Poor prognosis of retroperitoneal mixed extragonadal germ cell tumors in an HIV-infected man with severe immunosuppression and bilateral cryptorchidism: a case report.

BACKGROUND: Nonseminomatous germ cell tumors (NSGCTs) represent one of the main groups of germ cell tumors (GCTs), and they have a more invasive course than seminomatous GCTs. Human immunodeficiency virus (HIV) positivity is considered to be a risk factor for testicular seminoma patients, but reports about HIV-infected individuals with NSGCTs are rare. CASE PRESENTATION: We report a case of a retroperitoneal mixed extragonadal germ cell tumor in an HIV-infected man who has been diagnosed with bilateral cryptorchidism since birth. A 30-year-old man presented with a large heterogeneously mixed echo mass located in the right lower abdomen according to an abdominal ultrasound; he was HIV-positive and had a low CD4 count of 70 cells/ml in the followed test, which suggested severe immunosuppression, and ultrasound-guided biopsy histology revealed a malignant yolk sac tumor of the testis. First, the patient received combination antiretroviral therapy; then, to relieve his symptoms, an exploratory laparotomy and retroperitoneal neoplasm resection under general anesthesia were performed for subsequent treatment. The postoperative histopathological examination indicated that the patient exhibited malignant mixed GCTs of the undescended testis that were composed predominantly of yolk sac tumors with foci of embryonal cell carcinoma and seminoma; It is a rare type in various GCTs, especially in HIV-infected patients. After the operation, the patient underwent computed tomography follow-up scans at 1 week and 2 weeks, and the results showed that the size of the right inguinal mass gradually increased, which suggested a poor outcome. To limit the growth of the tumors, right inguinal mass resection under local anesthesia was performed 17 days after the initial operation, and pathological examination revealed mixed GCT metastasis. Subsequently, the patient received salvage chemotherapy with a regimen of cisplatin, etoposide, and ifosfamide. Unfortunately, the patient died 1 week after the first cycle of chemotherapy because of severe immunosuppression, a low platelet count and cancer cachexia. CONCLUSIONS: Because of severe immunosuppression, the treatment of advanced extragonadal NSGCTs in an HIV-infected patient resulted in a poor prognosis. This outcome should be considered in further research, and appropriate management for achieving long-term survival needs to be established.

Prognostic Differences: Epstein-Barr Virus-Associated Primary Leiomyosarcoma of the Spine Versus Spinal Leiomyosarcoma Metastases.

OBJECTIVE: The authors studied 6 cases of osseous leiomyosarcoma of the spine. Two of these cases were of immunocompromised human immunodeficiency virus (HIV)-positive patients with Epstein-Barr virus (EBV)-associated primary vertebral leiomyosarcomas. The remaining 4 cases were of patients with leiomyosarcoma metastases to the spine. METHODS: Each patient underwent surgical resection of their vertebral mass; however, the patients with the EBV-associated tumors had the best postoperative prognosis. RESULTS: The HIV-positive patients have had no further local recurrence, while the other 4 patients had rapid local recurrences requiring multiple surgical interventions. Furthermore, the patients living with HIV have lived longer with fewer leiomyosarcoma-related health complications. CONCLUSIONS: These findings suggest that EBV-associated vertebral leiomyosarcoma is of a less aggressive variety than metastatic leiomyosarcoma of the spine.

HPV-Related Retroperitoneal Squamous Cell Carcinoma of Unknown Primary: A Case Report.

A 56-year-old female was referred to our hospital due to a mass measuring 5 cm in size in the left pelvic cavity, which was found incidentally during a health examination by ultrasonography. Exploratory laparotomy was performed and the mass was located at the left retroperitoneal parametrium without invasion of the uterus and ovary. The pathology report confirmed squamous cell carcinoma. Even after further studies, we did not find any other primary lesion. Human papillomavirus (HPV) DNA chip test (HPV 9G DNA Membrane Kit, Biometrixtechnology Inc.) showed that the surgical specimen was positive for HPV 18. She received adjuvant chemotherapy and would receive radiation therapy for the possibility of occult gynecologic cancer. Retroperitoneal squamous cell carcinoma of unknown primary is extremely rare and little is known about it. It is reported that HPV may be associated with the disease. Hence, the result of HPV test could have an impact on finding a suspicious primary lesion and treatment modality in this case.

Plasmablastic lymphoma of the retroperitoneum in an HIV- and HCV-positive patient: hard to diagnose and harder to treat.

Plasmablastic lymphoma (PBL) is an aggressive diffuse large B-cell lymphoma (DLBCL) with plasmablastic features that was initially described in the oral cavity of HIV-infected individuals. PBL remains a diagnostic challenge given its close morphologic resemblance and overlapping immunophenotypic patterns to other B-cell lymphoid malignancies and plasmablastic plasma cell myeloma (PCM) with extramedullary involvement. The presence of serum monoclonal protein and radiographic evidence of lytic bone lesions favors the diagnosis of plasma cell myeloma over PBL. Distinguishing PBL from PCM is important as PBL is treated with a completely different chemotherapy regimen compared to PCM. PBL carries a guarded prognostic profile among DLBCLs with high relapse rate and poor median survival. We present a case of a 44-year-old HIV-positive man who presented with a large retroperitoneal mass associated with obstructive uropathy, sacral radiculopathy, and inferior vena caval compression. The mass was initially mistaken to be a PCM on histopathology; however, subsequent investigations revealed an extra-oral PBL with plasmacytic differentiation. To our knowledge, this will be the first case of PBL of the retroperitoneum in an HIV- and HCV-positive patient and the second one at this location in the English-language literature. In this report, key differentiating points between PBL versus PCM and newer therapeutic agents such as proteasome inhibitors have been discussed along with related review of literature.

The presence of human papillomavirus or p16 in six cases of retroperitoneal carcinoma.

OBJECTIVE: To describe six cases of unknown primary carcinoma of the retroperitoneum that were positive for human papillomavirus (HPV), a surrogate molecular marker for high-risk HPV (p16), or both. METHODS: Using the MD Anderson pathology database, females with confirmed HPV or p16 expression within retroperitoneal carcinomas of unknown primary were identified. Clinical data were collected by retrospective chart review. One pathologist reviewed all histology. Individuals with known primary were excluded. Data regarding individual demographics, presentation, Pap test history, pathology, HPV and p16 positivity, and outcome were analyzed using descriptive statistics. RESULTS: Six individuals were identified. The median age of the individuals was 43.5 years (range 27-54). Three malignancies (50%) were squamous and three (50%) were undifferentiated. Median follow-up was 12 months (range 6-48 months). Two of the six (33%) individuals had remote histories (more than 10 years) of abnormal Pap test results. All had normal gynecologic examination and Pap test results at diagnosis. Four tumors were HPV-positive (66%) and six were p16-positive (100%). All samples that were HPV-positive were also p16-positive. All individuals underwent treatment with chemotherapy, radiation, or both. One individual underwent initial attempt at resection that was unsuccessful. Two individuals are without evidence of disease, two have had progression of disease, and two have died of their disease. CONCLUSION: Pelvic masses of unknown primary may be HPV-related despite normal cervical examinations. LEVEL OF EVIDENCE: III.

Analysis of rhesus rhadinovirus microRNAs expressed in virus-induced tumors from infected rhesus macaques.

Rhesus rhadinovirus (RRV), a primate gamma-herpesvirus related to human Kaposi's sarcoma-associated herpesvirus (KSHV), causes a similar pattern of pathogenesis. Previously, RRV was shown to express 7 pre-microRNAs (pre-miRNAs) in latently infected cells. Using deep sequencing, we analyzed the pattern of small RNA expression in vivo using latently RRV-infected B-cell lymphoma and retroperitoneal fibromatosis tissues. We identified 15 virally encoded pre-miRNAs in both tumors, including all previously reported RRV pre-miRNAs. Although all 15 RRV pre-miRNAs, like all 12 KSHV pre-miRNAs, are located 3' to the conserved viral ORF71 gene and in the same transcriptional orientation, only one RRV miRNA is homologous to a KSHV miRNA. One previously identified RRV miRNA, miR-rR1-3, is actually a miRNA offset RNA (moRNA) derived from sequences located adjacent to pre-miR-rR1-3. Several other RRV-derived moRNAs were obtained, including one recovered >600 times. Together, this research provides a comprehensive list of the miRNAs and moRNAs encoded by RRV.

Venous outflow obstruction with retroperitoneal Kaposi's sarcoma and treatment with inferior vena cava stenting.

A 26-year-old man presented with acute renal insufficiency, and severe lower extremity swelling. Computed tomographic scan revealed retroperitoneal lymphadenopathy encasing both ureters and the inferior vena cava. He underwent placement of ureteral stents to relieve the obstruction and afterward underwent lymph node biopsy, which revealed Kaposi's sarcoma. He subsequently was diagnosed with acquired immunodeficiency syndrome. Abdominal and lower extremity venous duplex ultrasound did not show any evidence of deep vein thrombosis. The inferior vena cava measured 3.5 mm in diameter and was encased by retroperitoneal lymphadenopathy. Bilateral transfemoral venography and intravascular ultrasound demonstrated significant compression of the inferior vena cava below the renal veins. Endovascular treatment was followed with primary stenting under intravascular ultrasound guidance. His symptoms improved with reduction in swelling. At 1-year follow-up, the patient was ambulatory with mild symptoms, and on venography the iliac vein and inferior vena cava stents were widely patent.

High levels of retroperitoneal fibromatosis (RF)-associated herpesvirus in RF lesions in macaques are associated with ORF73 LANA expression in spindleoid tumour cells.

Two distinct lineages of rhadinoviruses related to Kaposi's sarcoma (KS)-associated herpesvirus (KSHV; Human herpesvirus 8), the causative agent of KS, have been identified. In macaques, the RV1 lineage is represented by retroperitoneal fibromatosis (RF) herpesvirus (RFHV), the homologue of KSHV, whilst the RV2 lineage is represented by rhesus rhadinovirus (RRV), a more distantly related virus. Real-time quantitative PCR was used to estimate the loads of RV1 and RV2 rhadinoviruses in simian acquired immunodeficiency syndrome-associated RF (SAIDS-RF), a neoplasm of macaques with similarities to AIDS-associated KS. Both RV1 and RV2 rhadinoviruses were detected in macaques with RF. The RV1 loads were 220- to 4300-fold higher in RF tumours than in spleen, showing a strong tumour association (mean loads of 1 800 000 vs 2900 copies per 10(6) cells in tumours and spleen, respectively). In contrast, RV2 loads in the RF tumours were 100-fold lower than RV1 loads and showed similar levels in tumours and spleen (mean loads of 16 000 vs 24 000 copies per 10(6) cells, respectively). Immunostaining with antibodies reactive against RFHV ORF73 latency-associated nuclear antigen (LANA) showed intense nuclear staining of the spindleoid RF tumour cells. Correlation of viral load and the number of LANA-positive cells indicated that RF tumour cells contained multiple copies of the RFHV genome per cell. This pattern of infectivity is similar to that seen in KS tumours latently infected with KSHV. Our study demonstrates similarities in the biology of KSHV and RFHV and supports a role for RFHV in the aetiology of SAIDS-RF.

RFHVMn ORF73 is structurally related to the KSHV ORF73 latency-associated nuclear antigen (LANA) and is expressed in retroperitoneal fibromatosis (RF) tumor cells.

Retroperitoneal fibromatosis herpesvirus (RFHV), the macaque homolog of the human rhadinovirus, Kaposi's sarcoma-associated herpesvirus (KSHV), was first identified in retroperitoneal fibromatosis (RF) tumor lesions of macaques with simian AIDS. We cloned and sequenced the ORF73 latency-associated nuclear antigen (LANA) of RFHVMn from the pig-tailed macaque. RFHVMn LANA is structurally analogous to KSHV ORF73 LANA and contains an N-terminal serine-proline-rich region, a large internal glutamic acidic-rich repeat region and a conserved C-terminal domain. RFHVMn LANA reacts with monoclonal antibodies specific for a glutamic acid-proline dipeptide motif and a glutamic acid-glutamine-rich motif in the KSHV LANA repeat region. Immunohistochemical and immunofluorescence analysis revealed that RFHVMn LANA is a nuclear antigen which is highly expressed in RF spindloid tumor cells. These data suggest that RFHV LANA is an ortholog of KSHV LANA and will function similarly to maintain viral latency and play a role in tumorigenicity in macaques.

Analysis of 4.3 kilobases of divergent locus B of macaque retroperitoneal fibromatosis-associated herpesvirus reveals a close similarity in gene sequence and genome organization to Kaposi's sarcoma-associated herpesvirus.

We previously identified retroperitoneal fibromatosis-associated herpesvirus (RFHV) as a simian homolog of Kaposi's sarcoma-associated herpesvirus (KSHV) in a fibroproliferative malignancy of macaques that has similarities to Kaposi's sarcoma. In this report, we cloned 4.3 kb of divergent locus B (DL-B) flanking the DNA polymerase gene from two variants of RFHV from different species of macaque with a consensus degenerate hybrid oligonucleotide primer approach. Within the DL-B region of RFHV, viral homologs of the cellular interleukin-6, dihydrofolate reductase, and thymidylate synthase genes were identified, along with a homolog of the gammaherpesvirus open reading frame (ORF) 10. In addition, a homolog of the KSHV ORF K3, the modulator of immune recognition-1, was identified. Our data show a close similarity in sequence conservation, gene content, and genomic structure between RFHV and KSHV which strongly supports the grouping of these viral species within the same RV-1 rhadinovirus lineage and the hypothesis that RFHV is the macaque homolog of KSHV.

Smooth muscle tumors of soft tissue.

This paper presents an overview of smooth muscle tumors occurring in deep soft tissue. Although the existence of leiomyomas of soft tissue has been questioned in the past, it appears that they do exist but are rare, and must be diagnosed using stringent histologic criteria that include no atypia and minimal or no mitotic activity. They segregate into two distinct clinicopathologic groups, one group occurring in patients of either sex in deep somatic soft tissue and the second occurring primarily in women in the pelvic retroperitoneum. The latter bear a histologic similarity to uterine leiomyomas. Leiomyosarcomas occur in retroperitoneum followed by deep somatic soft tissue and are diagnosed by the presence of nuclear atypia and essentially any level of mitotic activity. Leiomyosarcomas of deep somatic tissue commonly arise from small veins and their behavior can be predicted by a number of factors including age, grade, and "disruption" of tumor. Conversely, few factors have proved to be prognostically useful for leiomyosarcomas of the retroperitoneum, as nearly all prove fatal. Epstein Barr virus (EBV)-associated smooth muscle tumors are a recently emerging entity that occur in the setting of immunocompromise. Their behavior is closely tied to the immune status of the patient rather than to specific histologic features.

Establishment of an IL-2-dependent cell line derived from 'nasal-type' NK/T-cell lymphoma of CD2+, sCD3-, CD3epsilon+, CD56+ phenotype and associated with the Epstein-Barr virus.

A novel interleukin-2 (IL-2)-dependent cell line, HANK1, was established from a patient with CD56+ NK/T-cell lymphoma arising in the retroperitoneum. Morphologically, HANK1 is a pleomorphic large cell line with irregular nuclei, which contains azurophilic granules in the cytoplasm. Immunophenotypic analysis showed that HANK1 expressed CD2, CD3epsilon, CD56, TIA-1, granzyme B, and HLA-DR, but no other T-lineage markers. These features were the same as seen in the original tumour, and are highly characteristic of nasal and 'nasal-type' NK/T-cell lymphoma as described in the proposed W.H.O. classification. Genotypically, this cell line also demonstrated the germline configuration of the T-cell receptor beta, gamma and the immunoglobulin heavy chain genes and clonal integration of the Epstein-Barr virus (EBV) together with antigen expression with a type II latency pattern (LMP-1+ and EBNA2-). Furthermore, Southern blot analysis using the EBV termini as probes confirmed its derivation from the original lymphoma, and revealed that it contained multiple copies of the EBV genome. Dose-dependent growth on IL-2 was observed in an in vitro study with a doubling time of 3 d at maximal stimulation. These data indicate that HANK1 seemed to preserve the biological characteristics of the original tumour and therefore may serve as a good model for the further analysis of unusual 'nasal-type' NK/T-cell lymphoma.

Identification of two homologs of the Kaposi's sarcoma-associated herpesvirus (human herpesvirus 8) in retroperitoneal fibromatosis of different macaque species.

Simian retroperitoneal fibromatosis (RF) is a vascular fibroproliferative neoplasm which has many morphological and histological similarities to human Kaposi's sarcoma (KS). Like epidemic KS in AIDS patients, RF is highly associated with an immunodeficiency syndrome (simian acquired immunodeficiency syndrome [SAIDS]) caused by a retrovirus infection. Recently, a new gammaherpesvirus, called Kaposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8 (HHV8), has been identified in KS tumors, suggesting that KS has a viral etiology. Our previous experimental transmission studies and epidemiological data suggest that RF also has an infectious etiology. In order to determine whether a similar virus is also associated with RF, we have assayed for the presence of an unknown herpesvirus using degenerate PCR primers targeting the highly conserved DNA polymerase genes of the herpesvirus family. Here we provide DNA sequence evidence for two new herpesviruses closely related to KSHV from RF tissues of two macaque species, Macaca nemestrina and Macaca mulatta. Our data suggest that KSHV and the putative macaque herpesviruses define a new group within the subfamily Gammaherpesvirinae whose members are implicated in the pathogenesis of KS and KS-like neoplasms in different primate species.

Epstein-Barr virus-associated leiomyosarcomas in liver transplantation recipients. Origin from either donor or recipient tissue.

BACKGROUND: Leiomyosarcoma, a mesenchymal malignancy with smooth muscle differentiation, is extremely rare in children. Immunosuppression, due to either antirejection medication in organ transplantation recipients or human immunodeficiency virus infection (HIV), appears to constitute a predisposition. METHODS: Two cases of leiomyosarcoma in pediatric liver transplantation recipients were investigated and compared clinically with respect to site of origin and course of the disease and pathologically by routine histology and electron microscopy, by forensic DNA methodology for origin from donor or recipient tissue, and by EBER-1 in situ hybridization for evidence of latent Epstein-Barr virus (EBV) infection. RESULTS: A 9-year-old male developed a high grade, poorly differentiated leiomyosarcoma in his allografted liver 2 years after transplantation, and despite antineoplastic chemotherapy, he died of metastatic disease. The genotype of his tumor indicated an origin from allografted tissue. A 12-year-old female had a low grade retroperitoneal leiomyosarcoma involving the superior mesenteric vein. After resection, she remained disease free without chemotherapy. The genotype of her tumor indicated an origin from native tissue. In both tumors, latent EBV infection was documented. CONCLUSIONS: Neoplastic smooth muscle proliferation in immunosuppressed liver transplantation recipients is analogous to the more common posttransplantation lymphoproliferative disorder in involving transformation of either engrafted donor tissue or recipient tissue elsewhere in the body, in displaying a wide spectrum of histologic differentiation, grade and clinical behavior, and in exhibiting evidence of latent EBV infection.

The association of Epstein-Barr virus with smooth-muscle tumors occurring after organ transplantation.

BACKGROUND: Epstein-Barr virus (EBV) has been associated with nasopharyngeal carcinoma, some lymphomas, and lymphoproliferative disease after organ transplantation. Many lymphoproliferative tumors that occur after transplantation are clonal, a property that classifies them as neoplastic. Clonality can be determined by analysis of the extrachromosomal circular DNA episomes produced by EBV infection. METHODS: We describe three young children in whom smooth-muscle tumors developed 18 months to 5 1/2 years after liver transplantation with immunosuppression. We examined the tumors by microscopy and with immunohistochemical studies and molecular genetic analyses of the EBV DNA: RESULTS: The tumors were composed of spindle cells with smooth-muscle features and resembled those described in patients with the acquired immunodeficiency syndrome. Immunohistochemical analysis was negative for EBV latent membrane protein and EBV receptor (CD21), but positive for EBV nuclear antigen 2. In situ hybridization revealed nuclear EBV sequences, and molecular genetic analysis showed the EBV genome to be clonal in all three patients. CONCLUSIONS: Smooth-muscle tumors that developed after organ transplantation contained clonal EBV, suggesting that the virus has a role in the development of these neoplastic lesions.