Intramammary Angiomatoid Fibrous Histiocytoma, a Rare EWSR1 Rearranged Mesenchymal Neoplasm in a Previously Unreported Anatomic Location with Review of the Cleveland Clinic Experience.

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor that is most commonly reported to arise in the subcutaneous tissues of the upper extremities in adolescents and young adults. At present, the WHO classifies this neoplasm as a tumor of uncertain differentiation. AFH is most often clinically regarded as a tumor of intermediate risk due to low reported rates of recurrence and only rare occurrences of metastases. Its histomorphological hallmarks are a prominent lymphoid cuff surrounding a spindle cell neoplasm with syncytial-appearing cytoplasm. Several variant morphologies have been described. Genetically, the tumor is characterized by translocations involving the EWSR1 gene in over 90% of cases. A widening range of anatomical locations and morphological variants of AFH has been reported in the literature; however, neither anatomic location nor specific morphologic features have been shown to correlate with clinical/biological behavior. We report a unique case of AFH arising in the parenchyma of the breast. The neoplasm showed the typical histomorphology including a peripheral lymphoid cuff. The lesional cells in this case were found to be immunoreactive with desmin, and a positive EWSR1 result was confirmed by break-apart fluorescence in situ hybridization testing. To our knowledge, this is the first report of AFH arising in the breast parenchyma of a postmenopausal female.

Cutaneous Adnexal Cylindroma of Breast: Epithelial Immunoreactivities for GATA-3, Mammaglobin, and E-Cadherin Do Not Equate to a Mammary Ductal Neoplasm.

Cylindromas are benign epithelial neoplasms derived from cutaneous eccrine adnexal structures. These tumors are most commonly encountered on the head, neck, and scalp of older women. In rare instances, solitary cylindromas may arise at other body sites. In the current case, a cylindroma of the skin of the breast was diagnosed by complete excision. Immunohistochemical studies confirmed the tumor cells to be immunoreactive with cytokeratin AE1/3, cytokeratin 5/6, cytokeratin 7, p63, and SOX10. The neoplastic cells were also noted to be immunoreactive with markers typically expected to be positive in ductal epithelium of the breast including GATA3, mammaglobin, and E-cadherin. The case emphasizes the importance of correlating clinical setting, imaging studies, patient history, and careful microscopic evaluation in arriving at an accurate diagnosis. This case also illustrates the point that not all "breast" tumors that are confirmed to be positive for GATA3, mammaglobin, and E-cadherin are derived from mammary ducts.

Microtubule-associated protein-2: a new sensitive and specific marker for pulmonary carcinoid tumor and small cell carcinoma.

Microtubule-associated proteins (MAPs) are a major component of cytoskeleton family proteins associated with microtubule assembly. MAP-2 has been shown to be specifically expressed in neuronally differentiated cells. Pulmonary neuroendocrine carcinomas such as carcinoid tumors and small cell carcinomas are derived from neuroendocrine cells. We hypothesize that neuroendocrine cells may also express MAP-2, and therefore, MAP-2 may be used as a marker for pulmonary carcinomas of neuroendocrine differentiation. To investigate the utility of using MAP-2 expression to separate pulmonary neuroendocrine from non-neuroendocrine tumors, we examined the expression of MAP-2 immunohistochemically in 100 cases of pulmonary carcinomas. The immunoperoxidase method with antigen retrieval was used to characterize the expression of MAP-2, chromogranin, synaptophysin, and neuron-specific enolase in 25 small cell carcinomas, 25 carcinoid tumors, 25 adenocarcinomas, and 25 squamous cell carcinomas. All tumors were lung primaries. All 25 cases of carcinoid tumors (100%) as well as 23 of 25 cases (92%) of small cell carcinomas were positive for MAP-2. Four of 25 cases (16%) of adenocarcinomas were positive for MAP-2 and synaptophysin. Among the 25 squamous carcinomas, 4 cases (16%) were positive for MAP-2, 2 cases (8%) were positive for synaptophysin, 11 cases (44%) were positive for neuron-specific enolase, and none was positive for chromogranin. In conclusion, MAP-2 is a new sensitive and specific marker for the pulmonary tumors of neuroendocrine differentiation. We recommend that MAP-2 be added to immunohistochemical panels to separate non-neuroendocrine from neuroendocrine lung tumors.

Fine-needle aspiration for the diagnosis of primary epithelial tumors of the lacrimal gland and ocular adnexa.

Results of fine-needle aspiration (FNA) of solid-tissue neoplasms arising in the periocular glands are infrequently reported in the literature. To our knowledge, no previous series relating to this topic exist. Neoplastic processes that arise in the semiconfined area of the orbit behave as space-occupying lesions. Such lesions can exert significant pressure on the globe, be responsible for altered vision, and result in proptosis. When noninvasive techniques fail to confirm or rule out the suspicion of a neoplastic lacrimal or adnexal lesion, FNA may be of use in establishing a diagnosis in an efficient, reliable, timely, cost-effective, and safe manner. During the 14-yr interval from 1986-1999, 77 orbital/ocular needle aspiration biopsies were conducted by staff ophthalmologists at Allegheny General Hospital (Pittsburgh, PA). Review of the diagnoses for these specimens revealed seven primary solid-tissue lesions of the lacrimal gland and other adnexal glands, all arising in adult patients (age range, 45-92 yr; mean age, 74 yr). Primary lacrimal and adnexal gland neoplasms were found to represent approximately 9% of orbital fine-needle aspirations (7/79). The 7 cases included 3 lacrimal gland lesions diagnosed as benign mixed tumors, 3 lesions diagnosed as adenoid cystic carcinoma of the lacrimal gland, and 1 tumor diagnosed as sebaceous carcinoma of the meibomian holocrine glands. Cytologic diagnoses were rendered using standard criteria for salivary gland-type tumors. Tissue confirmation was available from surgical follow-up in 4 of the 7 cases, with 100% correlation. Although primary neoplasms of the lacrimal gland and glands of the eyelids are rare, accurate diagnoses of such lesions may be established with minimally invasive aspiration techniques. Preoperative aspiration biopsy diagnoses provide a great advantage to ophthalmic surgeons who routinely operate in a conservative fashion in an area of the body requiring great attention to cosmesis. Our experience indicates that FNA is a reliable and effective tool in the diagnosis and management of primary lacrimal and ocular adnexal tumors.

Fine-needle aspiration for the diagnosis of orbital hematolymphoid lesions.

Ocular and periocular hematolymphoid diseases are a diverse group of lesions affecting various soft tissue structures within the orbital cavity. Lymphoid proliferations in particular are among the most commonly diagnosed entities in orbital pathology. When noninvasive techniques fail to confirm or rule out the suspicion of orbital neoplasia, fine-needle aspiration (FNA) may be of use in establishing a diagnosis in a reliable, timely, cost-effective and safe manner. From 1986 to 1999, 79 orbital/ocular needle aspiration biopsies were conducted by staff ophthalmologists at Allegheny General Hospital. Slides from these cases and corresponding reports were pulled from the cytology files and grouped into the two broad categories of hematolymphoid and other. Specimens came from patients ranging in age from 14 to 88 years (mean, 64 years) with eight patients having known histories of hematolymphoid disorders. Immunocytochemical (ICC) studies were performed in 33% of the cases (14/43). Review of the diagnoses for the 79 aspiration specimens revealed 30 cases diagnosed as lymphoma/atypical lymphocytic infiltrate, cases diagnosed as inflammation or abscess, three cases diagnosed as plasmacytoma, three cases called suboptimal with scant inflammatory cells, and one case of Langerhans' cell histiocytosis. Hematolymphoid diagnoses accounted for 54% (43/79) of all diagnoses. Histologic correlation was available in 33% (14/43) of the cases (nine cases diagnosed as cytologically atypical/malignant and five cases called cytologically benign/suboptimal) with 100% correlation. Hematolymphoid lesions of the orbit are readily diagnosed by FNA. Because many hematolymphoid malignancies are treated as systemic or multiorgan system diseases and because ocular lymphomas may also involve the central nervous system, nonsurgical attempts at diagnosis have the potential to spare the patient procedural morbidity which may be associated with open biopsy. Our experience indicates that the combination of FNA, judicious use of immunocytochemical studies, and correlation with pertinent clinical information and imaging studies allows for reliable and effective classification and diagnosis of orbital hematolymphoid lesions.

Cytologic features useful for distinguishing small cell from non-small cell carcinoma in bronchial brush and wash specimens.

One blinded observer (C.D.S.) retrospectively reviewed 76 previously diagnosed and biopsy-confirmed malignant bronchial brush and wash specimens, 46 non-small cell and 30 small cell carcinomas, obtained from 55 patients. Each case was scored for the presence or absence of 36 standard criteria (architectural, cytoplasmic, and nuclear). Logistic regression analysis was used to determine which criteria were most useful for separating small cell from non-small cell lesions. Although no single criterion displayed 100% sensitivity and specificity for small cell cancer, univariate statistical analysis indicated that 3 individual criteria (nuclear molding, finely granular or "salt and pepper" chromatin, and scant delicate cytoplasm) were more than 90% sensitive and specific in cases of small cell carcinoma. The presence of nuclear molding alone provided the best fit for the logistic regression model. When nuclear molding was present, the odds of a small cell diagnosis increased more than 300-fold. Nuclear molding, finely granular or salt and pepper chromatin, and scant, delicate cytoplasm are the 3 most sensitive and specific cytomorphologic features traditionally used to separate small cell from non-small cell carcinoma. Nuclear molding alone represents the most significant cytomorphologic feature for distinguishing between these malignant lesions.

Small-cell variant of synovial sarcoma: fine-needle aspiration with ancillary features and potential diagnostic pitfalls.

We report a small-cell variant of synovial sarcoma examined by fine-needle aspiration (FNA) biopsy. The patient is a 23-yr-old female who had a synovial sarcoma involving the left infratemporal region, diagnosed at 7 yr of age, followed by a metastatic lesion involving the lung and chest wall 16 yr later. The chest wall metastases was sampled by FNA biopsy. The aspirate consisted of numerous, small, round cells with very high nuclear-to-cytoplasmic ratios. The cytomorphologic features could potentially be confused with other pediatric small round cell tumors. Ancillary studies demonstrated positive staining of the neoplastic cells for cytokeratin, epithelial membrane antigen (EMA), and CD99. The differential diagnosis of other small round cell tumors that may be mistaken for the small-cell variant of synovial sarcoma are presented. We believe that this is the first FNA report detailing the cytologic and ancillary features of the small-cell variant of synovial sarcoma.

Gastric zygomycosis diagnosed by brushing cytology.

A 66-yr-old man with a history of squamous cell carcinoma and small cell carcinoma of the lung presented with nausea, vomiting, and abdominal pain. After passing black stools, he underwent upper endoscopy which showed gastric ulceration. A gastric brushing was performed which showed numerous nonseptate, ribbon-like hyphae with right-angle branching. The cytologic features permitted a diagnosis of a zygomycotic infection which was confirmed by histologic examination. Despite appropriate antifungal therapy, the patient expired. To the best of our knowledge, this is the first case of gastric zygomycosis diagnosed by brushing cytology. We believe that gastric brushing cytology allows for rapid diagnosis of zygomycotic mycoses, due to the distinctive morphology of these organisms; however, histologic examination is still required for assessment of invasion.

Radioactive iodine-associated cytomorphologic alterations in thyroid follicular epithelium: is recognition possible in fine-needle aspiration specimens?

Editor's Note: There is a dilemma in the distinction between radiation effect and neoplasm in patients with thyroid nodules who have been previously treated with (131)I for Graves' disease. The difficulty is to identify the radiation changes and distinguish them from primary thyroid neoplasms. This paper addresses the time response of radiation therapy in the thyroid, as well as distinguishing features between radiation effect and primary carcinomas. Thyrotoxicosis is a condition resulting from presentation to the body's tissues of excessive quantities of thyroid hormones. Graves' disease is the most common cause of thyroid hyperfunction in the United States; this condition can be managed effectively by long-term antithyroid drugs, radioactive iodine ((131)I) therapy, or surgical intervention. The majority of American physicians prescribe (131)I, the most cost-effective therapy, for their patients with thyrotoxicosis. These patients who are closely followed for their existing thyroid pathology may be referred for fine needle aspiration of nodules. This review focuses on (131)I-associated cytologic changes in thyroid follicular epithelium in patients previously treated for underlying hyperthyroidism. Diagn. Cytopathol. 1999;21:207-210.

Image analysis of papillary thyroid carcinoma fine-needle aspirates: significant association between aneuploidy and death from disease.

BACKGROUND: Papillary thyroid carcinoma is the most common thyroid malignancy in the U.S. As many as half of patients with papillary carcinoma present with cervical lymph node metastases at the time of diagnosis. Metastatic disease involving cervical lymph node tissue has not historically been proven to correlate with a more aggressive course; however, distant metastases worsen prognosis. METHODS: Diagnostic fine-needle aspiration (FNA) smears from 26 primary and metastatic papillary carcinomas underwent Feulgen reaction and were studied by image analysis to determine DNA pattern, proliferation index, and the percentage of cells with DNA content >5C. The medical records of all the patients were reviewed for metastatic disease pattern and survival data. For metastatic pattern, two groups were defined: 1) confined to thyroid/local lymph node metastases/soft tissues of the neck involved by tumor, and 2) distant metastases. RESULTS: Among the 26 patients, 16 had "nonaggressive" DNA patterns described as diploid, abnormal diploid, or tetraploid, and 10 had "aggressive" DNA patterns described as aneuploid. Only 2 of the 16 patients in the "nonaggressive" DNA pattern group developed distant metastases, whereas 5 of the 10 patients in the aneuploid group developed distant metastatic disease. In addition, none of the 16 patients with "nonaggressive" DNA patterns died of disease, whereas 3 of the 10 individuals with DNA histograms interpreted as aneuploid did die of metastatic disease complications. CONCLUSIONS: Aneuploidy identified by image analysis of FNA of papillary thyroid carcinoma is significantly associated with death from papillary carcinoma (log rank test, P=0.027).

Diagnostic significance of 'benign pairs' and signet ring cells in fine needle aspirates (FNAs) of the breast.

Most breast mass lesions are readily characterized by FNA with cytodiagnosis. Occasionally, benign but markedly proliferative lesions are diagnostically difficult to separate from well differentiated malignancies. We present information pertaining to the diagnostic significance of two cytologic findings observed in breast aspiration specimens, namely pairs of stripped bipolar nuclei and signet ring cells (SRC). We have evaluated aspirate smears from 219 cases of histologically proven benign (n = 114) and malignant (n = 105) breast lesions. Both singlets and pairs of bipolar nuclei and SRC were enumerated, and their numbers were correlated to histological diagnosis. Closely associated pairs of stripped bipolar nuclei were found in 68% of benign lesions compared with only 3.8% of carcinomas, establishing their presence as a highly specific indicator of a benign process. Large numbers of such 'benign pairs' also favoured the diagnosis of fibroadenoma. SRC were identified in 66% of histologically proven carcinomas (67% of ductal and 70% of lobular). SRC were also present in 10% of histologically benign cases. In the malignant cases, SRC were most frequently noted in a single cell distribution or within small, loosely cohesive tissue fragments. In the benign instances, SRC were most commonly noted within large fragments, and many of these cells were proved by immunohistochemical reactions to be vacuolated myoepithelial cells. We conclude that the presence of bipolar nuclei in closely associated pairs suggests benignity and aids in the subclassification of benign breast masses. In addition, the presence of SRC does not aid in the classification of tumour subtype (ductal vs lobular), and the occurrence of such cells in the proper context should prompt surgical biopsy.

PAPNET computer-aided rescreening for detection of benign and malignant glandular elements in cervicovaginal smears: a review of 61 cases.

An increasing proportion of the recent cytodiagnostic literature has focused on automation of the Pap smear screening process in hopes of finding a feasible system to aid in the reduction of the number of reported false-negative cases. In a sense, these systems can be thought of as computer-driven sensitivity enhancers for better detection of abnormalities in smeared cervicovaginal specimens. The PAPNET system (Neuromedical Systems, Inc., Suffern, NY) relies on a neural network of artificial-intelligence technology to recognize the complex cellular arrays present in Pap smears, and was originally intended to aid in the identification of morphologically abnormal cells of squamous origin. Herein, we present the results of 61 smears containing a mixture of known diagnostically important benign, dysplastic, and malignant glandular cellular abnormalities which were reviewed by the PAPNET technology. The PAPNET system detected the diagnostic glandular material in 44 of the 45 benign cases reviewed (98% detection rate). In addition, the PAPNET technology identified abnormal cellular material in 15 of the 16 studied smears from patients with malignant/dysplastic morphology (94% detection rate). These data indicate that the PAPNET neural networks are capable of detecting cells with aberrant glandular cytomorphology. In both cases missed by the PAPNET system, the number of abnormal cells per slide was very low, indicating that as with human screeners, the capabilities of this semiautomated method may be exceeded when an extreme paucity of diagnostic cellular material is present in a given slide. Further and larger reviews of glandular abnormalities by automated technologies are needed to assess these systems for their true efficacy at diminishing false-negative cases.

Lymphoepithelioma-like carcinoma of the lung.

Primary lymphoepithelioma-like carcinoma of the lung is rare; only 26 case reports have been identified in the literature. The present report presents a case of a 67-year-old white man with a T1 N1 M0 lymphoepithelioma-like carcinoma of the lung. He presented with severe arthritic complaints that resolved after resection of the tumor. The majority of these tumors have occurred in Asian patients who have shown evidence of previous exposure to the Epstein-Barr virus.

Cerebrospinal fluid broth culture isolates: their significance for antibiotic treatment.

Enriched broth medium is routinely used as a supplement for agar plate culture of cerebrospinal fluid (CSF). To assess the clinical utility of broth cultures, 151 consecutive CSF bacterial and fungal isolates obtained from 91 patients were retrospectively reviewed for the effect of results on treatment. Treatment decisions associated with individual CSF specimens for which isolates were recovered from thioglycollate broth only were compared with the treatment decisions associated with CSF specimens for which isolates were recovered by agar plate culture. Treatment was defined as initiation of or change in antimicrobial therapy based on the reporting of CSF culture isolates. Thirty-six (24%) of the 151 isolates were recovered in broth only. Three (8%) of these 36 isolates (from 34 patients) resulted in treatment with antimicrobial agents; however, 2 of the 3 treated isolates (Candida tropicalis, Proteus mirabilis) were recovered from a second CSF specimen in agar plate culture within 24 hours. Thus, only a single isolate (3%; Staphylococcus epidermidis) was treated based solely on a positive broth culture result. In contrast, 60 (52%) of the 115 isolates recovered in agar plate culture from 23 (40%) of 57 patients were treated (staphylococci, 28; gram-negative bacilli, 14; Cryptococcus neoformans, 10; Streptococcus pneumoniae, 3; Streptococcus sanguis, 1; other, 4). We conclude that treatment with antimicrobial agents based on isolates recovered from CSF specimens in broth culture alone is infrequent and infer from the data that the use of CSF broth cultures contributes little to treatment decisions.

Fatal intracranial hemorrhage following pediatric oral surgical procedure.

Deaths during dental and oral surgical procedures may lead to litigation alleging malpractice. For this reason, and because of their sudden and unexpected nature, they often come to the attention of forensic pathologists. We review the clinical and anatomic findings of a 3-year-old boy who expired following an oral surgical procedure in the temporomandibular region. During the operation, perforation of the base of the skull occurred causing laceration of a branch of the middle meningeal artery and fatal subdural and epidural bleeding.

Acrylodan can label amino as well as sulfhydryl groups: results with low-density lipoprotein, lipoprotein[a], and lipid-free proteins.

Human plasma lipoprotein[a] and autologous low-density lipoprotein were reacted with the fluorescent probe 6-acryloyl-2-(dimethylamino)naphthalene (acrylodan) previously reported to be specific for sulfhydryl groups. Reaction kinetics were biphasic in both cases. The reaction of bovine serum albumin with acrylodan was also biphasic. Monophasic kinetics were observed when protein free sulfhydryl groups were blocked by carboxamidomethylation prior to acrylodan reaction. A significant increase in total fluorescence was observed in the reaction of acrylodan with proteins containing no free sulfhydryl groups and with polylysine. The rates of these reactions were highly sensitive to pH. Fluorescence changes due to dissolution of probe into hydrophobic protein or lipid domains were minimal as was reaction of probe with phospholipid head groups. When isolated from acrylodan-labeled Lp[a], apo[a], which contains no free sulfhydryl groups, contained covalently bound acrylodan. These results suggest that acrylodan can modify the lysine residues of lipid-free proteins and may modify not only the free sulfhydryl groups of low-density lipoprotein and lipoprotein[a] but also reactive amino groups. We conclude that under these conditions, the use of this probe to quantify free sulfhydryl groups in these lipoproteins is infeasible.