Section 3 -

Can you hear me now? Selected Lesions of the Ear Lester D.R. Thompson Southern California Permanente Medical Group Woodland Hills Medical Center Woodland Hills, CA

Ceruminous Adenoma Background Tumors arising from the ceruminal glands of the external ear canal can present a diagnostic dilemma because of their varied clinical and histological manifestations. While common in animals, tumors of this type are rare in humans and therefore are seldom seen by general surgical pathologists. Further adding to the confusion for pathologists and clinicians alike, is the variable nomenclature used to describe benign tumors of ceruminal gland origin: ceruminoma, ceruminal adenoma, syringocystadenoma papilliferum, mixed tumor, apocrine adenoma, and cylindroma. The varied clinical behavior, treatment alternatives, and long term patient prognosis of the different types of ceruminal gland neoplasms suggests that "ceruminal" appear somewhere in the diagnosis to convey the anatomic site of origin and the underlying tumor type. Clinical Features There is an equal gender distribution with a wide age at initial presentation although the 6th decade seems to be the mean age at initial presentation. Patients most frequently present with a mass lesion in the outer one-half of the external auditory canal accompanied by hearing changes and occasionally pain. Symptoms will be present for a variably duration with an average of just over one year. Pathologic Features Gross Findings Since the ceruminal glands are only found in the outer one third to one half of the external auditory canal, this is the location for these apocrine derived neoplasms. Therefore, it is important to obtain an accurate location of the biopsy from the surgeon, to exclude glandular neoplasms from the parotid gland or middle ear. As benign tumors, extension into the mastoid bone, middle ear, and base of the skull is not identified. Given the confines of the canal, the tumors are about 1 cm in greatest dimension. Microscopic Findings Ceruminal adenomas are circumscribed, although not truly encapsulated. Surface involvement can be seen, but ulceration often will obscure this relationship. These benign ceruminal neoplasms can be divided into three major groups based on specific histologic findings: ceruminal adenoma, ceruminal pleomorphic adenoma, and syringocystadenoma papilliferum. Ceruminal adenomas contain neoplastic cells arranged in a variety of different patterns. Whereas a glandular pattern predominates in most lesions, cystic spaces lined by a dual cell population are frequently noted. Ceruminal adenomas demonstrate a dual cell population composed of a inner luminal epithelial cells subtended by basal/myoepithelial cells adjacent to the basement membrane. The luminal cells frequently reveal apocrine-type decapitation secretion and/or contained yellow-brown cerumen (wax) granules. These latter two features assist enormously in confirming the ceruminal origin of the neoplastic cells. The tumors tend to have a low to moderate cellularity composed of cells with mild to moderate nuclear pleomorphism. Nucleoli can be found, necrosis is not seen, and rare mitotic figures can be counted. The presence of a more abundant myoepithelial cell population juxtaposed next to areas of myxoid-chondroid matrix material in the presence of ceruminal apocrine cells within the "duct-like" structures, confirms the diagnosis of a ceruminal pleomorphic adenoma. The apocrine decapitation secretion and cerumen (wax) is usually identified within the luminal cells of the duct-like structures of the pleomorphic adenomas. The syringocystadenoma papilliferum is similar to its skin counterpart and is quite rare in this location. Immunohistochemical Features The lesion cells usually react strongly and diffusely with keratin while only weakly and focally with epithelial membrane antigen. The dual cell population can be accentuated by strongly immunoreactive with CK7 in the luminal cells contrasted to strong and diffuse immunoreactivity with S-100 protein, CK5/6 and p63 in the basal-myoepithelial cells. Differential Diagnosis Paraganglioma, meningioma, schwannoma, middle ear adenoma and ceruminal gland adenocarcinoma are the principle differential diagnostic considerations given the anatomic location of ceruminal gland primaries. The "zellballen" architectural, slightly basophilic cytoplasm, nuclear pleomorphism, and chromogranin/synaptophysin and S-100 immunoreactivity will define a paraganglioma. Meningioma has a whorled or meningothelial growth, psammoma bodies, intranuclear cytoplasmic inclusions, and a single cell population (EMA is weakly expressed as well). Schwannoma usually affects the cerebropontine angle and not the external auditory canal, has palisading, a single cell population and a lack of glandular growth. Middle ear adenoma can have a similar biphasic tumor growth with a number of patterns similar to ceruminal adenoma. However, it arises within the middle ear, the nuclear chromatin distribution is "neuroendocrine," there are no decapitation apocrine secretions, there is a lack of cerumen, and the cells are immunoreactive with chromogranin and human pancreatic polypeptide. The most difficult differential is with ceruminal gland adenocarcinoma, whether "not further specified" type or adenoid cystic type. The ceruminal gland adenocarcinomas are much more cellular (sometimes difficult to assess on a small biopsy), have a more solid and infiltrating growth, have increased mitotic figures, including atypical forms, demonstrate moderate to severe nuclear pleomorphism, have prominent nucleoli in many cells, develop tumor necrosis, and in general lack cerumen. While any one of these features of ceruminal gland adenocarcinoma can be seen in ceruminal adenoma, it is the aggregate of the findings in either entity that helps with the diagnosis. Prognosis and Therapy While complete surgical removal of the tumor is ideal, it is frequently impossible due to the complex anatomy of the ear. Therefore, in a small percentage of patients, residual tumor may develop a recurrence. After additional surgery, the patients enjoy a disease free survival. Ceruminous Adenocarcinomas Malignant neoplasms derived from the apocrine (ceruminous glands) of the external auditory canal are rare. These neoplasms take the form of adenoid cystic carcinoma, mucoepidermoid carcinoma, and adenocarcinoma, not otherwise specified. Clinical Features These rare tumors arising from the ceruminal glands of the outer one third to one half of the external auditory canal seem to occur in men more frequently than women. Patients tend to be middle to older aged at presentation. Patients present with a mass, hearing changes (conductive hearing loss), drainage, pain, and/or neurologic deficits, most commonly facial nerve paralysis. Symptoms are frequently present for on average 8-12 months. Radiologic Features Imaging will often demonstrate invasion of middle ear by penetration of the tympanic membrane or of the bony wall of the deep external canal. It is most important to exclude involvement of the parotid gland, as adenoid cystic carcinomas may grow into the ear canal by direct extension. Evidence of metastasis to the ipsilateral preauricular lymph node can also be demonstrated by imaging. Microscopic Findings Tumors are often polypoid, ranging up to 3 cm. Histologically, all forms of this tumor are invasive. Tumors are solid to cystic, composed of infiltrating glandular to cribriform arrangement of epithelial cells. Uncommonly a dual cell population is noted, but is not the dominant histology. Ceruminous adenocarcinomas may be recognized by the eosinophilic character of the tumor cells, but apocrine type secretion and a myoepithelial layer are, unlike benign ceruminous adenomas, not usually present in the malignant form. Surface involvement is common. Tumors are cellular, with moderate to severe nuclear pleomorphism and irregular nucleoli. Increased mitotic figures, including atypical forms are present. The adenoid cystic type shows identical features to the same lesion growing from major and minor salivary glands, comprised of masses of small cells with hyperchromatic, carrot-shaped nuclei, surrounding punched-out round spaces containing a basophilic secretion. Nerve fiber invasion is frequent. Tumor necrosis, while uncommon, confirms a malignant diagnosis. Immunohistochemistry may highlight the basal cells if they are present (p63, S-100 protein), but the tumor cells are usually CK7 positive. Differential Diagnosis The most important aspect of the differential diagnosis is to exclude direct invasion from a parotid gland primary, best achieved through careful imaging. Metastatic adenocarcinomas (discussed below) may also be raised in the differential diagnosis, but a clinical history and unique histology should make the distinction. Prognosis and Therapy The prognosis is variable, depending upon the extent of the disease. The histologic sub-type does not seem to influence patient outcome. Multiple recurrences and often metastasis (lung rather than lymph nodes) may be seen. Interestingly, patients may survive >10 years with wide surgical excision (radical surgery) and radiation. Metastatic Neoplasms It is important to excluding neoplasms which directly invade from a contiguous site into the ear from metastatic tumors spread by blood or lymphatic channels from a noncontiguous site. Metastases to the ear and temporal bone generally occur late in the course of the cancer producing the metastases. While unusual in surgical pathology material during life, autopsy studies show temporal bone involvement in about 20% of patients, virtually all of whom also had disseminated malignant disease. Direct extension can be from meningioma, salivary gland or nasopharyngeal tumors. Clinical Features Older patients tend to be affected, with slight difference in gender distribution based on the anatomic site of the primary. Most lesions which metastasize to the ear and temporal bone are carcinomas and melanomas, with few lymphomas or sarcomas identified. Symptoms and signs of metastatic neoplasms in the ear are those of hearing loss, tinnitus, vertigo, nystagmus, facial palsy, otalgia, otorrhea, and external canal mass. Microscopic Findings Tumors which metastasize to the temporal bone may not yield readily identifiable pathology, but if they extend into more clinically amenable regions, such as the tympanic membrane, they may be more easily diagnosed. Breast carcinomas are the most common primary source, followed by lung, kidney, stomach, prostate, thyroid and larynx; cutaneous malignant melanoma sometimes metastasizes to the ear. In general, metastatic deposits maintain the phenotype of the primary. Rarely are the ear and temporal bone metastases the initial presentation of the disease, and consequently an extensive clinical or histologic work-up is seldom necessary. Occasionally, carcinomas may directly extend into the ear and temporal bone via the Eustachian tube and from the posterior fossa of the skull through the internal auditory canal. Likewise, parotid malignancies can invade the ear. Special Studies: Since primary adenocarcinoma of the ear and temporal bone is vanishingly rare, adenocarcinomas should be presumed to be metastatic. Estrogen and progesterone receptors and Her-2/neu may help with breast carcinoma, while PSA or PAP may identify a prostate carcinoma. TTF-1, CK7 and CK20 are all of value in separating lung and gastrointestinal primaries. Differential Diagnosis: Primary carcinoma would be the only real differential diagnosis, but ceruminous adenocarcinomas and primary adenocarcinoma, NOS, are both vanishingly rare. Immunohistochemical separation helps. Prognosis and Therapy The prognosis of tumors which have metastasized to the ear and temporal bone is generally dismal, a reflection of the underlying stage of the primary tumor. Surgery may be of value in selected cases, while adjuvant therapy can occasionally have a palliative effect. Suggested Reading Aikawa H, Tomonari K, Okino Y, Hori F, Ueyama T, Suenaga S, Bundo J, Tsuji K. 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