J. Carlos Manivel

Pleuropulmonary blastoma the so-called pulmonary blastoma of childhood

The authors studied 11 pediatric intrathoracic neoplasms that share clinicopathologic features and constitute a specific tumor in children. These neoplasms were intrapulmonary, mediastinal, or pleural‐based masses. A common histologic feature was the presence of small, primitive cells with blastematous qualities separated by an uncommitted stroma. Focal rhabdomyosarcomatous, chondrosarcomatous, and liposarcomatous differentiation was observed. Epithelial components had bland cytologic features and probably represented entrapped benign epithelium and/or mesothelium. The prognosis for these patients was grave; seven patients died of their disease 5 months to 2 years after diagnosis. Two patients have survived diseasefree for 10 and 12 years after diagnosis. Two recent cases are alive 14 and 32 months after diagnosis. This neoplasm constitutes a distinct entity which has been reported in the literature as pulmonary blastoma in children. It differs from pulmonary blastema in adults because of its variable anatomic location, primitive embryonic‐like blastema and stroma, absence of a carcinomatous component, and potential for sarcomatous differentiation. The designation of pleuropulmonary blastoma is suggested by the authors for these intrathoracic neoplasms of childhood rather than pulmonary blastoma for histogenetic and anatomic reasons. The clinicopathologic features, immunophenotypic and ultrastructural characteristics, possible histogenesis, and differential diagnosis of these neoplasms from other thoracopulmonary tumors in children serve as the basis for this report.

Gross cystic disease fluid protein-15 as a marker for breast cancer: Immunohistochemical analysis of 690 human neoplasms and comparison with alpha-lactalbumin

The identification of metastatic carcinoma of the breast may be difficult in the absence of a previous history of breast cancer. Various immunophenotypic markers have been introduced to aid in this process. A monoclonal antibody directed at a 15-kilodalton (kd) gross cystic disease fluid protein (GCDFP-15) was applied immunohistochemically to paraffin sections of 105 breast cancers and 585 nonmammary malignancies in order to assess its value in this context. In addition, GCDFP-15 was compared with another putative mammary epithelial marker, alpha-lactalbumin (ALA), with respect to sensitivity and specificity for a diagnosis of breast carcinoma. Overall, the rates of specificity and sensitivity and the predictive value of a positive result for GCDFP-15 were 95%, 74%, and 74%, respectively. Corresponding statistical parameters for ALA were 50%, 50%, and 23%. A consistent congruency between the reactivity patterns of primary and metastatic breast cancers was noted for GCDFP-15 but not for ALA. Besides mammary carcinomas, the major tumor types that expressed GCDFP-15 were carcinomas of the salivary glands, sweat glands, and prostate. Since the latter three types of lesions are unlikely to be diagnosed as metastatic breast cancer, statistical indices were recalculated after exclusion of these three tumor types. Following this exclusion, the adjusted rate of specificity of GCDFP-15 and the predictive value of a positive result for a diagnosis of metastatic carcinoma of the breast were each 99%. In contrast, predictive parameters for ALA were not altered. These results show that GCDFP-15 is a specific marker for breast cancer and is superior to ALA in this respect.

Clinical characteristics of post-transplant lymphoproliferative disorders☆

PURPOSE To study the histopathologic findings, clinical course, and therapeutic outcome of patients who developed a lymphoproliferative disorder after undergoing solid organ transplantation. PATIENTS AND METHODS A series of 26 patients who developed a lymphoproliferative disorder after solid organ transplant during a 27-year period were studied. RESULTS The 26 patients ranged in age from 6 to 68 years (median 42 years). The lymphoproliferative disorder was diagnosed from 1 to 211 months (median 80 months) after transplantation. The type of transplant was kidney (n = 21), heart or heart-lung (n = 4), or liver (n = 1). Most patients received azathioprine and prednisone, in addition to antilymphocyte globulin or cyclosporine, for post-transplant immunosuppression. Eight patients had lymphoma that could be classified according to the International Working Formulation (IWF-F, IWF-G, IWF-H). Sixteen patients had polymorphic lymphoma, and 2 patients were classified as having polymorphic lymphoid hyperplasia. Patients were staged by the Ann Arbor staging system. Nine patients had stage I disease, 4 stage II, 6 stage III, and 7 stage IV. Central nervous system, lung, or marrow involvement was present in 27%, 23%, and 14% of patients, respectively. In the 17 patients studied, immunophenotype was monoclonal B-cell (n = 12), malignant T-cell (n = 2), or polyclonal B-cell (n = 3). The initial therapeutic approach was generally a reduction in immunosuppression, but, thereafter, the approach to therapy varied. In patients with localized disease, surgical excision and/or involved field radiotherapy were utilized as applicable. For patients with more extensive disease, other approaches such as high-dose acyclovir, combination chemotherapy, or alpha interferon were utilized. Overall, 15 of 26 patients (58%) responded to systemic therapy or were rendered disease-free either by surgery or radiation, including 8 (31%) with a complete remission (CR). Only 3 of 9 patients responded to chemotherapy, whereas 4 of 13 patients responded to acyclovir (including 3 patients who experienced CR). Remission duration ranged from 8 to 122 months (median 32+ months). Twenty-one of 26 patients (81%) have died. Survival ranged from less than 1 to 122 months (median 14 months). CONCLUSION The outcome of patients with post-solid organ transplant lymphoproliferative disorders is poor, and the optimal approach to therapy is not clear. Newer therapeutic approaches are thus needed to improve the outcome of these patients.

Immunohistochemistry of germ cell and trophoblastic neoplasms

The immunoprofiles of 121 germ cell and trophoblastic neoplasms were defined, using a battery of antibodies against cytokeratin (CK), vimentin (VIM), epithelial membrane antigen (EMA), placental alkaline phosphatase (PLAP), S‐100 protein, leukocyte common antigen (LCA), UCHL‐1, LN‐2, carcinoembryonic antigen (CEA), neuron‐specific enolase (NSE), chromogranin A, Leu‐7, alpha‐fetoprotein (AFP), alpha‐1‐antitrypsin (AAT), and the beta subunit of human chorionic gonadotropin (BHCG). In addition to 85 neoplasms of testicular origin, the cases included eight ovarian germ cell tumors and 28 extragonadal neoplasms. All tissues had been subjected to formalin fixation and paraffin embedding. Similar immunoreactivity patterns were seen in gonadal and extragonadal neoplasms, gestational and nongestational choriocarcinomas, components of mixed germ cell tumors and their pure counterparts, and metastatic and primary lesions. Placental alkaline phosphatase was a sensitive marker of germ cell differentiation, and expression of this marker in the absence of EMA appeared to be a staining pattern unique to germ cell tumors. Both LCA and S100 were absent in neoplastic germ cells, and thus were useful in differentiating these tumors from malignant lymphoma and malignant melanoma, respectively. Cytokeratin was helpful in distinguishing seminomas/dysgerminomas from nonseminomatous germ cell tumors, although 10% of seminomas showed focal or diffuse cytokeratin reactivity. Finally, 75% of all germ cell neoplasms displayed NSE, calling the specificity of this determinant into question.

Malignant mixed müllerian tumors: An immunohistochemical study of 47 cases, with histogenetic considerations and clinical correlation☆

Forty-seven cases of malignant mixed müllerian tumors were reviewed histologically and studied immunohistochemically with three major objectives: to analyze the histogenetic relationship between the carcinomatous and sarcomatous components of these neoplasms, to ascertain the practical role of immunohistochemical studies in diagnosis and classification, and to determine the prognostic significance of immunohistochemically verified rhabdomyoblastic and neuroendocrine differentiation. Epithelial differentiation (cytokeratin and/or epithelial membrane antigen expression) was confirmed in all carcinomatous components; within the sarcomatous areas, it was identified among individual cells (60% of cases) and within poorly formed clusters of cells (57% of cases). There was a statistically significant tendency for concordant expression of alpha-1-antichymotrypsin, Leu-M1, S-100, Leu-7, and neuron-specific enolase between the carcinomatous and sarcomatous components of individual cases. These two findings provide evidence of common origin for the sarcomatous and carcinomatous components of these neoplasms. Histologic review of metastases in 21 cases revealed a biphasic composition in the majority of metastatic lesions (62%), another feature that further supports a common origin for the two components. From a practical standpoint, immunohistochemistry may be helpful in accentuating the biphasic pattern of these neoplasms and in verifying the presence of rhabdomyoblastic differentiation. In most cases, however, careful morphologic examination and thorough sampling will suffice for correct diagnosis and subclassification. The presence of heterologous, rhabdomyoblastic, or neuroendocrine differentiation did not have a statistically significant influence on survival; the last of these was associated with a tendency for a more rapidly fatal course.

A potential role for interleukin-8 in the metastatic phenotype of breast carcinoma cells.

This study shows a strong correlation between the metastatic potentials of breast carcinoma cell lines and their ectopic expression of interleukin-8 (IL-8). Correlations exist for both constitutive and induced levels of IL-8 released. A correlation was also observed between cell morphology, metastatic potential, and IL-8 profile. Metastatic lines are fusiform in appearance, whereas, nonmetastatic lines are epithelioid. The metastatic potential of two breast carcinoma lines was examined using an orthotopic model of spontaneous metastasis. Metastatic cells formed rapidly growing, poorly differentiated primary tumors that metastasized. Nonmetastatic cells formed rapidly growing differentiated primary tumors that did not produce detectable metastases. Comparison of IL-8 expression by the parental cells and cell cultures developed from primary and metastatic tumors, demonstrates that IL-8 released by cultured cells from the primary tumor is higher than that of the parental cells, and IL-8 released by cultured cells derived from the metastatic lung tumors is greater than that released by cultured cells derived from the primary tumor. These data demonstrate a strong correlation between the metastatic phenotype of a cell and its IL-8 expression, suggesting a role for IL-8 in promoting the metastatic potential of breast tumor cells.

Locally infiltrative glomus tumors and glomangiosarcomas. A clinical, ultrastructural, and immunohistochemical study.

Six cases of locally aggressive and/or potentially malignant glomus tumors are described. On the basis of clinical and pathologic criteria, the following classification is proposed. The first category is a locally infiltrative glomus tumor (LIGT) which has the usual glomus histologic features. The second group is a cytologically malignant tumor arising and merging with a typical glomus tumor, designated glomangiosar‐coma arising in a benign glomus (GABG). The third category and the most difficult to recognize is the de novo glomangiosarcoma (GADN), which must be distinguished from other round cell sarcomas. Most of these locally aggressive glomus tumors are vimentin positive and are immunoreactive for muscle‐specific actin. Electron microscopic examination in one GABG case showed cells with numerous micro‐filaments and pinocytotic vesicles; a second GADN case contained cells with microfilaments and an incomplete basal lamina. As a group these locally aggressive or potentially malignant glomus tumors are larger and more deeply located than the conventional glomus tumor. Although 50% of these tumors recurred locally, none have metastasized.

Placental-like alkaline phosphatase reactivity in human tumors: an immunohistochemical study of 520 cases.

Placental-like alkaline phosphatase (PLAP) activity has been reported in various human neoplasms of both somatic and germ cell types. The expression of PLAP was examined with a polyclonal antibody and the immunoperoxidase technique in formalin-fixed, paraffin-embedded sections of 37 germ cell neoplasms and 483 somatic tumors. The expression of keratin and epithelial membrane antigen (EMA) was concurrently assessed to determine whether these stains were helpful in distinguishing germ cell neoplasms from somatic tumors that might mimic them microscopically. All germ cell lesions were reactive for PLAP, but so were 62 somatic carcinomas, usually in female müllerian, intestinal, and lung cancers and less often in carcinomas of the breast and kidney. PLAP-reactive somatic tumors exhibited EMA and keratin positivity in the absence of prior protease digestion, whereas germ cell neoplasms failed to do so. Malignant mesotheliomas were nonreactive for PLAP, as were carcinomas of the nasopharynx, adrenals, liver, pancreas, stomach, prostate, and urinary bladder. PLAP is a highly sensitive but nonspecific immunohistologic marker of germ cell differentiation. However, non-protease-enhanced stains for keratin and EMA allow separation of germ cell and somatic carcinomas, despite their shared capacity for PLAP expression. In somatic neoplasms, PLAP immunoreactivity might be of potential use in predicting possible primary sources for metastatic tumors of unknown origin.

Hepatoblastoma: An immunohistochemical and ultrastructural study

The ultrastructural and immunohistochemical features of 19 hepatoblastomas were examined to evaluate the phenotypic expressivity of this solid embryonic neoplasm of childhood. Electron microscopy confirmed the embryonal and fetal characteristics of the neoplastic hepatocytes, but in addition, cells with features intermediate between these two cell types were identified. Dense bundles of collagen corresponding to the osteoid-like material by light microscopy surrounded nests of cells; the cells within this matrix stained for epithelial membrane antigen and vimentin and focally for cytokeratin, and they showed ultrastructural features of epithelial cells. The two cases of small cell hepatoblastoma reacted positively for vimentin and cytokeratin; the remaining 17 cases were immunoreactive for cytokeratin and alpha-fetoprotein, and some also for alpha 1-antitrypsin, ferritin, and vimentin. A histogenetic scheme based on our findings is proposed to explain the divergent morphologic features of this neoplasm.

Pseudosarcomatous myofibroblastic proliferations in the urinary bladder of children

Ten examples of a pseudosarcomatous myofibroblastic proliferation occurring in the urinary bladder children (aged 2 to 16 years) are reported. The lesions appeared as polypoid nodular masses of variable size with myxoid and hemorrhagic areas. They consisted of compact fascicles of elongated spindle cells with minimal atypia. Myxoid areas of variable extension and scattered inflammatory cells were constant features, whereas diffuse collagen deposition was not common. Despite the striking cellularity of some of the lesions, most showed minimal mitotic activity. Ultrastructurally the predominant cells had features of myofibroblasts. Six cases studied by immunocytochemical methods expressed vimentin and muscle‐specific actin. In addition, two of these cases expressed desmin and two others cytokeratin. Infiltration into the muscularis propria of the urinary bladder was demonstrated in six cases and into the perivesical soft tissues in two. However, none of the eight patients for whom follow‐up information is available has had local recurrence or metastasis develop 18 months to 6 years after surgical excision.