Immunoglobulin crystal-storing histiocytosis in a pleural effusion from a woman with IgA kapa multiple myeloma: a case report

BACKGROUND: Crystal-storing histiocytosis (CSH) is a rare disorder occurring in patients with lymphoproliferative diseases, predominantly multiple myeloma and low grade B-cell lymphoma. This report presents the first case of CSH diagnosed on pleural fluid from a patient with multiple myeloma (MM). CASE: A 79-year-old women with IgA kappa MM underwent thoracocenthesis and thoracic drainage because of a pleural effusion. Cytologic and immunocytochemical examination of pleural fluid revealed abundant histiocytic, CD68-positive cells with prominent intracytoplasmic, needlelike, crystalloid inclusions showing strong immunopositivity for IgA heavy and kappa light chains. Identical crystals were observed on an extracellular background. No myeloma infiltration was detected. Two weeks later, examination of new pleural fluid from the patient showed a similar cytologic picture, but, in addition, isolated plasma cell features were identified. They were too few for a meaningful determination of clonality. The patient died I month after the CSH diagnosis. CONCLUSION: This case illustrates the value of cytologic examination of serous fluids from patients with plasma cell dyscrasias, not only to evaluate possible infectious or neoplastic causes but also to diagnose CSH.     

Multiple myeloma. The diagnostic role and prognostic significance of exfoliative cytology

The clinical significance and diverse cytomorphologic spectrum of exfoliative cytology in multiple myeloma are presented from our 20-year retrospective and continuing prospective studies and from an extensive review of the literature. Of 370 myeloma patients studied retrospectively, 126 had at least one exfoliative cytologic specimen but only 6 had one or more specimens positive for myeloma. These included six pleural and two ascitic fluids and one sputum. In Papanicolaou-stained smears, myeoloma cells varied from essentially normal-appearing plasma cells to dispersed large malignant cells with little or no plasmacytoid features. Whereas all 203 cervical or vaginal, cerebrospinal, urine and bronchial specimens were negative for myeloma, 40% and 50% of the pleural and ascitic fluids, respectively, were positive. Four prospectively studied patients produced a total of seven positive serous fluid specimens. Follow-up data was available for eight patients with cytology positive for myeoloma. Six were dead within three months of the first positive specimen.     

Cervicovaginal and endometrial cytology in ovarian cancer

The clinical significance of cytologic examination was studied in 114 patients with ovarian cancer who had received preoperative cytologic examinations. The overall positive rate of the cytologic examinations was 26.3% (30 of 114): 22 (19.3%) of the 114 cases had positive cervicovaginal smears while 13 of 31 endometrial aspiration smears (41.9%) were positive. The positive rate was not related to the volume of ascites but rather to its presence or absence. Thus, if ascites was observed, the positive rate was about 2.1 times higher than if it was absent. In two of four cases of ovarian cancer with no endometrial invasion but a positive cytologic examination of ascitic fluid, fallopian tube specimens contained cancer cells; this suggests that ovarian cancer cells may reach the cervix and/or vagina by passing through the fallopian tube, particularly if ascites is present. Since cytologic examination, especially of endometrial aspiration smears, shows a high positive rate if ovarian cancer cells are observed in the abdominal cavity, cytology should be used as an important ancillary method for the assessment of ovarian cancer.     

Peritoneal implantation of endodermal sinus tumor of the pineal region via a ventriculoperitoneal shunt. Cytodiagnosis with immunocytochemical demonstration of alpha-fetoprotein

A 17-year-old male developed an endodermal sinus tumor in the pineal region that metastasized to the peritoneal cavity via a ventriculoperitoneal shunt and caused ascites. Neoplasm was diagnosed by cytologic examination of the peritoneal fluid, and the precise histologic nature of the neoplasm was confirmed by immunocytochemistry, which demonstrated alpha-fetoprotein in the neoplastic cells.     

Vaginal involvement in a woman with Darier's disease: a case report

BACKGROUND: Involvement of the female genital tract by Darier's disease, an unusual genodermatosis, is uncommon, and the manifestation of the disease in a cervicovaginal smear is exceptionally rare. CASE: A 39-year-old woman had an abnormal Pap smear caused by involvement of the female genital tract by Darier's disease. Cytologic examination showed features consistent with a low grade squamous intraepithelial lesion, but during a biopsy it was found to be vaginal involvement by Darier's disease. CONCLUSION: The correct interpretation of cytologic findings is not possible when the diagnosis of Darier's disease is not known since a low grade squamous intraepithelial lesion cannot be ruled out. This case underlines the importance of knowing the patient's medical histoiy in any moment of medical attention.     

Choroid plexus carcinoma. Report of a case with cytopathologic differential diagnosis

The cytopathologic features of choroid plexus carcinoma in the cerebrospinal fluid of a 13-month-old male infant were reviewed and compared with those of other small-cell malignant neoplasms of childhood and young adulthood involving the central nervous system. The cytologic features of the choroid plexus carcinoma (tight spatial clusters and isolated anaplastic cells with striking nuclear lobulation) were distinct from those of lymphoma, leukemia, neuroblastoma, ependymoma and pineal germinoma. However, the cells had a striking resemblance to those of anaplastic ependymoma and metastatic adenocarcinoma.     

The role of circulating miRNAs in multiple myeloma

Multiple myeloma(MM) is a common malignant hematological disease. Dysregulation of micro RNAs(mi RNAs) in MM cells and bone marrow microenviroment has important impacts on the initiation and progression of MM and drug resistance in MM cells. Recently, it was reported that MM patient serum and plasma contained sufficiently stable mi RNA signatures, and circulating mi RNAs could be identified and measured accurately from body fluid. Compared to conventional diagnostic parameters, the circulating mi RNA profile is appropriate for the diagnosis of MM and estimates patient progression and therapeutic outcome with higher specificity and sensitivity. In this review, we mainly focus on the potential of circulating mi RNAs as diagnostic, prognostic, and predictive biomarkers for MM and summarize the general strategies and methodologies for identification and measurement of circulating mi RNAs in various cancers. Furthermore, we discuss the correlation between circulating mi RNAs and the cytogenetic abnormalities and biochemical parameters assessed in multiple myeloma.     

Effusion cytology of endodermal sinus tumor of the colon. Report of a case

A three-year-old boy presented with a peritoneal effusion due to an occult endodermal sinus tumor in the ascending colon. Cytologic examination of the ascitic fluid revealed clusters of round plump cells that had large hyperchromatic nuclei, finely stippled chromatin, multiple prominent nucleoli and vacuolated or mucin-containing cytoplasm, features suggesting an adenocarcinoma. The colonic primary was discovered during emergency laparotomy performed due to suspected acute hemoperitoneum. Endodermal sinus tumor should be included in the differential diagnosis when cytologic features reminiscent of adenocarcinoma are encountered in a fluid specimen from a child, especially if there is a history of a gonadal or extragonadal childhood neoplasm.     

Crystalline deposits in ascites in a case of cryoglobulinemia

Crystalline inclusions were observed on routine cytologic studies of ascitic fluid from a patient with exudative ascites of undetermined cause. These inclusions were polymorphic, but frequently appeared as slender needles. They were seen most often in histiocytes and, less frequently, in mesothelial cells and plasma cells. Extracellular crystals were also seen. The crystals were also present in biopsy specimens of peritoneum, liver and bone marrow. Special studies by polarizing light microscopy, cytochemistry, electron microscopy and immunocytochemistry suggested that the crystals were most probably immunoglobulins synthesized by plasma cells. Some were excreted extracellularly and phagocytized by histiocytes. Further studies indicated that the patient had an indolent plasma-cell dyscrasia, resulting in excessive production of a monoclonal immunoglobulin. The immunoglobulin may have crystallized and become deposited in tissues, inciting chronic inflammatory changes. Massive deposits of crystals in the peritoneum, with the resultant inflammatory reaction, was possibly the cause of the formation of ascites.     

Cytologic diagnosis of mastocytosis by fine needle aspiration biopsy: a case report

BACKGROUND: Mastocytosis is an abnormal proliferation of mast cells and their subsequent accumulation in various organs. Diagnosis of mast cell disease relies on proper identification of abnormal mast cells. CASE: A 55-year-old man presented with a history of fever for several months, associated with night sweats, involuntary 20lb weight loss, progressive fatigue, weakness, worsening abdominal distention, shortness of breath, and diffuse lymphadenopathy. Physical examination and computed tomography (CT) showed hepatosplenomegaly, massive ascites, and generalized lymphadenopathy. Bone marrow biopsy with immunohistochemistry (ICH) studies revealed mastocytosis. CT-guided fine needle aspiration biopsy (FNAB) of the retroperitoneal lymphadenopathy was performed. The smears were cellular for a mixed population of mature plasma cells, eosinophils, left-shifted granular and lymphoid cells, and abundant abnormal mast cells. The mast cells had round to oval lobulated nuclei, some of which were binucleated or eccentrically located, with coarse, evenly distributed chromatin. Abundant pale cytoplasm contained numerous metachromatic granules. IHC studies and flow cytometry confirmed the cytologic diagnosis of mastocytosis. CONCLUSION: This case highlights the cytologic features of mastocytosis in FNA specimens. IHC stains and flow cytometry are helpful to confirm the cytologic diagnosis. To the best of our knowledge, this is the second case that describes the cytologic characteristics of mastocytosis.     

Production of metalloproteinase-7 (matrilysin) by human myeloma cells and its potential involvement in metalloproteinase-2 activation.

Matrix metalloproteinases (MMPs) play a critical role in bone remodeling and tumor spreading. Multiple myeloma (MM) is a plasma cell malignancy primarily localized within the bone marrow and characterized by its capacity to destroy bone matrix and to disseminate. We have reported recently that human myeloma cells were able to induce the conversion of pro-MMP-2 produced by the tumoral environment in its activated form. In the current study, we have investigated the mechanism involved in this process. We demonstrate that a soluble MMP constitutively produced by myeloma cells was responsible for pro-MMP-2 activation. Furthermore, we show that the soluble MMP, MMP-7, also known as matrilysin, was able to activate the MMP-2 produced in its latent form by bone marrow stromal cells. Finally, we demonstrate that myeloma cells constitutively produce MMP-7 with expected proteolytic activity. Our results suggest that MMP-7 produced by myeloma cells could participate in bone destruction and tumor spreading in MM, on one hand by its own proteolytic activity and on the other hand by its capacity to activate pro-MMP-2. These findings strengthen the idea that inhibition of MMP activity could represent an interesting therapeutic approach in MM.     

Cytologic diagnosis of olfactory neuroblastoma. Report of a case with multiple diagnostic parameters

We present the first case report of an olfactory neuroblastoma (esthesioneuroblastoma) diagnosed by cytologic examination. The patient was a 40-year-old male who had a 13-year history of "adenocarcinoma" of the nasal cavity until the correct diagnosis of olfactory neuroblastoma was made cytologically from pleural fluid shortly before his death. The cells had the typical features of rosette formation, scanty elongated cytoplasm, clustering of cells and nuclear compression resulting in an "onion-skin" appearance. Surgical specimens, several biopsies and fine needle aspiration of a metastatic deposit in a lymph node all showed, retrospectively, features of esthesioneuroblastoma. Electron microscopy showed membrane-bound dense-core secretory granules. Autopsy findings revealed multiple metastases but no tumor at the original site; that tumor had been treated with high-dose radiation therapy as well as systemic chemotherapy. Olfactory neuroblastoma is a rare tumor, but it is important to recognize because it has a better prognosis than the more commonly encountered malignancies of the nose.     

Epithelioid hemangioendothelioma of the lung diagnosed by transesophageal endoscopic ultrasound-guided fine needle aspiration: a case report

BACKGROUND: Epithelioid hemangioendothelioma is a rare vascular tumor of the lung and is also known as intravascular sclerosing bronchoalveolar tumor. Although it has relatively low malignant potential, extensive pulmonary involvement and systemic metastasis have been described. The cytologic features of these tumors are not very well defined, with only few case reports describing the cytologic findings of epithelioid hemangioendothelioma of the lung on fine needle aspiration. CASE: Endoscopic ultrasound-guided fine needle aspiration of a hilar mass was performed on a 25-year-old female. The cytology showed loosely cohesive sheets and clusters of epithelioid cells. The cellular features included large, irregular nuclei with nucleoli and a moderate amount of vacuolated cytoplasm. Rare cells had a suggestion of cytoplasmic lumen formation. Histologic examination of tissue fragments on the cell block revealed a tumor composed of rounded to spindled epithelioid cells in a background of light blue stroma. The endothelial differentiation was evidenced by cytoplasmic vacuoles and lumens, some of which contained erythrocytes. The endothelial nature of these cells was confirmed by positive staining with factor VIII and CD34. CONCLUSION: The cytomorphologic features of epithelioid hemangioendothelioma described in the literature and observed in our case are distinctive and can help with the interpretation of cytologic smears and prevent misdiagnosis.     

Mycosis fungoides with pulmonary involvement. Cytopathologic findings

In order to define the cytologic features of pulmonary involvement by mycosis fungoides, 15 respiratory cytology specimens from four patients with biopsy-proven pulmonary mycosis fungoides were reviewed. The presence in sputum smears of occasional small or large cerebriform mononucleated cells against a background of numerous atypical lymphocytic cells permitted an antemortem cytologic diagnosis of probable or definite dissemination of mycosis fungoides with pulmonary involvement. Similar cells were seen in aspiration smears. The lymphocytic infiltrates were similar to those in corresponding skin biopsies in each case. The distinctive cytologic findings in these cases may therefore help to determine the underlying etiology of pulmonary lesions and may contribute to the antemortem diagnosis of visceral dissemination of mycosis fungoides.     

Loss of p53 exacerbates multiple myeloma phenotype by facilitating the reprogramming of hematopoietic stem/progenitor cells to malignant plasma cells by MafB

Multiple myeloma (MM) is a serious, mostly incurable human cancer of malignant plasma cells. Chromosomal translocations affecting MAFB are present in a significant percentage of multiple myeloma patients. Genetically engineered Sca1-MafB mice, in which MafB expression is limited to hematopoietic stem/progenitor cells (HS/P-Cs), display the phenotypic features of MM. Contrary to many other types of cancer, it is not yet known if the p53 gene plays any essential role in the pathogenesis of this disease. Here, we show, taking advantage of the Sca1-MafB MM mouse model, that loss of p53 does not rescue the multiple myeloma disease, but instead accelerates its development and exacerbates the MM phenotype. Therefore, the efficiency of the MafB-induced MM reprogramming of normal HS/P-Cs to terminally differentiated malignant plasma cells is enhanced by p53 deficiency, in analogy to what happens in reprogramming to pluripotency. These results raise caution about interfering with p53 function when treating multiple myeloma.     

Loss of p53 exacerbates multiple myeloma phenotype by facilitating the reprogramming of hematopoietic stem/progenitor cells to malignant plasma cells by MafB

Multiple myeloma (MM) is a serious, mostly incurable human cancer of malignant plasma cells. Chromosomal translocations affecting MAFB are present in a significant percentage of multiple myeloma patients. Genetically engineered Sca1-MafB mice, in which MafB expression is limited to hematopoietic stem/progenitor cells (HS/P-Cs), display the phenotypic features of MM. Contrary to many other types of cancer, it is not yet known if the p53 gene plays any essential role in the pathogenesis of this disease. Here, we show, taking advantage of the Sca1-MafB MM mouse model, that loss of p53 does not rescue the multiple myeloma disease, but instead accelerates its development and exacerbates the MM phenotype. Therefore, the efficiency of the MafB-induced MM reprogramming of normal HS/P-Cs to terminally differentiated malignant plasma cells is enhanced by p53 deficiency, in analogy to what happens in reprogramming to pluripotency. These results raise caution about interfering with p53 function when treating multiple myeloma.     

Targeted knockdown of DJ-1 induces multiple myeloma cell death via KLF6 upregulation

Multiple myeloma (MM) is an incurable plasma B cell malignancy. Despite recent advancements in anti-MM therapies, development of drug resistance remains a major clinical hurdle. DJ-1, a Parkinson’s disease-associated protein, is upregulated in many cancers and its knockdown suppresses tumor growth and overcomes chemoresistance. However, the role of DJ-1 in MM remains unknown. Using gene expression databases we found increased DJ-1 expression in MM patient cells, which correlated with shorter overall survival and poor prognosis in MM patients. Targeted DJ-1 knockdown using siRNAs induced necroptosis in myeloma cells. We found that Krüppel-like factor 6 (KLF6) is expressed at lower levels in myeloma cells compared to PBMCs, and DJ-1 knockdown increased KLF6 expression in myeloma cells. Targeted knockdown of KLF6 expression in DJ-1 knockdown myeloma cells rescued these cells from undergoing cell death. Higher DJ-1 levels were observed in bortezomib-resistant myeloma cells compared to parent cells, and siRNA-mediated DJ-1 knockdown reversed bortezomib resistance. DJ-1 knockdown increased KLF6 expression in bortezomib-resistant myeloma cells, and subsequent siRNA-mediated KLF6 knockdown rescued bortezomib-resistant myeloma cells from undergoing cell death. We also demonstrated that specific siRNA-mediated DJ-1 knockdown reduced myeloma cell growth under a hypoxic microenvironment. DJ-1 knockdown reduced the expression of HIF-1α and its target genes in hypoxic-myeloma cells, and overcame hypoxia-induced bortezomib resistance. Our findings demonstrate that elevated DJ-1 levels correlate with myeloma cell survival and acquisition of bortezomib resistance. Thus, we propose that inhibiting DJ-1 may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM patients.     

Metastatic breast carcinoma in cerebrospinal fluid. A cytomorphometric study

A study was undertaken to quantitate the cellular characteristics of metastatic breast carcinoma in cerebrospinal fluid (CSF). Millipore filters of CSF from 15 patients with metastatic breast carcinoma were reviewed; 50 cells per case were evaluated when available. All cells in all cases shed singly or in loose clusters; tight balls or morulae were absent. All cells had regular, round-to-oval nuclei with finely granular chromatin. The majority of cells in all cases had single or multiple round nucleoli, granular cytoplasm with distinct borders and a mean nuclear-cytoplasmic ratio of close to 0.70. Cellular background, number of tumor cells per case, number and placement of nuclei and nuclear and cytoplasmic diameter varied both within and among the cases. There was significant variation in nuclear and cytoplasmic diameters both within and among the cases of infiltrating ductal carcinoma. Thus, the uniform appearance of the cells was due to consistent cytologic features, not to similarity in cell size. The cytologic profile of metastatic breast carcinoma is sufficiently characteristic to distinguish this tumor from other benign and malignant lesions that shed in the CSF.     

Gastrointestinal stromal tumor in ascitic fluid. A case report

BACKGROUND: There are few published data on the cytologic features of gastrointestinal stromal tumors (GISTs) in ascitic fluid and whether these features may mimic those of other malignancies. CASE: An 80-year-old woman presented with ascitics associated with multiple intraperitoneal masses. Cytologic examination of the ascitic fluid showed numerous three-dimensional clusters of epithelioid cells. These features and the presence of large, intracytoplasmic vacuoles raised a possible diagnosis of adenocarcinoma. However, mucin could not be demonstrated in the vacuoles, and the cells showed immunoreactivity for vimentin and c-kit but not for cytokeratins. Eighteen months earlier the patient had undergone a partial gastrectomy for a GIST, which predominantly comprised vacuolated, epithelioid cells. The immunoprofile of the primary tumor was identical to that of the ascitic fluid cells. CONCLUSION: GIST cells may closely mimic adenocarcinoma cells in ascitic fluid. Distinguishing between the two neoplasms has important clinical repercussions and is aided by histochemical and immunocytochemical studies--in particular, c-kit immunostaining.     

Productive ascites growth of heterohybridomas between Epstein-Barr virus-transformed human B cells and murine P3X63Ag8.653 myeloma cells

Heterohybridomas between Epstein-Barr virus-transformed human B cells and murine myeloma P3X63Ag8.653 cells were found to produce sizable quantities of human monoclonal antibodies in nude mouse ascites. Mice injected intraperitoneally with two of such heterohybridomas yielded several milliters of ascites fluid which contained nearly 100-fold higher anti-platelet activities than those in routine culture supernatants.