Basaloid Squamous Cell Carcinoma

Clinical Features
Basaloid squamous cell carcinoma (BSCC) is an uncommon, histologically distinct variant of squamous cell carcinoma. In the upper aerodigestive tract, it occurs primary at the base of the tongue, hypopharynx and larynx but has also been described in the palate, tonsil, buccal mucosa, floor of mouth, nasopharynx, nasal cavity, and trachea. Similar, if not identical tumors have also been observed in various sites below the clavicles, including the esophagus, lung, anus and uterine cervix.

It occurs primarily in males (82% of all cases) and in patients between 27 and 88 years of age (mean about 63 years). Symptoms vary according to site of origin. The most common are dysphagia, hoarseness, pain in the throat, otalgia, cough, hemoptysis, neck mass and weight loss.

Etiology
Although the etiology of the tumor is unknown, tobacco and alcohol abuse may be important as preliminary findings indicate that the majority of patients have been heavy smokers and consumers of alcoholic beverages. Epstein-Barr virus has been described in 3 patients from Hong-Kong with BSCC of the nasopharynx. The virus, however, has not thus far been described in BSCC in other sites. Human papillomavirus 16 and 18 have also been detected in BSCC of the anal canal. Whether the Epstein- Barr virus and human papillomavirus are etiologically related to BSCC remains to be determined. The cell of origin is also unknown. It has been postulated, however, that a totipotential cell lying in the base of the mucosa or in the salivary ducts may be the culprit.

Pathologic Features
BSCC varies from 1-6 cm in greatest dimension and is described as being hard and centrally ulcerated with submucosal infiltration. Because of the prominent submucosal involvement, the tumor is often thought to be a salivary gland or soft tissue neoplasm.

As the name implies, BSCC is composed microscopically of two components – basaloid and squamous cells. The basaloid cells are small and arranged in smooth contoured lobules, small clusters and cords.

The cells have scant cytoplasm and round nuclei that vary from hyperchromatic to vesicular. Nucleoli may or may not be present and mitoses are frequent. Small cystic spaces or even ductal differentiation may be seen in some of the basaloid lobules. The spaces may appear empty or contain material that sometimes stains light with periodic acid-Schiff or Alcian blue and negative with mucicarmine. Central comedonecrosis of the basaloid lobules is common as well as deposition of amorphous, eosinophilic material (hyalinosis) between tumor cells. There is often prominent nuclear palisading of the basaloid cells around the periphery of the lobules.

Although the basaloid component predominates, a definable element of squamous cell carcinoma should be present to make the diagnosis with confidence.

The squamous carcinoma may be in-situ or invasive and is typically well to moderately differentiated. If there is extensive surface ulceration, only dysplastic changes may be seen in the marginal epithelium. Some of the basaloid islands may also show squamous differentiation and when this occurs, the transition between the two components may be abrupt or show a zone of transition.

In about 5% of cases, BSCC may also exhibit a spindle component much like spindle cell carcinoma. The spindle cells are fibroblast-like in appearance but stain for cytokeratin.

Ultrastructural studies of BSCC have shown the basaloid cells to contain desmosomes, rare tonofilaments and free ribosomes, but few other organelles. Neurosecretory granules, myofilaments and secretory granules are absent. The cystic spaces, as noted above, contain either loose stellate granules or replicated basal lamina.

Immunohistochemistry
Banks et al studied 40 cases of BSCC. They observed that 79% were positive for AE1/AE3, 83% for EMA, 53% for CEA and 39% for S-100 protein. Diffuse, weak staining for neuron-specific enolase was seen in 75% of tumors but all were negative for chromogranin, synaptophysin, muscle-specific actin and glial fibrillary acidic protein. More recently, some BSCCs have been found to express vimentin.

Differential Diagnosis
It may be difficult or even impossible to make the diagnosis of BSCC on a small biopsy. The differential diagnosis in this discussion is limited to adenoid cystic carcinoma and small cell neuroendocrine carcinoma. Tables 1 and 2 show features that are helpful in separating these tumors.

Treatment and Prognosis
BSCCs are aggressive tumors. According to Raslan et al, 64% of patients either have or will develop cervical lymph node metastases and 44% will experience distant metastases (lungs, liver and bones). Although the majority of patients die of their disease within three years, some have lived as long as six years or more. Metastasis may manifest either basaloid or squamous components or both.

Because of the high frequency of regional and distant metastasis, the preferred treatment is surgery, including some form of neck dissection, with postoperative irradiation. Adjuvant chemotherapy should also be considered.

Although BSCC appears to be more aggressive than conventional squamous cell carcinoma, Luna et al indicate that when the two tumors are matched for anatomic site, stage and treatment, they actually have comparable survival rates. Their series, however, is very small and their conclusion needs to be verified by additional studies.

Seidman et al have called attention to the fact that patients with BSCCs may have a higher incidence of second primary tumors compared to other head and neck neoplasms. They reported two cases of BSCCs arising in the pyriform sinus and vallecula, respectively, each of which was associated with a second primary; a small cell carcinoma of the esophagus in the former and a squamous cell carcinoma of the palate in the latter.

Whether determining the DNA content of the tumor offers any prognostic significance is controversial.

Adenoid Cystic Carcinoma

Clinical Features
Adenoid cystic carcinoma (ACC) of the larynx is a distinctly uncommon tumor. In a review of 264 ACCs from all sites in the head and neck on file at the Memorial Hospital in New York, Spiro et al identified only 3 (1.1%) that originated in the larynx. As of 1993, only about 120 cases were reported in the larynx in a review of the world literature.

The tumor affects both sexes about equally and occurs over a broad age range, with a peak incidence between 50 and 70 years. Approximately 50-60% arise in the subglottic and 25-35% in the supraglottic larynx. Only 5-10% involve the glottis. Airway obstruction, dysphagia, hoarseness, cough, sore throat, and occasionally, pain are the usual presenting symptoms. Pathologic Features

ACCs are usually between 1-5 cm, firm, gray-white and sometimes deceptively well circumscribed. They are composed of two types of cells – epithelial (ductal), and myoepithelial – of varying proportion arranged in a tubular, cribriform and/or solid pattern. The nuclei tend to be small, dark, and angulated and devoid of nucleoli and mitotic activity. In some instances, particularly the solid or poorly differentiated type, the nuclei may be more vesicular, contain nucleoli and exhibit prominent mitoses, often with areas of necrosis. Perineural invasion is common, especially if the biopsy is large and enough section are taken. Dedifferentiated ACCs have also been described.

Immunohistochemistry
The epithelial (ductal) cells characteristically express CEA and EMA while the myoepithelial cells are positive for a variety of myoepithelial markers, such as smooth muscle actin, calponin, P-63, etc. ACC may also express C-Kit.

Differential Diagnosis

Table 1: Basaloid Squamous Cell Carcinoma (BSCC) Versus Adenoid Cystic Carcinoma (ACC)

Feature	BSCC	ACC
Lymph nodes	+	-
Cribriform pattern	focal	often prominent
Nuclei	vesicular, round	dark, angulated
Nucleoli	+/-	-
Mitoses	+	+/-
Squamous carcinoma	+	-
Perineural invasion	rare	frequent
Comedonecrosis	prominent	rare
Muscle specific actin	Neg. or focal	diffuse
Myoepithelial cells	-	+
P53	+	-
Ki-67	high	low
S-100	focal, dendritic cells	diffuse
C-Kit	+/-	+

Treatment and Prognosis
Surgery is the treatment of choice for ACC of the larynx, with the extent of the procedure being dependent on the tumor site. Because most are of subglottic origin, a total laryngectomy is usually required, whereas partial procedures may be sufficient for those involving the supraglottic larynx. A neck dissection is not warranted unless the lymph nodes are enlarged or have been shown to contain tumor. Radiation therapy may produce temporary regression, but rarely permanent control.

Although some studies have indicated a rather significant incidence of cervical lymph node metastases, especially for those arising in the supraglottic larynx, we suspect that in most of these cases the lymph nodes were involved by direct tumor extension or that the tumor was some other neoplasm incorrectly labeled as an ACC. In our experience, embolic nodal metastasis by ACC is infrequent.

Because of their rarity and lack of significant follow-up, the long-term prognosis is largely unknown. A few patients have succumbed to their disease within 21 months of diagnosis, whereas others have been reported to be alive and disease-free as long as 15 years or more. The absence of lymph node metastasis cannot be considered a favorable prognostic sign, for most ACC metastasize systemically through the blood stream, usually to lung, bone, or liver. Patients may, however, live many years after developing metastases.

Small Cell Neuroendocrine Carcinoma

Clinical Features
Primary small cell neuroendocrine carcinoma (SCNEC) of the larynx is a distinctly uncommon tumor, representing less than 0.5% of all laryngeal carcinomas. Although it was first described in the larynx by Oloffson and van Nostrand in 1972, only 125 cases were recorded in a review of the literature in 1991.

SCNEC of the lung, on the other hand, is a common tumor. Because the larynx is, in part, embryologically related to the lungs, it is not surprising that the tumor could also arise de novo in the larynx. The apparent rarity of SCNEC in this site and the length of time it has taken to recognize it as such is remarkable. In all likelihood the tumor has gone unrecognized and probably has been mislabeled as a poorly differentiated squamous cell carcinoma or as an anaplastic carcinoma.

In the larynx, the tumor is more common in men by a ratio of 3:1. Patients have ranged in age from 23-91 years. Only 3% occur in patients less than 40 years of age. Hoarseness and dysphagia, often associated with painless cervical lymph node metastases, are the most common symptoms. Most are heavy smokers.

Pathologic Features
Although SCNEC can occur anywhere in the larynx, most are of supraglottic origin. The tumors are often ulcerated and, as a consequence, there are no gross characteristics that distinguish it from ordinary squamous cell carcinoma.

As in the lung, SCNEC of the larynx can be divided microscopically into three types: oat cell, intermediate, and combined. The oat cell type, by far the most common variant, grows in the submucosa as sheets or ribbons of closely packed cells, with indistinct cytoplasm and round, oval, or spindled, hyperchromatic nuclei without nucleoli. Mitoses, necrosis, and lymphatic, vascular, and perineural invasion are common, as well as nuclear molding and DNA coating ("hematoxyphilia") of the walls of blood vessels. Rare rosette formation may also be seen. The mucosa is often ulcerated, but the marginal epithelium is free of significant dysplasia or in situ carcinoma.

The intermediate type of SCNEC has a growth pattern similar to the oat cell variant, but differs in that the cells are slightly larger and contain more cytoplasm. Combined SCNECs are defined as those tumors that contain, in addition to SCNEC, foci of squamous cell carcinoma or adenocarcinoma, or both. They represent 13.5% of all laryngeal SCNECs and generally have a prognosis similar to that of "pure" SCNEC.

Dense core neurosecretory granules are not uncommon in SCNECs and are usually located in the periphery of the cytoplasm.

Immunohistochemistry
The tumors are variably positive for cytokeratin, neuron specific enolase, synaptophysin, chromogranin and thyroid transcription factor.

Differential Diagnosis

Table 2. Basaloid Squamous Cell Carcinoma (BSCC) Versus
Small Cell Neuroendocrine Carcinoma (SCNEC)

Feature	BSCC	SCNEC
Growth	lobular	diffuse
Spindle cells	+/-	+
Nuclear molding	-	+
Nucleoli	+/-	-
Hyalinosis	+	-
Cyst-like areas	+	-
Peripheral palisading	+	-
In-situ or invasive squamous cell carcinoma	+	-
Synaptophysin, chromogranin, or Leu-7	-	+/-
34BE12 (keratin)	+	-
Inclusion body - cytokeratin positivity	-	+/-
Thyroid transcription factor	-	+/-
Neurosecretory granules on EM	-	+/-

Treatment and Prognosis
The clinical course of SCNEC of the larynx is aggressive, with early regional and distant metastases. Almost half of patients present with positive cervical lymph nodes and about 60-90% will develop distant dissemination, especially to the lungs, liver, and bones. In contrast to SCNEC of the lung, only 8% of SCNECs of the larynx metastasize to the central nervous system and then only as a preterminal event. The 2- and 5-year survival rates are, respectively, 16% and 5%.

Because most patients have disseminated disease at diagnosis, radical surgery (laryngectomy with neck dissection) is rarely indicated. Instead, a therapeutic protocol using a combination of local irradiation and chemotherapy, similar to that in pulmonary SCNEC is advocated. Because of early intralesional angiolymphatic invasion, survival does not necessarily correlate with the size of the tumor.

A few laryngeal SCNECs have been associated with paraneoplastic syndromes. Among these include the Schwartz-Bartter syndrome (hypersecretion of antidiuretic hormone), Eaton-Lambert syndrome (myasthesia gravis-like syndrome), and Cushing's syndrome (ACTH production).

References

Basaloid Squamous Cell Carcinoma

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Adenoid Cystic Carcinoma

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Small Cell Neuroendocrine Carcinoma

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