Bizarre Multinucleated Cells Research Articles

Multisystem ALK-Positive Histiocytosis With DCTN1::ALKFusion in an Adult, Responsive to Alectinib: Case Report and Literature Review.

Anaplastic lymphoma kinase (ALK)-positive histiocytosis has emerged as a clinically relevant diagnosis featuring a wide span of clinical presentations, which are unified by the presence of ALK-positive histiocytes on histopathology and molecular drivers involving the ALK kinase gene. This report presents an adult case of multisystem ALK-positive histiocytosis with xanthogranuloma-like features on histopathology that was responsive to ALK inhibition, and includes a review of ALK-positive histiocytoses with cutaneous involvement reported in the literature. A 56-year-old male developed a widespread eruption of red-brown papules on the face, trunk, and upper extremities. Histopathological evaluation revealed a well-circumscribed, nodular dermal infiltrate of epithelioid histiocytes with Touton giant cells, rare bizarre multinucleated cells, and focal emperipolesis. The lesional cells were positive for CD68 and ALK1 immunohistochemical stains, and negative for CD1a. Next-generation sequencing identified a DCTN1::ALK fusion. On imaging, he was found to have bone, lung, soft tissue, and salivary gland involvement. ALK inhibition was initiated with alectinib, resulting in rapid improvement of cutaneous lesions and eventual complete resolution of abnormal imaging findings, which was sustained at 24 months of follow-up. This case adds to the spectrum of ALK-positive histiocytoses and further demonstrates the positive response with targeted therapy.

Adult Granulosa Cell Tumor With High-grade Transformation: Report of a Series With FOXL2 Mutation Analysis.

Adult granulosa cell tumor (AGCT) is a low-grade malignant neoplasm with a significant propensity for late recurrence and metastasis. Almost all AGCTs are composed of cells with bland nuclear features and even when these tumors recur or metastasize, the nuclear features are almost always low-grade. We report 5 cases of AGCT in patients aged 37 to 88 years composed of areas of typical AGCT with low-grade morphology admixed with areas of high-grade morphology, with marked nuclear atypia, often with bizarre multinucleate cells and high mitotic activity; this is the first reported series of high-grade transformation in AGCTs. The high-grade areas often morphologically closely resembled juvenile granulosa cell tumor with abundant eosinophilic cytoplasm, significant mitotic activity, and intermediate sized follicles. Four cases were FIGO stage IA at diagnosis and 1 was stage IIIC with omental involvement. FOXL2 mutation analysis of both the morphologically low-grade and high-grade areas in 4 of 5 cases confirmed the presence of missense point mutation, c.402C>G, p.(Cys134Trp), providing conclusive evidence that the high-grade component represents transformation of typical AGCT rather than the coexistence of another sex cord-stromal tumor, such as juvenile granulosa cell tumor, which has been suggested for such neoplasms. In 3 of 4 cases where immunohistochemistry was undertaken, there was a striking difference between the p53 staining in the low-grade and high-grade components with wild-type staining in the former and diffuse mutation-type immunoreactivity in the latter, suggesting that TP53 mutation is likely to play a role in high-grade transformation. TP53 mutation analysis covering exons 4 to 10 was undertaken in 4 cases and TP53 mutations were identified in the high-grade component of 2 of the cases. In 1 case, there was diffuse block-type p16 staining in the high-grade component. Follow-up in the 4 stage IA neoplasms revealed no evidence of tumor recurrence in 3 (6 to 9 mo follow-up) while the other patient developed mediastinal, peritoneal, and pulmonary metastasis 17 months after diagnosis. High-grade transformation is uncommon in AGCTs and given that one of our cases was advanced stage at diagnosis, another exhibited widespread metastasis within a short period and there have been occasional case reports of aggressive behavior in AGCTs with high-grade transformation, this event may herald an aggressive clinical course.

Laparoscopic posterior pelvic exenteration for primary adenocarcinoma of the rectovaginal septum without associated endometriosis: A case report

The present report describes a case of laparoscopic posterior pelvic exenteration of a primary adenocarcinoma of the rectovaginal septum (PARS) without associated endometriosis. A 49-year-old woman was admitted to hospital for rectal bleeding. Imaging studies showed a 7-cm solid tumor located in the rectovaginal septum, presenting with invasion to the posterior aspect of the uterine cervix and the anterior rectal wall. The patient received laparoscopic posterior exenteration and rectosigmoid anastomosis followed by chemotherapy. There were no intra- or post-operative complications. Histopathological examination of the neoplastic tissue revealed moderate to severe cytological atypia with bizarre multinucleated cells and prominent mitotic figures. Histopathologically, R0 resection was achieved. No endometriotic lesions were confirmed in the primary tumor or other removed tissues. Immunohistochemistry showed positive staining for cytokeratin (CK)7, cancer antigen 125, vimentin, estrogen receptor and p53, but negative staining for CK20, progesterone receptor, p40 and thyroid transcription factor 1. Based on these findings and on the location of the tumor, the neoplasm was diagnosed as PARS without associated endometriosis, which may have arisen from metaplasia of the embryological Müllerian-duct remnants.

P1.15-005 Relationship Between MYC Family Status and Sensitivity to Aurora Kinase Inhibitors in Neuroendocrine and Other Lung Cancer Cell Lines

Recently, it has been reported that MYC-driven SCLC cell lines exhibit synthetic lethality with Aurora kinase (AURK) inhibitors. The aims of this study are to evaluate sensitivities to neuroendocrine (NE) lung cancer cell lines with or without any MYC family overexpression and/or amplification using representative AURK inhibitors and to investigate the associations between drug sensitivities, MYC family status and NE differentiation. We screened a panel of 62 cell lines including 33 SCLC, 18 other NE, and 11 NSCLC, with various MYC family status for growth inhibition upon AURK inhibitors. MYC family copy number, gene expression, and protein status were examined by quantitative real-time PCR, microarray and Western blotting. Relative cell growth was analyzed by MTS assay, and selective AURK A and B inhibitors, MLN8237 (Alisertib) and AZD1152 (Barasertib), respectively, were used in this study. Cell lines with IC50 values <0.1 μM were defined as sensitive. Drug effects on cell cycle and morphology were determined by flow cytometry and examination of formalin-fixed paraffin embedded cell pellets. Of 31 NE cell lines with MYC family overexpression/amplification, 21 (68%) and 18 (58%) were sensitive to Alisertib and Barasertib, respectively. All 20 NE (and most NSCLC) cell lines lacking MYC family overexpression/amplification were resistant to AURK inhibitors. There was an excellent concordance (86%) between response to the two AURK inhibitors. Both MYC family overexpression and amplification were predictive of sensitivity; however, some overexpressing lines had normal copy number. Cell cycle analysis showed a mitotic arrest in some sensitive cell lines with treatments of these drugs. Representative sensitive cell lines showed cell ballooning and bizarre multinucleated polyploid cells, which indicated cell cycle arrest in G2/M. MYC family overexpression/amplification in NE lung cancer cell lines confers sensitivity to AURK inhibitors in approximately 70% of cases. Lack of MYC family overexpression/amplification was always associated with drug resistance. MYC family overexpression may occur in the absence of gene amplification, and, thus, overexpression is a better predictor of sensitivity than amplification. We are currently investigating the mechanism of resistance in overexpressing NE cell lines and determining whether NE differentiation plays a role in drug sensitivity.

Mast cell sarcoma: a rare and potentially under-recognized diagnostic entity with specific therapeutic implications

Mast cell sarcoma is a rare, aggressive neoplasm composed of cytologically malignant mast cells presenting as a solitary mass. Previous descriptions of mast cell sarcoma have been limited to single case reports, and the pathologic features of this entity are not well known. Here, we report three new cases of mast cell sarcoma and review previously reported cases. Mast cell sarcoma has a characteristic morphology of medium-sized to large epithelioid cells, including bizarre multinucleated cells, and does not closely resemble either normal mast cells or the spindle cells of systemic mastocytosis. One of our three cases arose in a patient with a remote history of infantile cutaneous mastocytosis, an association also noted in one previous case report. None of our three cases were correctly diagnosed as mast cell neoplasms on initial pathological evaluation, suggesting that this entity may be under-recognized. Molecular testing of mast cell sarcoma has not thus far detected the imatinib-resistant KIT D816V mutation, suggesting that recognition of these cases may facilitate specific targeted therapy.

Three Cases of Systemic Atypical Granulomatous Disease in Moluccan Cockatoos (Cacatua Moluccensis): A New Syndrome

A 1.5-year-old male Moluccan cockatoo (Cacatua moluccensis) presented to Kansas State University Veterinary Medical Teaching Hospital with a 4-month history of lethargy and weakness. Hematologic and radiographic diagnostic testing revealed profound leukocytosis and coelomic and pulmonary granulomatous masses of unknown origin. The bird died during laparoscopic evaluation under general anesthesia. Necropsy revealed multiple pulmonary and hepatic soft-tissue nodules and an intracoelomic mass over the left kidney communicating with external subcutaneous masses and a pericloacal mass of similar gross appearance. Histopathologic findings identified a severe, disseminated, inflammatory infiltration of multiple tissues and multiple granulomas containing bizarre multinucleated cells. No causative agent of this granulomatous disease was identified. To our knowledge, this is the first report of systemic atypical granulomatous disease in Moluccan cockatoo. Traditional causes of granulomatous disease include mycotic disease, bacterial (ie, Mycobacterium) disease, and neoplasia. Attempts to identify an causative agent or neoplasia were unsuccessful. A retrospective review of pathology records revealed 2 additional cases with identical pathologic lesions. All 3 cases occurred in young Moluccan cockatoos and are assumed to be a disease of unknown origin that could be unique to this species.

High-grade Trichoblastic Carcinosarcoma

A case of low-grade trichoblastic carcinosarcoma was reported in 2004. Here we present the second case of this tumor, which, in contrast to the original example, may be classified as a high-grade neoplasm. A 92-year-old man presented with an ulcerated lesion on the left ear. The tumor was excised, and the patient had no evidence of recurrence or metastasis 6 years after surgery. Microscopically, the neoplasm demonstrated a fenestrated growth pattern with a slightly myxoid matrix in the background. Two clear components were identified: the first component was clearly epithelial with formation of small round nests, lobules, delicate strands, and small cribriform structures of basaloid cells with some degree of peripheral palisading, nuclear atypia, focal nuclear crowding, and frequent mitotic figures including abnormal forms. Each epithelial aggregation was invariably surrounded by one to three rows of cells with oval to round nuclei, which appeared very similar to specific trichogenic stroma seen in anagen follicles or in trichoblastomas; however, these stromal cells manifested atypical mitoses and cellular pleomorphism. The epithelial and stromal units frequently formed structures identical to follicular papillae associated with germs or "continuous germs" contiguous with "continuous papillae." Despite the close association throughout the tumor, the epithelial and the stromal cells were sharply separated, without transition between both elements. In foci, these stromal cells lost their follicular papillae-like arrangement and proliferated in a diffuse fashion and gradually blended with highly pleomorphic mononuclear spindle-shaped cells and bizarre multinucleated cells that grew in sheets in a highly vascular stroma. Immunohistochemically, the epithelial component showed diffuse staining for cytokeratins (AE1/AE3) and was negative for vimentin and CAM5.2. The stromal cells were positive for vimentin and negative for cytokeratin markers (AE1/AE3) and desmin. We view the present case and that previously reported in 2004 as authentic carcinosarcomas, and not as metaplastic (sarcomatoid) basal cell carcinomas. This conclusion is reached after analyzing the embryological development of the hair follicle, its normal histology and the morphology of cutaneous adnexal tumors with follicular differentiation.

Cerebrospinal Fluid Spread of Anaplastic Glioma

A 35-year-old woman presented with complex partial seizures that progressed to generalized tonic-clonic seizures in March 2002 and was found to have an infiltrating temporal lobe lesion upon receiving magnetic resonance imaging (MRI). Initial concern was for encephalitis or neoplasm. Biopsy of the lesion showed infiltrating glioma with possible neuronal component with a MIB-1 proliferation index focally of 4%. The tumor consisted of a uniformly dense population of mildly pleomorphic nuclei with little visible cytoplasm and no mitotic activity, no vascular cell proliferation, and no necrosis. Subsequent MRIs were stable until the December 2003 scan which showed increased signal on T2-weighted sequences MRI and increased enhancement. A repeat resection was consistent with a fibrillary glioma with anaplastic features— pleomorphic hyperchromatic nuclei with scant cytoplasm, nuclear molding and apoptosis, frequent bizarre multinucleated cells, frequent mitoses, and vascular proliferation with a MIB-1 index of greater than 50%; synaptophysin and pan-keratin stains were negative. The patient underwent treatment with involved field radiation and concurrent temozolomide therapy followed by adjuvant monthly temozolomide for 24 cycles with stable MRIs throughout treatment. After finishing the last cycle in February 2006, the patient developed dizziness and unsteadiness. A repeat brain MRI showed new enhancement in the right temporal resection cavity and also new enhancement surrounding the brainstem and cerebellar folia concerning for leptomeningeal gliomatosis (Figs 1A, 1B, and 1C; postcontrast T1-weighted, arrows). Pre-contrast (Fig 2 thoracic spine; A-T1-weighted; B-T2-weighted) and postcontrast (Fig 2 thoracic spine; C-T1-weighted) images of spine MRI showed marked, diffuse enhancement of subarachnoid space with nodular deposits of tumor (Fig 2C; arrow) nearly resembling a T2-weighted scan. A lumbar puncture for cerebrospinal fluid (CSF) was obtained and showed protein of 1,958, glucose of 66, WBC 333 (71% lymphocytes), and RBC (280,000). Cytology was positive for sheets of malignant cells with pleomorphic nuclei with high cytoplasmic to nuclear ratio consistent with glial origin (Fig 3). This constellation of findings is consistent with leptomeningeal seeding of glioma. The patient underwent an Ommaya reservoir placement and received intrathecal chemotherapy in addition to systemic chemotherapy. Despite several chemotherapy regimens, the leptomeningeal gliomatosis progressed on imaging and CSF cytology and the patient died 5 months later. CSF spread is recognized as a terminal pattern of progression in high-grade glioma patients. As new treatments improve local tumor control (24 months in this case), leptomeningeal seeding of gliomas appears to be increasingly evident. CNS parenchymal and blood-brain-barrier penetrating drugs, such as temozolomide, have improved the outcome of high-grade gliomas, but the penetration and distribution throughout the whole CSF system is an important issue that has yet to be addressed, especially with novel targeted agents. This issue was recently highlighted in a report of epidermal growth factor receptor inhibitor (gefitinib) for non– small-cell lung cancer with leptomeningeal metastases. Furthermore, the biologic underpinnings of this pattern should be investigated as they may provide insight into why such tumors are refractory to current treatments.

Disseminated primary diffuse leptomeningeal gliomatosis: a case report with liquid based and conventional smear cytology

BackgroundPrimary diffuse leptomeningeal gliomatosis is a rare neoplasm confined to the meninges without evidence of primary tumor in the brain or spinal cord parenchyma. Cerebrospinal fluid diversion via ventriculoperitoneal shunt may be used as a therapeutic modality. Herein, we describe the first report of cytologic findings of a case of this neoplasm with shunt-related peritoneal metastasis.Case presentationA 19-year-old male presented with a 6-month history of severe headaches. He had bilateral papilledema on physical exam. Cerebrospinal fluid examination was negative. Four months later a ventriculoperitoneal shunt was placed. Shortly thereafter, he was diagnosed with primary diffuse leptomeningeal gliomatosis based on the biopsy of an intradural extramedullary lesion adjacent to the lumbar spinal cord at a referral cancer center. The histology featured an infiltrating growth pattern of pleomorphic astrocytes with diffuse positivity for glial fibrillary acidic protein. A couple of months later he presented at our institution with ascites and an anterior peritoneal mass. Repeat cerebrospinal fluid cytology and fine needle aspiration of the mass confirmed disseminated gliomatosis. Cytologic characteristics included clusters of anaplastic cells of variable size, high nuclear to cytoplasm ratio and scant to moderate cytoplasm. Occasional single bizarre multinucleated cells were seen with eccentric "partial wreath-like" nuclei, clumped chromatin and prominent nucleoli. Patient expired 13 months after initial presentation.ConclusionDisseminated primary diffuse leptomeningeal gliomatosis should be considered in the differential diagnosis of chronic aseptic meningitis and in the presence of a peritoneal tumor in patients with ventriculoperitoneal shunts. Immunocytochemistry may be of diagnostic value.

Multinucleate cell angiohistiocytoma: a fibrohistiocytic proliferation with increased mast cell numbers and vascular hyperplasia.

Multinucleate cell angiohistiocytoma (MCAH) is an uncommon lesion clinically characterized by multiple papules usually located on the face and acral regions of elderly women. Histopathologically, MCAH is characterized by dermal vascular hyperplasia associated with increased number of factor XIIIa-positive fibrohistiocytic cells and multinucleate cells with scalloped borders. We report the clinical, histopathological and immunohistochemical features of three cases of MCAH, with ulstrastructural study in one of them. The patients were a woman and two men of 56, 40 and 70 years of age, respectively. They all had multiple dull-red papules, which had appeared over several years and were located on the face, the trunk and the dorsa of the hands, respectively. The reticular dermis presented a fibrohistiocytic proliferation of factor XIIIa-positive cells, with abundant bizarre multinucleate cells and vascular hyperplasia. Increased mast cell numbers were seen in all cases, often in apposition to multinucleate cells. Histopathological differential diagnosis of MCAH includes mainly angiofibromas and dermatofibromas, even though vascular hyperplasia can be prominent and has led to many authors to classify MCAH among vascular tumors. Bizarre multinucleate cells can be found in reactive, neoplastic and inflammatory lesions in many sites of the body, and mast cells can play a role in their morphogenesis.

Multinucleate cell angiohistiocytoma: a report of two cases

We report the clinical, histological and immunological features of two cases of multinucleate cell angiohistiocytoma (MCAH) in women of 32 and 53 years of age, respectively. Clinically, MCAH occurs mostly in middle-aged women and consists of crops of reddish-purple, dome-shaped papules especially on the limbs. Histologically, the reticular dermis presents an increased number of small vascular channels with plump endothelial cells embedded in a fibrohistiocitic stroma with numerous bizarre multinucleate cells. Bizarre multinucleated cells are not specific to MCAH; they can be observed in numerous other cutaneous conditions. However, MCAH presents quite distinctive clinico-pathological findings and may be easily differentiated from other cutaneous disorders.

Multinucleate cell angiohistiocytoma: a report of two cases

We report the clinical, histological and immunological features of two cases of multinucleate cell angiohistiocytoma (MCAH) in women of 32 and 53 years of age, respectively. Clinically, MCAH occurs mostly in middle-aged women and consists of crops of reddish-purple, dome-shaped papules especially on the limbs. Histologically, the reticular dermis presents an increased number of small vascular channels with plump endothelial cells embedded in a fibrohistiocitic stroma with numerous bizarre multinucleate cells. Bizarre multinucleated cells are not specific to MCAH; they can be observed in numerous other cutaneous conditions. However, MCAH presents quite distinctive clinico-pathological findings and may be easily differentiated from other cutaneous disorders.

Leiomyosarcoma of bone. A ciinicopathologic, immunohistochemical, and ultrastructural study of five cases

The authors identified five leiomyosarcomas (LMS) in a review of 13 nonmatrix-producing spindle cell sarcomas of bone. Only two were initially recognized as LMS; the others had been diagnosed as malignant fibrous histiocytoma (two) and fibrosarcoma (one). The patients, four of whom were women, ranged in age from 32 to 70 years. Sites included proximal humerus (two), distal femur (two), and rib (one). All tumors presented with clinical and radiographic features consistent with a diagnosis of primary bone neoplasms, although one probably represented a solitary metastasis from a primary uterine LMS. Radiographs showed lytic bone destruction with a moth-eaten appearance, and three cases had soft tissue extension. Histologically, all tumors showed broad, interlacing fascicles of spindle cells with pleomorphic nuclei, frequent mitoses, and necrosis. Two cases had a focal storiform pattern and bizarre multinucleated cells, and two other cases had focally prominent osteoclast-like giant cells. Extensive immunoreactivity for muscle actin was seen in all cases and for desmin in three. In each case, electron microscopy showed definite smooth muscle differentiation including cytoplasmic filaments with densities. At this writing, two patients are free of disease (including the patient with a presumed metastasis), one is alive with locally recurrent disease, and two are dead of disease. Experience suggests that LMS of bone is a distinct clinicopathologic entity that may be more common than previously recognized. Application of immunohistochemistry and electron microscopy to nonmatrix-producing bone sarcomas should facilitate diagnosis of additional cases.

An Autopsy Case of Malignant Histocytosis with Reed‐Sternberg‐like Cells

We report an autopsy case of malignant histiocytosis. The clinical course was rapidly progressive and terminated with jaundice and respiratory failure. Histologically, there was diffuse infiltration of large atypical cells in the liver, spleen, lymph nodes and bone marrow. It was of interest that these tumor cells contained a number of bizarre multinucleated cells histologically indistinguishable from Reed-Sternberg cells of Hodgkin's disease, and that these atypical cells expressed DAKO M1 (identical to Leu M1) and Ki-1 antigens and also showed binding to peanut agglutinin (PNA), representative markers of Reed-Sternberg cell. An absence of epithelial membrane antigen and presence of Leu M1 antigen in the tumor cells made a diagnosis of Ki-1 lymphoma unlikely. This case study showed that giant or pleomorphic cells indistinguishable histologically and phenotypically from Reed-Sternberg cells occur in malignant histiocytosis.