromosomal region, loss of heterozygosity at any one of three or four highly polymorphic microsatellite markers that spanned the region in question was considered evidence for allelic loss. A pathologist scored all tumors for seven tumor pathology and host interface parameters. Mean allelic loss across all eight regions was associated with mitotic index (P =.034) and inflammatory response (P =.005). For allelic loss at specific chromosomal regions, the most statistically significant trends were between overall tumor grade and 3p14.2-p13 (P =.014), mitotic index and 3p24.3-p14.3 (P =.026), 9p24.2-p21 (P =.004) and 18q12.3-q23 (P =.009), inflammatory response and 3p14.2-p13 (P =.008) and 9p24.2-p21 (P =.001), desmoplastic response and 9p24.2-p21 (P =.009), and pattern of invasion and 21q21-q22.2 (P =.015).
Our results suggest that genes involved in tumor suppression and oncogenesis can potentially be classified based on specific pathologic events in head and neck squamous cell carcinogenesis that they modify.
Prevalence of human papillomavirus type 16 DNA in squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young patients: a distinct clinicopathologic and molecular disease entity.
El-Mofty SK, Lu DW.
Washington University School of Medicine, St Louis, MO 63110, USA.
Am J Surg Pathol. 2003 Nov;27(11):1463-70. Abstract quote
Squamous cell carcinoma of the head and neck commonly affects patients in their sixth decade and older, particularly those with a prolonged history of alcohol and tobacco abuse. Less frequently, carcinomas occur in young individuals even in the absence of known risk factors.
The purpose of this study is to investigate a possible relationship between these tumors and human papilloma virus (HPV). Thirty-three cases of squamous cell carcinoma of the head and neck in young patients under the age of 40 years were studied: 15 oral, 11 tonsillar, and 7 laryngeal. HPV DNA was detected by polymerase chain reaction in 10 tonsillar and 2 laryngeal carcinomas and in none of the oral tumors. Of the 12 HPV-positive tumors, 11 were HPV16 and 1 was HPV31. HPV-positive tumors had a distinct nonkeratinizing basal cell morphology, they stained diffusely and strongly with p16 antibodies, had higher Ki-67 and lower p53 staining scores as compared with the conventional keratinizing HPV negative carcinomas.
It is concluded that in young patients high-risk HPV, particularly HPV16, is strongly associated with tonsillar squamous cell carcinoma and some cases of laryngeal, but not oral, tumors. The HPV-positive carcinomas have a distinct histopathologic and immunophenotypic features.
TYROSINE KINASES Expression of Protein Tyrosine Kinases in Head and Neck Squamous Cell Carcinomas
Weg M. Ongkeko, MD, PhD, etal.
Am J Clin Pathol 2005;124:71-76 Abstract quote
Protein tyrosine kinases (TKs) are overexpressed in many carcinomas and sarcomas.
We studied the expression of the following TKs in head and neck squamous cell carcinoma (HNSCC): platelet-derived growth factor receptor (PDGFR), c-kit, epidermal growth factor receptor (EGFR), and a serine-threonine kinase, Akt. Formalin-fixed, paraffin-embedded tumor blocks from 44 consecutive patients with primary HNSCC and 5 specimens of benign pharyngeal and laryngeal mucosa were retrieved for immunohistochemical analysis.
Of the specimens, 38 had enough material to stain for all 4 antibodies. The study included 21 pharyngeal (base of tongue, 14; tonsil, 6; soft palate, 1), 16 laryngeal, and 1 floor of the mouth carcinoma. All 4 kinases in the tumor samples were expressed highly (PDGFR, 95%-100%; EGFR, 38%-43%; c-kit, 50%-86%; p-Akt, 57%-81%), with EGFR, c-kit, and p-Akt significantly higher than in benign samples. None of the kinase expressions correlated with disease-free survival.
The expression of the kinases raises the possibility of treatment of HNSCC by tyrosine and serine-threonine kinase inhibitors.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES Cystic squamous cell carcinoma vs. branchial cleft carcinoma
Arch Pathol Lab Med 1976;100:311-314
Branchial cleft carcinoma, if it exists, is an extremely rare entity. For the tumor to be unequivocally diagnosed, the following criteria must exist:
Cervical tumor have occurred somewhere along a line extending from a point just anterior to the tragus of the ear, downward along the anterior border of the sternomastoid muscle to the clavicle
Histologic appearance of the growth must be consistent with an origin from tissue known to be present in branchial vestiges
Patient must have survived and have been followed by periodic examination for at least 5 years without the development of any other lesion which could possibly have been the primary tumor
Histology must demonstrate a cancer developing in the wall of an epithelial-lined cyst situated in the lateral aspect of the neck
Otherwise, possible occult sources of a squamous cell carcinoma include tonsillar crypt carcinomas arising deep within the crypts of the tonsils
PROGNOSIS AND TREATMENT CHARACTERIZATION DYSADHERIN
- Dysadherin Expression in Head and Neck Squamous Cell Carcinoma: Association With Lymphangiogenesis and Prognostic Significance.
Kyzas PA, Stefanou D, Batistatou A, Agnantis NJ, Nakanishi Y, Hirohashi S, Charalabopoulos K.
From the Departments of *Pathology and double daggerPhysiology, University of Ioannina, Medical School, Ioannina, Greece; and the daggerPathology Division, National Cancer Center Research Institute, Tokyo, Japan.
Am J Surg Pathol. 2006 Feb;30(2):185-193. Abstract quote
Dysadherin is a recently characterized cancer-associated cell membrane glycoprotein that has a crucial role to cell-cell adhesiveness.
The aim of this study was to examine dysadherin expression in head and neck squamous cell carcinoma (HNSCC). A total of 108 tissue specimens of patients with HNSCC were examined using immunostaining for dysadherin, E-cadherin, and the specific lymphatic endothelium marker D2-40.
We quantified dysadherin and E-cadherin expression, assessed intratumoral (ILD) and peritumoral lymphatic density (PLD), and examined the possible associations of all the above parameters with clinicopathologic features and outcome. Finally, we used double staining with dysadherin and D2-40 to examine the expression pattern of dysadherin simultaneously with the lymphovasculature environment of HNSCC. High dysadherin expression was correlated with higher clinical stage (chi, P = 0.01), with the presence of lymph node metastasis at the time of diagnosis (chi, P = 0.02), and with increased ILD (chi, P = 0.001).
We observed an impressive reverse association between increased dysadherin expression and decreased E-cadherin expression (chi, P < 0.001). Surprisingly, dysadherin-positive cancer cells usually gathered around areas of high intratumoral lymphatic vessel concentration, surrounding and invading small intratumoral lymphatics. Higher clinical stage and increased dysadherin expression were found to be the only significant independent prognostic factors for overall survival (hazard ratio, 3.94; 95% confidence interval, 1.09-14.27 for clinical stage; hazard ratio, 3.92; 95% confidence interval, 1.46-10.51 for dysadherin). The loss of intercellular adhesiveness and increased dysadherin expression seems to be related to lymphangiogenesis in HNSCC, but this should be confirmed by additional studies.
Dysadherin expression might be a promising prognostic marker for separation of patients at higher risk.
- Molecular and Clinicopathologic Comparisons of Head and Neck Squamous Carcinoma Variants: Common and Distinctive Features of Biological Significance.
Choi HR, Roberts DB, Johnigan RH, Sturgis EM, Rosenthal DI, Weber RS, Luna MA, Batsakis JG, El-Naggar AK.
Am J Surg Pathol. 2004 Oct;28(10):1299-1310. Abstract quote
To investigate, for the first time, the events associated with the phenotypic and clinical diversities of head and neck squamous carcinomas (HNSC), we performed molecular analyses on 92 primary tumors representing the entire spectrum of the morphologic subtypes using microsatellite markers at chromosome 3p, 4p, 8p, 9p, 11q, 17p, and 18q regions and correlated the results with the clinicopathologic features and patientsâ€™ survival. Loss of heterozygosity (LOH) at D9S168 and D9S171 markers on chromosome 9p regions was commonly identified in all subtypes. Distinctive alterations in certain subtypes were noted at chromosomes 3p, 4p, 8p, and 11p regions.
In general, less aggressive types (verrucous, papillary, and well-differentiated conventional) had a significantly lower LOH incidence than the more aggressive (basaloid, sarcomatoid, and high-grade conventional squamous carcinoma) categories. Significant association between LOH and age, stage, nodal status, and patient outcome was found. Survival analysis revealed that pathologic categorization (less versus more aggressive) and LOH at marker D11S4167 and D3S2432 are independent predictors of patientsâ€™ survival.
Our analysis also defined a set of limited markers that account for most of alterations within and across these tumor subtypes. Our study indicates that 1) certain genetic markers are common to all subtypes of HNSC supporting their early involvement in tumorigenesis, 2) inter- and intratumoral genetic differences evolve subsequently and may underlie their morphologic heterogeneity, 3) high incidence of LOH in certain regions characterizes aggressive tumors, 4) categorical classification and LOH at 11p and 3p regions independently correlated with patient survival, and 5) a limited set of markers identify the majority of genetic alterations in these tumors.
Does histologic grade have a role in the management of head and neck cancers?
Fortin A, Couture C, Doucet R, Albert M, Allard J, Tetu B.
Department of Radiation Oncology and Department of Pathology, L'Hotel-Dieu de Quebec, Quebec, Canada.
J Clin Oncol 2001 Nov 1;19(21):4107-16 Abstract quote
PURPOSE: High histologic grade is usually associated with a greater propensity to distant metastases (DM). Its role to predict DM in head and neck cancer is not yet defined. The aim of this study is to evaluate the role of histologic grade as an independent predictor of DM and to determine a subgroup of patients who may benefit from systemic chemotherapy.
PATIENTS AND METHODS: This is a retrospective study of 1,266 consecutive patients treated by definitive or postoperative radiotherapy between 1989 and 1997. All patients received at least 50 Gy. All stages and subsites of head/neck were included. DM rates were evaluated by the Kaplan-Meier method with a subsequent Cox analysis.
RESULTS: There is a strong correlation of grade with N stage (P <.000001). The metastases-free survival (MFS) was 98%, 90%, and 72% for grades 1, 2, and 3, respectively (P <.000001). In patients with N0 stage, MFS is always greater than 90%, whatever the grade. In the 222 N1 patients, MFS was more than 90% in grade 1 and 2 but dropped to 75% for grade 3 (P =.001). In patients with N2 and N3, MFS was 91%, 79%, and 59% for grades 1, 2, and 3, respectively (P =.008). The same conclusion is applicable when only patients with neck control are analyzed. In a Cox model, grade was an independent predictor of DM (P =.000001) as well as T stage (P =.003), N stage (P =.000001), and neck failure (P =.0003). Higher grade was also an independent predictor of survival (P =.02).
CONCLUSION: Patients with histologic grade 1 and grade 2 (except N3) are at low risk of DM. Patients with grade 2 and N3 or patients with grade 3 and N1 to N3 have a higher risk of distant metastases and should be considered for systemic treatment.
PHOSPHORYLATED NUCLEAR FACTOR-KAPPA B (p-NF-kB)
- Overexpression of phosphorylated nuclear factor-kappa B in tonsillar squamous cell carcinoma and high-grade dysplasia is associated with poor prognosis.
Zhang PL, Pellitteri PK, Law A, Gilroy PA, Wood GC, Kennedy TL, Blasick TM, Lun M, Schuerch C, Brown RE.
 1Division of Laboratory Medicine, Geisinger Medical Center, Danville, PA, USA  4Weis Center for Research, Geisinger Medical Center, Danville, PA, USA.
Mod Pathol. 2005 Jul;18(7):924-32 Abstract quote.
Intracellular signals along the epidermal growth factor receptor (EGFR)-Akt-nuclear factor-kappa B (NF-kappaB) pathway have been associated with carcinogenesis in various malignant neoplasms.
This investigation was to evaluate the expression of EGFR, phosphorylated(p)-Akt and p-NF-kappaB and correlate them with clinical outcomes in patients with squamous cell carcinoma of the tonsil. A total of 45 patients with squamous cell carcinoma of the tonsil were studied by immunohistochemistry to evaluate the expression levels of EGFR, p-Akt and p-NF-kappaB. Results for squamous cell carcinoma of the tonsil were compared with those for associated high-grade dysplasia and adjacent normal appearing epithelium, when present. In addition, tonsillar epithelium from non-neoplastic specimens of age-matched patients also was stained for the same markers.
High-grade dysplasia and squamous cell carcinoma of the tonsil demonstrated a similar pattern of expression, which differed from the pattern seen in the adjacent normal epithelium and tonsillar epithelium from normal controls (an overexpression for each of these three protein analytes in high-grade dysplasia and squamous cell carcinoma of the tonsil as demonstrated by immunohistochemistry). When markers from squamous cell carcinoma of the tonsil were correlated with survival status, only increasing levels of p-NF-kappaB immunoreactivity (a relative overexpression) were statistically significant predictors of poor survival. No markers in squamous cell carcinoma of the tonsil were significantly related to rate of recurrence. When analyzing marker scores from tissue with high-grade dysplasia, relative overexpressions of both p-Akt and p-NF-kappaB were significantly related to poor survival. Additionally, increasing levels of p-NF-kappaB immunopositivity from tissue with high-grade dysplasia were also significantly related to rate of recurrence. In summary, p-NF-kappaB, overexpressed in high-grade dysplasia and squamous cell carcinoma of the tonsil, is associated with worse prognosis in terms of high recurrence and poor survival, respectively.
This significant finding in patients with squamous cell carcinoma of the tonsil, in combination with previous animal and in vitro studies, suggests that p-NF-kappaB represents a potential therapeutic target in head and neck squamous cell carcinoma.
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