Ninety per cent of head and neck cancers are squamous cell carcinomas (SCC), the majority representing SCC of the anterior tongue. Understanding the biology of these sec may assist in the clinical management of the disease and reveal novel potential targets for therapy.

LM04 is a member of the LIM-only (LMO) family of transcriptional regulators, consisting ofLMOl-4. These proteins act as molecular adaptors, providing a scaffold for multiprotein complexes of DNA binding factors and transcriptional regulatory proteins, which play essential roles in cell fate determination. tissue patterning and organ development. 1 Aberrant expression of LM04 has been demonstrated in a number of cancer types, with particular attention being paid to its prognostic value and contribution towards tumorigenesis.

A 54-year-old woman presented with a 6-month history of a tender and swollen plaque appearing as a panniculitis affecting the left pretibial area. The initial histopathology revealed dermal and subcutaneous inflammation with interstitial histiocytes and mucinosis suggestive of either granuloma annulare or necrobiosis lipoidica. Over the subsequent 6 months the plaque grew progressively, despite treatment with topical corticosteroids under occlusion. Distal to the plaque reduced sensation developed in the limb. Biopsies of the nodular areas now revealed a dense dermal infiltrate of atypical spindle cells within a prominent myxoid stroma and a pleomorphic multinucleated epithelioid cell component. These features were those of an intermediate grade myxofibrosarcoma.

This soft-tissue sarcoma may initially masquerade clinically as a panniculitis and a granulomatous process on biopsy as in our patient, leading to a delay in surgical therapy.

Postmenopausal women with frontal recession may represent a diagnostic challenge, as frontal fibrosing alopecia and alopecia areata may be clinically difficult to distinguish. A 53-year-old postmenopausal woman presented with a progressive fronto-temporal marginal alopecia with sparing of her eyebrows. Scalp biopsy of the affected frontal hairline revealed peribulbar lymphocytic inflammation, but no evidence of lichenoid inflammation, perifollicular fibrosis or scarring. Whereas the pathology strongly favoured alopecia areata, the clinical features overlapped with frontal fibrosing alopecia, a variant of lichen planopilaris targeting the frontal scalp.

This paper presents an atypical clinical presentation of alopecia areata, which may be mistaken for frontal fibrosing alopecia.

The INK4A-ARF locus at chromosome 9p21 is frequently altered in head and neck squamous cell carcinoma (SCC) and encodes two distinct tumor suppressors, p16INK4A and p14ARF. This study addressed the role of p14ARF as a potential prognostic marker in this disease.

Experimental Design. p14ARF protein expression was assessed by immunohistochemistry in a cohort of 140 patients with SCC of the anterior tongue. Using univariate and multivariate Cox’s proportional hazards models, the outcomes examined were time to disease recurrence or death, with or without clinicopathologic covariates, including nodal status, disease stage, treatment status, Ki-67 staining, and molecular markers with known functional or genetic relationships with p14ARF (p16INK4A, p53, pRb, p21WAF1/CIP1, E2F-1).

Results. On multivariate analysis, p14ARF positivity (nucleolar p14ARF staining and/or nuclear p14ARF staining in ≥30% of tumor cells) was an independent predictor of improved disease-free survival (DFS; P = 0.002) and overall survival (OS; P = 0.002). This was further enhanced when p14ARF positivity was cosegregated with positive (≥1%) p16INK4A staining (DFS, P < 0.001; OS, P < 0.001). Patients whose cancers were p14ARF negative and p53 positive (>50%) had the poorest outcome (DFS, P < 0.001; OS, P < 0.001) of any patient subgroup analyzed.Conclusions. These data show that in patients with SCC of the tongue, combined nuclear and nucleolar expression of p14ARF protein predicts for improved DFS and OS independent of established prognostic markers.

Despite promising initial results, recent Phase III trials of the selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib (“Iressa”; AstraZeneca, Wilmington, Delaware) in advanced head and neck squamous cell carcinoma (HNSCC) have been equivocal. Cyclin D1, an EGFR target gene, is frequently overexpressed in HNSCC, has been implicated in its pathogenesis, and is strongly associated with poor prognosis in this disease. Therefore, we examined the relationship between deregulated cyclin D1 expression and sensitivity to gefitinib to determine whether this frequently occurring oncogenic change affected the cellular response to gefitinib.

Experimental Design. A panel of six EGFR-overexpressing HNSCC cell lines was used to correlate CCND1 gene copy number, cyclin D1 expression, and response to gefitinib. The effect of constitutive overexpression of cyclin D1 was assessed by establishing stably transfected clonal SCC-9 cell lines.

Results. Three of six cell lines displayed cyclin D1 amplification and/or overexpression, and these cell lines were resistant to gefitinib. SCC 9 clones overexpressing cyclin D1 continued to proliferate and maintained their S-phase fraction when treated with gefitinib, whereas empty vector control clones and the parental SCC 9 cells were profoundly inhibited and displayed marked reductions in S-phase. The resistance of cyclin D1-overexpressing clones and cyclin D1-amplified cell lines was associated with maintenance of cyclin D1 expression after gefitinib treatment.

Conclusions. These data suggest that deregulated cyclin D1 overexpression may be associated with resistance of HNSCC to EGFR inhibitors. Therefore, the role of cyclin D1 as a marker of therapeutic response and its utility as a prognostic marker in HNSCC warrant additional analysis.

Overexpression of E2F-1 is associated with increased invasiveness in head and neck squamous cell carcinoma cell lines in vitro, but its significance in vivo is unknown. This study sought to determine the relationship between E2F-1 and retinoblastoma protein (pRb) expression and disease outcome in squamous cell carcinoma (SCC) of the anterior tongue.

Experimental Design. pRb and E2F-1 protein expression was assessed by immunohistochemistry in a cohort of 145 patients with SCC of the anterior tongue. The outcomes examined were time to disease recurrence or death. The relationships between E2F-1 or pRb expression and outcome were assessed by univariate and multivariate Cox’s proportional hazards model, with or without clinicopathological covariates, including nodal status, disease stage, treatment status, and molecular markers (cyclin D1, p16INK4A, and Ki-67) previously measured in this cohort.

Results. On univariate analysis, increased expression of E2F-1 (>35% of positive-stained nuclei) was associated with increased disease-free survival (DFS; hazard ratio [HR]: 0.35; P = 0.04) and increased overall survival (OS; HR: 0.33; P = 0.06). Decreased expression of pRb (<50% positive nuclei) was associated with increased DFS (HR: 1.81; P = 0.06) but not with OS (P = 0.11). However, when considered simultaneously with other significant factors, i.e. lymph node status, p16INK4A protein expression, and histopathological grade, in the multivariate Cox’s proportional hazards model, the additional contributions of E2F-1 and/or pRb expression to DFS and OS were not statistically significant.

Conclusions. These data demonstrate that in patients with SCC of the tongue, overexpression of E2F-1 is associated with increased DFS and OS. However, this association is not independent of lymph node status, tumor grade, and p16INK4A expression. Among the cell cycle-regulatory molecules studied, p16INK4A expression is the most predictive molecular marker of disease outcome.