Case 1
Clinical history: 48 year-old female with acute myelogenous leukemia presents with sinusitis. Clinical concerns over a fungal sinusitis prompts a diagnostic biopsy of the sinonasal tract.
Choose the correct diagnosis:
a) reactive epithelial atypia
b) viral cytopathic effect
b) in-situ squamous cell carcinoma
Histologic findings:
The epithelial alterations are characterized by marked nuclear enlargement, hyperchromasia and pleomorphism. The enlarged nuclei measure up to 25 micrometers in diameter and are 5 to 8 times their normal size. The atypical nuclei are round to oval, but sometimes have irregular and misshapen contours. Most of the nuclei contain 1 or 2 prominent eosinophilic nucleoli, but classic viral inclusions bodies are not identified. The atypical cells occupy the full thickness of the epithelium but generally do not extend into excretory ducts. In some areas, the surface cells retain their cilia. Special stains for fungal organisms are negative.
Discussion:
Various cytotoxic drugs induce bizarre epithelial alterations including nuclear enlargement, hyperchromasia and pleomorphism. These alarming epithelial alterations can be widespread and have been noted in diverse organs and tissues. Most attention has focused on the epithelium lining the lower respiratory tract, but the chemotherapy-induced epithelial alterations lining the upper aerodigestive tract including the sinonasal tract have also been described (Bizarre epithelial atypia of the sinonasal tract after chemotherapy. Am J Surg Pathol 25:652, 2001). As seen in the present case, these alterations include striking nuclear enlargement, hyperchromasia, and pleomorphism. The typical patient is one who has undergone a chemotherapeutic regimen (+/- bone marrow transplantation) for a hematologic malignancy. Given the complex combinations of current chemotherapeutic regimens, it is difficult to pinpoint the specific inciting agent, but the alkylating agent cyclophosphamide has been identified as the single agent of common exposure.
The morphologic changes induced by chemotherapeutic agents can mimic a neoplastic process. Indeed, many studies have cautioned against misinterpreting chemotherapy-induced epithelial atypia as carcinoma. There are several factors that may render the sinonasal tract particularly susceptible to erroneous interpretation of chemotherapy-induced atypia. First, the sinonasal tract has not drawn much attention as a target of such cytotoxic effects, and few pathologists anticipate such alterations at this particular site. Second, when these changes do come across the microscope of an unwary pathologist, first time encounters tend to inopportunely occur during an intraoperative frozen section. At our institution, intraoperative frozen section is often requested to evaluate infiltrative processes involving the paranasal sinuses of oncology patients. In this setting, frozen section artifact tends to accentuate structural distortion and cytologic atypia while obscuring subtle differences between chemotherapy-related atypia and true dysplasia. In two of the initial study cases, the frozen sections were misdiagnosed as high-grade dysplasia. This diagnostic pitfall can be avoided by recognizing the sinonasal tract as a relatively common site of chemotherapy-related atypia, and by duly noting the clinical context of the biopsy. The diagnosis of squamous dysplasia should be made with extreme caution in any sinonasal biopsy from a patient exposed to chemotherapeutic agents, especially patients with hematologic malignancies who have been recently treated with cyclophosphamide.
Case 2.
Clinical history: 21 year-old woman with an oropharyngeal mass
Choose the correct diagnosis:
a) benign mixed tumor
b) myoepithelioma
c) carcinoma ex-mixed tumor
d) myoepithelial carcinoma
Histologic findings:
The tumor cells grow in a solid sheet-like arrangement at the center of the lesion, but as cords at the tumor’s periphery. The tumor is non-encapsulated but circumscribed, although there are areas where the tumor focally extends into adjacent soft tissues as it disrupts and splays skeletal muscle fibers. The tumor cells have a clear vacuolated cytoplasm. Their nuclei are bland, and mitotic figures are not easily appreciated. There is focally ductal differentiation, but this ductal component represents well under 2% of the tumor volume. The tumor is quite cellular lacking a chondromyxoid stromal component. By immunohistochemistry, the clear cells were found to be immunoreactive for cytokeratin, calponin, and S100 (focal).
Discussion:
Myoepithel salivary gland neoplasms are those that are comprised almost exclusively of myoepithelial cells. In reality, benign myoepithelial tumors (i.e. myoepithelioma) represent one extreme of the histologic spectrum of BMT. In fact, the distinction of a myoepithelioma from a BMT is very arbitrary. Some authors do not allow for any ductal differentiation, while others permit focal ductal differentiation as long as this component comprises no more than 5% of the tumor. Myoepithelial tumors tend to be very cellular with little intervening stroma. In fact, the presence of focal chondroid or osteoid differentiation is felt by some to exclude the diagnosis of myoepithelioma in favor of BMT.
The myoepithelial cell is sometimes difficult to recognize because of its diverse range of morphologies. Four basic cell types are recognized: the spindle cell type, the plasmacytoid cell type, the epithelioid cell type, and the clear cell type. Myoepithelial tumors can be comprised of any one of these cell types, either singly or in combination. Given the diversity of cell morphology, myoepithelial tumors may be mistaken for a variety of other tumor types. Here the use of immunohistochemistry can be very useful. The myoepithelial cell is consistently immunoreactive for cytokeratin, S100, smooth muscle actin and calponin.
The malignant counterpart of the benign myoepithelioma is the rare myoepithelial carcinoma. To make a diagnosis of myoepithelial carcinoma, one needs to document the myoepithelial nature of the tumor cells and the presence of malignancy. Invasive tumor growth is the most reliable feature of malignancy. Indeed, as is demonstrated in the present case, invasive growth can occur even in the absence of significant cytologic atypia and high mitotic counts.
Case 3.
Clinical history: 39 year-old man with indurated ulcer on lateral tongue.
Choose the correct diagnosis:
a) non-specific ulceration and inflammation
b) traumatic eosinophilic ulcer
c) ulcerated squamous cell carcinoma
Histologic findings:
The overlying surface epithelium is thickened and centrally ulcerated, but no significant dysplasia is recognized. There is downward proliferation of the epithelium into the submucosa. The ulcer is associated with an inflammatory infiltrate that is rich in eosinophils. The eosin-rich inflammatory infiltrate fills the submucosa and extends into skeletal muscle.
Discussion:
Traumatic eosinophilic ulcer is an uncommon lesion that usually affects the tongue. Its etiology is unclear, but trauma is believed to play a major role in the development of this lesion for the majority of patients. The lesion is notable for its propensity to mimic an invasive carcinoma based on its clinical appearance. Despite its alarming clinical features, traumatic eosinophilic ulcer is a benign and self-healing process that appears suddenly and then disappears after several weeks without the need for intervention.
The lesion can be recognized by its characteristic light microscopic appearance. The lesion contained a polymorphic inflammatory infiltrate that extends deep into the submucosa, underlying muscle, and salivary glands. The inflammatory infiltrate consistently includes numerous eosinophils and large mononuclear cells with pale nuclei. At times the reactive mononuclear cells are misinterpreted as malignant lymphoma. Sometimes the ulcer is associated with pseudoepitheliomatous hyperplasia, a finding that should not be mistaken as invasive squamous cell carcinoma.
Case 4.
Clinical history: Newborn with polypoid gingival mass
Choose the correct diagnosis:
a) granular cell tumor
b) congenital epulis
c) rhabdomyoma
d) alveolar soft part sarcoma
Histologic findings:
The surface epithelium is stretched and flattened over a dense cellular infiltrate filling the submucosa. The surface epithelium is not proliferative (e.g. no evidence of pseudoepitheliomatous hyperplasia). The cells filling the submucosa are round with vesicular nuclei and abundant pink, coarsely granular cytoplasm. There is no intervening stroma, although the tumor is dissected by a rich vascular network.
Discussion:
Congenital epulis (gingival granular cell tumor) is a benign lesion that exclusively occurs in newborns. There is a strong predilection for females. It consistently arises in the oral cavity along the crest of the alveolar ridge in the incisor area. Malignant transformation does not occur, and local recurrence is unusual even after incomplete excision.
In addition to certain clinical differences, there are subtle microscopic differences between congenital epulis and the closely related granular cell tumor. Specifically, congenital epulis is not associated with pseudoepitheliomatous hyperplasia of the overlying epithelium (there would be no reason to confuse congenital epulis with squamous cell carcinoma), congenital epulis demonstrates a greater degree of vascularity, and congenital epulis may sometimes incorporates rests of odontogenic epithelium (not present in the current case). The adult type of rhabdomyoma is also characterized by large polygonal cells with deeply eosinophilic granular cytoplasm, but well developed cross striations could usually be appreciated in this rare lesion. If uncertainty persist on the basis of morphologic features, a definite diagnosis can be established immunohistochemically: rhabdomyoma is desmin and myoglobin positive, while congenital epulis is S100 positive. Alveolar soft part sarcoma occurs in a relatively older group of patients, is characterized by an organoid growth pattern, and contains intracytoplasmic PAS-positive diastase-resistant crystalline material.
Case 5.
Clinical history: 6 year-old girl with conductive hearing loss and resection of a middle ear lesion believed to be a congenital cholesteatoma
Choose the correct diagnosis:
a) normal middle ear contents
b) choristoma, salivary gland type
c) teratoma
Histologic findings: The specimen consists of well formed accessory salivary gland lobules within fat.
Discussion:
The middle ear is lined by cuboidal epithelium (and respiratory epithelium to varying degrees), and its submucosa is made up of fibroconnective tissue. Salivary gland tissue is not a normal component of the middle ear. The presence of histologically normal tissue at a site where that tissue does not normally occur defines the choristoma. Only two types of choristomas are recognized in the middle ear: the glial choristoma and the salivary gland choristoma. Salivary gland choristomas of the middle ear are benign non-progressive lesions. Surgical removal is curative. Biopsy alone to establish the diagnosis is reasonable if surgical removal poses a risk of injury to the facial nerve.
Case 6.
Clinical history: 63 year-old woman with nasal obstruction
Choose the correct diagnosis:
a) normal respiratory mucosa
b) rhinosporidiosis
c) cylindrical cell papilloma
d) low grade papillary adenocarcinoma
Histologic findings:
A small biopsy was taken of an intranasal papillary lesion and submitted for frozen section analysis. Even in this small sample, one can discern both endophytic and exophytic growth components. The epithelium is multilayered and composed of cells with abundant pink cytoplasm. At the surface, the cells are ciliated. The epithelium is most striking for the abundant presence of round intraepithelial cysts filled with round pink secretions. These cysts are confined to the epithelium and do not occur in the submucosa.
Discussion:
The least common subtype of Schneiderian papilloma is the cylindrical cell papilloma. Architecturally this subtype is quite complex demonstrating papillary fronds and elaborate branching. Its growth usually demonstrates both exophytic and endophytic components. At higher power, multilayered columnar cells with striking eosinophilic cytoplasm and round nuclei characterize this subtype. This epithelium contains prominent small mucous-containing cysts, a feature that is frequently mistaken for the cysts seen in rhinosporidia. In contrast to rhinosporidia, the cysts of cylindrical cell papilloma are intraepithelial and do not occur in the submucosa.
The cylindrical cell papilloma has a predilection for the maxillary sinus, but often shows contiguous involvement of the lateral nasal wall. Like the inverted type of Schneiderian papilloma, the cylindrical cell papilloma has a marked potential for intramucosal spread. This tendency toward intramucosal spread is also felt to account for the high recurrence rate of these papillomas following surgical excision. Although it has been difficult to define the risk of malignant transformation of the cylindrical cell papilloma, it is probably closely related to the inverted papilloma with a malignant transformation rate of 10% to 13%.