Malignant Neoplasms of the Neck (Soft Tissue and Lymph Node)

Gross Findings

The metastatic lesions can range in size from 1.5 to 12 cm (average size of approximately 4 cm). There is often a thick, fibrotic capsule defining the well-circumscribed lymph node border. Tumors with extracapsular extension have irregular borders and infiltration into adjacent fibroadipose tissue or skeletal muscle. Matted lymph nodes of confluent metastases may be seen. The cut surface is unilocular or multilocular, with cyst(s) filled with granular, thick, tenacious, and purulent yellow-brown to hemorrhagic fluid.

Microscopic Findings

On microscopic examination, a dense, fibrous connective tissue capsule will often surround the lymph node that contains metastatic tumor ( Fig. 22.2 ). The cystic spaces are lined by a ribbon-like growth of squamous epithelium, which has a generally uniform thickness ( Fig. 22.3 ). Metastatic SCC can vary in appearance, ranging from transitional, basaloid, and nonkeratinizing morphology to a more conventional keratinizing squamous appearance. In some areas, metastatic tumor has an endophytic growth pattern, budding into the lymphoid stroma, whereas in other areas it is exophytic or papillary, with projections into the cyst spaces. The cyst contents are often washed away during fixation and histologic processing, leaving these variably sized spaces largely empty. For metastatic oropharyngeal HPV-related squamous cell carcinoma (HPV-SCC) in particular, the overall histologic appearance may be somewhat bland, recapitulating the normal squamous or transitional-type epithelium that is present in a normal deep tonsillar crypt ( Fig. 22.4 ). In exceptional cases of metastatic HPV-SCC, the tumor cells even retain cilia, an extremely rare finding in malignant neoplasms ( Fig. 22.5 ). Nonetheless, the cells are enlarged with a high nuclear to cytoplasmic ratio, no appreciable degree of surface maturation, and limited keratinization. Occasionally, an abrupt transition to remarkably atypical epithelium can be seen, facilitating the diagnosis ( Fig. 22.6 ). Because of the often bland histologic appearance on initial low-power examination, these lesions may require careful inspection to make the correct diagnosis. Notably, extranodular extension should be noted although for oropharyngeal HPV-associated primaries, it may not be associated with prognosis.

Specific rare variants of SCC that are nonkeratinizing or primitive appearing may need to be considered in the absence of HPV. Nasopharyngeal carcinoma is associated with a dense lymphocytic infiltrate (but may appear indistinct from normal lymph node), and tumor cells often have large vesicular nuclei and prominent nucleoli ( Fig. 22.7 ). NUT carcinoma is composed predominantly of a uniform undifferentiated epithelioid morphology, but careful histologic examination will usually identify abrupt small foci of keratinization ( Fig. 22.8 ).

Immunohistochemical and Molecular Findings

Immunohistochemistry is often not necessary for the recognition of SCC. However, tumor cells are positive with a variety of keratins (AE1/AE3, CK5, CK8, CK14, and CK19), although CK7 is usually negative. Squamous differentiation can be identified by p63 and its more squamous-specific isoform, p40, which is helpful for poorly differentiated tumors.

Given the high frequency (70%) of patients with HPV-SCC who present with cervical lymph node metastases, all cases of metastatic SCC in the neck should undergo testing for high-risk HPV. p16 is an excellent immunohistochemical surrogate marker for high-risk HPV; to be regarded as positive, nuclear and cytoplasmic staining should be present in at least 70% of tumor cells ( Fig. 22.9 ). The detection of HPV is helpful in localizing the primary oropharyngeal site but also has clinical implications given that HPV-SCC is associated with better outcomes in comparison to conventional SCC.

In most cases, p16 positivity is sufficient for identifying HPV-SCC if the histologic features (i.e., nonkeratinizing morphology) and clinical context (i.e., level 2 or 3 lymph node, oropharyngeal or unknown primary) are typical. However, there are more pitfalls in the interpretation of p16 in the neck than in the oropharynx because metastatic lung and skin carcinomas and even benign cysts can be p16 positive. For that reason, many laboratories follow positive p16 staining with confirmatory HPV detection by a more specific technique. High-risk HPV can be detected via in situ hybridization (ISH) or through amplification detection via sequencing. ISH has the advantage of assessing cellular location, which distinguishes between episomal and integrated virus by two distinct staining patterns: punctate (dot-like) staining with integrated virus and diffuse nuclear staining with episomal virus ( Fig. 22.10 ).

EBV can be detected in nasopharyngeal carcinoma by ISH ( Fig. 22.7 ). NUT carcinoma will show punctate nuclear immunoreactivity for NUT ( Fig. 22.8 ); NUTM1 rearrangements can be detected using fluorescence in situ hybridization (FISH) break-apart probe for the NUT locus on 15q14 or by sequencing the NUT-BRD4 fusion gene.

Fine Needle Aspiration

Aspirate smears of metastatic SCC are often quite cellular and, in many cases, dominated by anucleate squamous and debris from the cyst contents. Fragments of atypical squamous epithelium are often present, as well as individual atypical keratinocytes ( Fig. 22.11 ). Nuclear atypia, pleomorphism, increased nuclear to cytoplasmic ratio, and mitotic figures all help to confirm the diagnosis. All cytologic specimens, especially with cell block material of metastatic SCC should be assessed for high-risk HPV, and if initially negative, studies should be repeated on any subsequent surgical specimens. Notably, p16 immunostaining is less consistently strong and diffuse in cytology material than it is in tissue specimens.

Prognosis and Therapy

After the diagnosis of metastatic SCC is accurately classified, efforts toward identifying the primary tumor are typically undertaken and include extensive physical examination under anesthesia, pan-endoscopy (nasopharynx, larynx, esophagus, nasal cavity), and detailed, high-resolution CT or MRI studies of the oropharynx and Waldeyer ring area. Again, this search is informed by initial assessment of the metastatic lesion for the presence of high-risk HPV. If these studies do not identify the primary, then prophylactic lingual and palatine tonsillectomy, specifically on the ipsilateral side, should be performed, with complete embedding of the tonsils and thorough sectioning. Still, attempts at identifying the primary tumor will be defied in an appreciable proportion of patients (up to 10%). Radiation therapy in the region of Waldeyer ring, after selected lymph node dissection, will yield a good long-term clinical outcome of 70% to 80% survival at 5 years. Patients with HPV-SCC may be managed with intensity-modulated or brachy-radiation treatment. Concurrent radiation and multiagent chemotherapy may be used. A common complication of radiotherapy or chemotherapy is mucositis and xerostomia. Overall, HPV-SCC are associated with a better outcome (up to 80% 5-year survival, stage dependent) in comparison to conventional SCC of the upper aerodigestive tract (survival rates of <35% at 5 years).