Malignant inflammatory histiocytoma (inflammatory fibrous histiocytoma): report of a patient with four lesions

A patient with four subcutaneous inflammatory fibrous histiocytomas is presented. Three of these tumors developed synchronously. The neoplasms were examined by light and electron microscopy and were composed of well differentiated histiocytes, multinucleated histiocytes, and less differentiated cells. The ultrastructural findings support the histiocytic nature of this particular tumor.     

Systemic juvenile xanthogranuloma with multiple central nervous system lesions

Juvenile xanthogranulomatosis (JXG) is an uncommon histiocytic disorder that is usually benign and limited to the skin. The systemic form of JXG is rare and may be associated with severe morbidity and mortality especially in central nervous system (CNS) involvement. Here, we describe a six-year-old boy with disseminated skin lesions and neurological signs and symptoms. Diagnostic work up revealed multiple brain lesions. A skin biopsy and a stereotactic brain biopsy considered suggestive of systemic JXG. Treatment with prednisolone, vinblastine and methotrexate was successful with regression of skin and CNS lesions. The patient has been in remission for almost three years.     

Role of liver transplantation in the management of colorectal liver metastases: Challenges and opportunities

The liver is the most common site of colorectal cancer metastasis. Complete resection of the metastatic tumor is currently the only treatment modality available with a potential for cure. However, only 20% of colorectal liver metastases (CRLM) are considered resectable at the time of presentation. Liver transplantation (LT) has been proposed as an alternative oncologic treatment for patients with unresectable CRLM. This review summarizes the published experiences of LT in the setting of unresectable CRLM from the previous decades and discusses the challenges and future horizons in the field. Contemporary experiences that come mostly from countries with broader access to liver grafts are also explored and their promising findings in terms of overall survival (OS) and disease-free survival (DFS) are outlined along with their study design and methods. The rationale of establishing specific patient selection criteria and the dilemmas around immunosuppressive regimens in patients undergoing LT for CRLM are also highlighted. Additionally, this review describes the findings of studies comparing LT vs chemotherapy alone and LT vs portal vein embolization plus resection for CRLM in terms of OS and DFS. Last but not least, we present current perspectives and ongoing prospective trials that try to elucidate the role of LT for CRLM.     

Fine-needle cytology of cutaneous juvenile xanthogranuloma and langerhans cell histiocytosis

BACKGROUND:

In pediatric patients, a cutaneous nodule is usually diagnosed by performing an excisional biopsy, but fine‐needle cytology (FNC) is a safer and noninvasive diagnostic method widely used to obtain diagnostic specimens with little stress to the patient. The authors compared the ability of FNC and biopsy to differentiate Langerhans cell histiocytosis (LCH) from juvenile xanthogranuloma (JXG).

METHODS:

Correlating cytological results with histological findings, the authors reviewed 27 patients (15 males and 12 females; mean age, 37 months; range, 1 month to 14 years) admitted to the University of Padua Department of Pediatrics from 1998 to 2010.

RESULTS:

Cytology smears were adequate in all 27 (100%) patients: 14 (52%) were classified as having JXG, 12 (44%) as having LCH, and 1 (4%) as having a doubtful finding. A biopsy was also performed in 20 of these patients, and in all but 1, the 2 methods were completely concordant.

CONCLUSIONS:

FNC is safe and useful in the diagnostic workup of pediatric patients with cutaneous nodules and has no contraindications to its use as the initial diagnostic procedure. Cancer (Cancer Cytopathol) 2011;. © 2010 American Cancer Society.     

骨朗格汉斯细胞组织细胞增生症25例临床分析

 目的　分析骨朗格汉斯细胞组织细胞增生症（LCH）的临床特点,总结LCH诊断和治疗的方法。方法　回顾性分析2004年2月至2012年2月收治的25例经病理证实的LCH患者的临床资料及随访结果。结果　25例患者中男18例,女7例;中位年龄17岁。单发病灶17例,其中颅骨11例,多发病灶6例。首发症状多为疼痛和局部肿块,全身症状少见。主要症状多为局部疼痛,影像学表现为溶骨性改变,12例伴周围软组织肿胀。病理表现为分化好的组织细胞增生及大量嗜酸性粒细胞浸润,CD1a、S100、Vimentin、CD68免疫组织化学阳性率高。单发病例采用手术治疗为主,辅以放疗或化疗。多发病例以化疗为主,辅以放疗。仅累及骨的患者疗效满意,累及其他脏器的2例患者死亡。结论　骨LCH男性发病明显高于女性,好发于儿童和青少年,以单发病灶为多,颅骨侵犯多见。临床表现主要为局部疼痛和肿块,病理活组织检查是确诊的首选方法,治疗宜采用综合疗法。预后与骨病损范围和病理类型以及其他脏器受累情况,大部分病例预后好。     

Disseminated histiocytoses biomarkers beyond BRAFV600E: frequent expression of PD-L1

The histiocytoses are rare tumors characterized by the primary accumulation and tissue infiltration of histiocytes and dendritic cells. Identification of the activating BRAFV600E mutation in Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) cases provided the basis for the treatment with BRAF and/or MEK inhibitors, but additional treatment options are needed. Twenty-four cases of neoplastic histiocytic diseases [11 extrapulmonary LCH, 4 ECD, 4 extranodal Rosai-Dorfman disease (RDD), 3 follicular dendritic cell sarcoma (FDCS), 1 histiocytic sarcoma (HS) and 1 blastic plasmacytoid dendritic cell neoplasm (BPDCN)] were analyzed using immunohistochemical and mutational analysis in search of biomarkers for targeted therapy. BRAF V600E mutations were detected in 4/11 LCH and 4/4 ECD cases. A pathogenic PTEN gene mutation and loss of PTEN protein expression were identified in the case of HS. Increased expression of PD-L1 (≥2+/≥5%) was seen in 3/4 ECD, 7/8 LCH, 3/3 FDCS and 1/1 HS, with overall 81% concordance between 2 antibodies used in the study (SP142 vs. MAB1561 clone). These results show for the first time significant expression of the PD-L1 immune checkpoint protein in these disorders, which may provide rationale for addition of immune check-point inhibitors in treatment of disseminated and/or refractory histiocytoses.     

Malignant histiocytosis and related tumors. A clinicopathologic study of 42 cases using cytological, histochemical and ultrastructural parameters

Light and electron microscopical, immunohistochemical and clinical characteristics in 42 cases of malignant neoplasms, arising from true histiocytes, are described. These were separated in a lymphoma-like subtype, called true histiocytic lymphoma (29 patients) and a disseminated variant, called malignant histiocytosis (9 patients). In addition 4 related histiocytic tumors are discussed, including 2 tumors arising from interdigitating cells. Sinus pattern and cytologic features, especially 'window' nuclei, are emphasized as diagnostic criteria. Erythrophagocytosis was not a constant finding. Electron microscopic features, presence of acid phosphatase, acid alpha-naphthylacetate esterase, lysozyme, alpha 1-antitrypsin, alpha 1-antichymotrypsin, Ia-antigen and absence of B- and T-cell markers, were important in establishing the histiocytic nature or excluding a non-histiocytic tumor. A distinct male predominance existed (male:female = 2.5:1) with a higher relapse free period in females (p = 0.032). A high number of mitotic figures appeared to be a favourable sign, p = 0.020 and 0.019, for remission rate and relapse free period respectively. The degree of cell differentiation and the immunohistochemical pattern did not show a correlation with remission and relapse free period. Extranodal involvement and the presence of short profiles of endoplasmic reticulum were prognostically unfavourable signs. True histiocytic lymphomas showed a higher remission rate (p = 0.041) and relapse-free period (p = 0.017) than malignant histiocytosis.     

Intestinal Langerhans cell histiocytosis-like lesion in an adult presented with diverticulitis: a reactive or neoplastic condition?

The involvement of the gut by Langerhans cell histiocytosis (LCH) is very rare in adults; however this is usually observed with a disseminated disease in children. We report a 75-year-old male patient who underwent right hemicolectomy for a complicated intestinal diverticular disease. The surgical specimen revealed LCH-like proliferative lesion associated with diverticulitis. The overall morphological and immunohistochemical findings are indistinguishable from LCH. Systemic scans and subsequently performed bone marrow biopsies were free of disease. Although the HUMARA clonality assay cannot be assessed, the lack of evidence of LCH progression or disease elsewhere in the whole body strongly supported the possibility of an atypical reactive phenomenon probably due to the underlying intestinal diverticular disease. Therefore, it is important to avoid diagnosing such a unifocal Langerhans cell proliferation as LCH in patients with underlying pathologies in the absence of systemic involvement. Therefore, without knowledge of clonal status of a unifocal Langerhans cell proliferation, we recommend using the terminology of LCH-like lesion.     

Hepatic Langerhans cell histiocytosis: A review

Hepatic Langerhans cell histiocytosis (LCH) is characterized by proliferation and accumulation of Langerhans cells in the liver, causing liver dysfunction or forming a mass lesion. The liver can be involved in isolation, or be affected along with other organs. A common clinical hepatic presentation is cholestasis with pruritis, fatigue and direct hyperbilirubinemia. In late stages, there may be hypoalbuminemia. Liver biopsy may be required for the diagnosis of hepatic LCH. Histologic finding may be diverse, including lobular Langerhans cell infiltrate with mixed inflammatory background, primary biliary cholangitis-like pattern, sclerosing cholangitis-like pattern, and even cirrhosis at later stages. Because of its non-specific injury patterns with broad differential diagnosis, establishing a diagnosis of hepatic LCH can be challenging. Hepatic LCH can easily be missed unless this diagnosis is considered at the time of biopsy interpretation. A definitive diagnosis relies on positive staining with CD1a and S100 antigen. Liver involvement is a high risk feature in LCH. The overall prognosis of hepatic LCH is poor. Treating at an early stage may improve the outcome. Systemic chemotherapy is the mainstay of treatment and liver transplantation may be offered. New molecular markers involved in pathogenesis of LCH are being explored with a potential for targeted therapy. However, further studies are needed to improve outcome.     

Hepatosinusoidal leukaemia/lymphoma consisting of epstein-barr virus-containing natural killer cell leukaemia/lymphoma and T-cell lymphoma; mimicking malignant histiocytosis

Previously diagnosed cases of hepatosinusoidal T-cell lymphoma and malignant histiocytosis (MH) may include lymphoid neoplasms of natural killer (NK) cell lineage associated with Epstein-Barr virus (EBV). Such hepatosinusoidal neoplasms were found to demonstrate hepatomegaly but not lymphadenopathy, and all were diagnosed by a liver biopsy. Sixteen adult patients diagnosed with hepatosinusoidal leukaemia/lymphoma (six NK-cell leukaemia/lymphomas [NKLLs], five instances of MH, three T-cell malignant lymphomas [T-MLs], and two adult T-cell leukaemia/lymphomas [ATLLs] were examined for EBV by in situ hybridization, then were studied immunohistochemically and subjected to a DNA analysis. Among our five patients with MH, neoplastic cells showed T-cells, but no histiocytic markers, and they were considered to have either a T-cell or NK-cell lineage. All NKLLs, MHs and T-MLs, except for ATLLs accompanied by reactive hemophagocytic histiocytes, varied in number in each case. In situ hybridization revealed the presence of EBV in the nuclei of atypical cells in all of the six lymphoid neoplasms of NK-cell lineage. Each case of MH and each T-ML which represented EBV demonstrated no definite T-cell or histiocytic markers. Patients with ATLL did not reveal EBV. In all patients with hemophagocytosis, EBV was present in the nuclei of the neoplastic lymphocytes, but not in the hemophagocytic cells. Finally, the 16 cases were reclassified into eight cases with EBV -containing NKLLs, six T-MLs, and two ATLLs. In addition, no true histiocytic neoplasms were observed. The mechanism of hemophagocytosis may be therefore the production of lymphokines (macrophage-activating factors) by neoplastic lymphocytes. EBV-associated hepatosinusoidal leukaemia/lymphoma may thus contain a lymphoid neoplasm of NK-cell lineage, which made it difficult to be distinguished from the previously designated malignant histiocytosis.     

Hepatic Failure and Death due to New Onset T Cell Lymphoma

Introduction

Liver involvement is commonly seen in disseminated T cell lymphoma; however, it is rarely the presenting organ. Here, we describe a case of T cell lymphoma presenting as acute hepatobiliary disease leading to hepatic failure and death.

Discussion

Forty-seven-year-old male with history of cirrhosis (etiology undetermined), diabetes mellitus, and pancytopenia was admitted to ICU for hypotension and failure to thrive. He had icterus, minimal ascitis, and hepatosplenomegaly on physical examination. No lymphadenopathy was noted. Laboratory workup on admission showed elevated total bilirubin (10.1 mg/dl) and liver enzymes. Serology for acute viral hepatitis, human immunodeficiency virus, Epstein–Barr virus, and autoimmune hepatitis was negative. CT abdomen showed cirrhotic liver with heterogeneous arterial enhancement of the liver without definite mass lesions. Hospital course was complicated by progressively worsening hypotension, respiratory failure, profound acidosis, disseminated intravascular coagulation, and multi-organ system failure leading to death on hospital day 12. Autopsy of the liver showed cirrhotic changes with infiltration with atypical small lymphocytes confined to septa which were CD3 and CD5 positive (CD4 weakly positive, CD8, CD20, CD57, CD56, CD30, Alk-1, granzyme B, TIA1, and S100 negative). Unusual clinical/histological features include (1) initial clinical presentation of hepatic dysfunction without obvious physical signs of lymphoma, (2) negative workup for viral, toxic, autoimmune, and metabolic liver disease, (3) involvement of the entire liver, observed as heterogeneous enhancement of liver without any focal mass lesion as seen on CT scan, (4) an aggressive nature of disease, and (5) autopsy of liver with T cell infiltration confined to septa. Initial diagnosis was challenging due to unusual clinical presentation suggesting inflammatory hepatobiliary disease and the absence of enlarged lymph nodes.

Conclusion

In conclusion, early suspicion of this aggressive lymphoma is important and should be considered in the evaluation of a patient whose course is atypical for hepatitis. Even in the absence of a mass lesion or lymphadenopathy, hepatosplenic T cell lymphoma should be included in the differential diagnosis of acute hepatic dysfunction in a patient who has no evidence of viral, toxic, autoimmune, or metabolic liver disease.     

Treatment of recurrent hepatocellular carcinoma after liver transplantation

Aim: Liver transplantation (LT) is a curative treatment for localized hepatocellular carcinoma (HCC), but the recurrence rate after LT is about 10–20%, with a dismal prognosis. Little data exist as to the natural history, treatment outcome and optimal treatment of recurrent HCC after LT. We reviewed various treatment modalities given to patients with recurrent HCC after LT. Methods: Among 132 patients who underwent LT for localized HCC, we retrospectively reviewed medical records of 39 of the 132 patients who developed recurrent HCC after LT. We analyzed the clinical outcome of various treatment modalities and treatment‐related adverse events. Results: A total of 39 (29%) of the original 132 patients had recurrent HCC, most recurrences (82%) having occurred within 1 year after LT and involved extrahepatic lesions. Only seven patients had recurrent disease limited to the liver. The median overall survival from the initial treatment of all relapsed patients was 6.9 months. There were various initial treatment modalities, namely palliative systemic chemotherapy, trans‐catheter arterial chemo‐embolization/infusion (TACE/I), radiation therapy (RT), surgical resection and no treatment. The median overall survival was 9.5 months for first‐line chemotherapy, including those who had prior local therapy, 6.3 months TACE/I and 6.9 months for RT. Conclusion: Various clinical approaches have been used to treat patients with recurrent HCC after LT in a clinical setting. More effective strategies and clinical guidelines for recurrent HCC following LT must be established.     

朗格汉斯细胞肿瘤4例临床报道并文献复习

目的:探讨朗格汉斯细胞肿瘤临床表现、病理特点、治疗和预后。方法:描述一组成人朗格汉斯细胞肿瘤[包括3例朗格汉斯细胞增多症(LCH)和1例朗格汉斯细胞肉瘤(LCS)]患者的临床、病理表现、治疗情况等,并复习相关文献。结果:3例LCH患者分别为29岁女性、20岁男性以及35岁男性,临床受累脏器包括骨(2/3)、肝(2/3)、下丘脑-垂体(尿崩症)(2/3)、皮肤(1/3),淋巴结(1/3),甲状腺(1/3)、肺(1/3)。免疫组化为CD1 a(+)、S-100(+),2例患者经4个疗程化疗,1例达到部分缓解,另1例无效。1例LCS患者为77岁女性,以颈部淋巴结肿大起病,淋巴结病理诊断为LCS,病情进展迅速,多脏器受累,死于多脏器功能衰竭。结论:成人LCH少见,临床表现不特异,容易误诊、漏诊,治疗需个体化。LCS临床罕见,侵袭性强,进展快,预后差。     

Malignant hepatic vascular tumors in adults: Characteristics,diagnostic difficulties and current management

Malignant vascular tumors of the liver include rare primary hepatic mesenchymal tumors developed in the background of a normal liver parenchyma. Most of them are detected incidentally by the increased use of performing imaging techniques. Their diagnosis is challenging, involving clinical and imaging criteria, with final confirmation by histology and immunohistochemistry. Surgery represents the mainstay of treatment. Liver transplantation (LT) has improved substantially the prognosis of hepatic epithelioid hemangioendothelioma (HEHE), with 5-year patient survival rates of up to 81%, based on the European Liver Intestine Transplantation Association-European Liver Transplant Registry study. Unfortunately, the results of surgery and LT are dismal in cases of hepatic angiosarcoma (HAS). Due to the disappointing results of very short survival periods of approximately 6-7 mo after LT, because of tumor recurrence and rapid progression of the disease, HAS is considered an absolute contraindication to LT. Recurrences after surgical resection are high in cases of HEHE and invariably present in cases of HAS. The discovery of reliable prognostic markers and the elaboration of prognostic scores following LT are needed to provide the best therapeutic choice for each patient. Studies on a few patients have demonstrated the stabilization of the disease in a proportion of patients with hepatic vascular tumors using novel targeted antiangiogenic agents, cytokines or immunotherapy. These new approaches, alone or in combination with other therapeutic modalities, such as surgery and classical chemotherapy, need further investigation to assess their role in prolonging patient survival. Personalized therapeutic algorithms according to the histopathological features, behavior, molecular biology and genetics of the tumors should be elaborated in the near future for the management of patients diagnosed with primary malignant vascular tumors of the liver.     

Chirurgie du carcinome hépatocellulaire: de l’exérèse à la transplantation: indications actuelles et futures

Primarymalignant tumor of the liver, hepatocellular carcinoma (HCC) occurs almost always with an underlying chronic liver disease, commonly but not necessarily at cirrhosis stage. In developed countries, chronic hepatitis C and nonalcoholic fatty liver disease frequently associated with metabolic syndrome are the major risk factors for HCC, thus explaining its increasing incidence in the recent years. Liver transplantation, liver resection and radiofrequency ablation are the three potentially curative therapeutic possibilities available for the treatment of HCC. The choice of treatment depends on the following factors: a nontumorous liver, age, comorbidities of the patient, and size and number of the lesions. Liver transplantation (LT) appears to be the best theoretical treatment for removing all lesions with optimal margins and treating the underlying liver disease at the same time. However, graft shortage and stringent selection criteria for oncological reasons hamper its use in all patients. More than 10 years after their adoption by the transplant community, Milan criteria remain the corner stone of the indications of LT for HCC. Liver resection (LR) is an alternative option, particularly to treat HCC without cirrhosis or as a bridging therapy to LT. However, its significant operative risk and high rate of recurrence need to be considered before treatment. Radiofrequency ablation helps in the treatment of early-stage HCC with lower morbidity than LR, but its efficiency is impaired by the size of the lesion. Although LT offers the best chance for cure it is not suitable for all patients, and indications of treatment is still a matter of debate. Recent advances in molecular biology of the tumor and non-tumorous liver should help to better assess prognosis and thus to refine indications.     

Histologic and cytologic liver changes in 120 patients with malignant lymphomas.

The purpose of this study was to determine the frequency of liver involvement in malignant lymphomas. Non-specific liver changes were also registered. Percutaneous liver biopsy was performed on 120 patients with untreated malignant lymphomas. There were 38 patients with Hodgkin's disease, 42 with histiocytic and 40 with lymphocytic lymphomas. All the biopsy specimens were histologically and cytologically analyzed. Positive liver findings (lymphomatous infiltration) were observed in 27.5% of patients with lymphocytic, 23.8% with histiocytic lymphomas, and 7.8% with Hodgkin's disease. Liver involvement in non-Hodgkin's lymphomas was significantly higher (P less than 0.025) than in Hodgkin's disease. In the whole group of patients, there were non-specific liver changes: 23 chronic persistent hepatitis, 5 aggressive hepatitis, 9 liver steatosis and 4 liver hemosiderosis. Based on these results, it can be concluded that liver involvement with lymphomatous tissue is more common in non-Hodgkin's lymphomas. Knowledge of this is relevant for clinical staging and the treatment program. These findings also confirm that percutaneous liver biopsy is a valuable diagnostic procedure in the staging of malignant lymphomas.     

Hemophagocytic syndrome associated with CD8 positive T-cell chronic lymphocytic leukemia

We describe a case of hemophagocytic syndrome (HPS) associated with CD8-positive T-cell chronic lymphocytic leukemia (CD8 + T-CLL). A 68-year-old man with CD8 + T-CLL presented with fever, progressive pancytopenia, and lymphadenopathy. Laboratory findings showed a hyper-ferritinemia, abnormalities of coagulation tests, and liver and renal dysfunction with hypoproteinemia. He did not respond to any treatments and died of respiratory failure 10 days after the admission and 14 months after the onset of CD8 + T-CLL. Pathological findings of the autopsy demonstrated infiltration of CD8 + T-CLL cells in multiple organs along with the increase of histiocytes with prominent hemophagocytosis. Serum concentration levels of IL-6, soluble IL-2 receptor and VEGF were all elevated at admission. These findings revealed that he had a secondary HPS. It was suggested that HPS should be considered in patients with an unexplained cytopenia and a fever during the clinical course of CD8 + T-CLL.     

朗格汉斯细胞组织细胞增多症的研究进展

朗格汉斯细胞组织细胞增多症（LCH）是最常见的组织细胞增生症，是以 CD1a+／CD207+树突状细胞异常克隆增生的一类疾病。 LCH 临床表现复杂多变，异质性强，既有明显的炎症反应又有肿瘤的特性，其应被重新定义为炎症性髓系肿瘤。最近的研究发现 LCH 是髓系树突状细胞前体误分化的结果，而误分化的原因是 RAS-RAF-MEK-ERK 通路中的基因突变。采用这些基因抑制剂治疗 LCH 可能会有较好效果。随着前瞻性临床试验的进一步开展，分子靶向治疗可能会联合甚至取代传统的手术、化疗，成为 LCH 临床一线治疗方案。     

朗格汉斯细胞肿瘤4例临床报道并文献复习

目的：探讨朗格汉斯细胞肿瘤临床表现、病理特点、治疗和预后。方法：描述一组成人朗格汉斯细胞肿瘤[包括3例朗格汉斯细胞增多症（LCH）和1例朗格汉斯细胞肉瘤（LCS）]患者的临床、病理表现、治疗情况等,并复习相关文献。结果：3例LCH患者分别为29岁女性、20岁男性以及35岁男性,临床受累脏器包括骨（2／3）、肝（2／3）、下丘脑-垂体（尿崩症）（2／3）、皮肤（1／3）,淋巴结（1／3）,甲状腺（1／3）、肺（1／3）。免疫组化为CDla（＋）、S-100（＋）,2例患者经4个疗程化疗,1例达到部分缓解,另1例无效。1例LCS患者为77岁女性,以颈部淋巴结肿大起病,淋巴结病理诊断为LCS,病情进展迅速,多脏器受累,死于多脏器功能衰竭。结论：成人LCH少见,临床表现不特异,容易误诊、漏诊,治疗需个体化。LCS临床罕见,侵袭性强,进展快,预后差。