Pathology
Macroscopically, the lesion is a well-defined, cystic cavity within the auricular cartilage, often filled with clear to yellow viscous fluid, described as similar to olive oil, which can be "expressed". Microscopically, the skin surface is intact. The lesion is defined by an empty, irregularly shaped cavity or cleft, most often in the central area of the cartilage. Because the space is not lined by an epithelium it is called a "pseudocyst." Granulation tissue (a rich vascular proliferation with erythrocytes, histiocytes, and mixed inflammatory cells) is present in most lesions, usually at the edge of the cleft. Necrotic chondrocytes and the disappearance of elastic fibers may be seen at the edge of the cavities. The remaining cartilage is generally unremarkable.

Differential diagnosis
The clinical and histologic differential diagnosis includes relapsing polychondritis, chondrodermatitis nodularis helicis chronica (CNCH) and Kimura disease.

Patients with relapsing polychondritis (RP; systemic chondromalacia or polychondropathy) present at any age with one or more of the following progressive degenerative changes in the cartilages of the body: recurrent bilateral auricular chondritis, inflammatory polyarthritis, nasal chondritis, ocular inflammation, tracheal or laryngeal chondritis, and cochlea and/or vestibular damage. Other immunologically mediated diseases may be associated with RP (systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome). Although the gross findings are non-specific, there is an overall thickening to the cartilages (ear, nose, epiglottis, cricoid and tracheal rings). There is a loss of cartilage basophilia assuming a more eosinophilic quality. There is fragmentation of the cartilage with necrosis and lysis of the cartilaginous plates. The outer perichondrium (lining of cartilage) is permeated by a spectrum of inflammatory cells, including neutrophils, eosinophils, lymphocytes and plasma cells, frequently associated with edema or gelatinous cystic degeneration, although not "true" cystic degeneration. As the disease progresses, the degenerated fibrillar cartilage imperceptibly blends with the surrounding inflammatory cells leading to granulation type tissue and fibrosis. Other disorders, including sarcoid, infectious agents (tuberculosis, syphilis, various fungi, bacteria and viruses), lymphoma, and Wegener's granulomatosis should be excluded. Obtaining cultures or performing histochemical stains can help to rule out infectious organisms, while performing clinical tests for cartilage matrix proteins or antibodies to type II collagen (found uniquely in cartilage) may help in defining relapsing polychondritis. Corticosteroids or immunosuppressive agents are used to treat patients depending upon the severity of the disease.

CNCH (also called Winkler's disease) affects men more commonly than women and usually in an older age group at initial presentation. It usually presents as a painful, raised nodule on the superior helix with central skin ulceration. Painful nodule affecting only one side (probably due to perichondrial involvement), usually presenting as a raised discrete ovoid nodule about 1.5 cm in greatest dimension. Vascular compromise and solar damage have been considered in the etiologic role. Histologically, there is ulceration, hyperkeratosis, granulation tissue, and inflammation down to, but not including the cartilage. Granulation tissue is identified at the base of the ulcer along with mixed inflammatory cells. There may be involvement of the perichondrium, but not of the cartilage itself. Fibrinoid necrosis can be seen. The treatment of choice is steroids or complete surgical excision.

Kimura disease is a rare form of chronic inflammatory disorder of unknown etiology involving subcutaneous tissues, predominantly in the head and neck region and frequently is associated with regional lymphadenopathy and/or salivary gland involvement. This condition has a predilection for males of Asian descent and may clinically simulate a neoplasm. Most patients have peripheral blood eosinophilia and elevated serum IgE levels. The solitary masses invariably are associated with a lymph node and subcutaneous soft tissues. Characteristic histologic features of Kimura disease include preserved nodal architecture, florid follicular hyperplasia with reactive germinal centers, eosinophilic infiltrates, proliferation of post-capillary venules, sclerosis, polykaryocytes, proteinaceous deposits in the germinal centers, eosinophilic folliculolysis, germinal center necrosis, prominent eosinophilic microabscess, and IgE deposition in the germinal centers. Therefore, without a "lymph node" present, Kimura disease can be effectively eliminated from consideration.

Treatment
Curettage and pressure dressings have been used in the past, although excision or curettage is usually the treatment of choice. Anteriolateral wall excision produces the best cosmetic result rather than full-thickness excision.

Ceruminal Gland Adenomas

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 findings
There is an equal gender distribution with a wide age at initial presentation although the 6^th 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
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.

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
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.

Treatment
While complete surgical removal of the tumor is ideal, it is frequently impossible due to the complex anatomy of the ear and temporal bone. Therefore, in a small percentage of patients, residual tumor may develop a recurrence. After additional surgery, the patients enjoy a disease free survival.

Table 1: Microscopic features in a recent review of 41 cases from the AFIP

Feature Number Growth pattern Glandular 37 Cystic 32 Infiltrating 11 Solid 6 Papillary 8 Dual Population 39 Surface origin 8 Ulceration 3 Mitotic figures (mean per 10 HPF) 0.3 Atypical mitotic figures present 0 Pleomorphism Mild 30 Moderate 11 Severe 0 Cellularity Low 17 Moderate 20 High 4 Prominent nucleoli 16 Ceruminal apocrine decapitation secretion 40 Necrosis present 0 Cerumen/wax granules 36 Associated findings: Cholesteatoma 2 Dense, sclerotic fibrosis 6

Neuroendocrine Adenoma of the Middle Ear—NAME (Middle ear adenoma)

Introduction
Adenomas and carcinoid tumors of the middle ear are rare neoplasms with similar, if not indistinguishable morphologies. First described in 1976 these tumors have been the subject of much debate with regard to their similarities, differences, etiologies, and prognoses. Benign neuroendocrine lesions of the middle ear have been described by many names, including carcinoid tumor, middle ear adenoma, adenomatous tumor of the middle ear, adenocarcinoid, and amphicrine tumor, with carcinoid tumor and middle ear adenoma being the most accepted. It is probably best to think of these tumors as a single entity which display numerous different architectural patterns but similar cytomorphologic and immunohistochemical reactivity patterns.

Arguments against the diagnosis of a carcinoid tumor within the middle ear have stemmed primarily from its lack of paraneoplastic syndromes (i.e. "carcinoid syndrome") and lack of documented metastasis to regional lymph nodes or distant sites. Paraneoplastic systemic alterations due to the elaboration of hormonal products are a well-known feature of carcinoid tumors, especially the so-called "carcinoid syndrome" consisting of flushing, diarrhea, sweating, wheezing, and abdominal pain. When systemic changes are present, lung tumors tend to be large (>3.5 cm). The correlation of large tumor size to increased levels of hormone elaboration is logical, although these large tumors also have a greater frequency of liver metastasis that increases the chance of a paraneoplastic syndrome. The lack of systemic changes associated with tumors of the middle ear may be a function of their relatively small size (average <1.0 cm), since they do have immunoreactivity (although perhaps not systemic production) for hormone products such as serotonin, ACTH, glucagon, HPP, and somatostatin. The lack of documented metastasis of the tumors of the middle ear may be explained by the small size of the neoplasms and the relative lack of vascularity of the middle ear cavity. There is no easily identifiable progenitor cell within the middle ear, although an undifferentiated, pluripotential endodermal stem cell may still be present which may give rise to these neoplasms.

Although the neuroendocrine features of this tumor are not adequately depicted by "Middle Ear Adenoma", it is a correct description of the benign nature of the tumor and its location. "Neuroendocrine Adenoma of the Middle Ear" (NAME) may be an excellent potential alternative as it provides correct morphologic and behavioral depictions of this rare neoplasm.

Clinical
Patients present in the 5^th decade of life (average) with an equal gender distribution. Clinical presentation includes decreased hearing acuity, fullness, and tinnitus as the most common symptoms.

Pathology

Macroscopic findings
Patients present with unilateral disease. Most of the lesions are excised in a piecemeal fashion, with an overall small size (< 1cm) due to the anatomic confines of the middle ear. The tumor by definition occur within the middle ear and occasionally they may extend into the external auditory canal or into the mastoid bone and eustachian tube. There is usually intimate association with the ossicular chain. T umors are described macroscopically as avascular, soft or rubbery unencapsulated masses with a variegated cut surface. The lesions tended to be gray-tan, brown-red, or pale yellow.

Microscopic findings
Tumors are unencapsulated and most are of moderate cellularity. The tumors are predominantly composed of cuboidal-to-columnar cells with indistinct cytoplasmic borders. Flattened, irregular, plasmacytoid, and spindled morphologies are frequently described. The cytoplasm is eosinophilic and homogenous to finely granular. The nuclei tend to be round to oval with minimal pleomorphism. Moderate to severe nuclear pleomorphism is only occasionally observed. The chromatin is distributed in a "salt-and-pepper" pattern, most suggestive of a neuroendocrine origin, especially in the cells comprising the trabecular and solid patterns and those comprising the external cellular layer of the ductal structures. The nuclei are centrally or eccentrically placed, giving some cells a "plasmacytoid" appearance. Nucleoli are inconspicuous and mitoses are essentially absent. Architectural patterns include glandular spaces, trabeculae, festoons, ribbon-like patterns, anastomosing cords, and solid sheets with variable cohesiveness. The architecture varies between tumors and even within the same tumorwith most tumors displaying more than one pattern, although the glandular pattern predominates. The glandular pattern consists of duct-like structures with focal "back-to-back" gland configuration. The ducts are lined by a dual cell population composed of an inner (luminal), flattened, slightly more intensely eosinophilic cell surrounded by a basally positioned cuboidal to short columnar cell. The glandular lumen are occasionally filled with an amorphous, pink substance. Papillary structures are not identified. The "infiltrative" pattern is characterized by small irregular groups and strands of cells in a moderately desmoplastic stroma. This pattern give the illusion of tumor cells dissecting the collagen bundles in an uncontrolled and aggressive fashion. The cells tend to be smaller than those within the other patterns with a higher nuclear-to-cytoplasmic ratio, however, other features of true aggressiveness such as mitotic activity, pleomorphism, necrosis, bone, perineural, or lymph-vascular space invasion are not noted. Definitive surface derivation is not seen.

Immunohistochemistry
The tumor cells are immunoreactive with a variety of keratin antibodies, including cytokeratin cocktail, CK7, and CAM 5.2. Specifically, CK7 immunoreactivity specifically highlights the inner (luminal) layer of the glandular cells with a uniform and intense result, although it is only variably present. Neuroendocrine marker immunoreactivity includes chromogranin, NSE, synaptophysin, serotonin, glucagon, Leu-7, and human pancreatic polypeptide (HPP). Neuroendocrine markers are positive within the basal cell layer of the glandular elements while more diffusely positive in the other architectural patterns. Reactivity, however, is not uniform and varies both between cases and in level of intensity.

Ultrastructure
Electron microscopy demonstrated two distinct cell types, so-called Type A and Type B cells. The Type A cells are noted within the apical aspect of the glandular lumina and rarely scattered within the solid areas. These cells exhibit a flattened apical pole, and thin, elongated microvilli. Most significantly, these cells demonstrate exocrine activity with apically oriented 275-600 nm secretory granules composed of a flocculent dense core and an electron-lucent rim, representative of mucus granules. The granules are occasionally noted to fuse with the apical cellular membrane, thereby discharging their secretory product. The Type B cells are noted in the basal aspect of the glandular structures and are the predominant cell within the solid, trabecular, and ribbon-like formations. They are most noteworthy for their basally located 110-350 nm cytoplasmic dense-core granules neurosecretory granules that are surrounded by a thin halo and distinct limiting membrane. Furthermore, a transitional form exhibiting features of both Type A and Type B cells has also been described.

Treatment/Management
At surgery, the tumors are usually tightly adherent to the middle ear cavity, commonly encasing the ossicular chain. Complete surgical removal of the neoplasm, to include encased ossicles (if present), should be the treatment of choice. When the ossicular chain is involved but not removed, recurrence (re-growth) of the lesion is much more likely. Perforation of the tympanic membrane with extension into the external auditory canal is an occasional feature. However, destruction of or invasion into the surrounding bone has only rarely been reported, is not extensive in nature, and tends to bony erosion rather than destruction. The recurrence rate for these neuroendocrine neoplasms of the middle ear is quite small (<15%). When they do recur, it is usually related to re-growth of an incompletely excised tumor as opposed to an inherent biologic aggressiveness. Even if facial paralysis is identified, it does not seem to portend an adverse clinical outcome. These findings suggest mass-related compression of the facial nerve rather than direct neural invasion. In summary, if one defines "malignancy" by clinical aggressiveness and potential for metastatic spread, then the tumors of the middle ear should be regarded as benign.

References

Cystic chondromalacia

1. Heffner DK, Hyams VJ. Cystic chondromalacia (endochondral pseudocyst) of the auricle. Arch Pathol Lab Med 1986;110:740-743.
2. Mills SE, Gaffey MJ, Frierson HF. Atlas of Tumor Pathology: Tumors of the Upper Aerodigestive Tract and Ear. Armed Forces of Pathology, Washington D.C., 2000:398-400.
3. McAdam LP, O'Hanlan MA, Bluestone R, Pearson CM: Relapsing polychondritis. Prospective study of 23 patients and a review of the literature. Medicine 1976;55:193.
4. McCaffrey TV, McDonald TJ, McCaffrey LA: Head and neck manifestations of relapsing polychondritis: review of 29 cases. Otolaryngol 1978;86:473.
5. Hui PK, Chan JK, Ng CS et al. Lymphadenopathy of Kimura's disease. Am J Surg Pathol 1989;13:177-86.
6. Ioachim H, Ratch H. Kimura lymphadenopathy. In: Ioachim H, Ratch H, eds. Ioachim's lymph node pathology. Philadelphia: Lippincott-Raven, 2002:209-11.

Ceruminous neoplasms

1. Batsakis JG, Hardy GC, Hishiyama RH. Ceruminous gland tumors. Arch Otolaryngol 1967;86:66-9.
2. Collins RJ, Yu HC. Pleomorphic adenoma of the external auditory canal. An immunohistochemical and ultrastructural study. Cancer 1989;64:870-5.
3. Dehner LP, Chen KT. Primary tumors of the external and middle ear. Benign and malignant glandular neoplasms. Arch Otolaryngol 1980;106:13-9.
4. Garin P, Degols JC, Delos M, Marbaix E. Benign ceruminous tumours of the external ear canal. J Otolaryngol 1999;28:99-101.
5. Lynde CW, McLean DI, Wood WS. Tumors of ceruminous glands. J Am Acad Dermatol 1984;11:841-7.
6. Mansour P, George MK, Pahor AL. Ceruminous gland tumours: a reappraisal. J Laryngol Otol 1992;106:727-32.
7. Mills RG, Douglas-Jones T, Williams RG. 'Ceruminoma'--a defunct diagnosis. J Laryngol Otol 1995;109:180-8.
8. Thompson LDR, Nelson BL, Barnes EL. Ceruminous adenomas: a clinicopathologic study of 41 cases with a review of the literature. Am J Surg Pathol 2004;28: in press.

Neuroendocrine Adenoma of the middle ear (NAME; middle ear adenoma)

1. Batsakis JG. Adenomatous tumors of the middle ear. Ann Otol Rhinol Laryngol 1989;98:749-52.
2. Hardingham M. Adenoma of the middle ear. Arch Otolaryngol Head Neck Surg 1995;121:342-4.
3. Hyams VJ, Michaels L. Benign adenomatous neoplasm (adenoma) of the middle ear. Clin Otolaryngol 1976;1:17-26.
4. Ketabchi S, Massi D, Franchi A, Vannucchi P, Santucci M. Middle ear adenoma is an amphicrine tumor: why call it adenoma? Ultrastruct Pathol 2001;25:73-8.
5. Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999;340:858-68.
6. Latif MA, Madders DJ, Barton RP, Shaw PA. Carcinoid tumour of the middle ear associated with systemic symptoms. J Laryngol Otol 1987;101:480-6.
7. Manni JJ, Faverly DR, Van Haelst UJ. Primary carcinoid tumors of the middle ear. Report on four cases and a review of the literature. Arch Otolaryngol Head Neck Surg 1992;118:1341-7.
8. McNutt MA, Bolen JW. Adenomatous tumor of the middle ear. An ultrastructural and immunocytochemical study. Am J Clin Pathol 1985;84:541-7.
9. Mills SE, Fechner RE. Middle ear adenoma. A cytologically uniform neoplasm displaying a variety of architectural patterns. Am J Surg Pathol 1984;8:677-85.
10. Mooney EE, Dodd LG, Oury TD, Burchette JL, Layfield LJ, Scher RL. Middle ear carcinoid: an indolent tumor with metastatic potential. Head Neck 1999;21:72-7.
11. Murphy GF, Pilch BZ, Dickersin GR, Goodman ML, Nadol JBJ. Carcinoid tumor of the middle ear. Am J Clin Pathol 1980;73:816-23.
12. Ribe A, Fernandez PL, Ostertarg H, Claros P, Bombi JA, Palacin A, Cardesa A. Middle-ear adenoma (MEA): a report of two cases, one with predominant "plasmacytoid' features. Histopathology 1997;30:359-64.
13. Riches WG, Johnston WH. Primary adenomatous neoplasms of the middle ear: light and electron microscopic features of a group distinct from the ceruminomas. Am J Clin Pathol 1982;77:153-61.
14. Torske KR, Thompson LDR. Middle ear adenoma vs. carcinoid tumor: A review of the literature and a unifying concept of 48 cases of neuroendocrine adenoma of the middle ear (NAME). Mod Pathol 2002;15:543-555.
15. Zahtz GD, Zielinski B, Abramson AL. Benign adenoma of the middle ear cavity causing facial paralysis. Otolaryngol Head Neck Surg 1981;89:624-7.