Classification of human upper respiratory tract tumors.

An outline of human upper respiratory tumors is presented, based on the World Health Organization's classification of such tumors. The discussion and illustrations are devoted mainly to the nasal passages, and emphasis is placed on lesions that are potentially confusing because of problems of terminology or unusual histologic features. ImagesPLATE 1.PLATE 2.PLATE 3.PLATE 4.PLATE 5.PLATE 6.PLATE 7.PLATE 8.PLATE 9.PLATE 10.


Introduction
Some types of tumors can occur in almost any location in the upper respiratory tract (URT), while others are more limited in their specific areas of occurrence. Thus it is potentially useful to divide the classification of URT tumors into those affecting various anatomic subregions. Regarding the nasal passages, it is of some importance to distinguish between the nasal cavity proper and the nasopharynx (epipharynx) in the human, since some of the neoplasms found in these two locations have relatively specific characteristics depending upon which area is the site of origin. Distinctions between these two regions often are not given proper attention by many human pathologists.
Many animals have only a meager region that would correspond to the human nasopharynx (1), thus distinction from a relatively large nasal cavity may not be important in the pathology of such an animal. However, for purposes of comparative pathology it is important to know that the nasopharynx in man deserves its own place in the classification of tumors (2).
The following discussion of the histologic features of human URT tumors will be based on a slightly modified version (presented at the end of the article) of the classification of these tumors developed by the World Health Organization (3).

Tumors of the Nasal Cavity and Paranasal Sinuses Benign Epithelial Tumors
Papillomas arising from the sinonasal epithelium are an important group of tumors. Although benign, they have a tendency for recurrence and can become large and extensive. The stroma of these tumors often resembles that of common inflammatory nasal polyps, for which they are sometimes histologically misdiagnosed.
The characteristic features that enable microscopic diagnosis include the proliferated patterns of the thickened, neoplastic surface epithelium. Papillomas of the nasal septum grow with a generally exophytic (or classically papillomatous) architecture (Plate 1), while those of the lateral nasal cavity wall or paranasal sinuses include endophytic folded ribbons of peninsular epithelial projections that seem to push or invert into the underlying stroma (Plate 2). Thus the term "inverted" papilloma is commonly used for these lesions.
The convoluted epithelium of these papillomas is thicker than the normal respiratory epithelium, and usually very much so. Although the epithelium often has some columnar cells, particularly near the surface, much of the epithelium has usually developed a squamous or epidermoid quality. Frequently the epithelium is virtually all squamous. It is nonkeratinizing and rather immature squamous epithelium, however; therefore it has a so-called transitional quality. A few mucous cells may be found, attesting to the respiratory mucosal epithelial origin (as opposed to the epidermis of the nasal vestibule) for these tumors. The mucous cells sometimes lead to the formation of scattered microcysts within the papillary epithelium.
The cytoplasm of some of these papillomas may be modest in amount, and the lesions thus will appear moderately cellular. Some mitotic activity may be present away from the basal area, and so the papillomas can appear histologically active. However, nuclei are uniform, as is the polarity of the cells, and this helps to exclude a papillary carcinoma. Some of these papillomas retain a columnar or cylindrical cell population throughout their epithelium, together with a moderately abundant pink and oncocytoid granular cytoplasm (Plate 3). This variant of inverted papilloma has been called the cylindrical cell papilloma. Intraepithelial microcysts may be prominent.
Approximately 5 to 10% of inverted papillomas (particularly when found in the older patient) develop an associated squamous cell carcinoma. For the exophytic septal papillomas, this malignant transformation seems to be extremely rare.
Benign mixed tumors (pleomorphic adenomas) of salivary gland type can arise in the nasal cavity, usually from the nasal septum. Often the amount of cartilage is scant or even virtually absent, making histologic recognition difficult.

Malignant Epithelial Tumors
The most common malignancy in the human upper respiratory tract is squamous cell carcinoma. The histologic features of most variants of this type of tumor are well known to all pathologists. The most differentiated indicators are keratinization and intercellular bridges. These carcinomas can, of course, have varied degrees of differentiation (both among tumors in different hosts or within a given individual tumor). When the tumors are poorly differentiated (and without intercellular bridges or evidence of keratin) their recognition or categorization can become difficult.
Many nonkeratinizing squamous cell carcinomas tend to recapitulate the stratified surface epithelium from which they have arisen. They form ribbons of stratified epithelium which, together with a pavemented appearance of tumor cells, allows for recognition of their squamous nature. Some pathologists have used the terms "transitional" or "transitional cell" carcinoma for this variant.
Some nonkeratinizing squamous cell carcinomas have convoluted ribbons of epithelium growing in a pattern virtually identical to that of an inverted papilloma. Distinction may be difficult and misdiagnosis can be a problem. The carcinomas tend to have cells with, at least, slightly more nuclear variability, increased nuclear to cytoplasmic quantity ratios, and sometimes more mitoses than are found in the papillomas (Plate 4). However, these differences may be small or subtle. In many of the papillary carcinomas, a disturbance in cellular polarity with a somewhat jumbled up appearance of the tumor tissue can be helpful in diagnosis.
Although the respiratory epithelium can give rise to carcinomas with very clear squamous features, some nonkeratinizing respiratory epithelial carcinomas retain a columnar or cylindrical shape in many or most of their cells. These carcinomas have been called cylindrical cell carcinomas. Occasionally there may be some scattered mucus-containing cells or glandlike formations, and a distinction from an adenocarcinoma may be difficult. However, if a good ribbonlike pattern is maintained, these tumors may be more closely related to nonkeratinizing squamous cell carcinomas than to adenocarcinomas. Squamous cell carcinomas can undergo a remarkable transformation into a poorly differentiated spindle cell proliferation that can be extremely difficult to distinguish from a sarcoma (particularly a fibrosarcoma or a malignant fibrous histiocytoma). Indeed, the term carcinosarcoma has sometimes been used for these tumors, although they are, histogenetically, carcinomas. If an area of obvious squamous cell carcinoma with an apparent transition into the sarcomatoid component is found, the recognition of the tumor is not too difficult. However, in many tumors, the spindle cell transformation has become so predominant that the squamous carcinomatous portion is extremely scant or is obscured and not found. The sarcomatoid transformation can become so complete that many or all of the spindle cells lose their ultrastructural and immunohistochemical epithelial features (4). This seems to be an instance of biologic transformation becoming so wondrous as to blur the usual, assumed profound, distinction between carcinomas and sarcomas.
In contrast to the extreme alteration found in the spindle cell carcinomasjust discussed, verrucous carcinomas have such a very well-differentiated character that their diagnosis as carcinoma is often very difficult. Indeed, since they are thought to have virtually no metastatic potential (unless they undergo a more malignant transformation), they could be thought of as being in the border zone between benign tumors and frankly biologically malignant ones. These verrucous tumors have been considered carcinomas because of their capacity for invasive and destructive growth. However, their distinction from benign irregular hyperkeratotic (verrucoid) lesions is problematic, since they have no cytologic features of malignancy. The diagnosis rests upon clinical or histologic evidence (ideally both) of the destructively invasive growth.
Sinonasal adenocarcinomas include extremely welldifferentiated variants that histologically could be considered as adenomas. However, just like very welldifferentiataed acinic cell tumors of salivary glands (which histologically suggest adenomas but which have been proven to have some metastatic capacity), they are probably best considered to be low-grade adenocarcinomas (5). These tumors are composed mostly of epithelium that is one cell-layer thick and forms varied glandular, papillary, or cystic architectures (Plates 5 and 6). The individual cells may have a somewhat salivary acinic or oncocytoid character, or may be rather non-specific in appearance. Although some of these tumors may be derived from the mucoserous glands of the sinonasal tract, many seem to have developed from the surface epithelium (5).
Higher grade adenocarcinomas may either be moderately well differentiated or poorly differentiated. Roughly one-half of these tumors (5) have a resemblance to adenocarcinomas of the colon. Many have a moderately well-differentiated glandular and slightly papillary pattern composed of a layer of columnar cells with a suggestion of pseudostratification (Plate 7). While not prominently anaplastic, the nuclei are more variable than those of the low-grade adenocarcinomas and many are hyperchromatic. Mitotic figures are usually not hard to find.
Occasionally these adenocarcinomas will produce an overabundance of mucin and will resemble the so-called colloid adenocarcinomas that are sometimes found in the colon. Rarely a signet-ring adenocarcinoma may be found in the sinonasal tract.
Sinonasal adenocarcinomas that resemble colonic carcinomas have a relatively high association with occupational wood dust exposure. While some patients with this type of adenocarcinoma do not have a history of such exposure, and adenocarcinomas with a nonspecific histologic appearance may occasionally occur in a person with significant wood dust exposure, the correlation between wood dust and this particular histologic category of sinonasal adenocarcinoma is rather strong in most studies (6).
Adenoid cystic carcinomas histologically identical to those of salivary gland origin make up a significant proportion of sinonasal glandular tumors. They are very difficult to cure in this anatomic location.
Tumors resembling low-grade mucoepidermoid carcinomas of the salivary type have occurred in the sinonasal area, although they are very uncommon. Highgrade and poorly differentiated carcinomas with both squamoid and adenoid features can be found in the upper respiratory areas. Since they arise from the surface mucosal epithelium and are not clearly related to salivary high-grade mucoepidermoid carcinomas, perhaps adenosquamous carcinoma is the most appropriate term for these neoplasms.
Undifferentiated carcinomas are, of course, found in the upper respiratory tract. They may have a nonspecific large cell pattern, or they may be the small cell neuroendocrine or oat cell type (7).

Benign Soft Tissue Tumors
In addition to occasional hemangiomas, the nasal cavity can give rise to hemangiopericytomas. These tumors are prone to be misdiagnosed as many other types of neoplasia (8). In contrast to hemangiopericytomas in other locations, these sinonasal tumors are seldom histologically or clinically clearly malignant.
Smooth muscle tumors are rare in the upper respiratory tract, possibly because smooth muscle is not present except in vessel walls. This may also account for the fact that, when leiomyomas are found, these tumors often are vascular.
Benign myxomas occur in the sinonasal regions, particularly in young persons. Although benign, they can destroy bone. It is important to distinguish these tumors from the highly malignant embryonal rhabdomyosarcomas of this anatomic region, and immunohistochemistry can be helpful in this regard.
Schwannomas, neurofibromas, and fibrous histiocytomas occurring in the sinonasal tract are histologically similar to such tumors occurring in other anatomic locations.

Malignant Soft Tissue Tumors
High-grade fibrosarcomas are very uncommon in the sinonasal tract, and most fibrosarcomas of this region are slowly growing tumors of low histologic grade. These tumors are composed of interwoven fascicles of elongated, thin spindle cells (Plate 8). Mitotic figures are rare. Distinction from an aggressive fibromatosis can be difficult, but usually, at least, some areas are more cellular than generally would be expected with fibromatosis.
Some low-grade fibrosarcomatous sinonasal tumors have wavy nuclei and occasional S-100 positive cells. They may represent a low-grade variant of malignant schwannoma. They do not look typical for a cellular benign schwannoma and, unlike the latter, are not encapsulated or well demarcated at their edge. Higher grade sinonasal malignant schwannomas may occasionally occur.
Either sinonasal fibrosarcomas or malignant schwannomas may have an associated marked papillary hyperplasia of the respiratory epithelium. The cause of this is not clear, but the effect may be striking. Sometimes the papillary epithelial proliferation is misinterpreted as an inverted papilloma, and it can be so eye-catching that the actual neoplasm (the sarcoma) is overlooked by the histopathologist.
Sinonasal leiomyosarcomas can be very difficult to distinguish from fibrosarcomas and malignant schwannomas, and immunostrains do not always ensure distinction. Because of this the incidence of these leiomyosarcomas is somewhat uncertain, but they are probably very uncommon.
Rhabdomyosarcoma is an important tumor of the nasal passages and adjacent areas, occurring most often in children. The embryonal type is a spindle cell and frequently myxoid malignancy that sometimes may be misinterpreted as a benign tumor. The alveolar variant is seldom misdiagnosed as benign, but it may be difficult to distinguish from other round cell poorly differentiated malignancies. Immunostains are often helpful in resolving these problems.
Ewing's sarcoma, malignant fibrous histiocytoma, and malignant hemangiopericytoma may occasionally be found in this area. Angiosarcomas also occur, although they are probably very rare, and probably more rare than even the scant reported cases would suggest. Atypical reactive vascular proliferations in this anatomic location can easily be misdiagnosed as angiosarcoma (9).

Tumors of Bone and Cartilage
Osteomas are not uncommon in the sinonasal tract, particularly in the frontal sinus. Chondromas are less common and may be difficult to distinguish from lowgrade chondrosarcomas. Higher grade chondrosarcomas and also osteosarcomas occur in this region.
Fibrous dysplasia and ossifying fibroma are not infrequently encountered in the sinonasal tract. Growth patterns asjudged from radiographs are often important in distinguishing these two lesions. Sinonasal giant cell tumors are occasionally found, and when they are discovered in other locations, hyperparathyroidism must be excluded.

Tumors of Lymphoid and Hematopoietic Tissues
Although Hodgkin's disease would be extremely rare in the sinonasal tract, almost any type of non-Hodgkin's malignant lymphoma may present as an extranodal tumor in this location. Extramedullary plasmacytomas are not rare. Burkitt's lymphoma is an important undifferentiated B-cell lymphoma that frequently involves facial bones (especially in African children), although it also can involve other areas.
A diagnostically troublesome, destructive condition that has been referred to as "lethal midline granuloma" is, in reality, a type of malignant lymphoma, probably usually of T-cell type. Other recently popular names for this lymphoma are polymorphic reticulosis and, more to the point, malignant reticulosis. It causes problems in diagnosis, partly because the malignant cells are (at least in the initial stages of the malignancy) scattered among many nonneoplastic inflammatory cells. Most of the malignant cells may be relatively small and unobtrusive.

Miscellaneous Tumors
Odontogenic tumors can occur in the sinonasal tract. Sometimes, for example with an occasional ameloblastoma, the apparent site of origin may be significantly rostral to the odontogenic apparatus.
In contrast to the pharynx, childhood teratomas arising from the sinonasal tract proper are extremely rare. Less rare, but still very uncommon, malignant teratoid tumors in adults have been described (10). Small biopsies from these tumors may be diagnosed as many other types of tumors.
Primary sinonasal malignant melanomas are not extremely uncommon (although they are rare in the pharynx). When examining a poorly differentiated sinonasal malignancy, one should always keep the possibility of melanoma in mind. Olfactory neuroblastomas are an important tumor type. When this tumor is relatively well differentiated (Plate 9) with a prominent neurofibrillary matrix, it is not too difficult to diagnose. However, less well-differentiated examples can be confused with a multitude of other neoplasms. Distinction from carcinoma can be especially difficult. Even when some differentiation is present, neural rosettes may be interpreted as glands and vice versa. The distinction between these two types of structures can be quite difficult; it is complicated by the finding of keratin-positive epithelial cells and glandlike structures in occasional olfactory neuroblastomas (D. K. Heffner, personal observation). Some of these epithelial cells may be entrapped nonneoplastic cells derived from sinonasal glands (11) or surface epithelium. However, some have been intimately involved in the tumor in a fashion to suggest that they are part of the neoplastic population (D. K. Heffner, personal observation). Perhaps these epithelial structures are neoplastic representations of the sustentacular cells of the olfactory neuroepithelium from which these tumors derive.

Tumors of the Nasopharynx Benign Epithelial Tumors
Papillomas of sinonasal type (i.e., inverted papillomas) do not characteristically arise in the nasopharynx, although occasionally a nasal cavity papilloma may creep onto the nasopharyngeal side of the soft palate. Small oncocytic proliferations are not rare in the nasopharynx. Since most of these seem to be of quite small size and very limited growth potential, they most likely represent metaplasias with hyperplasia rather than neoplasias.
Although very uncommon, pleomorphic adenomas may be found in the nasopharynx. They should be distinguished from chordomas (a malignant tumor) for which they sometimes can be mistaken.

Malignant Epithelial Tumors
Most nasopharyngeal carcinomas (NPCs) are essentially poorly differentiated variants of squamous cell carcinomas. Only uncommonly do they have such differentiated features as intercellular bridges or keratin production. Although lacking keratin production, many NPCs retain a pavemented epithelial appearance (13) and ribbonlike architecture that suggests a faint squamous nature.
Many NPCs become quite poorly differentiated or essentially undifferentiated. Although these undifferentiated carcinomas are not always histologically distinguishable from undifferentiated carcinomas arising elsewhere, they often have a somewhat characteristic appearance (14). Groups of cells have a very syncytial cytoplasm, nuclei tend to overlap, nucleoplasm may be quite clear or washed out (even in properly fixed tissue), and nuclei are contrastingly quite prominent (Plate 10).
These carcinomas are associated with the presence of the Epstein-Barr virus genome in the tumor cells; conceivably, this association has something to do with the somewhat characteristic histologic features of these neoplasms.
Adenocarcinomas of the nasopharynx are scarce, but the adenoid cystic variant is not rare. Occasionally encountered are low-grade papillary adenocarcinomas that somewhat resemble thyroid carcinomas.
Among this group of tumors thejuvenile nasopharyngeal angiofibroma stands out as a characteristic tumor of the anatomic region. Although it may arise from the extreme posterior position of the upper lateral nasal cavity, it almost always presents with a prominent component in the nasopharynx. Although the histologic findings of benign fibrous tissue and vessels have been considered rather nonspecific, there are subtle aspects of the pattern of the tumor that usually allow for a specific histologic recognition (9).
Miscellaneous Tumors leratomas can arise in the nasopharynx of infants. Thmors of the mid-skull base such as pituitary adenomas, craniopharyngiomas, and menIngiomas may be found in the nasopharynx.
Tumors of the Larynx, Hypopharynx, and Trachea Many of the tumors discussed above can also occur in these anatomic regions ("Appendix"). Papillomas, associated with the human papilloma virus genome, are the most common benign tumors. Squamous cell carcinomas are relatively common. Poorly differentiated adenosquamous carcinomas are not rare, particularly in the hypopharynx. Spindle cell sarcomatoid carcinomas are not especially rare, and often present as polypoid exophytic masses. Occasionally neuroendocrine carcinomas of the supraglottic larynx are encountered that often contain calcitonin and may be mistaken f6r metastatic medullary carcinoma of the thyroid.
Among soft tissue tumors, benign granular cell tumors are found, especially in the true vocal cords. Synovial sarcomas can occur in this region.
Among bone tumors, chondrosarcomas (usually low grade) of the laryngeal skeleton deserve mention.