Additionally, folliculotropism has been seen in some patients with mycosis fungoides lacking follicular mucinosis. Many cases of mycosis fungoides are also characterized by band-like papillary dermal fibrosis and "wire-loop" sclerosis of the papillary dermal vasculature. Invariably, these cases are associated with lymphocytes that have convoluted nuclei, as well as plasma cells and occasional eosinophils. It is likely that some of these patients either have mycosis fungoides or will develop definitive lesions. There is pagetoid spread of this epidermotropic lymphoid infiltrate with minimal dermal component. Clinically, men over 60 years old present usually with diffuse erythroderma, palmoplantar hyperkeratosis, alopecia, and pruritus. The pagetoid reticulosis variant of mycosis fungoides1352 presents typically as a verrucous plaque on the extremities and does not progress clinically. The prognosis for pagetoid reticulosis is excellent, without reports of extracutaneous dissemination or diseaserelated deaths. Histologically, epidermal hyperplasia, hyperkeratosis, and a striking infiltrate of convoluted mononuclear cells in a pagetoid pattern are seen. A mixed infiltrate of small nonneoplastic lymphocytes and histiocytes may be seen in the underlying superficial dermis. The adnexae can also be penetrated by the infiltrate of polymorphous lymphoid cells. Clinically, patients are usually in their sixth decade of life, and the male to female ratio is 2-3: 1. Regression of the tumor may occur in 25% of patients, but this does not have evident impact on prognosis. An accompanying infiltrate of small reactive lymphocytes, macrophages, and eosinophils is often observed. Pleomorphic carcinomas, melanomas, and sarcomas, including perhaps epithelioid angiosarcoma, might also be considered in a given case. The infiltrate typically effaces the epidermis, often resulting in necrosis or ulceration. The lesions are now classified into four different morphologic patterns, type A, B, C, or D1357,1362-1365 based on nuclear morphology. Type A consists of a wedge-shaped infiltrate of pleomorphic cells with histiocyte-like features similar to those of Reed-Sternberg cells. Type B has a mycosis fungoides­like pattern of small lymphocytes and expresses an immunophenotype similar to classic mycosis fungoides. Type C consists of monomorphous large T cells with a phenotype similar to that of type A, but without the mixed inflammation. The recently described type D is similar to primary cutaneous Lymphomatoid Papulosis Clinically, lymphomatoid papulosis1358-1360 is characterized by chronic, recurrent, self-limited, multiple, papular to nodular cutaneous lesions at different stages, usually occurring on the trunk and limbs of young adults. The lesions are of varying stages, are papular or papulonecrotic, and may persist for a variable amount of time, usually resulting in a benign course. T-cell receptor gene rearrangements occur in approximately 60% of cases and may be monoclonal or polyclonal in individual lesions. Furthermore, monoclonal proliferations do not necessarily indicate that lymphoma will develop in an individual patient. The differential diagnosis includes conventional mycosis fungoides, and clinical correlation is necessary. Granulomatous Slack Skin Granulomatous slack skin1368-1370 is a rare subtype that consists of slowly developing zones of lax skin in the axillae and inguinal regions that occurs predominantly in men and has a good prognosis. Clinically, approximately one third of the affected patients have Hodgkin lymphoma, but some patients may have classic mycosis fungoides. Histologically, a diffuse mononuclear infiltrate is present containing macrophages and multinucleate giant cells and T lymphocytes with convoluted nuclei. Because of the obvious dramatic clinical presentation of these patients, clinical correlation is important to arrive at the correct diagnosis. Clinically, patients usually have ulcerated and necrotic eruptive papules, nodules, and tumors with frequent dissemination to other visceral sites. Some of these lesions may be angiocentric, as well as showing invasion of adnexal structures. Cases with a + phenotype are now included in the category of cutaneous T-cell lymphomas. Clinically, patients present with subcutaneous nodules and plaques, usually on the legs or trunk. The clinical presentation is slightly different from that of classic mycosis fungoides. Patients may also present with multiple papules or nodules, but lack patches or plaques. The neoplastic infiltrate may be accompanied by a mixed inflammatory cell population. The presence of a hemophagocytic syndrome often heralds a rapidly progressive clinical course with a poor prognosis. Histologically, the pleomorphic tumor cells infiltrate the subcutis diffusely and are associated with macrophages, erythrophagocytosis, necrosis, and karyorrhexis. Rimming of individual adipocytes by neoplastic T cells is the characteristic, but not specific, feature. Cases once considered subcutaneous panniculitis­like T-cell lymphomas with a / subtype, are now classified in this category. Lesions present as eroded to ulcerated patches and deep tumors that are commonly located on extremities of adults. Mucosal and extranodal sites are frequently involved, but the bone marrow, lymph nodes, and spleen are spared. The histologic pattern can be predominantly epidermotropic, dermal, or subcutaneous. Subcutaneous infiltrates show rimming of neoplastic cells around individual adipocytes, similar to subcutaneous panniculitis­ like T-cell lymphoma, but dermis and/or epidermis also are involved. These lymphomas follow a highly aggressive course with a 5-year survival of 11%; the majority of patient deaths occur in the first year as a result of tumor progression or hemophagocytic syndrome. The four subtypes are acute, chronic, lymphoma, and smoldering; a cutaneous type limited to the skin has been proposed. The microscopic features may be indistinguishable from those of mycosis fungoides. Prognosis depends on the clinical subtype, with chronic and smoldering forms having a longer survival. The clinical course of the disease is aggressive, with the median survival less than 12 months. Medium-sized pleomorphic lymphocytic infiltrates are present in the dermis and subcutis and show prominent localization and destruction of blood vessels. Primary Cutaneous Peripheral T-Cell Lymphoma, Unspecified Lymphomas within this group do not meet criteria for placement in any of the other categories, including the provisional categories. Cutaneous B-Cell Lymphoma Fewer than 30% of primary cutaneous lymphomas are B-cell lymphomas. However, most B-cell lymphomas affecting the skin occur in conjunction with visceral or nodal disease. The typical clinical presentation of cutaneous B-cell lymphoma is a plaque or nodule, either singly or in clusters, occurring in adults. Unfortunately, H&E alone often will not differentiate these lymphomas from a host of benign simulators, including some bite reactions, reactive hyperplasia (pseudolymphomas), some infectious agents, some T-cell lymphomas, leukemic infiltrates, and some rare plasma cell infiltrates. Unless the H&E evidence is unequivocal, it is useful in many cases to perform a lymph node biopsy for definitive typing or else to apply special stains to the skin biopsy material, such as markers for immunoglobulins, light chains, and B- or T-cell lineage markers. Primary Cutaneous Follicle Center Cell Lymphoma Primary cutaneous follicle center cell lymphoma1379-1382 is composed of follicle center cells, centrocytes, and centroblasts that can have a follicular, diffuse, or mixed growth pattern. It is the most common type of primary cutaneous B-cell lymphoma and appears to differ both clinically and biologically from large cell lesions that occur on the leg (described later). The patients present with a solitary nodule, papule, plaque, or tumor usually located on the head and neck or upper trunk. The prognosis is excellent, having a greater than 95% 5-year survival, and extracutaneous manifestations are uncommon. Histologically, the cutaneous infiltrates are nodular or diffuse, usually sparing the epidermis. The nodules are similar to germinal centers of lymph nodes; however, no tingible body macrophages are present. Early lesions are mostly centrocytic, containing cells with small to large cleaved nuclei, with fewer centroblastic cells, which are large and contain prominent nucleoli. Admixtures of reactive T cells may be present in the infiltrate, and residual reactive germinal centers may be seen. In the later stage tumorous lesions, a larger population of centroblastic cells and fewer reactive T cells are noted. Rapidly growing lesions may have a monomorphous infiltrate of centrocytes, as well as multilobated cells and immunoblasts. Bcl-2 is usually negative, but if positive, it may indicate cutaneous involvement by a systemic follicle center cell lymphoma. Primary Cutaneous Marginal Zone B-Cell Lymphoma Primary cutaneous marginal zone B-cell lymphoma1383-1385 is a lymphoma of small lymphoplasmacytoid cells, small lymphocytes, and plasma cells with monotypic cytoplasmic Ig (cIg) in paraffin sections. Clinically, patients present with solitary or multiple cutaneous or subcutaneous tumors on the extremities. Association with Borrelia burgdorferi infection has been reported in some countries. Histologically, nodular or diffuse infiltrates of small lymphoplasmacytoid cells, small lymphocytes, and plasma cells are present that can be associated with centrocytes and centroblasts. The lymphoplasmacytoid cells and plasma cells are often located at the periphery of the infiltrate and have a monomorphous appearance. Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type these primary cutaneous diffuse large B-cell lymphomas1388 are typically located on the legs and contain mostly centroblasts and immunoblasts. Despite the similarity histologically to follicular center cell lymphomas, these have a poorer prognosis, with a 5-year survival of approximately 50% and dissemination to extracutaneous sites, for reasons that are not clear. Histologically, the lesions are composed of diffuse, nonepidermotropic infiltrates of centroblasts, large centrocytes, and immunoblasts, similar in appearance to primary large cell lymphomas of soft tissue or bone. Intravascular Large B-Cell Lymphoma Intravascular large B-cell lymphoma1389-1391 was once considered an endothelial lesion (malignant angioendotheliomatosis), but is now known to be an intravascular B-cell lymphoma with a relatively poor survival rate at 5 years, especially if sites other than skin are involved. Patients present with violet patches and plaques on the legs and trunk, often thought to be subcutaneous. Histologically, the dermal and subcutaneous blood vessels are dilated and stuffed with tumor cells that are somewhat pleomorphic. Primary Cutaneous Diffuse Large B-Cell Lymphoma, Other Lymphomas in the primary diffuse large B-cell lymphoma, other, group1329 do not meet criteria for placement in any of the other primary cutaneous B cell categories. Histologically, a dermal infiltrate of monotonous medium-sized cells with blastoid morphology is present. Basal cell carcinomas almost never metastasize unless they have been present for many years and have attained large size or deep infiltration. When they do metastasize, they usually follow local lymphatic drainage sites before they become widely disseminated. The ones most likely to metastasize are the malignant acrospiromas (acrospirocarcinomas), papillary digital adenocarcinomas,694,696 sebaceous carcinomas, and Merkel cell carcinomas. Sentinel node dissection for melanoma presupposes that most of them develop local spread to lymph nodes in a relatively predictable fashion, although it remains unproved whether this technique will affect long-term survival. In addition, these lesions sometimes give rise to metastases many years after the discovery and treatment of the primary tumor. It is very uncommon, for instance, for dermatofibrosarcoma or so-called cutaneous leiomysarcoma to develop secondary lesions. Histologically,1398,1398a,1399 the metastatic lesions may mimic the primary tumor or they may be so pleomorphic that immunohistochemical or ultrastructural studies may be needed to suggest the origin of the primary, especially when the primary is unknown. Some patterns of tumor growth are more suggestive than others; these include choriocarcinoma, hepatocellular carcinoma, seminoma, Leydig cell tumor, and renal cell carcinoma. Some lesions, such as prostatic adenocarcinoma (prostate-specific antigen) and thyroid carcinoma (thyroglobulin and calcitonin) have characteristic antigens that help in their identification. Ultrastructure can be useful in the identification of malignancies, but is used less frequently today than in previous years because of sampling error and increased reliance on (and access to) sensitive immunohistochemistry. For instance, the presence of desmosomes in carcinomas, intercytoplasmic or intracytoplasmic lumina in adenocarcinoma, melanosomes in melanomas, and dense core granules in carcinoid and neuroendocrine carcinoma are but a few examples of the types of organelles and structures that can aid in establishing a diagnosis. Despite the use of ancillary techniques to aid in identification of a particular lesion, clinical follow-up is an extremely important adjunct, especially when the metastatic lesion is the presenting sign, because some primary lesions (especially in the lung) may be difficult to detect. Burgess J T, Smith W B, Keeling J H 1994 Seborrheic keratosis with trichilemmomas masquerading as melanoma. Diaz Cascajo C, Reichel M, Sánchez J L 1996 Malignant neoplasms associated with seborrheic keratoses: an analysis of 54 cases. Maize J C, Snider R L 1995 Nonmelanoma skin cancers in association with seborrheic keratosis: clinicopathologic correlations. In: Proceedings of the twentieth seminar of the American Society of Clinical Malignancies Metastatic to the Skin Thousands of cases have been reported of all types of malignancies metastatic to the skin,1397,1398,1398a but few systematic attempts have been made, most of which are retrospective studies, to find patterns of metastases. It is estimated that cutaneous metastases develop in fewer than 10% of all patients with cancer, but it is difficult to compare the studies by different authors. In men, the most common primary malignancies were carcinoma of the lung (24%), carcinoma of the large intestine (19%), melanoma (13%), and squamous cell carcinoma of the oral cavity (12%). In women, the most common primary malignancies were carcinoma of the breast (69%), carcinoma of the large intestine (9%), melanoma (5%), and carcinoma of the ovary (4%), although this study antedated the significantly increased incidence of lung cancer in women. The anterior trunk region was a common site of metastatic tumor, whereas the skin of the lower extremities was involved infrequently.

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Ophthalmologists are reluctant to remove clinically suspicious lesions using procedures that disrupt vision if there is a reasonable chance that the pathologist will describe the lesion as benign. It is of little comfort for an ophthalmologist to tell the patient, "Look, we removed the tumor, and thankfully it was benign! Both nevi and melanomas of the iris tend to expand the iris stroma, and architectural features do not separate these lesions reliably. As with nevi in other areas, iris nevus cells tend to feature nuclei that appear "hollowed out. Most iris melanomas lack epithelioid cells typical of aggressive uveal melanomas, zones of necrosis, inflammation, and evidence of proliferation (by identifying mitotic figures or calculating the proliferation index). The separation of nevus from melanoma histologically is further complicated by a distinctive subset of nevi that feature a plaque of nevus cells over the surface of the iris. The surface plaque is typically composed of tightly packed spindle-shaped cells with cytologically benign nuclear features. Toward the lower right side, scattered tumor cells appear to have no relationship to the collagenous strands of the choroid. Tissue in the upper two thirds assumes the morphologic appearance of fibrillary, almost neural-appearing smooth muscle. The smooth muscle of the anterior segment derives embryologically from neural crest. Pathologists should report the presence of the surface plaque and make special mention of the presence of this plaque at the lateral margins. The nevus surface plaque may spread over the entire surface of the iris, leading to glaucoma if the angle is compromised. Nevi of the Ciliary Body and Choroid Ideally, surgical pathologists would never encounter eyes removed for nevi. It has been estimated that uveal nevi are detectable in 10% of the white population. Nevi of the choroid are typically well circumscribed and composed of spindle-shaped melanocytes, typically lacking nucleoli. Amelanotic nevi may affect the ciliary body and may contribute to glaucoma if the angle is diffusely replaced by nevus. Amelanotic nevi in this location may be confused histologically with mesectodermal leiomyomas82 of the ciliary body; the smooth muscle of the ciliary body is derived embryologically from neuroectoderm, not mesoderm. Diffuse uveal pigmentation with involvement of the adjacent sclera, congenital melanosis oculi, is actually a congenital nevus of the iris, ciliary body, and choroid. This lesion may be identified in the context of uveal melanomas, especially in white patients. However, melanocytomas may affect the ciliary body and may be confused with melanoma. On occasion, these tumors may enlarge and compress the lens, causing sectoral cataract. Ciliary body melanocytomas may cause elevations in intraocular pressure (by infiltrating into the angle, by rotating the ciliary body forward to close the angle, or following spontaneous necrosis and the liberation of considerable melanin into the aqueous humor-melanocytomalytic glaucoma). By contrast, the cells of most pigmented uveal melanomas vary in size and shape, as do their nuclei and nucleoli. Melanomas of the Ciliary Body and Choroid Melanomas of the ciliary body and choroid may be amelanotic or pigmented to varying degrees. Ophthalmologists have become increasingly accurate in discriminating uveal melanomas from lesions that simulate them clinically. In the unlikely event that the ophthalmologist removes an eye in error for what is believed to be a melanoma, the pathologist is likely to encounter a choroidal hemorrhage, a cavernous hemangioma, or a metastasis to the choroid, lesions that should not present much difficulty in the histologic diagnosis. It has been recommended that certain histologic features be noted on pathology reports when evaluating enucleation specimens for uveal melanoma. Cell Type In practice, the Callender classification represents a spectrum of morphologies (see Table 29-6). For example, considerable disagreement exists about the number of epithelioid cells that must be present for a tumor to shift from a mixed cell designation to an epithelioid melanoma. Some studies have abandoned the rigid classification scheme outlined in Table 29-6 and record only the presence or absence of any epithelioid cells. Spindle cell melanomas are tumors composed of a either a mixture of spindle A and spindle B cells or tumors composed exclusively of spindle B cells. Tumors composed of a mixture of spindle and epithelioid cells-the majority of uveal melanomas-are designated mixed cell melanomas. Melanomas composed predominantly of epithelioid cells are designated epithelioid melanomas. In general, prognosis is indicated by the proportion of epithelioid cells present in a tumor. These loops stain positively for laminin and fibronectin and are distinct from fibrovascular septa, which may be present in uveal melanomas but lack independent prognostic significance. The cells are so heavily pigmented as to obscure visualization of most of the nuclei. Histologically, melanocytomas are composed of uniformly large, highly pigmented cells that are round to polygonal or spindled. The presence of spindled melanocytoma cells may signify a locally aggressive course with local infiltration, but these lesions are still considered benign. Melanomas have been reported in association with melanocytomas, but in general, uveal nevi (with the exception of congenital melanosis oculi) are not considered melanoma precursor lesions. In many melanocytomas, it may be impossible to detect nucleoli without bleaching the tissue sections. Nuclei are small, round, and uniform in size, typically centrally positioned, and may contain small nucleoli. Note that the cells are large with centrally placed nuclei that are cytologically bland. Extraocular extension Some tumors infiltrate into the sclera along emissary vessels and nerves. It may be advisable to attempt to trace this finding through serial or step sections to determine whether the tumor extends to the surface of the sclera. It may be helpful to measure the diameter of the extraocular extension with an ocular micrometer because some oncologists contend that microscopic extraocular extension does not pose a risk to the patient. There are no lymphatics within the eye, and uveal melanomas typically disseminate by a hematogenous route to the liver. However, when extraocular extension involves the conjunctiva, metastasis to the regional lymph nodes is possible. Growth pattern Tumors that are relatively flat and diffuse (diffuse melanomas) tend to be associated with an aggressive clinical course. Melanomas that grow circumferentially in the ciliary body following the course of the major arterial circle of the iris (ring melanomas) are also associated with an aggressive clinical course. If neither pattern is mentioned in the report, the ophthalmologist will reasonably conclude that the tumor is localized. Size Unlike cutaneous and conjunctival melanoma, the elevation of the tumor (the vertical measurement) lacks prognostic significance. If this was not recorded at the time of gross examination, the measurement may be taken from the glass slide. Cell type Callender first described the association between cell morphology (cell type) and outcome in 1931. Despite the discovery of numerous molecular and cytogenetic markers, cell type remains an independent prognostic factor in most studies. Spindle A cells are elongated and contain a nucleus with a central fold (as seen in Brenner tumors of the ovary). The nuclei of spindle B cells lack a central fold and feature a prominent nucleolus. Epithelioid cells typically have abundant cytoplasm, open nuclei, and large, pleomorphic nucleoli. Proliferation In many studies, the number of mitotic figures identified in 40 high-power (40×) fields (hpf) is recorded as a prognostic characteristic. Proliferation indices using Ki67 also have prognostic significance and may be recorded in place of mitotic counts. Tumor-infiltrating lymphocytes Tumors showing >100 lymphocytes per 20 (40×) hpf have been shown to carry a poorer prognosis than those with <100 per 20 hpf. Vasculogenic mimicry patterns this tumor characteristic is easily detectable and highly reproducible between pathologists. Cytogenetics Monosomy 3 and other cytogenetic abnormalities have been associated with adverse outcome. This technique has been shown to discriminate between patients with an excellent outcome and those at high risk of metastasis. Cytogenetics Multiple cytogenetic abnormalities, most notably monosomy 3, have been associated with an adverse outcome in uveal melanoma. Monosomy 3 is not distributed randomly throughout the tumor, and random fineneedle aspiration biopsy sampling may not yield cells that are prognostically representative of the most aggressive tumor cell population. The loops have been shown to be positive for laminin and heparin sulfate proteoglycan. They have been shown to conduct plasma and possibly red blood cells and are formed by highly invasive tumor cells through a process known as vasculogenic mimicry. Early data indicate that tumor cells with this profile are distributed homogeneously throughout the tumor, unlike the heterogeneous distribution of tumor cells with monosomy 3. The observation that no patients with a class 1 gene expression profile die of metastatic melanoma raises the question of whether this assay has identified a molecular profile of a uveal melanocytic nevoid lesion99 (see the introduction to this chapter). Folberg R, McLean I W, Zimmerman L E 1984 Conjunctival acquired melanosis and malignant melanoma. Folberg R, McLean I W, Zimmerman L E 1985 Primary acquired melanosis of the conjunctiva. The cells are polygonal, the nuclei are pleomorphic, and the nucleoli are prominent. Sinard J H 1999 Immunohistochemical distinction of ocular sebaceous carcinoma from basal cell and squamous cell carcinoma. Tahery D P, Goldberg R, Moy R L 1992 Malignant melanoma of the eyelid: a report of eight cases and a review of the literature. Scott I U, Karp C L, Nuovo G J 2002 Human papillomavirus 16 and 18 expression in conjunctival intraepithelial neoplasia. Rao N A, Font R L 1976 Mucoepidermoid carcinoma of the conjunctiva: a clinicopathologic study of five cases. Huntington A C, Langloss J M, Hidayat A A 1990 Spindle cell carcinoma of the conjunctiva: an immunohistochemical and ultrastructural study of six cases. Jakobiec F A, Bhat P, Colby K A 2010 Immunohistochemical studies of conjunctival nevi and melanomas. Ackerman A B, Sood R, Koenig M 1991 Primary acquired melanosis of the conjunctiva is melanoma in situ. Damato B, Coupland S E 2008 Conjunctival melanoma and melanosis: a reappraisal of terminology, classification and staging. Clin Experiment Ophthalmol 36: 786-795 29 Tumors of the Eye and Ocular Adnexa 2115 38. Griffith W R, Green W R, Weinstein G W 1971 Conjunctival malignant melanoma originating in acquired melanosis sine pigmento. Folberg R, McLean I W 1986 Primary acquired melanosis and melanoma of the conjunctiva: terminology, classification and biologic behavior. Jakobiec F A, Folberg R, Iwamoto T 1989 Clinicopathologic characteristics of premalignant and malignant melanocytic lesions of the conjunctiva. Mehta M, Jakobiec F, Fay A 2009 Idiopathic fibroinflammatory disease of the face, eyelids, and periorbital membrane with immunoglobulin G4-positive plasma cells. Kivela T 1999 Trilateral retinoblastoma: a meta-analysis of hereditary retinoblastoma associated with primary ectopic intracranial retinoblastoma. Juarez C P, Tso M O 1980 An ultrastructural study of melanocytomas (magnocellular nevi) of the optic disk and uvea. Folberg R, Hendrix M J, Maniotis A J 2000 Vasculogenic mimicry and tumor angiogenesis. Folberg R 2010 the molecular classification of uveal melanocytic lesions: an important discovery in context. Robertson D M, Winkelmann R K 1984 Ophthalmic features of necrobiotic xanthogranuloma with paraproteinemia. Levin L A, Jakobiec F A 1992 Optic nerve tumors of childhood: a decision-analytical approach to their diagnosis. Stern J, Jakobiec F A, Housepian E M 1980 the architecture of optic nerve gliomas with and without neurofibromatosis. Broughton W L, Zimmerman L E 1978 A clinicopathologic study of 56 cases of intraocular medulloepitheliomas. Bunt A H, Tso M O 1981 Feulgen-positive deposits in retinoblastoma: incidence, composition, and ultrastructure. Kopelman J E, McLean I W, Rosenberg S H 1987 Multivariate analysis of risk factors for metastasis in retinoblastoma treated by enucleation. The inner ear is composed of a specific form of inert bone, a virtually nonmitotic sensory area, and nerves. Its tumors are mainly those of Schwann cell lineage, the only relatively labile cells in that region. The middle ear is lined by a simple flat epithelium, but its ability to respond briskly to inflammation by the production of glands (mucosal metaplasia) explains why adenoma is the most common middle ear neoplasm. The external ear is a specialized appendage of the skin, and its neoplasms largely reflect the range seen in other cutaneous areas. Classification of these embryologic anomalies was first introduced in a classic work by Walter Payton Work, M.

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A thin eosinophilic cuticle may be present along the luminal border, and the lumen sometimes contains eosinophilic secretion. Occasionally, the glandular structures are abortive, manifesting as aggregates of vacuolated or signet ring cells. They possess round or angulated nuclei and scanty cytoplasm with indistinct cell borders. Nuclear pleomorphism is usually mild, and mitotic figures are usually few or absent. The elongated tubules are lined by a single layer of ductal epithelial cells surrounded by a single or multiple layers of basaloid cells. This is the architectural pattern in which glandular lumens are most easily and consistently found. The tubules can be apparently coiled on themselves, producing a necklace appearance. They are often embedded in abundant hyaline stroma, to the extent that they may become "strangulated. The solid pattern is characterized by smooth-contoured or focally jagged sheets and islands of closely packed basaloid cells. The basaloid cells, in comparison with those seen in the cribriform and tubular patterns, usually exhibit more significant nuclear pleomorphism and mitotic activity. A, Cribriform islands admixed with occasional tubules-this field alone is indistinguishable from pleomorphic adenoma or basal cell adenoma. Practically all the spaces in the cribriform islands (containing lightly basophilic mucin) are pseudocysts surrounded by basaloid (modified myoepithelial) cells, and they are filled with lightly basophilic mucin. B, Uncommonly, the true glandular lumens in the cribriform islands are very prominent. In this case, the glandular spaces are empty, whereas the pseudocysts contain basophilic mucin. The dedifferentiated component is usually represented by poorly differentiated adenocarcinoma, sarcomatoid carcinoma, or undifferentiated carcinoma. These cells express cytokeratin, S100 protein (usually patchy staining), actin (variably), calponin, and p63. Although c-kit is expressed in ductal cells,327,328 clinical trials using specific tyrosine kinase receptor inhibitor (imatinib) show no beneficial effects. In this example, the cystic spaces in the cribriform islands are filled with eosinophilic hyaline material rather than mucin. A, Tubules within the basaloid cell islands are abortive, being represented by groups of vacuolated "signet ring" cells. B, Basaloid cells appear separated because of accumulation of intercellular fluid or mucin. The solid pattern also predicts for distant metastasis even for early stage (T1 or T2, N0) tumor. The tubules have an inner layer of cells with eosinophilic cytoplasm and an outer layer of basaloid cells. This field alone is indistinguishable from basal cell adenoma or pleomorphic adenoma. B, the basaloid cells in the solid variant exhibit a greater degree of nuclear atypia and mitotic activity compared with conventional adenoid cystic carcinoma. Distinction from epithelial-myoepithelial carcinoma and polymorphous low-grade adenocarcinoma is discussed under their corresponding sections. The claimed value of c-kit immunoreactivity for diagnosis of adenoid cystic carcinoma has not been substantiated. The right field depicts the preexisting adenoid cystic carcinoma, comprising basaloid cells with interspersed pseudocystic spaces. The left field shows the poorly differentiated (dedifferentiated) solid tumor composed of much larger, pleomorphic, and mitotically active cells. The overall survival probabilities are 90% at 5 years, 83% at 10 years, and 67% at 20 years. Therefore lifelong follow-up is imperative even after apparently complete excision. Macroscopic Appearances Acinic cell carcinoma is often circumscribed with an incomplete capsule, but it can be multinodular or infiltrative. Microscopic Appearances Acinic cell carcinoma typically forms a solitary mass or multiple nodules and invades in broad fronts. The tumor is compactly cellular with little sclerotic stroma except for occasional traversing fibrous bands. The tumor often reveals a mixture of growth patterns comprising several cell types that recapitulate the acinarintercalated duct unit. The tumor cells are most commonly arranged in organoid sheets traversed by ramifying delicate blood vessels, sheets punctuated by microcystic spaces, cords, intertwining solid or near-solid tubules, and coalescent acini. The microcystic pattern is the most characteristic growth pattern, although it is not invariably present. Formation of these microcysts is thought to result from lack of ducts to conduct away secretions and breakdown products, causing accumulation of fluid between the cells. The microcystic spaces differ from microglandular spaces in that the surrounding cells generally lack orientation around the spaces. Similar to their normal counterparts, the neoplastic acinar cells possess basophilic granular cytoplasm and basally located nuclei. Ann Otol Rhinol Laryngol 99: 1007-1009 sion of the surrounding parenchyma or nerves and usual prominence of cribriform structures. The solid type of adenoid cystic carcinoma poses special problems in differential diagnosis from basal cell adenocarcinoma and basaloid squamous cell carcinoma (Table 7-10). Acinic Cell Carcinoma Definition Acinic cell carcinoma is a neoplasm demonstrating at least focal differentiation toward serous acinar cells. Clinical Features the most frequent sites of occurrence are the parotid gland (84%) and submandibular gland (4%), followed by the buccal mucosa, upper lip, and palate. Scattered within the basaloid islands are small to solid tubules lined by luminal cells with eosinophilic cytoplasm Rare Basaloid cells predominant Luminal cells sparse 1. Basaloid cells with pale and atypical nuclei and frequent mitoses; true glandular cells rare 2. A, this figure shows the prototypic appearance of this tumor type: invasion in pushing fronts, violaceous staining quality of the tumor cells, microcystic spaces, and interspersed lymphoid aggregates. Note the typical microcystic pattern of the large tumor islands, which are separated by sclerotic septa. Nonspecific glandular cells are also present that are generally small, with eosinophilic to amphophilic cytoplasm, often forming sheets. Uncommon cell types include vacuolated cells with a solitary or multiple clear vacuoles. They are prone to ischemia and infarction, which occurs spontaneously or after fine-needle aspiration. This rare variant is characterized by large cystic spaces lined by simple or stratified cuboidal epithelium with some papillary projections. A, the tumor is punctuated by irregular-shaped small cystic spaces (empty or containing blood in this case). The cells that surround the spaces do not show specific orientation around the space; this feature distinguishes the microcystic pattern from a microglandular pattern. Note also the violaceous color of the cytoplasm, as commonly observed in acinic cell carcinoma. B, Tumor islands interspersed with many microcystic spaces, some containing eosinophilic secretion. D, Rarely, some microcystic spaces have a microglandular appearance (upper field), with lining cells regularly aligned around the spaces. A, Some cells contain abundant basophilic granules, consistent with acinar cell differentiation. Smaller cuboidal cells are admixed with apparent differentiation toward intercalated ducts. C, Polygonal tumor cells with amphophilic cytoplasm and sparse small basophilic granules. This rare variant comprises closely packed round cystic spaces filled with homogeneous eosinophilic colloid-like material, highly reminiscent of thyroid follicles. The follicles are lined by intercalated duct-like cells and nonspecific glandular cells. Immunostaining for thyroglobulin is helpful for ruling out a thyroid follicular neoplasm. Dedifferentiated Acinic Cell Carcinoma Dedifferentiation of acinic cell carcinoma to a high-grade adenocarcinoma, poorly differentiated carcinoma, or undifferentiated carcinoma can rarely occur at presentation or in the recurrent tumor. This rare variant is characterized by follicles containing eosinophilic colloid-like material. C, the intraluminal component consists of pseudopapillae with no fibrovascular cores. D, the intraluminal component may take the form of a protruding nodule with a microcystic pattern. A, the left field shows a typical acinic cell carcinoma with microcystic growth pattern. The right field shows a high-grade carcinoma with a solid growth pattern (dedifferentiated component). B, the tumor cells of acinic cell carcinoma are bland looking (left), whereas those of the high-grade carcinoma exhibit larger nuclei with significant nuclear pleomorphism. Dedifferentiated acinic cell carcinoma is associated with rapid tumor growth, significant pain, facial nerve palsy, bulky tumor, and an extremely poor prognosis. However, the value of amylase staining is limited because only 15% of cases are positive. The normal serous cells show moderate apical membranous staining, and the distal intercalated duct cells show variable weak to moderate apical staining. A, the most common growth patterns are microcystic (left field) and papillary-cystic (right field), occurring alone or in combination. B, Tumor islands punctuated by microcysts, which are empty or contain eosinophilic or basophilic secretion. In contrast to acinic cell carcinoma, basophilic cytoplasmic granules are conspicuously absent. The mainstay of treatment is complete surgical excision with or without postoperative radiotherapy. Microscopic Features the tumor is largely circumscribed with focally invasive borders. The tumor grows in the form of microcystic to cribriform islands, tubulocystic glands, papillary cystic structures, and sometimes thyroidlike follicles. Bluish mucin and eosinophilic secretions are readily found in the glandular lumens. The tumor cells are cuboidal to polygonal, with eosinophilic granular or multivacuolated cytoplasm. The nuclei are oval with finely granular chromatin and/or small distinct nucleoli. The cytologic composition corresponds to the intercalated duct, vacuolated, and nonspecific glandular cells as originally described in acinic cell carcinoma, whereas acinar cells with basophilic zymogen granules are conspicuously absent. In occasional cases, some tumor islands are surrounded by a layer of p63+ abluminal cells, indicating the presence of a focal intraductal (in situ) component. The tumor characteristically shows extensive and strong staining for S100 protein. Each nucleus contains one normal fused red-green (or yellow) signal, one separate red signal, and one separate green signal. Macroscopic and Microscopic Appearances Grossly, most tumors are circumscribed but nonencapsulated, with a light tan to gray glistening cut surface. Despite the gross circumscription, infiltrative growth is obvious histologically, with invasion of salivary gland lobules or adjacent adipose tissue or muscle. The cribriform plates appear as islands of tumor cells interrupted by round, rarefied spaces that are empty or filled with mucoid material. Papillary or papillary-cystic pattern consists of dilated cysts with small intraluminal papillary projections. Extensive and strong immunoreactivity for S100 and mammaglobin can aid further in the distinction. Other designations include lobular carcinoma,369 terminal duct carcinoma,370 and low-grade papillary adenocarcinoma. Only rarely does it occur in the major glands, where it mostly represents the malignant component in carcinoma ex pleomorphic adenoma. Highly variable growth patterns are present in different areas of the same neoplasm. The tumor cells have round pale nuclei with evenly distributed fine chromatin and indistinct nucleoli. The tumor cells may assume cuboidal, columnar, spindled, or polygonal shapes, but the bland cytologic features are always maintained. Although some authors consider myoepithelium to be an integral component of this tumor type,321,384 myoepithelial cells are absent or at most present very focally at the lightmicroscopic level. A, this shows a highly characteristic swirling pattern, resembling sclerosing adenosis of the breast. A, the tubules are lined by ductal cells only, without an underlying layer of basal or myoepithelial cells. The tumor cells show a high nucleus to cytoplasm ratio and more hyperchromatic nuclei. The most commonly involved site is the tongue, but the soft palate, buccal mucosa, tonsils, and lip can also be involved.

Usage: p.o.

The tumor may have an infiltrative growth pattern within smooth muscle, but this does not indicate malignancy; despite the fact that several cases of regional lymph node involvement have been reported suggesting malignant potential,88-90 most patients do well after surgical resection. However, rare reports exist of local invasion and distant metastasis (to liver and bone) raising the potential for malignancy especially when these tumors arise in the region of the ampulla of Vater. A, Note the trabecular arrangement of epithelioid cells with prominent microvasculature, which simulates a paraganglioma. B, Spindle cell proliferation and occasional ganglion-like cells simulate a ganglioneuroma. Although almost 70% of cases arise in the adrenal gland or intra-abdominal sympathetic chain, at least 20% arise in the thorax (including the thymus). Calcification within the tumor may appear as chalky-white or yellowish punctate areas, and specimen radiography may demonstrate this to much better advantage. This neurofibrillary matrix, which has been likened to neuropil of the central nervous system, may form the center of rosettes (or pseudorosettes). This adrenal gland is from a 26-day-old girl who died of congenital heart disease. Tumor expands the medullary compartment of the adrenal and is well demarcated with pushing borders. B, In situ neuroblastoma has an intact adrenal capsule at the top of the field with a thin remnant of cortex beneath. C, A representative field of in situ neuroblastoma is indistinguishable from classic childhood neuroblastoma. The tumor had few areas that were cytodifferentiated corresponding to ganglioneuroblastoma. A rare large cell variant with large nuclei and prominent nucleoli appears to be especially aggressive. Other unusual histopathologic features have been reported, such as a sclerosing pattern, spindle-shaped neuroblasts, stromal hyalinization, and dense lymphoplasmacytic infiltration, some of which may be related to the phenomenon of regression. Ganglion cell differentiation is evidenced by (1) nuclear and cytoplasmic enlargement, (2) distinct cell borders, and (3) increased cytoplasmic eosinophilia. Nuclei may be eccentrically situated with margination of chromatin, and a prominent nucleolus may be seen. The vast majority of the tumor resembled ganglioneuroma with a prominent spindle cell (schwannian) matrix, but in several areas a small component of ganglioneuroblastoma was seen. With use of the Shimada classification, this tumor would be in the intermixed stroma-rich category. Residual adrenal cortex is apparent around the cystic tumor, and blood-tinged fluid was present within it. B, Representative section of the tumor in A shows irregular nests of neuroblastoma separated by hemorrhage. The inner aspect of this cystic tumor contains blood and much fibrin exudate, and residual cortex can be seen at the top of the field. Many nuclei have small dot-like nucleoli, but no evidence of ganglion cell differentiation was seen. This tumor would be designated stroma rich, intermixed, in the Shimada classification. The entry point into this classification system is evaluation of the "character" of the stroma, and here two general categories are recognized: (1) stroma-rich tumors with an extensive spindle cell, schwannian component and (2) stroma-poor tumors with prominent neurofibrillary background. The stroma-rich tumors (Table 28-1) are divided into a favorable prognosis subgroup (well differentiated and intermixed; see. The histologic features used in the stroma-poor tumors are indicated in Table 28-2. Confirmation of favorable and unfavorable prognostic subsets in ganglioneuroblastoma, nodular. This grading system had the following advantages: use of familiar terminology and histologic features and relative ease of assessment because the degree of differentiation did not need to be determined. An increased number of ferritin-positive cells and loss of S-100 protein positivity have been correlated with a poor prognosis. Neurofilaments and dense-core neurosecretory granules were also present in other fields. B, A few dense-core neurosecretory-type granules are present along with free polyribosomes. Granules are often round, regular, and uniformly dense and surrounded by a limiting membrane. The cut surface has a bulging, pale, coarsely trabecular appearance resembling a "fibroid" or leiomyoma. An abundant spindle cell matrix is seen that can resemble a schwannoma or neurofibroma. Mature ganglion cells are present, but the number, density, and distribution of these cells may be quite variable. In some cases conspicuous finely granular brown pigment resembling lipofuscin or neuromelanin may be seen within ganglion cells. Occasionally some ganglion cells may be associated with a layer of smaller cells suggesting satellite cells. Note interlacing fascicles of spindle cells resembling Schwann cells along with cytodifferentiated ganglion cells. Arias-Stella J, Valcarcel J 1976 Chief cell hyperplasia in the human carotid body at high altitudes: physiologic and pathologic significance. Heath D, Edwards C, Harris P 1970 Post-mortem size and structure of the human carotid body. Lack E E, Perez-Atayde A R, Young J B 1985 Carotid body hyperplasia in cystic fibrosis and cyanotic heart disease. Lack E E, Cubilla A L, Woodruff J M 1979 Paragangliomas of the head and neck region. Papaspyrou K, Mann W J, Amedee R G 2009 Management of head and neck paragangliomas: review of 120 patients. Bradshaw J W, Jansen J C 2005 Management of vagal paraganglioma: is operative resection really the best option Boedeker C C, Ridder G J, Schnipper J 2005 Paragangliomas of the head and neck: diagnosis and treatment. Fishbein L, Nathanson K L 2012 Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Baysal B E 2003 On the association of succinate dehydrogenase mutations with hereditary paraganglioma. Wasserman P G, Savargaonkar P 2001 Paragangliomas: classification, pathology and differential diagnosis. Feldman S A, Eiden L E 2003 the chromogranins: their role in secretion from neuroendocrine cells and as markers for neuroendocrine neoplasia. Chetty R, Pillay P, Jaichand V 1998 Cytokeratin expression in adrenal phaeochromocytomas and extra-adrenal paragangliomas J Clin Pathol 51: 477-478 54. Grimley P M, Glenner G G 1967 Histology and ultrastructure of carotid body paragangliomas: comparison with the normal gland. Tischler A S, Kimura N, McNicol A M 2006 Pathology of pheochromocytoma and extra-adrenal paraganglioma. Zuckerkandl E 1901 Ueber nebenorgane des sympathicus im retroperitonaealraum des Menschen. Fries J G, Chamberlin J A 1968 Extra-adrenal pheochromocytoma: literature review and report of a cervical pheochromocytoma. Moran C A, Rush W, Mena H 1997 Primary spinal paragangliomas: a clinicopathological and immunohistochemical study of 30 cases. Clinicopathologic study of 31 cases with special reference to immunocytology and ultrastructure. Gupta R, Howell R S, Amin M B 2009 Paratesticular paraganglioma: a rare cause of an intrascrotal mass. A lesion that may be misdiagnosed as urothelial carcinoma in transurethral resection specimens. Carney J A 1999 Gastric stromal sarcoma, pulmonary chondroma and extra-adrenal paraganglioma (Carney triad): natural history, adrenocortical component and possible familial occurrence. Stratakis C A, Carney J A 2009 the triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. McWhinney S R, Pasini B, Stratakis C A 2007 Familial gastrointestinal stromal tumors and germ-line mutations. Cancer 60: 1776-1781 2084 28 Tumors of the Autonomic Nervous System, Including Paraganglia 104. Hachitanda Y, Tsuneyoshi M 1994 Neuroblastoma with a distinct organoid pattern: a clinicopathologic, immunohistochemical and ultrastructural study. An assessment of the significance of histologic maturation in neuroblastoma diagnosed beyond infancy. Dehner L P 1988 Classic neuroblastoma: histopathologic grading as a prognostic indicator. Kliewer K E, Cochran A J 1989 A review of the histology, ultrastructure, immunohistology, and molecular biology of extraadrenal paragangliomas. Sundararajan V, Robinson-Smith T M, Lowry A M 2003 Duodenal gangliocytic paraganglioma with lymph node metastasis: a case report and review of the literature. Beckwith J B, Perrin E V 1963 In-situ neuroblastomas: a contribution to the natural history of neural crest tumors. Report of 3 cases with special emphasis on its association with the syndrome of inappropriate secretion of antidiuretic hormone. Urol Radiol 9: 9-15 28 Tumors of the Autonomic Nervous System, Including Paraganglia in situ hybridization on tumour imprints and bone marrow smears. Nature 455: 883-884 Triche T J 1990 Differential diagnosis of neuroblastoma and related tumors. Am J Surg Pathol 8: 19-29 Aguirre P, Scully R E 1983 Testosterone-secreting adrenal ganglioneuroma containing Leydig cells. Am J Surg Pathol 7: 699-705 Khan A N, Solomon S S, Childress R D 2010 Composite pheochromocytoma-ganglioneuroma: a rare experiment of nature. Hunter C J, Shimada H, Asch M 2007 An unusual case of neuroblastoma with angiomatoid features. Most pathologists are accustomed to focusing their attention on the diagnosis and prognostic features that guide therapy. The diagnosis of neoplasms of the eye and adnexa adds an additional dimension: the pathologist must provide information that also helps the surgeon to preserve vision, a therapeutic goal that may assume equal importance to the treatment of the neoplasm itself. For many patients, the fear of losing vision is at least as intense as the fear of losing their lives. For example, little normal tissue is typically resected around ophthalmic malignancies in the interest of preserving vision. Therefore, although histopathologic diagnosis of basal cell carcinoma of the eyelid or squamous dysplasia of the conjunctival epithelium may not be difficult, communicating precise information about margins of resection can be exceptionally challenging. To cite another example, the classification of conjunctival melanomas and their precursors1,2 is different from that used for cutaneous melanoma-not because ophthalmic pathologists are uneducated or contrary-but because the classification used in the conjunctiva was designed to assist ophthalmologists in the clinical differential diagnosis and management of these conditions. Although cutaneous and conjunctival melanomas originate in an epithelial compartment, uveal melanomas originate in mesenchymal compartments-the choroid, 2086 ciliary body, and iris-and there are therefore no counterparts to in situ melanoma in the uvea. Some neoplasms, while seldom encountered in a practice of general surgical pathology, are encountered commonly if the pathologist works with ophthalmologists with busy practices. The eyelid contains the highest concentration of sebaceous glands in the body, and, in our laboratory, sebaceous carcinoma is encountered far more frequently than squamous cell carcinoma. Thus pathologic changes that suggest the diagnosis of bowenoid actinic keratosis in the eyelid may well represent the pagetoid intraepidermal distribution of sebaceous carcinoma. Therefore this chapter focuses on those entities that either are unique to the eye and its adnexa or require the pathologist to consider the impact on vision as well as longevity in describing findings. An introductory section to each anatomic site provides information about functional anatomy so that the pathologist understands the rationale behind the resection technique employed. This information should also assist pathologists during the gross examination of tissues, which is the first step in the examination of tissues. Although most ophthalmic neoplasms do not develop preferentially in men or women, a distinctive age distribution is seen for these tumors. Whether the pathologist prefers to check clinical information before reviewing slides or prefers an "unbiased" approach to histopathologic differential diagnosis, the final report must reflect the "reality check" of clinical context. In this chapter, discussions of specific tumor types emphasize pitfalls in the histologic differential diagnosis of ophthalmic neoplasms and techniques by which pathologists can supply ophthalmic surgeons with a report that can be used to guide therapy. Neoplasms or surgical interventions that distort the eyelid may lead to imperfect eyelid closure, painful corneal exposure, and possibly corneal infection and ulceration. The eyelid skin and adjacent skin at the medial canthus along the bridge of the nose are non­hair-bearing (glabrous). For this reason, large resections of eyelid skin necessitate replacement by eyelid tissue from the opposite eyelid. Large resections of eyelid tissue and tissue from around the eyelid may require painstaking reconstruction, and, for this reason, oculoplastic surgeons tend to resect tumors with only a minimum amount of normal tissue surrounding the lesion. Fortunately, surgeons are able to resect nearly one third of the lower eyelid and accomplish primary closure without grafting. By severing the lateral canthal ligament (a trivial surgical maneuver), surgeons are able to resect nearly half of the lower eyelid and still accomplish primary closure. This information may be helpful in guiding discussions between the pathologist and ophthalmologist regarding the management of tumor resections with positive margins. The dermis of the eyelid contains only loosely arranged collagen; no analogue to the reticular dermis exists in the eyelid. Apocrine glands are present within the eyelid and may give rise to simple cysts (apocrine hidrocystomas), which are relatively common, or, rarely, to malignant neoplasms, including mucinous carcinoma. Because most eyelid neoplasms originate at this site, the pathologist should insist on examining a tissue section that includes this transition zone when commenting on margins of a full-thickness eyelid resection. The overlying epidermis appears thick and disorganized secondary to diffuse pagetoid growth of tumor cells.