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LEF-1 is a nuclear transcription factor of the Wnt pathway that regulates multipotent skin stem cell differentiation. β-Catenin is considered a transcriptional coactivator that interacts with LEF-1.This study evaluates LEF-1 in a variety of odontogenic and salivary tumors and determines the prevalence of β-catenin coexpression. Ninety-eight salivary gland tumors and 51 odontogenic tumors were evaluated for LEF-1 and β-catenin immunohistochemical staining. Positivity was defined as at least 2+ intensity in more than 50% of tumor cells, which required a composite score of 6 or more. LEF-1 was positive in 64% (7/11) of calcifying cystic odontogenic tumors (CCOT). Nuclear β-catenin was present in 82% (9/11) of CCOT. Coexpression of LEF-1 and nuclear β-catenin was noted in all LEF-1-positive CCOT. Strong and diffuse LEF-1 expression was seen in 69% (11/16) of basal cell adenocarcinomas (BCAC) and 63% (5/8) of basal cell adenomas (BA). Nuclear β-catenin was present in 50% (4/8) of BA and 43% (6/14) of BCAC. For BA, 4 of 5 LEF-1-positive tumors showed coexpression of β-catenin, and for BCAC, 5 of 9 LEF-1-positive tumors showed coexpression. In conclusion, this study documents for the first time the presence of LEF-1 expression and nuclear β-catenin coexpression in select basaloid salivary gland tumors and various odontogenic tumors. We demonstrate LEF-1 expression in both BA and BCAC preferentially over other salivary gland tumors suggesting some utility as a diagnostic marker.

Malignant salivary gland epithelial tumors are histologically diverse with at least 24 recognized distinct entities. In general, malignant tumors account for 15% to 30% of parotid tumors, 40% to 45% of submandibular tumors, 70% to 90% of sublingual tumors, and 50% of minor salivary tumors. Common malignancies include mucoepidermoid carcinoma, adenoid cystic carcinoma, acinic cell carcinoma, salivary duct carcinoma, carcinoma ex pleomorphic adenoma, polymorphous lowgrade adenocarcinoma, and myoepithelial carcinoma. Each tumor type has its own unique histologic variants and prognostic pathologic features, and only mucoepidermoid carcinomas have a formalized grading system. The molecular pathogenesis of certain tumors, such as mucoepidermoid carcinoma and adenoid cystic carcinoma, has recently begun to be elucidated.

Background and Purpose We wanted to evaluate the efficacy, defined as 2-year disease-free survival (DFS), and safety of bevacizumab/chemoradiation in preoperative and adjuvant settings for patients with stage II/III rectal cancer. Patients and Methods Eligible patients had stage II/III rectal adenocarcinoma, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, and adequate organ function, and received preoperative (cohort A) or adjuvant (cohort B) treatment at physician discretion. Patients received 5-fluorouracil (5-FU) as an intravenous infusion (IVCI) 225 mg/m 2 /d on days 1-42, bevacizumab 5 mg/kg intravenously (I.V.) on days 1 and 15 (cohort A), or every 2 weeks (cohort B), with radiation therapy to 50.4 Gy. After surgery (cohort A) or chemoradiation (cohort B), FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) and bevacizumab were administered for 4 months and then bevacizumab was given alone for up to 1 year. Results Sixty-six patients (cohort A = 35; cohort B = 31) were enrolled from August 2006-April 2009: median age was 57 years; male patients, 62%; ECOG PS 0, 75%; stage II/III, 31%/69%. In cohort A, the complete pathologic response (pCR) rate was 29% (11% microscopic residual disease, 49% gross disease). Four patients did not undergo surgery (toxicity, 2 patients; progressive disease, 1 patient; patient decision, 1 patient). One- and 2-year DFS for cohorts A/B were 85%/not reached and 97%/89%, respectively (median survival not reached for either cohort). Frequent grade 3/4 toxicity included diarrhea (A cohort, 14%; B cohort, 29%), neutropenia (A cohort, 14%, B cohort, 23%), mucositis (A cohort, 23%, B cohort, 0%), and fatigue (A cohort, 6%, B cohort, 10%). Other serious toxicity included bowel perforation and pelvic infection (cohort A, 1 patient each), bowel perforation (2 patients), anal wound dehiscence (1 patient), perianal infection (2 patients), and rectovaginal fistula (1 patient) (cohort B), without treatment-related death in either cohort. Conclusions Bevacizumab can be added to standard preoperative and adjuvant chemoradiation in most patients with expected and manageable toxicity and may increase treatment efficacy.

Objectives/Hypothesis: From the 1950s through the 1960s, an unknown number of oropharyngeal squamous cell carcinomas (SCCs) presented with metastases to cervical lymph nodes from an unknown primary (SCCUP) and were not recognized as oropharyngeal in origin. At present, pathologic evaluation of SCCUP for human papillomavirus (HPV) improves discovery of occult oropharyngeal SCC and may partially explain increased incidence of HPV-positive oropharyngeal SCC. Study Design: Retrospective cohort study. Methods: A retrospective study of 13 cases of SCCUP diagnosed from 1956 to 1969 was performed. The probability of these cases of metastatic SCC to originate from the oropharynx was assessed by characterizing their morphology (keratinizing vs. nonkeratinizing) and HPV status by in situ hybridization and p16 immunostaining. Results: Two cases of nonkeratinizing SCC positive for HPV by in situ hybridization and p16 immunohistochemistry were identified. These cases were most likely of oropharyngeal origin. Conclusions: These two cases can be added to the other 15 cases of HPV-positive primary oropharyngeal SCC identified in our department from 1956 to 1969. When determining the incidence of HPV-positive oropharyngeal SCC before the 1970s, a correction factor of about +13% (2/15) accounting for modern pathologic workup of SCCUP during the last couple of decades may be appropriate. Laryngoscope, 2012

Although at least 24 distinct histologic salivary gland carcinomas exist, many of them are rare, comprising only 1% to 2% of all salivary gland tumors. These include epithelial-myoepithelial carcinoma, (hyalinizing) clear cell carcinoma, basal cell adenocarcinoma, cystadenocarcinoma, low-grade salivary duct carcinoma (low-grade cribriform cystadenocarcinoma), oncocytic carcinoma, and adenocarcinoma not otherwise specified. Few tumors (clear cell carcinoma and basal cell adenocarcinoma) have unique molecular correlates. Benign tumors, although histologically less diverse, are far more common, with pleomorphic adenoma and Warthin tumor the most common salivary gland tumors. Many benign tumors have malignant counterparts for which histologic distinction can pose diagnostic challenge.

PEComas are a family of neoplastic lesions that share overlapping morphology, immunohistochemistry, and ultrastructure that include angiomyolipoma, lymphangioleiomyomatosis, clear cell "sugar" tumor of the lung as well as similar tumors occurring in a variety of visceral, cutaneous and soft tissue sites throughout the body. The defining histopathological features are epithelioid cells with a perivascular distribution containing clear to pale eosinophilic granular cytoplasm and a round-to-oval centrally located nucleus with an inconspicuous nucleolus. Immunohistochemically, coexpression of melanocytic (HMB-45 and/or Melan-A) and myoid markers are characteristic. In the present study, we describe three PEComas occurring in the head and neck (nasal cavity and larynx) and discuss the behavior of these distinctive tumors and review the literature of head and neck PEComas. The importance of recognizing this entity will ensure its consideration in the differential diagnosis of tumors of the head and neck with a similar morphology. The histogenesis of PEComas still remains elusive and additional cases with a prolonged follow up remain important to accurately determine the behavior of these distinctive tumors. Complete surgical excision still remains the treatment of choice for histologically benign PEComas.

Tissue repositories maintained by pathology departments represent an abundant resource of clinically annotated human specimens. The storage expenses associated with pathology archives are known to administrators of most pathology departments. However, such basic repository characteristics as the quality of stored materials, ease of access, and search and retrieval rates are often unclear. The aims of our work were to design a framework to assess the quality of a historic pathology archive, to propose the definition of “archive integrity,” and to provide benchmarks for tissue block retrieval rates and DNA integrity. We share our experience with scanning approximately 120,000 pathology reports from 1956 to 1979 into an electronically searchable archive, with a $9,000 budget, completed in 6 weeks. Several ethical and legal considerations that shaped the technical side of this project are discussed.

BACKGROUND AND PURPOSE: The larynx is a rare site for primary NHL. Fewer than 100 cases have been reported in the literature, with the largest imaging review involving only 4 patients. We describe the findings of laryngeal lymphoma on CT, PET, and MR imaging and identify features that may distinguish laryngeal lymphoma from the far more common laryngeal squamous cell carcinoma. MATERIALS AND METHODS: Multi-institutional retrospective chart review revealed 20 patients with histopathologically proved laryngeal lymphoma. Pretreatment CT, PET, and MR images were reviewed by a head and neck radiologist, focusing on extent of tumor, cervical lymph node involvement, and enhancement patterns. RESULTS: Patients ranged from 30 to 90 years of age with a mean of 63 years at the time of initial diagnosis and a 2:1 female predominance. The average tumor size was 37 ± 19 mm. In all patients, laryngeal lymphoma involved the supraglottis but also extended into the glottis (65%) and hypopharynx (60%). The subglottis was less frequently involved (35%). Laryngeal cartilage invasion and cervical lymphadenopathy were each seen in 20% of patients. Lymphoma was consistently FDG-avid (100%) and usually enhanced uniformly with iodinated contrast (73%). Necrosis and calcification were not seen in any cases. CONCLUSIONS: Although laryngeal lymphoma is rare, particular imaging features suggest this diagnosis. A large uniformly enhancing supraglottic tumor without central necrosis and without cervical lymphadenopathy is a characteristic finding of lymphoma. Similar to squamous cell carcinoma, lymphoma may extend into the subglottis, pharynx, and laryngeal cartilages.

The aim of this study is to characterize personal consultation practice in salivary pathology and to identify most common diagnostic challenges. Seven hundred sixty consultation requests were prospectively indexed over 12 months, and 205 cases of salivary type tumors were identified. The following data were recorded: anatomic site, patients' age and gender, geographic origin of cases, diagnoses by submitting pathologist and consultant, and turn-around time. Final diagnosis was offered by submitting pathologist in 77 of 205 cases (37.5%). The definitive diagnosis was provided to contributors in 188 of 205 cases (91.7%); diagnostic limitations and potential adequacy issues were addressed in 17 remaining cases. The average turn-around time was 4.4 days. The three most common diagnostic problems were acinic cell carcinoma, epithelial myoepithelial carcinoma, and adenoid cystic carcinoma. Pathologists' adherence to recommendations by Association of Directors of Anatomic and Surgical Pathology regarding consultation practice is described.

Background Ceruminal gland carcinomas are rare neoplasms confined to the skin lining the cartilaginous part of the external auditory canal. Design Retrospective. Results The patients included 11 men and 6 women, aged 33–82 years (mean, 59.5 years). Patients presented clinically with a mass of the outer half of the external auditory canal (n = 14), hearing changes (n = 5), drainage (n = 4), or paralysis of the facial nerve (n = 3). The polypoid masses ranged in size from 0.5 to 3 cm in greatest dimension (mean, 1.8 cm). Histologically, the tumors demonstrated a solid to cystic pattern, composed of an infiltrating glandular to cribriform arrangement of epithelial cells. Histologic features included a dual cell population (although not the dominant histology), increased cellularity, moderate to severe nuclear pleomorphism, irregular nucleoli, increased mitotic figures (mean, 3/10 HPF), including atypical forms, and tumor necrosis (n = 2). Tumors were divided into three types of adenocarcinoma based on pattern of growth and cell type (ceruminous, NOS [n = 12], adenoid cystic [n = 4], mucoepidermoid [n = 1]). CK7 and CD117 highlighted the luminal cells, while S1-00 protein showed a predilection for the basal cells of ceruminous and adenoid cystic carcinomas. Metastatic adenocarcinoma or direct extension from salivary gland neoplasms are the principle differential considerations. Surgical resection was used in all patients with radiation used in four patients. Eleven patients were alive or had died of unrelated causes without evidence of disease (mean, 11.2 years); six patients had died with disease (mean, 4.9 years), all of whom had developed local recurrence. Conclusion Ceruminous-type carcinomas, with the exception of ceruminous mucoepidermoid carcinoma, all demonstrated a dual cell population of basal myoepithelial-type cells and luminal apocrine cells. The specific histologic sub-type does not influence the long-term patient outcome.

Metastatic renal cell carcinoma (RCC) can pose diagnostic challenges in the head and neck often resembling benign and malignant oncocytic lesions. Immunohistochemical panels have been reported to help with this differential but are not entirely specific or sensitive. We have noticed that p63 routinely stains salivary gland oncocytomas but not metastatic RCC. Nineteen oncocytomas, 9 cases of oncocytosis, 9 oncocytic carcinomas and 16 head and neck metastatic RCC were studied. Morphologic features evaluated were cytoplasmic character (clear versus oncocytic), Fuhrman nuclear grade, mitotic rate, growth pattern, presence of lumens/blood lakes and stromal characteristics. Tumors were stained with antibodies to p63, renal cell carcinoma marker (RCCm), CD10, and vimentin. Eight benign oncocytic tumors (29%) had clear cell features while 6 metastatic RCC (37%) had oncocytic features. Median Fuhrman nuclear grade was 2 in oncocytoma and oncocytosis and 3 both oncocytic carcinoma and metastatic RCC. Mitotic rates were only significantly different between benign oncocytic tumors and metastatic RCC. All oncocytomas had lumina compared to half of metastatic RCC, all of which also demonstrated blood lakes. Seven benign oncocytic tumors (25%) and 5 oncocytic carcinomas (56%) had RCC-like vascular stroma. All primary salivary gland tumors were positive for p63, predominately in basal cell-type distribution. None of the metastatic RCC was positive. RCCm was entirely specific but lacked sensitivity for metastatic RCC while CD10 and vimentin showed variable sensitivity and specificity. While clinical history and morphology usually are adequate, demonstration of p63 staining can definitively exclude metastatic RCC from the differential diagnosis of similar appearing tumors in salivary glands, namely oncocytoma and oncocytic carcinoma, with 100% specificity and sensitivity. While RCCm, CD10, and vimentin performed adequately, they were significantly less reliable than p63 with both false positives and false negatives.

To further define the clinicopathologic spectrum of epithelial-myoepithelial carcinoma (EMCa), we report the gross, histologic, and immunophenotypic characteristics of 61 tumors seen within a 30-year-period. The mean age at presentation was 60.9 years, with a female predominance (1.5:1). The most common sites were parotid (62.1%), sinonasal mucoserous glands (10.3%), palate (8.6%), and submandibular (8.6%). Most EMCas showed a characteristic nodular/multinodular growth pattern and classic biphasic tubular histology. However, new morphologies in EMCa such as ancient change (8.2%), "Verocay"-like change (3.3%), and sebaceous differentiation (13.1%) were noted. Specific histologic variants were dedifferentiated EMCa (3.3%), oncocytic EMCa (8.2%), EMCa ex pleomorphic adenoma (1.6%), double-clear EMCa (3.3%), and EMCa with myoepithelial anaplasia (3.3%). All cytokeratin cocktails selectively highlighted the epithelial component well. Of the myoepithelial markers, p63, smooth muscle actin and vimentin performed best. Bcl-2 and c-kit were frequently positive (66.7% and 69.2%, respectively). p53 was highly expressed only in 1 dedifferentiated EMCa. The recurrence rate was 36.3% (median disease-free survival 11.34 y), but death was rare with 5-year and 10-year disease-specific survivals of 93.5% and 81.8%, respectively. The most important univariate predictors of recurrence were margin status (log rank P=0.006), angiolymphatic invasion (P=0.002), tumor necrosis (P=0.004), and myoepithelial anaplasia (P=0.038). Thus, EMCa is generally a low-grade tumor with a broader morphologic spectrum than previously thought, with several key features predictive of recurrence. Immunohistochemistry can aid diagnosis by highlighting the biphasic nature of the tumor.

Salivary duct carcinoma is a rare but highly aggressive tumor of the salivary glands that has poor prognosis. There is no effective cure for this tumor. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear receptor family with diverse biological functions that include mediation of adipocyte differentiation, regulation of the monocyte-macrophage anti-inflammatory activity, and inhibition of tumor cell proliferation. Natural (prostaglandin J2, PG-J2) and synthetic (thiazolinediones) PPARgamma ligands with anti-proliferative agonist activity have been identified. The expression of PPARgamma has been demonstrated in human colorectal, pancreas, breast, and prostate cancers but has never been explored in salivary duct carcinoma. The aim of our study was to investigate the expression patterns of PPARgamma in salivary duct carcinoma, a finding that may provide a mechanism for treating patients with this highly aggressive tumor. Archival formalin-fixed tissues from 15 salivary duct carcinoma cases were analyzed for PPARgamma expression by an immunohistochemical staining method using a monoclonal antibody against the PPARgamma. The tissue sections were subjected to antigen retrieval by a steam heat method. All the cases of salivary duct carcinoma originated from the parotid gland. Immunohistochemistry analyses showed positive expression of PPARgamma in 12 (80%) cases, whereas 3 (20%) were negative. Of the positive cases, 9 (75%), 2 (17%) and 1 (8%) showed strong, moderate, and weak staining, respectively. All staining was cytoplasmic. Nuclear staining was not observed. We conclude that PPARgamma is frequently (80%) expressed in salivary duct carcinoma, often at high levels, and is topographically located in the cytoplasm. The high-level expression of PPARgamma may provide a potential molecular target for the treatment of salivary duct carcinoma using agonist ligands.

Distinguishing thyroid follicular adenoma from minimally invasive or encapsulated angioinvasive carcinoma can be diagnostically challenging. In some cases, tumors are distorted, fragmented, or stripped of their capsule, and a definitive diagnosis becomes nearly impossible. In other cases, the foci of capsular and/or vascular invasion are subtle, thus making the diagnosis of carcinoma difficult. We developed a microdissection genotyping assay for assessing a panel of tumor-suppressor genes for loss of heterozygosity mutations. The frequency of allelic loss (FAL) in follicular-derived neoplasms correlates with the histologic aggressiveness of the tumor. Furthermore, we calculated the amount of genetic heterogeneity within each tumor, as a second important measure of a tumor's ability for clonal expansion and a surrogate marker for its malignant potential. The follicular adenomas had a low FAL (average 9%) and low intratumoral heterogeneity (5% variability). The minimally invasive and encapsulated angioinvasive carcinomas had an intermediate FAL (average 30%) and intermediate intratumoral heterogeneity (10% variability). The widely invasive carcinomas had a high FAL (average 53%) and high intratumoral heterogeneity (24% variability). Although a larger retrospective study is needed to correlate genotyping studies with patient outcome and prognosis, our results indicate that performing a mutational genotyping assay can stratify tumors into the histologically well-defined categories of adenomas, minimally invasive/angioinvasive carcinomas, and widely invasive follicular carcinomas.

Malignant blue nevus is a rare melanocytic tumor that is described by some authors as a variant of malignant melanoma, whereas others regard it as a distinct entity. To our knowledge no molecular studies of this tumor have been performed, although the molecular pathogenesis of conventional melanomas has been extensively described. We present a case of malignant blue nevus that developed in a 15-cm congenital blue nevus on the back of a 41-year-old man. Subsequent regional lymph node and lung metastases developed within 1 and 29 months, respectively. We performed a molecular analysis for loss of heterozygosity on microdissected samples from the spectrum of benign to malignant blue nevus, using a panel of eight genes (MTS1, MXI1, CMM1, p53, NF1, L-myc hOGG1, and MCC), many of which are commonly associated with conventional melanomas. No loss of heterozygosity was detected, despite informativeness in seven genes. We suggest that malignant blue nevus may represent a distinct entity with a different molecular pathway to tumorigenesis than that of conventional melanomas.

The clinical significance of microscopic papillary thyroid carcinoma (PTCa) is controversial. Many authors think that microscopic PTCa (1 cm) have the same pathogenetic origin as clinically sized papillary carcinomas (1 cm). Despite the fact that all clinical risk prognostication schemes have the size of the tumor as a primary category, small tumors do have malignant potential and can metastasize. There is growing evidence that small PTCa have the molecular translocations between the proto-oncogene RET and various activating partner genes that are characteristic of clinically sized PTCa. This study used a microdissection and genotyping assay to study the patterns of loss of heterozygosity of tumor suppressor genes in microscopic and clinically sized PTCa. Our results indicate that all PTCa harbor mutations with similar frequencies and distribution patterns, regardless of the size of the tumor. These data are further evidence that microscopic and clinically sized PTCa are pathogenetically related.

Psammoma bodies in the thyroid are common in glands with papillary thyroid carcinoma. Psammoma bodies that are not associated with tumor cells, however, represent a diagnostic problem for pathologists. Should we treat isolated psammoma bodies as representing metastatic disease? This study included patients who had non–tumorassociated psammoma bodies in their thyroids or in the perithyroidal lymph nodes. Clinical, pathologic, and follow-up information was obtained for the patients. Our results indicate that 27 of 29 patients had a contralateral or an ipsilateral tumor, the majority of which were papillary. We noted a high frequency of microscopic carcinomas (12/27) and of tall cell variants of papillary thyroid carcinoma (8/27 cases). Based on these findings, we recommend that thyroid glands with non–tumor-associated psammoma bodies and no histologically identified carcinoma be entirely submitted to identify any microscopic carcinoma. If no carcinoma is identified in a lobectomy, discussion with the surgeon should indicate the need for close clinical follow-up. Psammoma bodies are considered by many pathologists to be a reliable diagnostic feature of papillary thyroid carcinoma. Psammoma bodies are round to oval calcifications that have lamellations and should be distinguished from dystrophic calcification and calcified colloid. They occur predominantly in the classic form of papillary carcinoma but

Salivary duct carcinoma (SDC) is an uncommon, pathologically distinct entity characterized by its morphologic resemblance to ductal carcinoma of the breast and highly aggressive behavior. Approximately two thirds of patients die within 4 years of initial diagnosis despite aggressive, combined surgical resection and radiotherapy. Review of the literature indicates that androgen receptor (AR), a marker frequently detected in prostatic carcinoma, is expressed in over 90% of SDCs, whereas two common breast carcinoma markers, estrogen and progesterone receptors (ER and PR), are expressed in only 1.3% and 6% of the tumors, respectively, by immunohistochemistry. This hormonal profile suggests that SDC, in contrast to its histiologic similarity to ductal carcinoma of the breast, is immunophenotypically more related to prostatic carcinoma. To substantiate this hypothesis, we performed immunohistochemical staining of 13 cases of SDC for the presence of AR and two prostatic markers, prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). Our results showed multifocal, scattered, moderate immunostaining for PAP and diffuse, moderate immunostaining for PSA in seven (58.3%) and two (16.7%) cases, respectively. These results create a potential diagnostic challenge to surgical pathologists who are dealing with a metastatic adenocarcinoma of AR+/PSA+/-/PAP+/- phenotype, particularly in male patients of unknown primary. Metastatic salivary duct carcinoma should be given serious thought if clinical investigation fails to reveal a prostatic primary. The immunophenotypic homology that exists between SDC and prostatic carcinoma also suggests that antiandrogen therapy as used in the treatment of prostatic carcinoma might be beneficial in patients with metastatic SDC when all other conventional modalities fail.

Microdebriders are being used with increasing frequency in endoscopic sinus surgery to provide precise removal of soft tissue and bone with simultaneous suction and irrigation. To date, no one has analyzed whether histopathology of tissue processed through a microdebrider is maintained. Fifteen tissue samples (squamous cell cancer, esthesioneuroblastoma, lymphoma, sarcoma, inverted papilloma, benign thyroid, and nasal mucosa) were processed though a microdebrider in various modes and speeds. Pathology slides were developed, coded, and presented as unknowns to the pathologist for diagnosis. Specimens taken from routine biopsy techniques were then compared to those passed through the microdebrider. The study found no significant loss of morphologic features in the tissue passed through the microdebrider. The microdebrider may be used for both routine and oncologic procedures without altering the histopathology necessary for diagnosis.

Branchial cleftlike cysts of the thyroid gland are rare lesions. Although initially described in patients with chronic lymphocytic thyroiditis, these cysts have been reported in a variety of histologic settings. We present 2 case studies, 1 in a 30-year-old woman and 1 in a 50-year-old man. The mode of presentation and management of these cases, along with a literature review, is discussed in brief.

The present study examined the possibility of using a tissue subsample to estimate the total number of Schistosoma japonicum eggs in the liver or an intestinal section. Sixteen male Landrace/Yorkshire crossbred pigs were each infected with 500 S. japanicum cercariae and killed 12 weeks post infection. Five-gram samples were taken from specific areas of the liver, colon, caecum and rectum, and tissue egg counts (TECs) were determined by digestion of the tissue sample in 3% KOH for 18 h according to a standard procedure. The rest of each tissue was also processed to determine whole tissue egg counts. For the liver, counts from 5-g samples taken from the left medial and left lateral lobes were not significantly different from counts for the whole liver, but counts from 5-g samples from the right lateral, right medial and central lobes differed significantly from whole liver counts. Variable results were obtained for 5-g samples from six specific points in the colon in comparison with the whole colon counts. This latter result corresponded well to observed gross pathological findings indicating patchy egg deposition in the large intestine. One 5 g sample from either the caecum or rectum could not be used to estimate the whole tissue egg count because of the high variability in the counts. The results suggest that the processing time of liver tissue can be greatly diminished by using a 5 g subsample from a specific liver lobe to estimate the TEC of the whole organ.

BACKGROUND Transforming growth factor-α (TGF-α) and epidermal growth factor receptor (EGFR) mRNA are up-regulated in squamous cell carcinoma of the head and neck (SCCHN) tissues. METHODS Immunohistochemical staining with monoclonal antibodies to TGF-α and EGFR was undertaken to identify the cellular origin in tissue obtained from cancer patients and controls and to determine the correlation between mRNA expression levels and two methods of immunohistochemical evaluation. RESULTS TGF-α protein staining occurred in the suprabasal layers and spared the basal layer of normal controls. Conversely, in histologically normal mucosa from SCCHN patients, TGF-α was present throughout the epithelium, including the basal layer. EGFR staining was negligible in normal mucosa from control patients without cancer and relatively increased in SCCHN tissues. Increasing staining intensity was correlated with worsening dysplasia and closer proximity to the tumor. Using computerized image analysis to quantify the intensity of immunostaining, the mean optical density (MOD) of TGF-α staining in histologically normal mucosa (P = 0.049) and tumors (P = 0.005) from SCCHN patients was significantly higher than in control normal mucosa from noncancer patients (1.9- and 1.7-fold, respectively). EGFR MOD was also greater in the histologically normal mucosa (P = 0.009) and tumors (P = 0.006) from SCCHN patients than in control normal mucosa (1.8- and 1.9-fold, respectively). For both TGF-α (P = 0.668) and EGFR (P = 0.116), the MOD was similar for both tumor and histologically normal mucosa from SCCHN patients. CONCLUSIONS TGF-α and EGFR protein expression is increased early in head and neck squamous cell carcinogenesis and can be quantitated by computerized image analysis of immunohistochemical staining. Altered distribution of TGF-α protein in histologically normal mucosa from SCCHN patients compared with control mucosa from patients without cancer suggests a switch from a paracrine to an autocrine pathway. Cancer 1996;78:1284-92.

Intracytoplasmic lipid content reflects the metabolic state of parathyroid cells, and staining for this is a useful adjunct in the evaluation of parathyroid glands excised in the treatment of hyperparathyroidism. The procedure, however, is not without limitations, as the unexpected presence of lipid in abnormal, hyperfunctioning glands or its absence in normal glands is occasionally encountered. In this study, the authors review the oil red O staining patterns of 524 parathyroidectomy cases to determine the validity of the stain as well as possible clinical and pathologic correlations. Twenty-seven cases (5.2%) were identified with problematic oil red O staining on which adequate clinical follow-up and pathologic material were available for review. Mean follow-up time was 32 months for this subgroup. The most common problem was the presence of lipid within adenomas (19 cases) or hyperplastic glands (6 cases). Markedly decreased or absent lipid in normal, adenoma-associated glands was seen in two cases. The intensity and distribution of lipid staining in hyperfunctioning glands varied. In four cases, 2/19 adenomas and 2/5 hyperplasia, diffuse positivity, similar to normal parathyroid, were observed. If weak or only focally strong staining patterns are considered to be consistent with hyperfunctioning glands, only six cases, two adenomas, two hyperplasias, and two normal glands could not be resolved. Oil red O stain is useful in diagnosing abnormally functioning parathyroid glands, and, if attention is paid to the staining pattern, few atypical patterns are encountered. Int J Surg Pathol 3(3):163-168, 1996

Ameloblastic fibrosarcoma, the malignant counterpart of the ameloblastic fibroma, is a rare odontogenic tumorcharacterized by benign epithelium and a malignant fibrous stroma. We have compared nuclear DNA content of five ameloblastic fibrosarcomas and three ameloblastic fibromas by image analysis. The three ameloblastic fibromas were diploid, whereas 1 of 5 ameloblastic fibrosarcomas was aneuploid. There was no correlation with histologic grade and aneuploidy. These five new cases were also added to a review of the literature, bringing the total cases of reported ameloblastic fibrosarcomas to 51. The ameloblastic fibrosarcoma occurs at a later age (mean, 27.5 years) compared with reported ameloblastic fibromas (mean, 14.6 to 22 years), which supports a step-wise malignant transformation. There was histologic documentation that 44% of ameloblastic fibrosarcomas developed in ameloblastic fibromas. In view of this data and of the reported cumulative recurrence rate of 18.3% for ameloblastic fibroma, it is recommended that ameloblastic fibromas be treated with complete surgical excision and long-term follow up rather than simple curettage or enucleation.

The case of a 76-year-old white woman with squamous cell carcinoma of the thyroid gland arising in a background of Hashimoto's thyroiditis is presented. Squamous cell carcinoma of the thyroid gland is a very rare and aggressive tumor, and only a few cases are reported as arising in Hashimoto's thyroiditis. Although Hashimoto's thyroiditis alone does not necessarily predispose patients to malignancy, the finding of a prominent nodule in such a patient should suggest the possibility of malignancy, and an aggressive search and treatment regimen, including surgical intervention, should be pursued.

OBJECTIVE To learn about the effects of cranial base surgery. DESIGN Cohort study with a mean follow-up of 30 months. SETTING Population-based. PATIENTS A consecutive sample of 183 patients who underwent cranial base surgery; 118 patients had malignant skull base tumors, the majority of which were previously treated; 50 had benign tumors; 9 had congenital malformations of the skull base; 3 had inflammatory lesions, and 3 had traumatic defects of the skull base. MAIN OUTCOME MEASURES Disease-free interval, overall survival, and rate of complications and functional status. INTERVENTION Cranial base surgery was followed by radiotherapy (in previously untreated patients). RESULTS After completion of follow-up (mean, 30 months), 30 (25.4%) patients had died of their malignant tumors and 8 (6.8%) had died of other causes. One patient (0.84%) was lost to follow-up. The overall cancer survival rate without regard to histologic type was 67% (63% with no evidence of disease). Among the patients who were treated for benign neoplasm, 72% had no evidence of disease at a mean follow-up of 39 months. The group of patients with congenital malformations and inflammatory and traumatic lesions demonstrated successful correction of their presurgical problem with skull base surgery. One patient (who had invasive aspergillosis) died of disease. The overall surgical-medical mortality rate was 2%; the complication rate was 33%, and the Karnofsky performance score was improved or unchanged after surgery in 83% of patients. The average duration of surgery, number of blood transfusions used, and length of the hospital stay were 10 hours, 3 units, and 15 days, respectively. CONCLUSIONS Cranial base surgery is a valid surgical technique for treatment of cranial base afflictions. In this study it was found to be beneficial in controlling benign and malignant disease and to be the treatment of choice for selected congenital malformations, trauma, and inflammatory lesions.

Clear cell carcinoma or hyalinizing clear cell carcinoma (CCC) and clear cell odontogenic carcinoma (CCOC) are rare, low-grade and typically indolent malignancies that can be diagnostically challenging. In this study the clinicopathologic, histologic, and immunohistochemical features of 17 CCCs and 12 CCOCs are examined. The differential diagnosis of clear cell malignancies in the head and neck is discussed. The relationship of CCCs and CCOCs to other clear cell tumors on the basis of their immunohistochemical staining patterns is postulated.

Oncocytic mucoepidermoid carcinoma poses diagnostic challenge because of its histologic overlap with other oncocytic salivary gland lesions, including Warthin tumor. Although the prognostic value of the t(11;19) MECT1-MAML2 fusion gene has been established in mucoepidermoid carcinoma, its diagnostic use in discriminating oncocytic mucoepidermoid carcinoma from histologic mimics is unexplored. We evaluated the translocation status in 14 cases of oncocytic mucoepidermoid carcinoma using a MAML2-11q21 break-apart probe spanning the entire chromosome region of the MAML2 gene and correlated these findings with clinicopathologic parameters including age, sex, stage, predominant growth pattern, grade, and p63 immunostaining pattern. All oncocytic mucoepidermoid carcinomas were parotid tumors with a mean patient age of 54.6 years (range, 9-85) and a female to male ratio of 5:2. Grade distribution was as follows: low grade, 9; intermediate grade, 2; and high grade, 3. The histologic patterns observed were as follows: solid, 4; cystic, 8 (of these, 5 had Warthin-like lymphoid stroma); and mixed, 2. Solid oncocytic mucoepidermoid carcinomas showed a diffuse p63 staining pattern, whereas cystic oncocytic mucoepidermoid carcinomas showed staining of the outer layer of intermediate cells ranging from a bilayer to areas of complex multilayering and plaque-like proliferation. Ten (71%) of the 14 cases showed a MAML2 rearrangement by fluorescence in situ hybridization. No correlation was seen between rearrangement status and histologic grade, growth pattern, or p63 staining pattern. However, we demonstrate that the presence of MAML2 rearrangement can be used as supportive evidence to distinguish oncocytic mucoepidermoid carcinoma from other oncocytic lesions.

Objective To reappraise the clinical and histologic variables associated with a more aggressive outcome in polymorphous low-grade adenocarcinoma (PLGA). Design Retrospective cohort. Setting University hospital. Patients Twenty-four patients with PLGA treated from January 1, 1973, through December 31, 2005. Main Outcome Measure Analysis of clinical and pathologic variables in 30 biopsy or resection specimens from 24 patients. Results Only 4 PLGAs were not initially diagnosed as such. However, 8 non-PLGAs (thus excluded) were incorrectly diagnosed as PLGA. Most carcinomas (14 of 24 [58%]) were palatal. Recurrent carcinomas had a significantly higher mitotic rate (2.7 mitoses per 10 high-power fields) compared with primary tumors (1.2 mitoses per high-power fields, P = .046), and 3 of 7 (43%) recurrences showed progression to an intermediate-grade histologic type. No patient died of disease. Median disease-free survival was 12.8 years. Four of 24 patients (17%) had regional lymph node metastases, 3 with carcinomas of the base of the tongue. One PLGA metastasized to the subcutaneous tissue of the face, orbit, and lungs at 19.6 years. An extrapalatal site was the only significant determinant of disease-free survival ( P = .03). Conclusions Diagnosis of PLGA remains a challenge. Extrapalatal carcinomas appear to behave in a more aggressive fashion than those of the palate, and cancer arising from the base of the tongue frequently metastasizes to the cervical lymph nodes, suggesting a role for neck dissection in these patients. Recurrent cancers show evidence of histologic progression, justifying an aggressive approach to achieving initial complete excision.

Objective Basal cell adenocarcinoma of a minor salivary gland is extremely rare. The goal of this report is to increase awareness of this rare disease and to review and discuss the differential diagnosis and important considerations in treatment. Study Design Case report and review of the literature. Methods Case report of a basal cell adenocarcinoma of a hard palate minor salivary gland and review of the literature of basal cell adenocarcinoma. Results Basal cell adenocarcinomas are slow-growing tumours that most commonly involve the parotid gland and very rarely involve minor salivary glands. Although recurrence rates for these tumours are high, mortality rates are low. Histological diagnosis is important to distinguish this tumour from adenoid cystic carcinoma given the significant difference in disease prognosis. Conclusions Diagnosis of these tumours must be made histologically. Recommended treatment options include wide local excision with radiotherapy reserved for close surgical margins or for local recurrence.

Aims: To describe seven cases of sinonasal seromucinous hamartoma. Materials and results: The clinicopathological and immunohistochemical features of seven seromucinous hamartomas were analysed. There were four men and three women. Six lesions involved the posterior nasal septum and one the lateral wall. Size ranged from 6 to 40 mm. Four patients had no recurrences. One patient had local recurrences 24 and 60 months after diagnosis. The masses were covered by respiratory epithelium. Their stroma was oedematous to fibrous and contained invaginated respiratory epithelium forming glands and cysts, cysts with cuboidal to flat epithelium, and small serous glands, ducts and tubules with lobular and irregular haphazard patterns. One case had numerous glands surrounded by hyalinized basement membrane with features of respiratory epithelial adenomatoid hamartoma (REAH). One case had focal REAH-like changes. Both respiratory and serous components were positive for cytokeratin (CK) 7 and CK19. The serous component lacked myoepithelial cells when stained for CK14, p63, calponin and muscle-specific antigen in five cases. Conclusions: Seromucinous hamartomas show a broader histopathological appearance than previously reported. The serous proliferation in these lesions lacks myoepithelial cells. The presence of occasional REAH-like features and common location in the posterior nasal septum suggest a spectrum from pure seromucinous hamartoma to REAH.

Background Follicular dendritic cell sarcoma (FDCS) arises from nonlymphatic antigen-presenting cells found in lymph node B-cell follicles. This extremely rare tumor, which usually arises in lymph nodes, does occur in extranodal head and neck sites such as the tonsil and soft palate. Methods A retrospective review of the patient followed at the University of Pittsburgh Medical Center from 1993 to the present was performed. Conclusions This is the first reported case of an FDCS of the thyroid. A review of the literature provides useful information to aid in detection, treatment, and outcome of this unusual soft tissue malignancy. © 1999 John Wiley & Sons, Inc. Head Neck 21: 273–275, 1999.

Parathyroid lipoadenomas and lipohyperplasias are rare histologic variants with both an increase in stromal fat and parenchyma. We report the most comprehensive single institution series of lipoadenomas and lipohyperplasias to date and review the literature. Eight lipoadenomas and 3 lipohyperplasias (27 y period) were reviewed. The mean age was 60.3 years (range: 50 to 77 y) with a female predilection (1.75:1). The most common symptoms on presentation were fatigue (55.6%) and bone/joint pain (44.4%). Only 1 patient was euparathyroid. Ultrasound localized lipoadenomas in 50% of tested cases whereas sestamibi was successful in 71.4%. Despite increased stromal fat (median: 50%), the weight and the appearance of large, occasionally nodular expansions of parathyroid parenchyma within the fatty stroma distinguished lipoadenomas and lipohyperplasias from normal parathyroid tissue; none of the cases were misclassified as normal on frozen section. Mean weight for lipoadenomas was 1553 mg (range: 173 to 4587 mg), whereas the mean weight for lipohyperplasia glands was 389.1 mg. Variant morphologies included follicular patterned, oxyphil predominant, and thymic elements (thymolipoadenoma). In 1 lipohyperplasia case, not all glands were involved. Oil Red O stains showed decreased intracytoplasmic lipid in most cases. Median follow-up was 9.2 months (range

High-grade transformation of adenoid cystic carcinoma (ACC) (previously referred to as dedifferentiation) is a rare phenomenon that does not fit into the traditional ACC grading schemes. The importance and minimal criteria for distinction from solid (grade III) ACC are not well established. We report 11 new cases and review the literature to further define the profile of this tumor. The median age was 61 years (range: 32 to 72 y) with a male predominance (male to female ratio of 1.75:1). The most commonly involved sites were sinonasal (4/11) and submandibular (4/11). Lymph nodes were pathologically positive in 4/7 (57.1%) cases. Distant metastases to the lung (n=2) and soft tissue of the shoulder (n=1) were observed. Five of 9 patients (55.6%) died, all within 5 years with a median overall survival of 12 months. Histologically, ACC with high-grade transformation was distinguished from conventional ACC by nuclear enlargement and irregularity, higher mitotic counts, and the loss of the biphasic ductal-myoepithelial differentiation. Useful supportive criteria were prominent comedonecrosis and fibrocellular desmoplasia. The most common morphologies for the high-grade component were poorly differentiated cribriform adenocarcinoma and solid undifferentiated carcinoma. Micropapillary and squamoid patterns were occasionally present. Ki-67 and p53 labeling indices were elevated in the high-grade components, though c-kit and cyclin-D1 were not. ACC-high-grade transformation is a highly aggressive salivary gland tumor with a variety of histologic patterns. The high propensity for lymph node metastases suggests a role for neck dissection in patients with this rare tumor.

Protein products of tumor suppressor genes are often involved in regulating the cell cycle, and aberrant expression can correlate with underlying genetic mutations. Mutations in the p16 gene have been detected at relatively high rates in squamous cell carcinomas of the oral cavity. However, immunohistochemical staining for the protein product has not been examined as a diagnostic tool for identifying dysplastic lesions in the oral cavity. Sixty cases of biopsies of reactive, inflammatory, and dysplastic lesions of all grades were stained with an antibody to p16INK4A and analyzed for which layer of the epithelium had positive cells. Staining was seen only in the basal or lower third in keratoses and mild dysplasias and was seen in the mid and upper thirds in moderate to severe dysplasia. The staining across larger fragments of biopsied epithelium highlighted skip lesions, with strong staining restricted to dysplastic regions. Inflammatory lesions, including chronic ulcers, showed absent or minimal basal layer staining with p16INK4A. In this preliminary study, p16INK4A shows promise as to a potential marker to aid in recognizing the presence of dysplasia in squamous mucosa of the head and neck, particularly in subtle lesions, and in an inflammatory or ulcerated background.

Warthin's tumors are benign lesions of the head and neck that have a characteristic morphologic appearance. The etiology of Warthin's tumors is controversial and whether they are true neoplasms or developmental malformations continues to be debated. In this study, we examined 12 Warthin tumors with a molecular and immunohistochemical approach. Immunostains for p53 and p16ink were performed. The epithelial and lymphoid components of each lesion were microdissected and PCR was performed for 13 microsatellite markers at or near common tumor suppressor genes. The results were analyzed semiquantitatively using capillary electrophoresis. Frequency of allelic loss was calculated. The epithelial component of all tumors was negative for p53 and p16ink. By molecular genotyping there was only one case that had one locus with allelic imbalance, while the remainder had no evidence of clonal allelic loss. The immunohistochemical and molecular results in this study lend support to the hypothesis that Warthin tumors are non-neoplastic, as there was no evidence of aberrant staining for tumor suppressor gene protein products and no evidence of consistent clonal allelic losses.

Primary sclerosing mucoepidermoid carcinomas with eosinophilia (SMECE) of the thyroid gland are rare tumors that can present diagnostic difficulties to the pathologist due to the unusual histologic features. Furthermore, the etiology of these tumors has been debated in the literature, with some authors believing that the tumors arise from remnants of the ultimobranchial body (UBB, solid cell nests) and others proposing that they arise from follicular epithelial cells. Because SMECE often occur in glands with chronic lymphocytic thyroiditis and UBB hyperplasia, and do not stain like follicular or parafollicular cells, it is likely that the tumors do arise from UBB/solid cell nests. In this study, we provide additional evidence for this relationship, by demonstrating that SMECE stain strongly positive for p63, which is a new marker for UBB/solid cell nests.

The relationship between chronic lymphocytic thyroiditis (CLT) and papillary thyroid carcinoma (PTC) is a subject of controversy. Some investigators suggest a causal relationship, whereas others regard the two as only a coincidental occurrence. An additional complicating factor is the presence of atypical nuclei frequently found within lymphoid infiltrates in CLT, which resemble those in PTC. The finding of the RET-PTC translocations in CLT has been reported by two independent groups of investigators, suggesting that the areas of nuclear atypia in CLT are neoplastic rather than reactive. In the present study, we report additional molecular findings that support the hypothesis that the atypical nuclear changes in CLT may be preneoplastic or neoplastic. We microdissected small areas with atypical nuclei in glands with CLT and observed loss-of-heterozygosity mutations of tumor suppressor genes. These genetic mutations are evidence of clonal preneoplastic or neoplastic changes in the follicular cells of CLT. The clinical malignant potential of these minute foci is likely to be very small but remains to be determined.

Eagle syndrome includes elicitation of pain on swallowing, turning the head, or extending the tongue. The syndrome is thought to be caused by irritation of the glossopharyngeal nerve, most commonly caused by its impingement against an elongated styloid process. We present a rare case of a granular cell tumor presenting as Eagle syndrome. Granular cell tumors orignate from Schwann cells and are most common in the subcutaneous tissue of the head, neck, and oral cavity, especially the tongue. A granular cell tumor is typically benign and solitary, rarely malignant. The differential diagnosis, diagnostic algorithm, and treatment are presented.

Chordomas are midline, slowly growing, and locally destructive tumors derived from vestigial remnants of the notochord. We present an unusual case of a cervical vertebral chordoma with extensive chondroid change that aggressively recurred in the anterior larynx and surrounding neck structures, and subsequently in the mediastinum, resulting in the death of the patient. Recent literature has investigated and debated the significance of chondroid elements in chordomas as a differential diagnostic and a prognostic indicator. In particular, the use of immunohistochemical stains for cytokeratin and mesenchymal markers in these areas as a means of distinguishing true from pseudocartilage has received much attention. In this study, we used a spectrum of cytokeratin subtypes (CK 7, 20, 5/6, AE1/3) to further characterize these chondroid areas, and observed that they were positive for the majority of the cytokeratin subtypes, suggesting pseudo, rather than true, cartilaginous change. Clinicopathologic features of this lesion and the recent literature are reviewed.

Background: Salivary duct carcinoma (SDC) is a rare, highly aggressive neoplasm that primarily affects the major salivary glands. It is a distinct clinicopathological entity characterized by its morphologic resemblance to ductal carcinoma of the breast, a high incidence of regional lymph node metastasis, and distant dissemination. Frequent expression of androgen receptor (AR) but not estrogen receptor or progesterone receptor in SDCs suggests that SDC bears a close immunophenotypic homology with prostatic carcinoma. An AR-mediated autocrine growth pathway consisting of epidermal growth factor receptor (EGFR) and its ligand, transforming growth factor a (TGF-a), has been implicated in the carcinogenesis of prostatic carcinoma. Androgens, in the presence of AR, mediate their mitogenic effects on prostatic cancer cells by up-regulating the transcriptional and translational activities of EGFR and TGF-a. Through an autocrine mode of action, TGF-a produced in the tumor cells binds to its receptor, EGFR, which is also expressed by these cells, resulting in a proliferative response. Objective: To investigate whether a TGF-a/EGFR autocrine pathway is present in SDCs. Design: Retrospective analysis of the expression of AR, EGFR, and TGF-a in 12 SDCs. Setting: An academic medical center. Results: Salivary duct carcinoma expresses AR, TGF-a, and EGFR in 11 (92%), 8 (67%), and 11 (92%) of 12 cases, respectively. Conclusion: An AR-mediated TGF-a/EGFR autocrine pathway may be implicated in the tumorigenesis of SDC. Arch Otolaryngol Head Neck Surg. 2001;127:1075-1079

The neuromuscular hamartoma (also referred to as the neuromuscular choristoma or benign triton tumor) is a rare developmental lesion composed of mature elements of both striated muscle and nerve. To date, less than 20 cases have been reported in the English language literature. The majority of these have involved large nerves, such as the sciatic or brachial plexus, but cutaneous lesions have also been reported. We report 2 cases that involve the head and neck and that are among the few described in this location. The majority of cases have been described in infants and young children. However, 1 of our cases (and at least 1 previously reported case) occurred in an adult. While surgical excision has been the most widely used form of therapy, a few cases have been complicated by and/or associated with a second lesion, such as a fibromatosis or lymphangioma.

1. Tyloxapol, trace-labelled (50-100 microCi/animal) with 3H or 14C, was administered intratracheally in a surfactant formulation (EXOSURF Neonatal) to the male rabbit in a total tyloxapol dose of 5 mg/kg. Urine, faeces, expired air, and blood were collected for up to 10 days following tyloxapol administration. 2. Over 5 days, 3H-tyloxapol-related radioactivity in the urine (13.4%) and faeces (27.4%) accounted for a major fraction of the labelled dose. However, urine also contained an additional 13% of the dose as tritiated water. Expired air accounted for only 4.2% of the dose. At the end of the study, an additional 35.6% of the radioactive dose was found in tissues and the carcass, mainly in the lung (27.4%) and to a lesser extent in the liver (2.8%) and kidney (0.4%). Levels of radioactivity in other tissues, including whole blood, were low. 3. Over a separate 10-day study, faecal (30.4%) and renal (9.7%) elimination of 14C-tyloxapol accounted for 40% of the radioactive dose, with expired air accounting for much less (2.7%). At the end of the study, additional radioactivity was recovered from the lung (43.9%) and to a lesser extent from the liver (3.8%) and kidney (0.3%). The half-life for the elimination of total radioactivity from the lung was estimated to be 10-12 days. 4. These data indicate that, following intratracheal administration, tyloxapol and metabolites were retained by the lung, released slowly into the systemic circulation, and eliminated through faecal and renal excretion.