Salivary duct carcinoma in situ of the parotid gland.

AIMS: To describe three cases of purely in situ salivary duct carcinoma, so as better to define the entity. METHODS AND RESULTS: Three primary tumours of the parotid gland are presented, in each case composed of cysts and ducts and lined by high nuclear grade epithelial cells. All parts of each tumour were surrounded by a myoepithelial cell rim and there was no evidence of invasion. The tumour cells expressed immunohistochemical markers seen in invasive salivary duct carcinoma of usual (high-grade) type. In two cases the androgen receptor (AR) reaction was strong, but there was no immunohistochemical expression of HER2 protein or gene amplification by in situ hybridization. In the remaining case, fewer nuclei stained for AR, but both HER2 protein and gene amplification were demonstrated. CONCLUSIONS: Salivary duct carcinoma in situ is morphologically similar to breast ductal carcinoma in situ and, although our cases are few, salivary duct carcinoma in situ can possibly be subdivided into luminal and non-luminal cell types, as can analogous mammary neoplasms. The present study cannot determine whether low-grade cribriform cystadenocarcinoma, architecturally similar but immunohistochemically different, is part of the spectrum of salivary duct carcinoma in situ, or whether it represents a separate entity.

Non-invasive (intracapsular) carcinoma ex pleomorphic adenoma: recognition of focal carcinoma by HER-2/neu and MIB1 immunohistochemistry.

AIMS: Non-invasive carcinoma ex pleomorphic adenoma is defined as a carcinoma arising within the boundaries of a pleomorphic adenoma (PA), but which fails to display invasion beyond the capsule of host PA. Alternative names are intracapsular, in situ, or focal carcinoma. The true nature of non-invasive carcinoma ex-PA is still controversial; for example, it is not clear whether it represents early but genuine carcinomatous changes with the genetic make-up of malignant cells, or simply cytological, possibly metaplastic or 'bizarre' changes in PA. Strong overexpression and amplification of HER-2/neu protein has recently been demonstrated in invasive carcinoma ex-PA. In addition, data from breast cancer studies suggest that amplification of HER-2/neu and overexpression of its gene product is mainly involved in the initiation of breast oncogenesis. We sought to establish whether this method could help to demonstrate that what is described as non-invasive carcinoma ex-PA is really a genuine malignancy, albeit in an early phase. METHODS AND RESULTS: Eleven cases of non-invasive carcinoma (in situ) ex-PA were studied for HER-2/neu status using immunohistochemistry and fluorescent in-situ hybridization (FISH). Cells of focal non-invasive carcinoma ex-PA were strongly positive for HER-2/neu protein, while the cells of the maternal PA were always negative. Two cases of low-grade non-invasive myoepithelial carcinoma ex-PA were negative. In four cases out of a total of six tumours studied by FISH, we detected amplification of HER-2/neu gene signals in tumour cells of focal, non-invasive, carcinoma. CONCLUSIONS: The current data suggest that non-invasive carcinoma ex PA is a genuine carcinoma within a PA. However, the presence of cyto-nuclear atypia is not sufficient to make a definite diagnosis of malignant change, which requires a combination of morphology and immunohistochemistry.

Polymorphous low-grade adenocarcinoma of the salivary glands with transformation to high-grade carcinoma.

AIMS: Polymorphous low-grade adenocarcinoma of the minor salivary glands is an infiltrative neoplasm characterized by bland-looking tumour cells arranged in diverse architectural patterns. It is considered to be of low-grade malignant potential in that nodal metastases are seen in only a minority, and distant spread is rare. Even more unusual is the transformation of polymorphous low-grade adenocarcinoma to a histologically high-grade carcinoma, i.e. dedifferentiation. In this paper, we describe the clinicopathological and immunohistochemical findings in two further examples. METHODS AND RESULTS: Two patients presented each with a tumour of the palate. Histopathological examination showed the typical morphological, cytological and immunohistochemical features of a polymorphous low-grade adenocarcinoma. In one case there was a second component of high-grade carcinoma showing nuclear atypia, markedly increased mitotic activity and MIB1 index, as well as prominent zones of necrosis. It expressed epithelial markers and androgen receptors, and thus resembled salivary duct carcinoma. Similar tumour tissue was observed in one of the cervical nodal metastases, which was biopsied at the same time as the palate. In the second patient, a high-grade component was discovered when the tumour recurred in the palate 13 years after the initial biopsy. Whilst morphologically similar to that in first case, there were significant immunohistochemical differences such as retention of some of the polymorphous low-grade adenocarcinoma profile and absence of androgen receptor expression. CONCLUSIONS: Polymorphous low-grade adenocarcinoma was first described relatively recently, and as experience with it continues to accumulate, it is becoming clear that late recurrences and metastases, whilst still infrequent, may not be quite as rare as previously thought. Reports of histological transformation are even scarcer, and most occurred at least 13 years after the polymorphous low-grade adenocarcinoma was initially recognized. It is a real possibility that this phenomenon, like clinical progression, may also be encountered more often as time passes. Therefore, we believe that, whilst polymorphous low-grade adenocarcinoma is certainly far less aggressive than, for example, adenoid cystic carcinoma, it nevertheless remains a true malignancy with a potential to prove fatal in a minority of patients.

Sclerosing polycystic adenosis of parotid gland with dysplasia and ductal carcinoma in situ. Report of three cases with immunohistochemical and ultrastructural examination.

We describe three cases of sclerosing polycystic adenosis (SPA) of the parotid gland, a salivary condition analogous to fibrocystic disease of the breast. For the first time, immunoreactivity for oestrogen and progesterone receptors was demonstrated, suggesting a possible participation of hormone stimulation in its pathogenesis. In addition, all our cases showed foci of dysplasia of the ductal epithelium, which in one case was severe enough to amount to carcinoma in situ. This feature that has not previously been reported in SPA.

Spindle cell myoepithelial tumours of the parotid gland with extensive lipomatous metaplasia. A report of four cases with immunohistochemical and ultrastructural findings.

We report four cases of parotid gland tumours composed predominantly of spindle-shaped myoepithelial cells and mature adipocytes. The central portion of one tumour showed extensive adipose differentiation, whereas in the peripheral parts there were small foci of ductal epithelium arranged in cords and tubules within an abundant myxoid stroma. The other cases were adipose spindle cell myoepitheliomas without an obvious glandular component. Under high-power examination, a transition between modified spindle-shaped myoepithelial cells and adipocytes was observed, and this was confirmed with immunohistochemistry. Ultrastructurally, the modified myoepithelial cells showed intracytoplasmic tonofilaments, bundles of actin microfilaments and lipid droplets. A possible pathogenesis is proposed of true metaplastic transformation of myoepithelial cells to adipocytes. This lesion is important to identify correctly, as inadequate surgery can lead to recurrence.

Metaplastic (infarcted) Warthin's tumour of the parotid gland: a possible consequence of fine needle aspiration biopsy.

AIMS: The metaplastic (or infarcted) variant of Warthin's tumour is characterized by replacement of much of the original oncocytic epithelium by metaplastic squamous cells, along with areas of extensive necrosis, fibrosis and inflammatory change. The pathogenesis is unknown, but it is most likely to be vascular in origin. An association with a previous fine needle aspiration (FNA) has been suggested, and this is explored further. METHODS AND RESULTS: Nine metaplastic Warthin's tumours were collected from several centres: all arose in the parotid gland, and all showed the characteristic histological features. Eight had previously undergone FNA some 1-4 months before surgery; the other case had had an incisional biopsy. CONCLUSIONS: It is important to recognize metaplastic Warthin's tumour, because the differential diagnoses of this benign neoplasm include mucoepidermoid and squamous carcinoma, both primary and metastatic. The tumours in this study followed FNA or biopsy, and we believe this association is unlikely to be coincidental. Although many metaplastic Warthin's tumours clearly arise spontaneously, we conclude that the balance of probabilities favours the view that FNA is capable of causing metaplastic change in a Warthin's tumour, and may have done so in these cases. If so, this previously unusual subtype will become increasingly common, as FNA becomes more widely used (and its value appreciated) in the investigation of patients with a mass in the neck.

Cribriform adenocarcinoma of the tongue: a hitherto unrecognized type of adenocarcinoma characteristically occurring in the tongue.

AIMS: We report a review of our institutional and consultation files in order to select cases of hitherto unrecognized type of adenocarcinoma occurring in the tongue. MATERIALS AND RESULTS: Eight cases of a characteristic adenocarcinoma of the tongue resembled solid and follicular variants of the papillary carcinoma of the thyroid. All the tumours were unencapsulated and were divided by fibrous septa into lobules. Major parts of the lesions were composed of areas with solid and microcystic growth patterns. The most striking cytological feature was that the tumour nuclei were pale-staining with a 'ground glass' quality, and they often appeared to overlap. Immunohistochemically, the tumours expressed cytokeratin and S100 protein and, focally, actin; thyroglobulin was negative. Ultrastructurally the cells had clefted nuclei, and the cytoplasm contained a few mitochondria, lysosomes and Golgi apparatus. Many tumour cells had combined features of both myoepithelial and secretory differentiation-well formed microvilli on their apical borders and bundles of microfilaments. At first presentation, all eight patients had metastases in the regional neck lymph nodes, but all are alive 2-6 years after the initial excision and irradiation. CONCLUSION: We describe a distinctive type of adenocarcinoma of the tongue, for which we propose the name cribriform adenocarcinoma of the tongue (CAT). CAT usually presents with metastases in the neck lymph nodes at the time of presentation. We hypothesize that the tumour might arise from the thyroglossal duct anlage.

Oncocytic myoepithelioma and pleomorphic adenoma of the salivary glands.

Twenty oncocytic myoepitheliomas (MEs) and pleomorphic adenomas (PAs) were composed of interlacing fascicles of swollen spindle-shaped or/and epithelioid oncocytic myoepithelial cells showing intense finely granular immunoreactivity with anti-mitochondrial antibody. Focal vacuolation of the cytoplasm of oncocytic myoepithelial cells and their gradual transition into sebaceous metaplasia were observed in 3 cases. Another unusual feature found in 5 cases was the presence of slit-like adenomatoid spaces lined with double-layered oncocytic myoepithelium closely resembling Warthin's tumour. The nuclei of oncocytic cells were characterized by enlargement, hyperchromasia and polymorphism, which should not be confused with malignancy. Oncocytic change in myoepithelial cells in MEs and PAs can cause pitfalls in the differential diagnosis of salivary gland tumours. We describe some unusual histological features associated with onococytic metaplasia in benign myoepithelial cell-derived salivary gland tumours, hoping to help to avoid the overdiagnosis of malignancy.

Malignant adenomyoepithelioma of the breast with mixed osteogenic, spindle cell, and carcinomatous differentiation.

A 50-year-old woman had a malignant tumor of the left breast, which recurred twice, metastasized, and caused death after 39 months. Histologically, the original neoplasm and the first recurrence comprised an adenomyoepithelioma, in addition to a sarcoma composed of trabeculae of mature and immature bone, osteoid, and partly calcified, dense collagenous tissue. The trabeculae were lined by alpha-smooth muscle actin-positive mononuclear tumor cells, which also extended into the stroma. Similarly, scattered osteoclastlike, multinucleate giant cells were present in the stroma and in the region of the trabeculae. This same pattern of adenomyoepithelioma and osteosarcoma also was seen in the last recurrence, together with a proliferation of undifferentiated malignant spindle-shaped cells. The last biopsy also contained a separate small focus of invasive ductal carcinoma of usual type. It was concluded that this, apparently unique, tumor probably represented an adenomyoepithelioma in which a metaplastic sarcoma of osteogenic and undifferentiated types developed from the myoepithelial element, and in which a carcinoma developed from the epithelial component.

Well-differentiated acinic cell carcinoma of salivary glands associated with lymphoid stroma.

In a multicenter study, 69 acinic cell carcinomas of the salivary glands were identified, of which 12 constituted what the authors believe to be a distinct subgroup. Their most noticeable feature was a dense lymphoid stroma with well-developed germinal centers, surrounding a sometimes scanty epithelial component, which in each case had a microcystic growth pattern. All these tumors were enveloped by a thin fibrous pseudocapsule, thus mimicking an intraparotid lymph node containing a metastasis. All 12 cases showed low MIB1 proliferative activity, with a mean index of 1.7% (range, 0.5 to 3.7). All patients remained well without recurrence or metastasis in followup periods of 19 months to 14 years. A second subgroup of nine acinic cell carcinomas also possessed a heavy lymphoid stroma with germinal centers, but its distribution was more patchy than in the first subgroup, and in addition, the fibrous pseudo-capsule was incomplete or absent. In each case the epithelial growth pattern was other than microcystic. These tumors had significantly higher MIB1 indices (mean, 17%; range, 3.4 to 45). In contrast to the first subgroup, only three of nine patients remained well with no further disease. The other six patients developed recurrences or metastases, and two died of disseminated cancer. In view of the clinical and pathological data, it is speculated that the tumor foci lacking lymphoid stroma in each of the second subgroup possibly represented a clone of high-grade malignancy arising within a low-grade acinic cell carcinoma with lymphoid stroma.

Metastatic carcinoma of the prostate presenting as parotid tumour.

Two patients are described in each of whom metastatic prostatic carcinoma presented as a tumour of the parotid gland. In one, primary prostate cancer had been diagnosed three years prior to the appearance of what was believed clinically to be an unrelated salivary lesion. In the other a neck swelling was the first indication of disease, although subsequent investigation revealed widespread metastases. Biopsy of each tumour showed an adenocarcinoma with immunohistochemical expression of prostate markers. These cases, and the six previous reports, illustrate the need to consider metastatic carcinoma from the prostate in the assessment of any malignant tumour of the salivary glands in men of advancing years.

Assessment of proliferative activity using the MIB1 antibody help to distinguish polymorphous low grade adenocarcinoma from adenoid cystic carcinoma of salivary glands.

Salivary polymorphous low grade adenocarcinoma (PLGA) and adenoid cystic carcinoma (AdCC) bear a superficial histological and immunophenotypic resemblance to each other, but can usually be separated by conventional microscopic examination. However, this is not always so, such as with PLGAs displaying plentiful cribriform structures, and when only limited tissue from small biopsies is available for study. Twenty-one cases of PLGA and 20 cases of AdCC from the surgical pathology files in Plzen, Exeter and Helsinki were incubated with the MIB1 antibody using the supersensitive avidin-biotin peroxidase technique after microwave pretreatment. The antibody recognizes the cell cycle associated antigen Ki-67 on routinely processed formalin-fixed paraffin-embedded tissues. The percentage of positively stained tumor cell nuclei constituted the MIB1 index. It was found that the PLGAs had a mean MIB1 index of 2.4% (range 0.2-6.4), while the AdCCs had a mean value of 21.4% (range 11.3-56.7). Within the PLGA group, the 12 tumors which did not form micropapillae had a somewhat lower mean MIB1 index (1.4%) than those nine in which such structures constituted a significant but minor component (3.4%). These results indicate that the MIB1 index was significantly higher in the AdCCs than the PLGAs and that the figures showed no overlap zone. We conclude, therefore, that immunohistochemical staining with the MIB1 antibody appears to be a potentially useful supplementary diagnostic tool in differentiating difficult cases of PLGA from AdCC.

Ossifying fibromyxoid tumor of soft parts: a report of 17 cases with emphasis on unusual histological features.

Ossifying fibromyxoid tumor of soft parts is an unusual benign neoplasm, with a tendency for local recurrence. Its typical microscopic appearance is that of a multinodular proliferation of round to spindle shaped cells separated by fibrous bands in which bone formation is often seen. Herein, we present the clinicopathologic features of 17 examples of this tumor with particular emphasis on some unusual histopathologic features that may place pitfalls in the diagnosis of this tumor, including satellite micronodules, mucinous microcysts, absence of myxoid areas, crush artifact, multiple microcalcifications, epidermoid cysts, atypical chondroid differentiation with binucleate lacunar cells, pericytic growth pattern, and malignant change. Awareness of these unusual morphologic features should lead to a search for areas displaying the more typical features of ossifying fibromyxoid tumor to arrive at a correct diagnosis.

Metastatic renal cell carcinoma presenting as an aural polyp.

Renal cell carcinoma may metastasize to the head and neck region at different stages of its evolution. We present a case of an undiagnosed renal cell carcinoma presenting as an ear polyp, and discuss the difficulties of the diagnosis and the management of these tumours.

Merkel cell carcinoma of the skin.

Primary neuroendocrine carcinoma of the skin or Merkel cell carcinoma is an aggressive primary neoplasm. It is commonly seen in the elderly, on the head, neck and extremities, where it can mimic a benign or less malignant skin tumour. Pathological examination shows a generally dense growth of small dark cells, with immunohistochemical evidence of neuroendocrine differentiation. The microscopic appearance is very similar to metastatic oat cell carcinoma from the lung and this must be excluded by clinical means and appropriate imaging studies. In this study we present 13 new cases of Merkel cell carcinoma (the largest published series in the UK) and summarize 214 cases from the literature in which the survival data are given. In our series, 5 of 13 patients died from spread of the Merkel cell carcinoma. From this and other studies, it appears that early diagnosis and wide local excision may be the only way to prolong survival. No other adjuvant therapy has proved effective.

Clear cell malignant myoepithelioma of the salivary glands.

Previous reports of monomorphic clear cell carcinoma of the salivary glands have shown inconsistent results with immunohistochemistry, especially for S-100 protein, and this has led to uncertainty about the nature of these tumours. We believe that much can be explained by considering this group as comprising not one but two separate neoplasms, one epithelial and the other myoepithelial. The former has been described as hyalinizing clear cell carcinoma--it generally occurs in the minor salivary glands, and strongly expresses cytokeratins but not S-100 protein or alpha smooth muscle actin. In contrast, this study presents five primary malignant tumours of the major salivary glands also composed largely of a single population of clear cells, but displaying histological and immunohistochemical features of myoepithelial differentiation, such as the formation of collagenous spherules and expression of S-100 protein and actin. A small number of similar tumours have been reported previously. We, therefore, believe that these neoplasms represent a clear cell variant of malignant myoepithelioma (myoepithelial carcinoma).

Benign myoepithelioma of the salivary glands: a true entity?

Myoepithelioma is a rare neoplasm of the salivary glands which is now recognized as an individual entity in the revised WHO classification. In this study, eleven benign tumours are presented. Most patients gave a history of a slowly enlarging mass, which was cured by surgical excision. However, one case recurred several times over 50 years, and another still has residual tumour and removal is not possible. The histological appearances included solid, myxoid and reticular growth patterns, composed predominantly of spindle shaped or plasmacytoid (hyaline) cells. Many of the tumours also contained occasional small ducts. All 11 tumours were positive for S-100 protein, variable reactions being seen for various other antigens--keratins, human milk fat globulin, carcinoembryonic antigen, alpha smooth muscle actin and vimentin. It is probable that myoepithelioma constitutes one end of a biological spectrum which also includes pleomorphic adenoma and some (non-membranous) basal cell adenomas. In practice, however, we still advocate retention of myoepithelioma as a separate diagnostic category, on the grounds that it has a range of distinctive microscopic appearances and poses its own unique problems in correct identification.

Classification of salivary gland tumours--a brief histopathological review.

Tumours of the salivary glands display a wide variety of histological appearances, and vary in behaviour from totally benign to high grade and usually fatal malignancies. Over the past 40 years several classification schemes have been proposed, of which the most comprehensive and accurate are those of the Armed Forces Institute of Pathology (AFIP) and the World Health Organization (WHO) which were both revised in 1991. They are readily applicable by practising surgical pathologists, and encompass most of the range of tumours likely to be encountered. If I have a slight preference, it is for the WHO classification which is more concise. This paper briefly discusses each tumour, and highlights the changes from previous classifications, including the proper recognition of several newly described tumours which are distinct clinico-pathological entities. Neither of the new schemes solves every problem, and brief attention is drawn to defects. These are minor, and do not significantly detract from the advantages of both new classifications, which represent a major advance in our ability to understand these often perplexing tumours.