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Background Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. Methods We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. Results Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. Conclusions The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.

Background Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. Methods We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. Results Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. Conclusions The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.

Context Congenital generalized lipodystrophy, type 4 (CGL4) is a rare autosomal recessive disorder caused by mutations in caveolae-associated protein 1. Patients with CGL4 also have myopathy and cardiomyopathy with a predisposition for sudden death due to ventricular arrhythmias. However, the underlying pathology for these morbidities remains unknown. Therefore, we report on an autopsy of a Hispanic boy with CGL4. Case Description Our patient had early-onset generalized lipodystrophy, feeding difficulties, myopathy, atlanto-axial dislocation, and learning disabilities. He was diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) at age 8 years, had poor compliance with medications, and died suddenly at age 15.3 years. Autopsy showed marked loss of subcutaneous and omental fat with no inflammatory cells in adipose tissue and normal adipocytes in the parathyroid glands. There were adipocytes interdigitating cardiac muscle fibers, with fibro-fatty infiltration in the right ventricle, near coronary sinus, and atrioventricular node. There was no evidence of coronary heart disease. The quadriceps femoris muscle did not show adipocyte infiltration, inflammation, or fibrosis. The muscularis mucosa layer was thickened in the esophagus and at the gastro-duodenal junction, and the esophagus had prominent, large nerves in the subserosa. The liver weighed 3000 g, with minimal chronic inflammation and steatosis in 40% of parenchyma, primarily in zones 2 and 3. There was no spermatogenesis in the spermatic tubules. Conclusions Our data suggest that fibro-fatty infiltration of the right ventricle may contribute to CPVT in patients with CGL4. Thick muscularis mucosa and large nerves in the esophagus likely contributed to dysphagia and dysmotility. A lack of spermatids suggests infertility in affected male patients.

Aims Familial partial lipodystrophy, Dunnigan variety (FPLD), is an autosomal dominant disorder due to missense mutations in the lamin A/C gene and is characterized by gradual loss of subcutaneous fat from the extremities and trunk, fat accumulation in the head, neck and intra-abdominal areas, insulin resistance and its metabolic complications. We studied autopsy findings in two patients with FPLD to determine fat distribution and organ involvement. Results Patient 1, a 66-year-old woman with the R482Q mutation, had diabetes mellitus, dyslipidaemia, and coronary artery disease and died suddenly. Autopsy confirmed the typical body fat distribution and further revealed excess fat deposition in the subpectoral regions extending to the axillae, in the axillary lymph nodes and in the retroperitoneum. Atherosclerotic vascular disease including old infarcts of the myocardium, temporal lobe and kidneys were noted. Severe amyloidosis of the pancreatic islets and grouped muscle atrophy of the quadriceps and diaphragmatic muscles were present. Patient 2, a 29-year-old woman belonging to a pedigree with the R62G mutation, died of hyperlipidaemia-induced acute pancreatitis. Autopsy of patient 2 revealed extensive pancreatitis, hepatic steatosis and polycystic ovaries. Conclusions Our study confirms typical body fat distribution and describes new sites of excess fat deposition. Our data show predisposition to atherosclerosis and polycystic ovaries and suggest that pancreatic amyloidosis may underlie development of hyperglycaemia in FPLD patients. Diabet. Med. 19, 1022–1025 (2002)

Castleman's disease of the hyaline vascular subtype is an uncommon lesion; experience with fine-needle aspiration (FNA) of this tumor is limited to rare case reports. We describe the cytologic, flow cytometric, and immunohistochemical findings in two cases initially sampled by FNA. Two females, aged 40 and 26 yr, were found incidentally to have an oropharyngeal and a mediastinal mass, respectively. Neither complained of systemic symptoms, and both had a normal routine laboratory workup. FNA followed by surgical excision in both cases was consistent with Castleman's disease of the hyaline vascular type. In the appropriate clinical context, a mature small lymphoid population associated with larger atypical cells, which are consistent with follicular dendritic cells, can be suggestive of Castleman's disease. Confirmation of a polytypic B-cell population by flow cytometry, supported by immunohistochemistry, is very helpful. However, definitive distinction from Hodgkin's lymphoma on FNA is probably not possible.

Where and how frequently p53 abnormalities are involved in the development of pleomorphic adenoma (PA) and its malignant progression to carcinoma was investigated. The presence of p53 gene abnormalities was analyzed in eight patients with carcinoma in pleomorphic adenoma (CPA) by polymerase chain reaction (PCR)-based assays and immunohistochemistry. Normal salivary gland tissue, adenomatous, transitional and carcinomatous areas were microdissected from archival microslides and analyzed for allelic deletions of the p53 gene using two microsatellite markers at the p53 locus; dinucleotide (CA)n repeat and pentanucleotide (AAAAT)n repeat. Loss of heterozygosity (LOH) of the p53 gene was detected in 5796 of adenomas, 86% of transitional lesions and 86% of carcinomas. In contrast, overexpression of p53 oncoprotein was noted immunohistochemically in 13% of adenomas, 50% of transitional areas and 75% of carcinomas. All of the tumors with immunoreactivity for p53 oncoprotein demonstrated LOH. Moreover, when LOH was present in adenomatous or transitional areas, the identical LOH was always detected in the corresponding carcinomatous areas in the same CPA tumors. These findings indicate that p53 gene mutation is an early event and occurs frequently at an early stage of precancerous lesions and may be responsible for most cases of malignant transformation of PA.

Abnormalities of the p53 tumor suppressor gene were investigated in 22 foci from 14 adenoid cystic carcinomas (ACC) by polymerase chain reaction (PCR)-based assays for dinucleotide (CA)n and pentanucleotide (AAAAT)n repeat polymorphisms and by immunohistochemical staining for oncoprotein expression. Adenoid cystic carcinomas were divided into lower grade (tubular and cribriform) subtypes and higher grade (trabecular and solid) subtypes. Histologically identified tumor cells were precisely microdissected from archival microslides and were used for molecular analysis. The overall frequency of p53 gene mutations detected by PCR-loss-of-heterozygosity (LOH) analysis was 57% and was higher than the frequency of over-expression of p53 oncoprotein detected by immunostaining (43%). In the molecular analysis of individual histological subtype foci, the number of foci with p53 gene mutation was significantly greater in the higher grade subtype foci than in the lower grade subtype foci and was greatest in solid-type foci (100%). In all six tumors in which histologically different foci were present in the same tumors, mutations of the p53 gene were detected. When tumor heterogeneity of the p53 gene was present among different histological foci in the same tumors, the mutations were always detected in the higher grade foci. When lower and higher grade foci were present in the same tumors, the identical mutations detected in the lower grade foci were present in the corresponding higher grade foci. These findings indicate that abnormalities of the p53 gene are involved in carcinogenesis and/or progression of this tumor and, furthermore, suggest that molecular analyses of ACC may provide information of prognostic importance.

Background. Telomerase, an enzyme associated with cellular immortality, is expressed by most malignant cells and is inactive in most normal somatic cells, with the exception of proliferative stem cells, male germ cells, and activated lymphocytes. The measurement of telomerase activity in clinically obtained tissue samples may provide useful information as both a diagnostic and prognostic marker. In this study, we sought to determine whether telomerase activity might prove helpful in the assessment of benign and malignant thyroid tumors. Methods. A modified, semiquantitative polymerase chain reaction-based telomeric repeat amplification protocol assay was used for detection of telomerase activity in 59 samples obtained at thyroidectomy, including 15 thyroid cancers, 22 benign thyroid diseases, and 22 adjacent normal thyroid tissues. Results. Four of 13 differentiated thyroid carcinomas (30%) and 2 of 2 medullary carcinomas (100%) expressed telomerase activity. Unexpectedly, we also detected activity in 3 of 22 (14%) adjacent normal thyroid tissues and 6 of 22 (28%) benign thyroid diseases. Pathologic review of the telomerase-positive benign specimens revealed that many contained extensive lymphoid infiltrates with germinal centers (six of nine, 67%), as did two of four telomerase-positive papillary carcinomas. Conclusions. In contradistinction to other epithelial carcinomas, telomerase does not appear to be fre quently reactivated in differentiated thyroid carcinomas.

BACKGROUND The macrofollicular variant of papillary thyroid carcinoma that is the subject of this study has only recently been characterized. Information about its morphologic spectrum and biologic behavior is limited. METHODS The authors reviewed 29 examples, including 17 previously reported cases. The clinical and pathologic features of five patients who had the macrofollicular variant of papillary thyroid carcinoma with a minor insular component were analyzed in detail. The insular component in thyroid carcinomas has been associated with aggressive clinical behavior. RESULTS The ages of the 5 patients ranged from 31 to 70 years; the mean age was 40 years. Three patients presented with a palpable thyroid nodule and two with a large thyroid mass of long duration. The latter two tumors, which metastasized, were the largest (8 and 11 cm) and showed extrathyroidal and blood vessel invasion. All five tumors were composed predominantly of macrofollicles (>50%) and had a minor insular component that comprised less than 5% of the tumor mass. In most tumors, the macrofollicles were lined by cells with large, clear, grooved nuclei, and all five contained areas of conventional follicular variant of papillary thyroid carcinoma. In the two that metastasized, however, the lining of many macrofollicles consisted of cuboidal cells with small, hyperchromatic, follicular-type nuclei. Only the macrofollicular component was identified in the metastatic deposits in these two patients. All five patients were alive at last follow-up, two with metastases; but follow-up for this study is limited. CONCLUSIONS A minor insular component is an additional feature of the macrofollicular variant of papillary thyroid carcinoma that may aid in diagnosis and does not appear to have an adverse effect on the excellent prognosis of patients with these tumors. Cancer 1997; 80:1110-6. © 1997 American Cancer Society.

BACKGROUND Although carcinoid tumors of the gastrointestinal tract are relatively common, their occurrence in the esophagus is exceedingly rare. The authors report a case of an atypical carcinoid presenting in the cervical esophagus of an 82-year-old woman. METHODS The tumor was studied with routine, silver, and immunohistochemical techniques for cytokeratin, chromogranin, and various secretory products. In addition, the literature was reviewed for carcinoid tumors of the esophagus and the findings summarized. RESULTS The esophageal tumor showed focal necrosis, atypical cytologic features, and increased mitotic activity. It stained diffusely for chromogranin and focally for serotonin; thus it was considered an atypical carcinoid. The patient was free of disease 9 months after excision. On review of the literature, 13 additional cases of esophageal carcinoid were found. The average age of the patients was 60 years with a male predominance of 6:1; the most common presenting symptoms included dysphagia and weight loss. The majority of tumors occurred in the submucosa of the lower esophagus, and ranged in size from 1 to 12 cm. All patients except one had surgical treatment, three received adjuvant radiotherapy or chemotherapy. Although follow-up was limited, survival correlated with stage; seven of ten Stage I or II patients were disease free whereas three of four Stage III or IV patients had died of disease; the fourth patient is alive with brain metastases. CONCLUSIONS Esophageal carcinoid tumors are exceedingly rare neoplasms. They usually occur in the lower esophagus of males who present with dysphagia. Survival statistics are limited, but appear best correlated with disease stage. Cancer 1997; 79:1476-81. © 1997 American Cancer Society.

The objective of this study was to describe CT and MR findings in patients with allergic fungal sinusitis (AFS). CT and MR images were examined from 10 patients with histologically proven AFS. All patients demonstrated CT evidence of central sinus high attenuation and T2-weighted MR signal void corresponding to surgically proven areas of thick inspissated allergic mucin. AFS is a distinct clinical entity with a highly specific radiographic appearance based on CT and MRI.

OBJECTIVE Islet amyloidosis may be one mechanism for pancreatic islet β-cell loss that is associated with the development of NIDDM. However, the question remains whether chronic overstimulation of insulin and islet amyloid polypeptide (IAPP) secretion in states of insulin resistance could lead to formation of islet amyloidosis and hence NIDDM in some patients. We studied pancreatic islet pathology in congenital generalized lipodystrophy, a genetic syndrome of extreme insulin resistance that may provide some clues. RESEARCH DESIGN AND METHODS Our patient was a 24-year-old African-American woman with congenital generalized lipodystrophy. Severe acanthosis nigricans was noted in her since age 6. At ages 12 and 16, normal and impaired glucose tolerances, respectively, were noted on oral glucose tolerance tests but were accompanied by extreme fasting and post-prandial hyperinsulnemia. Overt diabetes developed at age 18 and she required ∼180 U of insulin daily. Immediately after an accidental death at age 24, an autopsy was performed. Pancreatic histology was studied in detail using routine methods and immunohistochemical techniques. RESULTS Some scarring of the pancreas as a result of previous episodes of acute pancreatitis was observed. Severe amyloidosis was noted in 89% of the islets, sparing those that were rich in pancreatic polypeptide-secreting cells. Amyloid deposits stained intensely on immunostaining with antibodies against amylin. Marked paucity of β-cells was evident. The ratio of β- to α-cells was reduced to 1:1 (normal ratio ∼ 4:1). CONCLUSIONS These observations suggest that chronic presence of extreme insulin resistance may induce premature and severe islet amyloidosis as well as β-cell atrophy.

Immunologic studies have demonstrated that the vast majority of hematolymphoid neoplasms previously designated as "histiocytic" are lymphoid in origin. Consequently, malignancies of macrophage lineage are considered rare by most authors; indeed, their existence is doubted by some. Herein we report two cases of malignant histiocytic neoplasms (malignancies of macrophage lineage) of the small intestine. Both patients presented in the 7th decade with symptoms related to an abdominal mass. The polypoid tumors protruded into the intestinal lumen, extended through the entire thickness of the bowel wall, and involved regional lymph nodes. Microscopically, sheets of large pleomorphic histiocytic cells infiltrated around crypts and were associated with an admixture of bizarre giant cells and inflammatory cells. Mitotic figures were easily found. Ultrastructurally, the cells lacked desmosomes and had indented or kidney-shaped nuclei and cytoplasm containing mostly lysosomes and dense lipid droplets. In both cases, paraffin section immunohistochemistry revealed reactivity of tumor cells for CD45RB (LCA), CD45RO (A6), CD68 (KP1), CD15 (LeuM1), and lysozyme. Frozen section immunohistochemistry performed in one case further supported the macrophage phenotype. Southern blot studies of this case did not reveal immunoglobulin or T-cell receptor beta chain gene rearrangements. One patient initially treated by surgery only died of disease 3 years after diagnosis. The second patient is alive and disease-free 2 years following postoperative combination chemotherapy. The diagnosis of malignant histiocytic neoplasms requires the use of a panel of immunohistochemical markers and may be supported by electron-microscopic studies.

We studied seven examples of the solid variant of adenoid cystic carcinoma of the uterine cervix in postmenopausal women who presented with vaginal bleeding and a large ulcerated or polypoid cervical mass. The tumors lacked the characteristic cribriform pattern of conventional adenoid cystic carcinoma. The neoplastic cells were small, undifferentiated, or basaloid and grew in cords, nests, trabeculae, and nodules. Foci of squamous cell carcinoma were seen in three tumors and areas of necrosis in four. A characteristic feature was the production of abundant periodic acid-Schiff's procedure (PAS)-positive basement membrane material that was immunoreactive for collagen IV and that in some areas compressed tumor cells. Electron microscopy on three cases showed globules and cylinders of redundant basal lamina. The tumor cells were joined by desmosomes and contained bundles of tonofilaments. Material similar to basement membrane material appeared to be intracytoplasmic in two tumors. No neurosecretory granules or myoepithelial cells were found. Four deaths were tumor related. Two patients are currently alive, but with local recurrence or metastases; another is alive and well 19 months after surgery. We believe that the solid variant of adenoid cystic carcinoma of the cervix is a distinctive neoplasm that should be separated from small cell carcinomas with or without endocrine features, adenoid basal cell carcinoma, and squamous cell carcinoma.

The clinical and pathologic features of four cases of benign mesenchymoma in which mature cartilage represented the predominant component are reported. the distinctive histologic feature in all four cases was a lobular proliferation of cartilaginous tissue exhibiting a spectrum of hyaline cartilage, fibrocartilage, myxoid cartilage, and cartilage with ossification and even bone marrow formation, intimately associated with mature adipose tissue and vascular elements. the localization of these tumors was in the proximity of a bone, but not attached to the periosteum or in continuity with a joint. Because these lesions may be mistaken for other cartilaginous neoplasms of soft tissue, recognition of this entity has potentially important diagnostic and therapeutic implications in that mutilating surgery may be avoided.

During a 2-year period 5 men positive for the human immunodeficiency virus (HIV) presented with 6 testis tumors among a total of 3,015 men seen at our hospital acquired immunodeficiency syndrome (AIDS) clinic. This testis tumor incidence of 0.2% is 57 times that of the United States average of 3.5 cases per 100,000 men. Two patients were only HIV positive and 3 others already had AIDS-related complex for 2 to 15 months at the time of tumor diagnosis. Tumor histology was mixed germ cell tumor in 4 patients, pure seminoma in 1 and Burkitt's lymphoma in 1. Patients underwent routine staging evaluations. Three patients had low stage mixed germ cell tumor (clinical stage 1 or 2A) and underwent retroperitoneal lymphadenectomy, which revealed pathological stage 1 or 2A disease in 1 and 2, respectively. These patients did not receive adjuvant chemotherapy. Two patients had advanced mixed germ cell tumor (clinical stage 2C) or Burkitt's lymphoma (clinical stage 4) and received combination chemotherapy from the onset. Outcome was evaluated with regard to progression of HIV disease and tumor status. The 2 patients who were only HIV positive remained so for 9 and 48 months. The 3 patients with AIDS-related complex had progression to AIDS within 1 to 9 months and 2 of these patients died 1 1/2 and 7 months after tumor diagnosis. All 3 patients with resected low stage disease had tumor recurrence within 1 to 9 months and were begun on platinum-based combination chemotherapy. The risk of false low clinical staging and early tumor progression may be higher in HIV positive men than in other testis tumor patients. Patient ability to tolerate chemotherapy and to obtain a satisfactory tumor response appeared to be primarily related to lack of progression of HIV disease to frank AIDS.

Hyalinizing clear-cell carcinoma (HCCC) is a recently described distinctive salivary gland neoplasm. Because of its cytoplasmic clearing and the bland nuclear features, HCCC resembles other tumors. The authors describe the cytomorphologic features of four cases of HCCC in fine-needle aspirates (FNA) and discuss the differential diagnosis. Fine-needle aspirates from 4 patients with primary HCCC of minor salivary glands were reviewed. Smears were stained with Diff-Quik and Papanicolaou stains. The cytologic features of the epithelial and the stromal components were analyzed. Cell blocks were prepared, and findings were correlated with prior or subsequent surgical specimens in each case. The smears contained numerous cohesive small and large epithelial cell groups and sheets which had sharp outlines and showed focal nuclear overlapping. The cells had uniform round to ovoid nuclei, granular chromatin, and small nucleoli. The abundant, well-defined cytoplasm was clear in many cells but denser in others. No myoepithelial cells or hyaline globules were identified. HCCC seems to have characteristic cytomorphologic findings on FNA smears. Because these cytologic features are not specific, and overlap with those of a number of salivary gland neoplasms that contain clear cells, a high level of suspicion, clinico-pathologic correlation, and examination of cell blocks are necessary to suggest the diagnosis. A diagnosis of HCCC by FNA was suspected in 3 of the 4 cases reported here.

Objectives. The identification of reliable prognostic factors to guide the selection of patients at high risk of harboring subclinical metastases in penile cancer is important. We evaluated traditional pathologic variables and deoxyribonucleic acid (DNA) flow cytometry to determine the prognostic significance of these variables for the subsequent development of lymph node metastases. Methods. Clinical data and pathologic specimens were retrospectively reviewed from patients treated surgically at university-affiliated hospitals from 1958 to 1987. Pathologic analysis (grade, depth of invasion, and pathologic stage) and DNA flow cytometry were performed on specimens from 46 patients with invasive penile carcinoma and complete medical records. Pathologic variables were compared with DNA flow cytometry results in patients who never developed lymph node metastasis (32 patients, median follow-up 121 months) and in those who presented with or developed proved lymph node metastases (14 patients, median follow-up 18 months). Results. The distributions of diploid and nondiploid tumors were similar in patients with or without lymph node metastasis. In addition, there was no significant difference in the grade distributions of tumors with respect to lymph node status. Patients with positive nodes more commonly had tumors that invaded greater than 0.5 cm or that exhibited pathologic Stage T2 or greater (deep invasion). All 14 patients who presented with or subsequently developed metastasis had deep primary tumors. Thirteen of 36 patients with clinically negative nodes had superficially invasive tumors (pathologic Stage T1 and depth of invasion 0.5 cm or less), and none developed metastasis (median follow-up 124 months [range 58 to 240]). Tumor grade was significantly related to the likelihood of deep invasion but was not an independent prognostic factor for metastasis. Conclusions. DNA flow cytometry does not add prognostic information to that obtained by pathologic assessment in patients with invasive penile carcinoma. The presence of pathologic Stage T2 or greater or depth of invasion greater than 0.5 cm defines a group of patients at high risk of inguinal node metastasis. A novel finding was that patients with minimally invasive lesions (0.5 cm or less) and no evidence of corporal invasion (pathologic Stage T1) have little risk of inguinal node metastasis. Close observation of reliable patients meeting these criteria may be a safe alternative to prophylactic lymphadenectomy.

Dermoid cysts of the head and neck are rare lesions comprised of epidermal and mesodermal elements. We report a dermoid cyst presenting in the middle ear of the youngest patient reported to date. Structures of endodermal descent were also identified, but, given that the entire middle ear mucosa is of endodermal origin, specific classification as a teratoma would be imprecise. This lesion is interesting in that it did not directly involve the mastoid. Possible embryologic sites of origin are discussed.

The complications of posterior fossa surgery continue to decrease in incidence as our collective experience broadens. Most complications are seen in the immediate postoperative period and the minimized by careful attentiveness to subtle changes in mental status, vital signs, and cranial nerve examination. Long-term follow-up is necessary to identify tumor recurrence, but strict imaging protocols as yet do not exist to facilitate the early identification of recurrent disease, as recurrence is very rare. We report the first case of secondary mucocele formation in the middle ear cleft following translabyrinthine excision of an intracanalicular acoustic neuroma. This complication was found in the fourth postoperative year on routine magnetic resonance imaging, which itself followed previously normal contrasted magnetic resonance imaging in the second postoperative year. The genesis of this complication and possible treatment options are discussed.

Adenoid cystic carcinomas (ACC) constitute approximately 20% of malignant salivary gland tumors. Several histological types of ACC are recognized and may coexist in a single tumor. The authors divided ACC into lower grade (tubular and cribriform subtypes) and higher grade (trabecular and solid) subtypes. A preliminary analysis of 10 ACCs showed a relatively high incidence of loss of heterozygosity (LOH) at the p53 and RB genes and low or absent K-ras mutations and LOH at chromosomal loci 3p, 5q, 8p, and 9p. From 21 tumors, the authors carefully microdissected and analyzed 36 subtype foci. Three interrelated pieces of evidence indicate that the relatively poor prognosis higher grade subtype arises from one or more of the lower grade subtypes via progression events associated with mutations in the p53 or RB genes. First, the number of mutations (both LOH and microsatellite alterations) at either gene is greater in higher grade foci than in lower grade foci; second, multiple mutations (two and occasionally three) are present in only higher grade foci; and third, when lower and higher grade foci are present in the same tumors, identical mutations plus other mutations are present in the corresponding higher grade foci. These findings suggest that molecular analyses of ACCs may provide information of prognostic importance.

Pleomorphic adenoma (PA) is the most common benign tumor of salivary glands. Carcinomas in pleomorphic adenomas (CPAs) may arise by malignant transformation of the epithelial components of PAs. Occasionally, transitional zones containing cells with histological features intermediate between those of the benign PA and carcinomatous components of CPA are identified. After careful microdissection of archival microslides, the authors studied 12 cases of CPAs and their attendant adenomatous and transitional areas for mutations in the p53, RB, and K-ras genes, and at chromosomal loci 5q and 9p. The authors failed to find mutations in the K-ras gene or 9p locus. A relatively high rate of mutations (loss of heterozygosity [LOH] and microsatellite alterations) at the p53 gene were detected in CPAs (58%), and at somewhat lower frequencies at the RB gene (33%) and chromosomal location 5q (17%). Mutational frequency in the associated transitional and adenomatous areas were slightly lower than in the corresponding CPAs. No mutations were detected in adenomatous or transitional areas unless they also were present in the corresponding CPAs. Mutations of these three genes were absent in four cases of CPA, and in seven PAs without malignant change. These findings indicate that most CPAs arise from adenomas as the result of mutations in the three genes, especially p53. In addition, other, as yet unidentified genes may also be involved both in the development of PA and in its malignant progression to CPA. Mutational analysis of PAs may provide information of prognostic importance.

According to the field cancerisation theory the entire upper aerodigestive tract has been mutagenised, thereby placing the affected individual at risk for the development of one or more cancers. To investigate this concept we studied the respiratory epithelium in lungs bearing cancer, including bronchi, bronchioles and alveoli. After identifying preneoplastic and preinvasive lesions by light microscopy, we determined the DNA content of their nuclei in Feulgen-stained sections using a high-performance digitised image analyser. Archival material from 35 resected cases of non-small-cell lung cancer (NSCLC) was selected, including 16 central tumours (mainly squamous cell carcinomas) and 19 peripheral tumours (mainly adenocarcinomas) and five resected cases of metastatic tumour from extrathoracic primary sites. Of the NSCLCs, 31/35 (89%) were aneuploid, as were 60% of the metastases from extrathoracic sites. Multiple, focal areas of preneoplasia or preinvasive carcinoma were present in the selected cases. The lesions ranged in severity from hyperplasia through metaplasia and dysplasia to carcinoma in situ. Aneuploid preinvasive lesions were not noted in association with the four diploid tumours but were present only when the accompanying NSCLC was aneuploid. With both central and peripheral tumours, aneuploid preneoplastic lesions were more frequent in the peripheral parts of the lung (bronchioles or alveoli) than in the central bronchi. Both the degree and incidence of aneuploidy increased with progressive severity of morphological change. Aneuploidy was not found in preinvasive lesions accompanying the five metastatic cases. Our findings provide strong support for the concept of field cancerisation. Images Figure 1 Figure 2

Fibrous neoplasms of the adult larynx are uncommon and can be benign, locally aggressive, or malignant. From January 1, 1987 to December 31, 1991, 189 adult patients underwent partial or total laryngectomy for laryngeal neoplasms at the University of Texas Southwestern Medical Center-affiliated hospitals. During this period, three (1.6%) patients were treated for fibrous neoplasms of the larynx. All three lesions arose in the true vocal fold. In one patient, a local recurrence within 6 months following partial laryngeal resection necessitated total laryngectomy. All three patients are alive and disease-free 1 to 4 years following definitive surgery. We present these cases and discuss computed tomographic (CT), histopathologic, and electron microscopic (EM) findings. Based on this experience, surgical treatment of these lesions is recommended, the extent of which is guided by clinical, radiologic, and pathologic evaluation. © 1994 John Wiley & Sons, Inc.

The authors report a case of metastatic prostate cancer masquerading as a primary lung tumor. Histologically, the lung tumor displayed eosinophilic crystalloids in the malignant glands typical of those previously described in prostatic adenocarcinoma. Review of histologic material from 30 additional patients with metastatic prostate cancer failed to reveal crystalloids in the metastases. Seven patients with histologic material from locally advanced prostatic adenocarcinoma, defined as spread to the rectum, bladder, or nonnodal pelvic soft tissue, were also reviewed. One of these patients demonstrated crystalloids in the bladder extension of locally advanced prostatic adenocarcinoma. Although rare, the presence of crystalloids may be used as strong evidence for the prostatic origin of an adenocarcinoma of uncertain origin.

We present the fifth case of rhabdomyomatous mesenchymal hamartoma, the first reported in a female infant. The patient is an otherwise healthy 3-day-old Latin American infant, the product of an uneventful pregnancy and term delivery by a primigravida 23-year-old. Otolaryngic consultation was obtained when a 4-mm polypoid mass was noted within the left naris. Histopathology revealed the characteristic central core of mature skeletal muscle with extension peripherally into the glandular and follicular dermal structures. Although primarily of cosmetic significance, a possible association with other anomalies has been reported.

Papillary (PC) and follicular (FC) thyroid carcinomas may have a focal or predominant insular component (IC). This study correlates histologic behavior with the extent of the IC of these tumors.Forty-one thyroid carcinomas (17 follicular variants [FV] of PC, 24 FC) with focal or predominant IC were reviewed. The tumors were stained with carcinoembryonic antigen, thyroglobulin, and calcitonin. DNA ploidy analysis was done on 18 tumors on paraffin-embedded tissue. The IC was correlated with age, stage of disease, follow-up, and ploidy analysis by Fisher's exact two-tailed test.No tumor was purely insular. IC was minor (10-40% tumor area) in 16 and predominant (50-90%) in 25. Nuclear features in IC included typical FC nuclei in 14, FVPC nuclei in 16, and intermediate-type nuclei in 16 tumors. Vascular invasion was seen in 22, necrosis in 10, and sclerotic stroma in all. Fourteen tumors were confined to the thyroid, 13 showed regional spread, and 9 had distant metastases; five patients are dead of disease and six are alive with disease. Thirteen tumors were diploid, three tetraploid, and two hyperdiploid aneuploid. There was no correlation of quantity of IC with tumor stage, follow-up status, or ploidy.IC within PC and FC does not adversely affect prognosis.

Six men who had undergone hip replacements for degenerative joint disease or trauma subsequently had radical prostatectomies or cystoprostatectomies with bilateral pelvic lymph node dissections for adenocarcinoma of the prostate or transitional cell carcinoma of the urinary bladder. The hip prostheses implanted in three patients were known to contain cobalt-chromium alloy and titanium. The pelvic lymph nodes ipsilateral to the hip prosthesis in five patients and the bilateral pelvic nodes in the only patient with bilateral hip prosthesis had dark brown or black cut surfaces. These lymph nodes did not contain carcinoma but showed florid sinus histiocytosis characterized by large polygonal histiocytes filling and expanding sinuses and interfollicular regions. The foamy histiocytes contained cobalt-chromium and titanium microparticles by light microscopy, ultrastructure, and energy-dispersive x-ray microanalysis. The lymph nodes uninvolved by the histiocytic reaction lacked the heavy metal microparticles. Four cases were found to have a small number of polyethylene particles, which might have contributed to the histiocytic response. By immunohistochemistry, the foamy cells displayed immunoreactivity for lysozyme, alpha-1-antitrypsin, alpha-1-antichymotrypsin, and cathepsin D, providing additional support for their histiocytic derivation. To our knowledge, this is the first time that microparticles of cobalt-chromium and titanium that migrate from hip prostheses to pelvic lymph nodes have been shown to elicit a distinctive type of florid sinus histiocytosis. Pathologists should be aware of this characteristic foreign-body tissue response to avoid confusion with other types of sinus histiocytosis or with metastatic carcinoma.

We describe 11 patients with a distinctive salivary gland neoplasm. Most of the patients were adult women who presented with a painless mass. Nine tumors arose in minor salivary glands of the oral cavity (82%). Microscopically, they were characterized by the formation of trabeculae, cords, islands, and/or nests of monomorphic clear cells that were glycogen rich and mucin negative and were surrounded by hyalinized bands with foci of myxohyaline stroma. Cells with eosinophilic and granular cytoplasm were also noted. Both cell types showed minimal nuclear pleomorphism and a very low mitotic index. The neoplasms all had infiltrative borders. Immunohistochemically, the tumor cells expressed cytokeratins and epithelial membrane antigen, but not S-100 protein and smooth muscle actin. Ultrastructurally, the tumor cells contained abundant glycogen, desmosomes, peripheral tonofilaments, and prominent interdigitating microvilli without actin myofilaments or dense bodies. These immunohistochemical and ultrastructural findings provide evidence of epithelial differentiation without myoepithelial differentiation. For these tumors, we propose the name, hyalinizing clear cell carcinoma (HCCC). These are low-grade malignant neoplasms. Two patients had ipsilateral cervical lymph node metastases at presentation, but with surgical excision and either preoperative or post-operative radiotherapy in three cases, eight of 10 patients with clinical follow-up are alive and well without evidence of recurrence. The mean clinical follow-up is 3.6 years, with a range of 6 months to 11 years. One patient died as a result of surgery, another died of unrelated causes, and one patient was lost to follow-up.

BACKGROUND Although there have been several reports of cytologic features for salivary duct carcinoma (SDC), it still can be difficult to diagnose patients with these tumor accurately at the time of fine-needle aspiration (FNA). Review of the literature indicates that, immunohistochemically, SDC expresses androgen receptor (AR) in the majority of patients. The authors investigated the cytologic characteristics and utility of AR immunostaining on cytologic smears for the diagnosis of patients with SDC. METHODS FNA and imprint smears from four patients with SDC were stained with Papanicolaou and periodic acid-Schiff (PAS). Immunostaining for AR on paraffin sections and imprint smears of SDC was performed, including 51 benign and other malignant salivary gland tumors. RESULTS The smears were cellular and contained three-dimensional clusters, flat sheets, and scattered epithelial cells with necrotic backgrounds. A cribriform architectural pattern was noted in many of the tumor sheets. The tumor cells were large polygonal, spindle, and round to oval, and had abundant, finely granular, or vacuolated cytoplasm. Intracytoplasmic vacuoles were PAS negative. The nuclei were hyperchromatic, medium to large in size, round to oval in shape, and often had prominent nucleoli. All SDC tumors expressed AR. Two patients with carcinoma in (pleomorphic adenoma) showed a focal, comedo carcinoma pattern in which AR positive nuclei were observed. Other salivary gland tumors were completely negative for AR. CONCLUSIONS The cytologic features of high-grade adenocarcinoma with a variety of cell morphologies, flat sheets of tumor cells with a cribriform pattern, and necrotic backgrounds are characteristic findings in patients with SDC. Immunostaining for AR on cytologic smears is useful for the diagnosis of these patients. Cancer (Cancer Cytopathol) 2001;93:344–350. © 2001 American Cancer Society.

Fine-needle aspiration has assumed a large role in the evaluation of head and neck masses. It has been found to be simple, quick, accurate, and cost-effective in the workup of patients with unknown head and neck masses. This article reviews these advantages and the role of fine-needle aspiration in the evaluation of head and neck masses.

The magnetic resonance imaging (MRI) features of two cases of malignant lymphoproliferative disease involving skeletal muscle are presented. In both cases involved muscles were quantitatively and subjectively hypointense to fat on T1-weighted spin echo images, hypointense or isointense on T2-weighted spin echo images, and hyperintense on short tau inversion recovery (STIR) images. The findings suggest that lymphoproliferative disease should be considered as an etiology of a skeletal muscle lesion that is hypointense or isointense to fat on T2-weighted spin echo magnetic resonance images.

Synovial chondrometaplasia, also known as synovial chondromatosis, is a rare disease affecting the synovial membrane and characterized by a nodular proliferation of metaplastic cartilage. It most commonly involves large joints such as the knee, hip, and elbow, but its presence in unusual locations such as small joints and the temporomandibular joint has been described. To our knowledge, this is the first case report of synovial chondrometaplasia involving the costovertebral joint in a patient with a previous injury to that area.

We report 17 cases of a distinctive variant of encapsulated papillary carcinoma that is likely to be confused with macrofollicular adenoma or nodular goiter. The tumors showed the unusual combination of macrofollicles and foci of the conventional follicular variant of papillary carcinoma. Macrofollicles occupied over 50% of the cross-sectional area of the tumors. The macrofollicles were lined either by cells with large ground-glass nuclei, cells with large but less pale nuclei with stippled chromatin, or cuboidal cells with hyperchromatic nuclei. Solid foci were present in four tumors, and a focal insular growth pattern was noted in a fifth tumor. All patients were females ranging in age from 15 to 69 years (mean, 35.4 years). Despite the large size of the tumors (mean diameter, 4.8 cm), only two metastasized to cervical lymph nodes. One of these neoplasms showed extrathyroidal extension, while the other widely invaded the thyroid tissue through the tumor capsule. Multicentric foci of papillary carcinoma with a follicular nonsclerosing growth pattern were demonstrated in the contralateral lobe in two thyroid glands. All patients with follow-up were alive and symptom-free 2 months to 6 years following surgery.

Two intranodal spindle cell neoplasms are described that were interpreted as leiomyomas. Both occurred in young men. The first case involved a single peripancreatic lymph node of a patient with acquired immune deficiency syndrome (AIDS) who died of AIDS-related infection. The second case simulated a parotid gland tumor because of its location in an intraparotid lymph node in an otherwise asymptomatic patient. Both neoplasms were composed of interlacing fascicles of spindle cells with blunt-ended nuclei that seemed to arise from the walls of blood vessels. The tumor cells were immunoreactive for muscle-specific actin but were desmin negative. These leiomyomas expand the clinical and morphologic spectrum of primary spindle cell neoplasms of lymph nodes.

• AllergicAspergillussinusitis is a well-defined clinical and histologic entity, although surprisingly few reported cases have yielded any fungal growth on culture. Taking advantage of recent changes in the identification and classification of certain groups of fungi, we were able to identify a specific fungal organism in 19 of 22 consecutive patients with a histologic diagnosis of allergic fungal sinusitis over the past 2½ years.Aspergilluswas found in only one patient, while an organism in the family of dematiaceous fungi was found in 18 patients. Of these patients, the genusBipolariswas the most commonly represented, whileExserohilum, Curvularia, andAlternariaspecies were seen with less frequency. Thus, it appears thatAspergillusmay not be the most common etiologic agent in allergic"Aspergillus"sinusitis. Allergic fungal sinusitis is not unusual and its incidence may be increasing. On initial clinical evaluation it may be easily mistaken for malignancy or invasive fungal disease with the potential for overly aggressive treatment. Preoperative suspicion of allergic fungal sinusitis based on clinical and roentgenographic findings along with careful communication with the mycology laboratory about the possibility of dematiaceous fungal growth are necessary for proper diagnosis. (Arch Otolaryngol Head Neck Surg. 1991;117:174-178)

Disposable plastic biopsy forceps were compared prospectively to reusable stainless steel forceps. Thirty consecutive patients underwent a total of 249 biopsies, 124 with the disposable forceps, and 125 with reusable forceps. Biopsy locations included the esophagus, stomach, small intestine, colon, and common bile duct. Specimens were compared microscopically to determine overall surface area, depth, adequacy, and diagnostic result. The disposable biopsy forceps yielded specimens which were 37% smaller when compared with the reusable forceps. In five of the comparisons, minor differences in histological findings were noted between the two groups of biopsy specimens, but these differences did not alter the pathological diagnosis. However, in three cases in which superficial specimens were obtained, an underlying carcinoma was missed with the disposable forceps. Our study documents the utility of disposable biopsy forceps for mucosal lesions. In addition, there were 11 mechanical failures in 38 biopsy attempts with the plastic biopsy forceps. These forceps appear to be limited in their capacity to obtain adequate specimens from firm tissue or when submucosal biopsy samples are required, and they will require refinements in design to duplicate specimen quality obtained by traditional reusable forceps. Disposable forceps are particularly suitable for biopsy of mucosal lesions in patients with possible communicable disease, and they should help to reduce cross-contamination in the gastroenterology laboratory.

A histopathologic analysis of regional lymph node specimens in 48 patients with previously untreated squamous cell carcinoma of the larynx was performed to determine which parameters, if any, correlated with 3-year patient survival. The presence of sinus histiocytosis in lymph nodes containing metastatic squamous cell carcinoma was statistically related to survival (P < .007). Multivariate analysis confirmed the independent significance of this variable compared to tumor stage, nodal status, and extracapsular spread from lymph nodes. Previous studies have linked improved survival with an active immunologic response in head and neck cancer patients. However, few studies have examined a homogeneous group of patients who all underwent the same type of treatment. This study's findings support the concept that an active immunologic response in lymph nodes has prognostic significance in squamous cell carcinoma of the larynx.

In 1983, Katzenstein, et al. first described a form of noninvasive sinusitis in adults, which was histologically identical to allergic bronchopulmonary aspergillosis, with mucin-containing eosinophils, Charcot-Leyden crystals, and fungal elements resembling Aspergillus species. The authors have treated six pediatric patients ages 8 to 16 who had findings typical of allergic Aspergillus sinusitis. All patients presented with nasal polyposis and progressive facial deformity. All patients had computed tomography findings of diffuse expansile sinus disease and four patients had evidence of bony erosion, raising the suspicion of malignancy. At surgery, all were found to have multiple sinuses densely packed with greenish-black inspissated mucin. Therapy consisted of wide surgical drainage with careful follow-up and nasal steroids.

This report describes the clinicopathologic features of a 55-yr-old man found to have a bleeding, postbulbar duodenal ulcer and fasting hypergastrinemia. Gastric analysis revealed pentagastrin-fast achlorhydria. Healing of the ulcer was documented 8 wk after vagotomy, antrectomy, gastrojejunostomy, and a course of sucralfate therapy. The etiology of the postbulbar ulcer was uncertain. This is the first documented case of a duodenal ulcer with pentagastrin-fast achlorhydria.