Diagnostic histopathologic criteria in pediatric tumors: an eclectic review.

Malignant tumors of infants and children, unlike their adult counterparts, are commonly undifferentiated or show minimal evidence of differentiation. Because of this, many of these tumors pose a formidable dilemma to the general pathologist in distinguishing one from another. A broad sampling of the more common malignant neoplasms and of newly recognized histologic subtypes which are restricted more or less to the pediatric age group is presented. The minimal microscopic criteria required to establish a diagnosis are given using widely accepted pathologic classifications and seminal journal references as a guide. Ancillary microscopic features, helpful histochemical stains, immunohistochemistry, and ultrastructural morphology are described for most tumors. Histologic distinction from diagnostic mimickers is discussed. Where appropriate, histologic grading and tumor subclassification are presented and their prognostic relevance is reviewed.

Analysis of functional renal allograft tolerance with single-dose rapamycin based induction immunosuppression.

The induction of transplantation tolerance is one of the primary goals following solid organ transplantation. The combination of a single dose of rapamycin (RAPA) with a short course of cyclosporine (CsA) has been shown to induce transplantation tolerance in the nonfunctional rat heterotopic cardiac transplant model. The purpose of this study was to assess this effective induction protocol in a functional renal transplant model. Male ACI (RTl(a)) and Lewis (RT1(1)) rats were used as donor and recipients respectively. Allografts received a single RAPA dose of (1.5 mg/kg) combined with CsA (10 mg/kg) 12-14 hr prior to transplantation. CsA (5 mg/kg) was given daily on days +1 - +7. Untreated Lewis to Lewis isografts served as histological controls. Chimerism, assessed in recipient skin, and intragraft interleukin (IL) 10 expression was determined utilizing PCR and RT-PCR techniques respectively. Treated animals and isografts were sacrificed 120-130 days posttransplant for functional and histological evaluation. Allografts (n=9) were functionally tolerant with serum creatinine (0.77+/-0.1 vs. 0.88+/-0.1; P=0.275), blood urea nitrogen (37.6+/-4.6 vs. 23.3+/-1.9; P=0.123), and 24 hr protein excretion (27.0+/-4.4 vs. 17.9+/-5.2; P=0.131) similar to single kidney ACI controls. Histologically, 45% (4/9) allografts were indistinguishable from isografts with no evidence of rejection, and were considered immunologically tolerant. Donor/recipient chimerism was not detected. All immunologically tolerant allografts had evidence of intragraft IL-10 expression. Rejecting allografts and isografts did not express intragraft IL-10. This study confirms the efficacy of pre-engraftment single-dose RAPA combined with CsA in inducing true immunologic tolerance in this stringent functional renal transplant model. The expression of intragraft IL-10 in tolerant recipients suggests a Th-2 shift as the mechanism of tolerance in this model.

Pediatric thyroid nodules: disease demographics and clinical management as determined by fine needle aspiration biopsy.

OBJECTIVE: The prevalence of thyroid nodularity in children has been estimated to be 1.8%. The reported prevalence of specific diseases which comprise these nodules is conflicting as evidenced by a reported range of malignancy of 2 to 50% in solitary nodules. In order to better classify pediatric (< 18 years old) thyroid disease and evaluate the utility of fine needle aspiration biopsy (FNAB) in this patient population, we retrospectively reviewed 66 FNABs from 64 thyroid nodules and 2 perithyroid lymph nodes from 57 patients. PATIENTS: The study was composed of 8 males and 49 females who ranged in age from 1 to 18 years old (mean = 13.1). DESIGN: Surgical and/or clinical follow-up was obtained in all patients. The 66 FNAB diagnoses were initially classified into specific diseases. However, for the purpose of this review, the cases were classified as: 3 insufficient, 51 benign, 8 suspicious, and 4 malignant. RESULTS: There were no "false positives" and one "false negative" (a papillary carcinoma was misdiagnosed as a benign nodule). Overall, 10 patients (18%) had malignant thyroid lesions, including 8 papillary carcinomas and 2 follicular carcinomas. Benign diagnoses included benign nodule, cyst, lymphocytic thyroiditis, granulomatous thyroiditis, hyperplasia, and abscess. CONCLUSIONS: The prevalence of malignancy in pediatric patients with thyroid nodules was 18%. We conclude that, because of its high diagnostic accuracy and minimal invasiveness, FNAB is useful in the management of pediatric thyroid nodules.

Metachronous soft-tissue masses in children and young adults with cancer: correlation of histology and aspiration cytology.

We describe a series of 28 fine needle aspiration biopsies (FNAB) of soft tissue from 22 patients. Four patients had two separate FNABs, and one had three aspiration procedures. The patient population was limited to children and young adults (age range, 2 months to 29 years; mean, 16 years) who were known to have diverse forms of cancer, and who subsequently developed a mass in the peripheral soft tissues (including breast). The interval between the time of diagnosis of the primary malignant neoplasm and FNAB ranged from 1 day to 17 years (mean, 39 months). All FNAB diagnoses were confirmed by subsequent surgical open biopsy or clinical follow-up greater than 1 year. No complications occurred from the procedure. The cytomorphology is presented in selected cases and correlated with the patient's original tissue histopathology. Twenty aspirates were diagnosed as cytologically malignant, one as suspicious for malignancy. Seven were considered benign. None were unsatisfactory. One false-positive and no false-negative cytologic diagnoses were obtained. The overall accuracy of FNAB diagnoses was 96%, while sensitivity was 100% and specificity 88%. Sites of aspiration included soft tissues of the head and neck (seven cases), trunk (eight cases), breast (four cases), and extremities (nine cases). Malignant cytologic diagnoses included sarcoma (thirteen), seminoma (two), lymphoma/leukemia (two), melanoma (one), undifferentiated neoplasm (one), and neuroblastoma (one). Electron microscopy of aspirated cells was used to confirm the diagnosis in two cases. Fine needle aspiration biopsy of soft tissue masses from children and young adults with cancer demonstrates a high diagnostic accuracy, and its use is justified in this population.

Application of fine needle aspiration biopsy to pediatrics.

Fine needle aspiration (FNA) biopsy cytology is a technique rarely used in children, although it is increasingly used in a routine fashion for the evaluation of masses in adults. We reviewed our experience with FNA in patients 16 years of age and younger from the period 1973 to 1987. FNA diagnoses were confirmed either by subsequent surgical biopsy, autopsy, or clinical follow-up for a minimum period of 1 year. One-hundred twelve FNA procedures were performed in 107 patients. Patient age distribution was as follows: newborn to 5 years of age, 37 aspirates; 6 to 11 years of age, 39 aspirates; and 12 to 16 years of age, 36 aspirates. Fifty-five patients were female. Of the 112 aspirates, 70 were diagnosed as benign disorders, 39 were diagnosed as malignant, one was diagnosed as unsatisfactory, and two were considered suspicious for malignancy. The most common sites of involvement for benign lesions were lymph node (31 sites), soft tissue (13 sites), and thyroid (12 sites). The most common sites for malignancies were lymph node (12 sites), bone (eight sites), and soft tissue (eight sites). Of the malignant aspirates, 20 were from primary neoplasms, three were from locally recurrent neoplasms, and 16 were from metastatic neoplasms. Two false-positive and one false-negative diagnoses yielded sensitivity and specificity rates of 97%, and a predictive value of a positive FNA of 95%. Our experience indicates that selective application of FNA is a useful and important step in the evaluation and management of mass lesions throughout the entire age range of infancy and childhood.

Role of intraoperative cytopathology in pediatric surgical pathology.

Studies regarding the efficacy of intraoperative cytopathology (IOC) of surgical specimens in the pediatric population are almost non-existent, despite their recent popularity in adults. To determine the utility of IOC in children, we examined 58 cases from 54 pediatric patients (neonate to 18 years of age) who had cytologic smears performed in addition to or instead of frozen section (FS) examination during their surgical procedure. Knowing only the patient's age, sex, anatomic site, and any pertinent radiographic or historic data, three pathologists independently reviewed and issued a diagnosis using only the IOC smears. Subsequently, in 28 cases that also had accompanying FS examination, both IOC and FS analysis were interpreted for a composite final diagnosis. Three cases were judged unsatisfactory because of sparse cellularity of smears. Correct classification of the smears as being benign or malignant for each pathologist was 98%, 94%, and 94% using IOC alone and 98%, 94%, and 96% using combined IOC and FS examination. The most frequent anatomic sites were bone (15 cases) and lymph node (14 cases). The most common diagnoses were malignant small round cell tumor (22 cases) and benign lymphoid tissue (10 cases). The records of all 55 cases were reviewed in the second phase of our study. Twenty-seven cases (49%) were found in which IOC diagnoses were rendered without a concurrent FS examination. These were correctly interpreted in 26 of 27 cases (96%) in the determination of a benign versus malignant disease process. The tissue sample measured < or = 2 cm in 15 of 27 cases (56%) in this latter group. Intraoperative cytopathology diagnoses in this group were rendered by various faculty members on call for FS examination and, in some cases, by fifth-year residents with faculty supervision. Without minimizing the degree of difficulty in the interpretation of pediatric IOC, we conclude that it serves as a useful supplement in FS diagnosis and, in some situations (particularly when tissue is limited), can replace histologic FS examination.

Extrarenal Wilms' tumor: an analysis of four cases.

During a review of Wilms' tumor, four located external to the kidney were identified. Patient age ranged from 7 months to 4 years; three were female. One neoplasm was located in the parametrial connective tissue to the left of the uterus; both kidneys were radiographically normal. Three neoplasms were located in the right retroperitoneum adherent to the surface of the ipsilateral kidney, but separated from the parenchyma by a thick fibrous capsule. Two were attached to the upper pole, while the third was attached to the midportion of the kidney. Radiologic studies showed displacement of all three kidneys, but intravenous pyelogram (IVP) revealed no calyceal distortion. All four neoplasms were favorable histology Wilms' tumor: one was monophasic epithelial type, one was monophasic blastemal type, and two had a mixture of stromal, epithelial, and blastemal tissue. No teratomatous elements were present. Immunoperoxidase staining for cytokeratin (AE-1, AE-3, CAM 5.2), vimentin, and epithelial membrane antigen (EMA) showed the strongest focal positive staining of tubular structures with CAM 5.2, and slight staining with EMA. Staining reaction to vimentin was variable, but negative in most areas. Three tumors extracted from paraffin were diploid by quantitative flow cytometric DNA analysis; in one case, flow cytometry could not be performed. Clinical follow-up from 2 years to 6 years showed all children to be alive without evidence of disease. Based on the similarity to conventional renal Wilms' tumor, these findings support the hypothesis of displaced mesonephric/metanephric rests for the origin of extrarenal Wilms' tumor.

Fine-needle aspiration biopsy cytology of giant-cell tumor of tendon sheath.

Localized nodular tenosynovitis, better known as giant-cell tumor of tendon sheath (GCTTS), is a common neoplasm that has a peak incidence in the fourth to sixth decades of life. Few reports exist elucidating the cytologic features of this lesion obtained by fine-needle aspiration biopsy (FNAB). The authors describe five patients, aged 8-50 years, in whom GCTTS was diagnosed by FNAB cytology. In four of the patients, the lesion was excised, and the FNAB diagnosis of GCTTS was confirmed; surgical excision is pending in one patient. A diagnosis of malignancy was not suggested in any of the patients. The tumors were .7-5 cm in greatest dimension. In two patients, GCTTS affected the ankle; the hand was affected in the other three. Aspiration smears were cellular in four cases. All but one case contained several multinucleate osteoclast-type giant cells; in addition, binucleate cells were common. The nongiant cell population was dispersed principally as single cells that had a cytologic appearance mimicking histiocytes and osteoblasts. Anisonucleosis was minimal, and nuclear pleomorphism was distinctly absent in both single and multinucleate cells. Mitotic figures were infrequent, except in one case. The diagnosis of GCTTS can be made or at least strongly suggested using FNAB when the cytologic and clinical features are combined.

Aspiration cytopathology of malignant melanoma in children. A morphologic spectrum.

Malignant melanoma (MM) is an uncommon neoplasm in the practice of pediatric cytopathology. The clinical and morphologic features of three white children with this neoplasm diagnosed by fine needle aspiration biopsy are described. All cytologic diagnoses were subsequently confirmed histologically. Two children were 16 years old and one was 9 years old. Two patients had metastatic MM to head and neck lymph nodes. In one of these children, a prior diagnosis of MM was known, whereas in the other it was unsuspected. A primary melanoma of the iris developed in the third child. The cytopathology of these children are similar to that described in adults. With the cytologic similarities, some striking differences were seen. Principal among these was the abundance of melanin in one case, its uneveness in another, and its absence in a third. The variation in individual cell morphology among the three cases is also described. Malignant melanoma is a rare neoplasm of children that can be recognized by fine-needle aspiration cytopathology.

Dendritic reticulum cells and immunophenotype in aspiration biopsies of lymph nodes. Value in the subclassification of non-Hodgkin's lymphomas.

Twenty-seven lymph node aspirates were identified for which histologic confirmation of non-Hodgkin's lymphoma was subsequently obtained. Fifteen aspirates interpreted as reactive hyperplasia were also examined. All aspirates were studied by immunoperoxidase on cytospin preparations with the use of antibodies DRC1, kappa, lambda, CD3, CD5, and CD20. The follicular lymphomas could not be identified reliably by morphologic examination of aspirate smears. Clusters of DRC1-positive (DRC1+) cells were present in seven of seven follicular lymphomas, one of one mantle zone lymphoma, and one of seven small lymphocytic lymphomas. Rare DRC1+ cells were present in one of one diffuse mixed and one of seven large cell lymphomas. One lymphoblastic, one Burkitt's, and two diffuse small cleaved cell lymphomas had no DRC1+ cells. None of the seven follicular lymphomas was CD5 positive (CD5+), whereas five of the seven small lymphocytic lymphomas were CD5+. Conversely, all seven follicular lymphomas were CD20-positive (CD20+), but only one of seven small lymphocytic lymphomas was CD20+. Nineteen of the lymphomas, including all 7 of the follicular lymphomas, were either kappa or lambda positive. The other eight lymphomas were T-cell (1), B-cell (1), true histiocytic (1), or "null" cell (5). The reactive aspirates had both kappa- and lambda-positive B-cells. Seven of the 15 had clusters of DRC1+ cells. To further evaluate these antibodies, the authors studied 29 additional, surgically biopsied, non-Hodgkin's lymphomas that had not been aspirated. Similar results were obtained, except that three of five diffuse small cleaved cell lymphomas had DRC1+ cells. DRC1, in conjunction with antibodies to CD5, CD20, kappa, and lambda, helps to distinguish follicular lymphoma from small lymphocytic lymphoma. DRC1 is not useful in separating reactive hyperplasia from follicular lymphoma.

Lymphoglandular bodies in fine-needle aspiration cytology smears.

Lymphoglandular bodies (hyaline bodies or lymphoid globules), when found in cytology smears from fine-needle aspirates, have long been accepted as being diagnostic of lymphoid tissue. To investigate the validity of this association as it relates to malignant tumors, we examined cytologic smears from 132 fine-needle aspirates of malignant neoplasms. Three experienced observers independently scored Diff-Quik-stained smears as to cellularity and number and size of lymphoglandular bodies. Discrepancies were resolved by consensus. Results of the fine-needle aspiration biopsies revealed 6 of 104 nonlymphoid malignancies with easily identifiable lymphoglandular bodies (defined as > 2 lymphoglandular bodies per high-power field) and 3 with numerous lymphoglandular bodies (> 10 per high-power field). These tumors consisted of two cases of small-cell carcinoma, four non-small-cell carcinomas, one ganglioneuroblastoma, one melanoma, and one seminoma. The tumors had few, if any, lymphocytes. Of the 28 lymphomas, 5 had easily identifiable lymphoglandular bodies and 19 had numerous lymphoglandular bodies. Although lymphoglandular bodies in the background of cytologic smears taken from malignant tumors are useful in alerting the pathologist to the possibility of lymphoma, there are exceptions.

Serum chloride--a CAP survey.

The laboratory measurement of serum chlorides by participants in the 1978 CAP Chemistry Survey Programs are evaluated. The method-system most widely used was some form of an automated colorimetric system. Electrometric, mercurimetric, and ion-selective methods followed in that order. All methods provided clinically comparable data. Interlaboratory precision was best with the use of ion-selective electrodes and the widest with mercurimetric methods.

Fine needle aspiration biopsy cytology as an adjunct in the diagnosis of childhood sarcoidosis.

Fine needle aspiration biopsy cytology performed in three children with sarcoidosis expedited clinical investigation and diagnosis of their disease. Each patient had a different clinical presentation; in two of them lymphoma was part of the initial differential diagnosis. Aspiration cytology in all cases revealed collections of epithelioid histiocytes, and multinucleate foreign body-type giant cells, without accompanying necrosis or acute inflammation. A diagnosis of non-caseating granulomas consistent with sarcoidosis was made in all aspirates. Special stains for identification of organisms performed on the smears of one case, and culture of aspirate material from one case were negative. Subsequent serum angiotensin converting enzyme levels in all patients were elevated. Chest x-ray films in all patients showed mediastinal and hilar lymphadenopathy. One patient had an interstitial pulmonary infiltrate. All patients responded to steroid therapy. Fine needle aspiration biopsy can be a useful diagnostic tool in the evaluation of children with suspected sarcoidosis.

Fine needle aspiration cytopathology of malignant lymphoma.

Morphologic features allowing the cytopathologist to distinguish a reactive lymph node from a malignant lymphoproliferative disorder and to distinguish Hodgkin lymphoma from non-Hodgkin lymphoma are presented in concert with pertinent immunophenotypic profiles of various lymphomas. The limitations and diagnostic pitfalls of aspiration cytopathology in the diagnosis of lymphoma and lymphoid aspirates are also discussed.

Fine-needle aspiration biopsy: application to pediatric head and neck masses.

Fine-needle aspiration biopsy cytology is widely used to screen masses in adults. The authors present a series of 89 fine-needle aspiration biopsies performed between January 1973 and December 1988 on 86 pediatric patients with clinically significant head and neck masses. All fine-needle aspiration diagnoses were confirmed by subsequent surgical biopsy, autopsy, or clinical follow-up for a minimum of 18 months. Of 21 tumors identified, 19 were malignant. Of the 89 aspirations performed, 67 required no subsequent surgical biopsy. In 11 of these cases, metastatic or recurrent tumor was diagnosed and appropriate therapy instituted. Fifteen of the 89 aspirates revealed previously undiagnosed tumors requiring surgical intervention. One false-negative and two false-positive results were obtained. No radical treatment resulted from the false-positive diagnoses, and no patient delay in treatment occurred because of the false-negative result. The sensitivity was 94.4%, and the specificity was 97.1%. The usefulness and cost-effectiveness of fine-needle aspiration is stressed.

Fibromatosis colli. The utility of fine-needle aspiration in diagnosis.

BACKGROUND: Fibromatosis colli (FC), also known as sternocleidomastoid tumor of infancy, is a benign spindle cell lesion of the sternocleidomastoid muscle. It usually is seen in the first few weeks of life and is the most common cause of a neck mass in the perinatal period. Although FC may lead to congenital muscular torticollis requiring surgical intervention, if the diagnosis of FC is certain, the usual initial treatment option is conservative management. OBJECTIVE: To show the utility of fine-needle aspiration in the diagnosis of FC. PATIENTS: Five cases in which fine-needle aspiration was used in the evaluation of patients with FC were identified retrospectively by a search of the cytopathology files of the State University of New York Health Science Center at Syracuse and the Virginia Commonwealth University, Medical College of Virginia, Richmond. RESULTS: Fine-needle aspiration yielded an initial diagnosis of FC in 4 of the 5 cases. Smears made from the aspirated material were of low cellularity, but showed a characteristic population of spindle-cell fibroblasts. In addition to these fibroblasts, a variable amount of degenerating skeletal muscle was present in the background. CONCLUSION: With the collaborative efforts of otolaryngologists and pathologists, fine-needle aspiration can be used to confirm a clinical diagnosis of FC while avoiding the expense and risk of open biopsy.

Angiosarcoma of the heart in an adolescent. A light and electron microscopic and immunohistochemical study.

A cardiac angiosarcoma occurred in the right atrium of a 15-year-old boy. Unusual features included the patient's young age and the antemortem pathologic diagnosis of the tumor.

Touch imprints in the intraoperative diagnosis of anterior mediastinal neoplasms.

OBJECTIVE: To evaluate the accuracy of intraoperative diagnosis of mediastinal lesions using touch imprints and frozen sections. DESIGN: We studied touch imprints and frozen sections from 21 anterior mediastinal lesions retrospectively. The lesions included six cases of non-Hodgkin's lymphoma, eight thymomas, two thymic carcinomas, three Hodgkin's disease cases, and two seminomas. Slides were reviewed independently by each of the three authors, and diagnoses were recorded. RESULTS: Depending on the observer, the correct diagnosis was obtained on touch imprints alone in 76% to 81% of cases. On frozen sections alone, the correct diagnosis was made in 67% to 86% of cases. In 86% to 100% of cases, the correct diagnosis was made on either touch imprint or frozen section. CONCLUSIONS: As with frozen sections, the most common significant error in interpreting cytology preparations was in distinguishing thymic epithelial tumors (thymoma and thymic carcinoma) from lymphoma. On a modified Wright-Giemsa-stained imprint, epithelial cells in a thymoma may be inconspicuous. Clues to their presence include cells with a spindled nuclear shape or a small distinct nucleolus. The epithelial cells have scant cytoplasm with indistinct cell borders. Clumping of cells is often not prominent in lymphocytic thymomas, but may be present in epithelial or mixed lymphocytic and epithelial tumors. With practice, one can learn to recognize thymic epithelial cells on touch imprints. Familiarity with this simple inexpensive technique could improve the accuracy of intraoperative diagnosis of anterior mediastinal lesions.

Steroid cell tumor of the ovary in a child.

An 8-year-old girl exhibited severe, progressive virilization of 2 years' duration associated with markedly elevated circulating testosterone concentrations. Based on her initial clinical presentation and results of a chemical evaluation, she was originally thought to have non-classic 21-hydroxylase deficiency, but her condition did not respond to corticosteroid therapy. Further evaluation confirmed the presence of an ovarian neoplasm. The excised ovary contained an attached gray-brown mass. Light microscopic and ultrastructural examination revealed the mass to be a steroid cell tumor. Because Reinke's crystals were not present, it was designated to be a steroid cell tumor not otherwise specified. This case represents one of 22 reported cases of steroid cell tumor occurring in children described in the literature, most of which have been associated with heterosexual precocity. To our knowledge, steroid cell tumors are benign when they occur in prepubertal children. Although they are rare, steroid cell tumors of the ovary should be considered in cases of childhood virilization.

Fine-needle aspiration cytopathology in diagnosis and classification of malignant lymphoma: accurate and reliable?

Diagnosis of malignant lymphoma by fine-needle aspiration biopsy (FNAB) remains a topic of skepticism and controversy. Because of the limitations of pure morphology, subclassfication of non-Hodgkin malignant lymphoma (NHML) by FNAB often requires ancillary studies which impose a challenge not typically required of other FNAB diagnoses. Despite the dubiousness expressed by many, the evidence shows that a large percentage of NHML cases can be recognized and correctly classified using FNAB. Diagnostic accuracy is dependent on several factors including the type of NHML. The emergent WHO classification of lymphomas is one that appears to more readily accommodate the cytologic methods for NHML diagnosis.