Rapidly progressive dementia due to intravascular lymphoma: A prion disease reference center experience.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare extranodal lymphoma that is characterized by the selective growth of neoplastic cells in blood vessels, representing a potentially treatable cause of rapidly progressive dementia (RPD). Given its diverse clinical and instrumental presentation, it is often misdiagnosed with more common RPD causes, for example, Creutzfeldt-Jakob disease (CJD) or vascular dementia. METHODS: This study presents the clinical and histopathological characteristics of four IVLBCL cases that we diagnosed post-mortem over 20 years among over 600 brain samples received as suspected CJD cases at our prion disease reference center. RESULTS: Our patients exhibited various presenting symptoms, including behavioral disturbances, disorientation, and alertness fluctuations. The diagnostic tests performed at the time, including blood work, cerebrospinal fluid (CSF) analyses, electroencephalography, and neuroimaging, yielded nonspecific and occasionally misleading results. Consequently, the patients were repeatedly diagnosed as variably having CJD, epilepsy, vascular dementia, and encephalitis. The stored CSF samples of two patients tested negative at prion real-time quaking-induced conversion (RT-QuIC), which we performed afterwards for research purposes. Neuropathological analysis revealed a differential involvement of various brain areas, with frontotemporal neocortices being the most affected. CONCLUSIONS: Our results confirm the significant clinical and instrumental heterogeneity of IVLBCL. Neuropathological evidence of the preferential involvement of frontotemporal neocortices, potentially conditioning the clinical phenotype, could be relevant to reach an early diagnosis. Finally, given the therapeutic implications of its misdiagnosis with CJD, we emphasize the utility of prion RT-QuIC as a test for ruling out CJD in these patients.

Miliary tuberculosis-associated hemophagocytic lymphohistiocytosis with a high level of soluble interleukin-2 receptor successfully treated with concomitant recombinant thrombomodulin: A case report.

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disease characterized by a highly inflammatory state due to the abnormal activation of T lymphocytes and macrophages. Miliary tuberculosis (MTB) is a rare cause of HLH and its clinical appearances occasionally resembles that of intravascular lymphoma (IVL). A 76-year-old woman presented with persistent fever and fatigue. Abnormal laboratory findings showing thrombocytopenia (13,000/µL), hypofibrinogenemia (101 mg/dL), hyperferritinemia (2,312 ng/mL), and markedly elevated soluble interleukin-2 receptor (sIL-2R) level (32,200 U/mL), in addition, hemophagocytosis in the bone marrow (BM) smear, were suggestive of IVL-associated HLH. The pathology of the BM biopsy specimen showed granuloma with non-caseous necrosis, and culture tests using sputum, gastric fluid, urine, and peripheral and bone marrow blood revealed the presence of Mycobacterium tuberculosis, leading to the final diagnosis of MTB-associated HLH. Anti-TB medications and corticosteroids were administered, but thrombocytopenia, hypofibrinogenemia, and hyperferritinemia persisted. Concomitant use of recombinant thrombomodulin (rTM) enabled regression of clinical status. In this case, BM biopsy served as the diagnosis of MTB-associated HLH, although IVL-associated HLH is initially suspected by an extremely high level of sIL-2R. Furthermore, this case report informs that using rTM could improve the outcomes of MTB-associated HLH.

MRI characteristics of ventral vertebral venous plexus occlusion due to lymphoma in a large breed dog.

Intravascular lymphoma is a rare presentation of lymphoma with a predilection to the central nervous system (CNS). A 9-year-old male-neutered Collie presented with a 3-month history of lymphadenopathy and a 6-day history of an acute onset, progressive, painful, symmetrical L4-S3 myelopathy. Magnetic resonance imaging revealed multifocal extradural spinal cord compressions from L3 to L6 secondary to a bilaterally enlarged and occluded ventral vertebral venous plexus (VVVP). Histopathology revealed low-grade lymphoma within the venous plexus in the lumbar vertebral column, tracheobronchial lymph nodes, and tonsils. Intravascular lymphoma should be considered a differential diagnosis for enlarged VVVP causing compression of the spinal cord.

Skin biopsy in the diagnosis of intravascular lymphoma: A retrospective diagnostic accuracy study.

BACKGROUND: The yield of skin biopsies in the evaluation of intravascular lymphoma (IVL) is largely unknown in Western patients. Most data supporting this test come from Asian populations, in which both prevalence and disease presentation seem to differ. OBJECTIVE: To determine the yield and diagnostic properties of skin biopsy in the evaluation of IVL. METHODS: We reviewed skin biopsy pathology reports of 50 patients being evaluated for IVL to calculate the diagnostic yield of this test. An additional 6 patients, who underwent skin biopsies after the diagnosis of IVL was made by other means, were included to calculate the sensitivity and specificity of our index test. RESULTS: Skin biopsy samples were positive for 5 of the 50 patients being investigated for IVL. Sensitivity was 50% and specificity was 100%. LIMITATIONS: Only pathology reports containing IVL as an indication for the biopsy were retrieved. This might have excluded patients in whom the disease was considered but was not deemed likely enough to be listed as the indication for the test, inflating our estimative of skin biopsy yield. CONCLUSION: A relatively high diagnostic yield was found in the evaluation of IVL among patients with a diverse presentation in a Western hospital.

Intravascular pseudolymphomatous angiosarcoma: A new finding potentially mistaken for intravascular lymphoma.

Pseudolymphomatous infiltrates associated with angiosarcoma are a rarely reported phenomenon. Recognition of this reactive process is critical to making an accurate diagnosis, both in diagnosing the angiosarcoma and in avoiding an incorrect diagnosis of lymphoma. Here, we present a novel histopathologic pattern, angiosarcoma with a prominently intravascular atypical lymphoid component, mimicking intravascular T-cell lymphoma. Interestingly, serial biopsies in this case revealed a progressive increase in lymphocyte density and intravascular component over time. Despite prior reports of improved progression-free survival and overall survival of patients with pseudolymphomatous angiosarcoma, this patient showed rapid disease progression.

Intralymphatic histiocytosis in healing cellulitis: Case report and review of the literature.

Intralymphatic histiocytosis (ILH) is a rare skin benign condition observed in a variety of inflammatory settings. It is characterized by the presence of ectatic dermal lymphatic vessels containing aggregates of histiocytes. Associated conditions that have been identified include rheumatoid arthritis, metallic orthopedic implants, inflammatory bowel disease, and malignancies of the breast, skin, and colon. Some cases with no attributable underlying cause have been described. The pathophysiology of ILH is not well understood. It has been proposed that it may represent macrophage migration during immune activation. Herein, we present the first description of ILH observed in the healing phase of cellulitis on the skin of the breast. Awareness of this possibility is important when the diagnosis of intravascular carcinomatosis is being considered.

Life threatening rare lymphomas presenting as longitudinally extensive transverse myelitis: a diagnostic challenge.

Background and aims - Description of two cases of rare intravascular large B-cell lymphoma and secondary T-cell lymphoma diagnosed postmortem, that manifested clinically as longitudinally extensive transverse myelitis (LETM). We discuss causes of diagnostic difficulties, deceptive radiological and histological investigations, and outline diagnostic procedures based on our and previously reported cases. Case reports - Our first case, a 48-year-old female was admitted to the neurological department due to paraparesis. MRI suggested LETM, but the treatments were ineffective. She died after four weeks because of pneumonia and untreatable polyserositis. Pathological examination revealed intravascular large B-cell lymphoma (IVL). Our second case, a 61-year-old man presented with headache and paraparesis. MRI showed small bitemporal lesions and lesions suggesting LETM. Diagnostic investigations were unsuccessful, including tests for possible lymphoma (CSF flow cytometry and muscle biopsy for suspected IVL). Chest CT showed focal inflammation in a small area of the lung, and adrenal adenoma. Brain biopsy sample from the affected temporal area suggested T-cell mediated lymphocytic (paraneoplastic or viral) meningoencephalitis and excluded diffuse large B-cell lymphoma. The symptoms worsened, and the patient died in the sixth week of disease. The pathological examination of the presumed adenoma in the adrenal gland, the pancreatic tail and the lung lesions revealed peripheral T-cell lymphoma, as did the brain and spinal cord lesions. Even at histological examination, the T-cell lymphoma had the misleading appearance of inflammatory condition as did the MRI. Conclusion - Lymphoma can manifest as LETM. In cases of etiologically unclear atypical LETM in patients older than 40 years, a random skin biopsy (with subcutaneous adipose tissue) from the thigh and from the abdomen is strongly recommended as soon as possible. This may detect IVL and provide the possibility of prompt chemotherapy. In case of suspicion of lymphoma, parallel examination of the CSF by flow cytometry is also recommended. If skin biopsy is negative but lymphoma suspicion remains high, biopsy from other sites (bone marrow, lymph nodes or adrenal gland lesion) or from a simultaneously existing cerebral lesion is suggested, to exclude or prove diffuse large B-cell lymphoma, IVL, or a rare T-cell lymphoma.

Canine Cerebral Intravascular Lymphoma: Neuropathological and Immunohistochemical Findings.

Intravascular lymphoma (IVL) is a rare angiotropic large-cell lymphoma in which neoplastic lymphocytes proliferate within the lumina of small blood vessels in the absence of a primary extravascular mass or leukemia. This study included 10 cases of canine IVL restricted to the CNS. Dogs had an average age of 8 years and neurological signs mainly referred to brain involvement such as depression, seizures, and ambulatory deficits. Gross examination at necropsy showed focal extensive or multiple hemorrhagic areas mainly distributed in the telencephalon and diencephalon. Histopathologically, numerous veins and capillaries were filled with neoplastic lymphoid cells, accompanied by edema, hemorrhage, and thrombosis. Immunohistochemistry (IHC) for CD3, CD20, and PAX5 was performed to phenotype the neoplastic lymphocytes. IHC for CD44 and CD29 were used to investigate the pathogenetic mechanism leading to the intravascular aggregation of the neoplastic lymphocytes. The same IHC panel was applied to 8 cases of primary and metastatic canine CNS lymphoma in order to compare IVL immunoreactivity. Three IVLs were typified as T-cell, 3 as B-cell, and 4 as non-T non-B. Neoplastic lymphocytes showed marked expression of CD44 in all IVL cases, and CD29-immunolabeled cells were observed in 4 IVLs. CD44 immunoreactivity was consistent with the findings reported in human IVL, suggesting a predisposition to the formation of lymphocyte aggregates. CD29 was inconsistently immunonegative in canine IVL, confirming only partially the pathogenetic mechanism suggested for the human counterpart.

[The value of healthy skin biopsy in the diagnosis of intravascular B-cell lymphoma: A case report and systematic literature review]. / Intérêt de la biopsie cutanée en peau saine dans le diagnostic du lymphome B intravasculaire : cas clinique et revue systématique de la littérature.

BACKGROUND: Intravascular large B-cell lymphoma (ivLBCL) is a rare blood dyscrasia that is difficult to diagnose. Healthy skin biopsies may prove useful in diagnosis of the condition. Herein we report a case of ivLBCL diagnosed using this type of examination, and we provide a literature review to determine the sensitivity of such testing. PATIENTS AND METHODS: A 67-year-old woman was hospitalised for unexplained prolonged fever (UPF) and impaired general well-being. Laboratory tests revealed inflammatory syndrome, elevated LDH>2000IU/L, hepatic cytolysis and decreased prothrombin time at 47 %. Analysis for infection and medical imaging ruled out both an infectious or inflammatory origin and solid tumour. A healthy skin biopsy enabled confirmation of the diagnosis of ivLBCL. DISCUSSION: This clinical case illustrates the value of healthy skin biopsy in establishing a diagnosis of ivLBCL in patients hospitalised for UPF. Following a systematic literature review in PubMed/Medline, we included eight studies involving at least three patients designed to assess the value of healthy skin biopsy in the diagnosis of ivLBCL. The diagnostic sensitivity of this approach ranged from 67% to 100%, with a sensitivity of 100% being seen in four of the eight studies. Details of the biopsy sites were available in three studies and diagnostic sensitivity was similar overall between samples taken from the thigh, abdomen and arms. CONCLUSION: Healthy skin biopsy sampling from at least two sites constitutes a sensitive and relatively non-invasive procedure for early diagnosis of ivLBCL.

[Intravascular lymphoma simulating relapse of breast cancer: An original clinical case]. / Lymphome intravasculaire simulant une récidive de cancer du sein : une présentation clinique originale.

BACKGROUND: Intravascular lymphoma is a rare form of non-Hodgkin's lymphoma with varied but highly evocative clinical presentations, particularly in terms of dermatology. Histological examination of the skin may be sufficient to allow diagnosis. PATIENTS AND METHODS: Herein, we report the case of a 75-year-old woman with a history of infiltrative ductal carcinoma of the left breast who was hospitalised for neurological evaluation following repeated falls. During the course of her hospital stay, the patient's neurological state deteriorated rapidly, and onset of marked laboratory-documented inflammatory syndrome was observed, together with disseminated intravascular coagulation (DIC). At the same time, she developed orange-peel type skin lesions on her left breast followed by a rapidly-spreading livedoid infiltrated plaque on her side. The skin biopsy enabled a diagnosis to be made of intravascular lymphoma based on immunohistochemical demonstration of intravascular tumoral proliferation of lymphoid cells expressing CD45 marker and B-cell marker CD20, as well as Bcl2, MUM 1 and CD5. DISCUSSION: Intravascular B-cell lymphoma is a rare subtype of diffuse large B-cell lymphoma. It carries a poor prognosis and the clinical appearance varies extremely widely. The signs are primarily neurological and dermatological. Because of the varied nature of presentations as well as the rarity of the disease, diagnosis may be delayed, with worsening of the prognosis of the disease, which nevertheless requires rapid and aggressive management. However, the appearance of infiltrated and livedoid lesions on the trunk or limbs is evocative and skin biopsy constitutes a readily accessible diagnostic tool that offers rapid confirmation.

[Diffuse large B-cell lymphoma relapsing with intravascular large B-cell lymphoma-like perivascular and intravascular lesions].

A 64-year-old woman was diagnosed with diffuse large B-cell lymphoma (DLBCL) in 2013. After eight courses of R-CHOP therapy followed by local irradiation of the remaining retroperitoneal soft tissue shadow, complete response was confirmed on 18F-2-fluoro-2-deoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT). Early in 2016, patient's serum LDH and soluble IL-2 receptor levels elevated. With suspected recurrence of DLBCL, FDG-PET/CT was performed that showed no lymphadenopathy or abnormal FDG uptake. By the end of July 2016, the patient developed fever and night sweating. Intravascular large B-cell lymphoma (IVLBCL) was suspected, and the patient underwent random skin biopsies, which revealed large atypical cells infiltrating peripheral and intravascular regions of the subcutaneous adipose tissue. Cell morphology, immunostaining, and PCR analysis of the immunoglobulin heavy chain gene suggested the recurrence of DLBCL. Despite salvage chemotherapy and autologous peripheral stem cell transplantation with high-dose chemotherapy, approximately 15 months later, DLBCL recurred and involved the lungs. The patient again received chemotherapy and achieved a second remission. Because DLBCL may recur like intravascular lymphoma, the same tests used for IVLBCL diagnosis are required in cases of suspected recurrence of DLBCL based on clinical and laboratory findings.

Intravascular lymphoma forming massive aortic tumors complicated with sarcoidosis and focal segmental glomerulosclerosis: a case report and literature review.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma characterized by proliferation of B cells within small vessels. Herein, we report a case of a 77-year-old man who presented with IVLBCL and massive tumor formation on the aortic wall who was previously diagnosed with sarcoidosis and focal segmental glomerulosclerosis (FSGS). To our knowledge, this is the first reported case of an IVLBCL with aortic tumor formation. CASE PRESENTATION: A 77-year-old ambulatory man with sarcoidosis and FSGS had neurological symptoms for nine months. The patient presented to the emergency department with sudden left leg pain, and was diagnosed with acute femoral artery occlusion. Emergency thrombectomy was performed subsequently. Pathological evaluation of the thrombi revealed that its surface was filled with large atypical B cells. Bone marrow biopsy showed infiltration of large atypical B cells within the small vessels. IVLBCL was suspected and further examination was planned, but the patient died due to sudden respiratory and cardiac arrest on hospital day twelve. Autopsy revealed intravascular tumors adherent to the aortic arch, left ventricle, and the abdominal aorta. All enlarged lymph nodes and the ventricular septum of the heart showed hyalinized lesions with granular formation consistent with sarcoidosis. The patient was diagnosed with IVLBCL with aortic tumor formation complicated with sarcoidosis and FSGS. CONCLUSIONS: IVLBCL may present with tumor formation on the aortic wall. Although the cause of its affinity to the aortic wall is yet unknown, autopsy findings imply that arteriosclerosis may have contributed to the tumor formation. The literature suggests that T-cell abnormalities could possibly be the common etiology of intravascular lymphoma, sarcoidosis, and FSGS.

Subacute Methotrexate Encephalopathy Mimicking Ischemic Stroke With Dynamic Changes on Magnetic Resonance Imaging.

We report a 35-year-old woman who suddenly developed left hemiparesis and dysarthria at 13days after treatment with intrathecal and intravenous methotrexate for intravascular large B cell lymphoma with possible central nervous system infiltration. Seven hours after onset, she developed further right hemiparesis and aphasia. However, the majority of neurologic symptoms disappeared spontaneously and completely by 34hours. We also recorded the dynamic progression and regression of abnormal signals in the bilateral corona radiata on diffusion-weighted imaging, in parallel with neurologic symptoms. The rapid reversal of MR abnormalities and neurologic symptoms allowed us to diagnose methotrexate encephalopathy, and exclude intravascular large B cell lymphoma recurrence and regular brain infarction. The case provides new data on the dynamic changes of abnormal signals on magnetic resonance imaging in methotrexate encephalopathy over a short recovery time.

[Clinical and pathological characteristics of intravascular lymphomas]. / Klinische und pathologische Charakteristika intravaskulärer Lymphome.

Intravascular B­cell lymphomas (IVL) are rare neoplasms that can manifest at any age (mean age ~62-63 years). About half of the cases are associated with Epstein-Barr virus. The most common sites of manifestation are the brain, skin, and bone marrow. The diagnosis is difficult due to unspecific clinical presentation and laboratory changes. FACS (fluorescence-activated cell sorting) and clonality analysis from peripheral blood and radiological findings are often not diagnostic. The most sensitive and most specific diagnostic method is the histopathological and immunohistochemical evaluation of a tissue biopsy. Because of the rarity of this disease, little is known about therapy and prognosis, whereby therapy is mainly similar to non-IVL lymphomas. The prognosis is poor; median survival after diagnosis is approximately one year.

Cutaneous intravascular natural killer/T cell lymphoma with peculiar immunophenotype.

Intravascular lymphoma (IVL) is a rare entity. Most cases are a variant of extranodal diffuse large B cell lymphoma, and fewer than 10% of the published cases are of T cell origin. Only intravascular B cell lymphoma is recognized as a distinct entity in the most recent World Health Organization (WHO) classification of lymphoproliferative disorders. We describe a case of cutaneous natural killer (NK)/T IVL, with a cytotoxic immunophenotype and Epstein-Barr virus (EBV) positivity. However, our case was immunohistochemically negative not only for T cell receptor (TCR)-ßF1 and TCR-γ (TCR-silent), but also for CD56, making it the first triple-negative NK/T IVL case to be described. We urge recognition of this NK/T cell lineage intravascular lymphoma due to its particular immunophenotypical profile and its unvarying relationship with EBV. Its occurrence should not be considered a coincidence, but rather a key aspect of the pathogenic background of this haematological neoplasm.

Limited Role of Random Skin Biopsy in the Diagnosis of Intravascular Lymphoma in Adult Patients with Hemophagocytic Lymphohistiocytosis.

BACKGROUND/AIMS: This study examined the role of random normal skin biopsy in the diagnosis of intravascular lymphoma (IVL) in adult Western patients with clinically diagnosed hemophagocytic lymphohistiocytosis (HLH). METHODS: In a retrospective chart review study, we analyzed a total of 59 skin biopsies that were performed to diagnose IVL in 21 adult patients with HLH seen at Stanford Hospital between 2004 and 2016. RESULTS: Out of the 59 skin biopsies, 42 were taken from clinically normal-appearing skin and 17 from clinically abnormal-appearing skin. None of the 59 biopsies revealed a diagnosis of primary or metastatic malignancy, regardless of the malignancy history, clinical presentation, and biopsy and histopathologic characteristics. A review of 8 positive IVL cases at Stanford Hospital including 1 case associated with HLH showed 1 positive diagnosis by a targeted skin biopsy and other positive diagnoses by bone marrow (n = 4), lung (n = 2), brain (n = 2), muscle (n = 1), and nerve (n = 1). CONCLUSION: Random skin biopsies have a limited role in diagnosing IVL in adult patients with HLH, in the setting of a single academic institution in the USA. A review of the literature emphasizes the role of a full body skin exam with a selective skin biopsy in these patients.

Random skin biopsy in the diagnosis of intravascular lymphoma.

BACKGROUND: Random skin biopsy (RSB) is a method for diagnosis of intravascular lymphoma (IVL). However, the indications for RSB to diagnose IVL have not yet been established. The aim of this study was to determine the appropriate indications for RSB to diagnose IVL. METHODS: Thirty-two patients with fever of unknown origin (FUO) and without skin lesion underwent RSB for diagnosis of IVL. Clinical data, including fever, neurological symptoms, hematologic disorders, organomegaly, bone marrow (BM) study, hypoxemia and serum level of lactate dehydrogenase (LDH), were evaluated. RESULTS: Seven of 32 patients were definitively diagnosed with IVL. In addition to FUO, 2 IVL patients also suffered from dyspnea and neurological disorders. Patients who had FUO with accompanying hematologic disorders, high LDH, negative BM study and no lymphadenopathy or hepatosplenomegaly had a significant tendency to have IVL by RSB (P = .03). FUO with hypoxemia was also identified as a significant indication for RSB (P = .02). CONCLUSIONS: RSB is a reliable method for diagnosis of IVL, especially in patients with FUO and any 1 or more of the 4 following abnormalities: (1) hematologic abnormalities; (2) high serum LDH; (3) hypoxemia; and/or, (4) unusual neurological symptoms with co-existing hematologic abnormalities and without lymphadenopathy, hepatosplenomegaly or BM abnormality.

Hemorrhagic hypopyon as presenting feature of intravascular lymphoma, a case report.

BACKGROUND: Herpes uveitis has been previously reported to present with hyphema, but hemorrhagic hypopyon is rarely reported as a herpetic uveitis manifestation. We report a case of herpes simplex virus (HSV) presenting with hemorrhagic hypopyon, and speculate on the underlying pathophysiology with relation to an intravascular lymphoma which was subsequently diagnosed as a result. CASE PRESENTATION: We present a case wherein a 62-year-old Japanese rheumatoid arthritis woman, with HSV uveitis, presented with hemorrhagic hypopyon in the anterior chamber and a fever with photophobia. Patient was treated with antiviral drugs which improved the hyphema and corneal lesions, but lesions recurred 3 months later. This rare presentation of HSV induced uveitis, and its subsequent recurrence, aroused suspicion of an additional hypopyon-inducing pathology. On account of previous history of lung opacities and elevated LDH, intravascular lymphoma was eventually diagnosed via lung biopsy. She was treated for the lymphoma which also completely resolved all ocular symptoms without any recurrence as of 1.5 years later. CONCLUSION: The exceedingly rare presentation of hemorrhagic hypopyon may have been enabled by an interaction of the HSV with the intravascular lymphoma. HSV involvement was indicated by the dendritic lesions, IgG assay, and response to anti-viral drugs. The ocular involvement of the intravascular lymphoma seems to be indicated by virtue of the anti-tumor drugs completely resolving all ocular symptoms.