Recommendations for an Approach to Random Skin Biopsy in the Diagnosis of Intravascular B-Cell Lymphoma.

Intravascular B-Cell Lymphoma (IVBCL) is a rare type of extranodal large B-cell lymphoma where clonal B-cells selectively home to and replicate in the lumen of small vessels. Random skin biopsy (RSB) of uninvolved skin is a reputable tool to diagnose this protean entity and thus dermatologists are involved in its diagnosis. A literature review was completed to derive an approach to RSB in these patients to maximize diagnostic yield of IVBCL and minimize morbidity. Based on this review, data from 27 patients where clinical signs and symptoms and results of investigations were able to be linked to a positive diagnosis of IVBCL from RSB from 11 papers from 2003 to 2021 were analyzed. Following this analysis, RSB should be considered when there are no clinical skin findings and there is an elevated lactate dehydrogenase in the absence of lymphadenopathy and presence of fever of unknown origin, thrombocytopenia, anemia, and ferritinemia. Three to four RSBs from the thigh, abdomen and/or posterior upper arm should be performed via either incisional or telescoping punch biopsies and should include senile/cherry angioma(s) if present. If RSB results in a diagnosis of IVBCL, hematology should be consulted for further management. Consideration of a false negative biopsy or alternative diagnoses should be explored if RSB is negative for IVBCL. Following a standard approach for RSB in these patients will increase diagnostic yield of IVBCL while decreasing the risk of harm to the patient.

Diagnosis of intravascular large B cell lymphoma: novel insights into clinicopathological features from 42 patients at a single institution over 20 years.

This study aimed to clarify the comprehensive clinical, laboratory, pathological and imaging features of intravascular large B-cell lymphoma (IVLBCL) using data on 42 IVLBCL patients diagnosed at our hospital over the past 20 years. The majority of patients were diagnosed via random skin biopsy (29/42, 69·0%) followed by bone marrow biopsy alone (8/42, 19·0%). Characteristic features included persistent fever (41/42, 97·6%), decreased performance status (≥2) (100%), hypoxaemia (32/40, 80·0%), impaired consciousness (19/42, 45·2%), hypoalbuminemia (42/42, 100%) and extreme elevation of lactate dehydrogenase and soluble interleukin 2 receptor levels. Brain magnetic resonance imaging showed abnormal findings in 32/37 patients (86·4%). Hyperintense lesion in the pons was a peculiar finding that was unrelated to the neurological deficits. Positron emission tomography-computed tomography revealed a high incidence of bone marrow (26/34, 76·5%), spleen (19/34, 55·9%) and adrenal gland (9/34, 26·5%) involvement. Neurolymphomatosis was noted in 6 patients during the course of the disease. About 60% of IVLBCL patients in whom in vivo diagnosis was possible survived more than 5 years with combination chemotherapy. Our observations provide additional insight into the diagnosis of IVLBCL and indicate that early disease recognition via random skin biopsy combined with imaging, enables in vivo diagnosis of the disease and improved survival for many patients.

[Cauda equina syndrome as the first presentation of intravascular large B-cell lymphoma: a lung biopsy case].

A 65-year-old male was admitted for bladder and rectal dysfunction with lower-limb sensory disturbance. Although no abnormalities were detected on magnetic resonance imaging of the brain and spinal cord, an elevation in the serum anti-cytomegalovirus (CMV) -IgM level and pneumonia suggest viral meningomyelitis. However, steroid pulse and anti-CMV treatments did not resolve the patients' symptoms. Lung and skin biopsies revealed an invasion of atypical lymphoid cells into small vessels, consistent with intravascular large B-cell lymphoma (IVLBCL). Chemotherapy comprising R-CHOP and intrathecal administration of methotrexate resolved neurological complications quickly, and the patient remains in complete remission after 2 years. Notably, IVLBCL with cauda equina syndrome is highly rare.

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.

Optimizing random skin biopsies: a review of techniques and indications for intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVLBCL), a rare subtype of malignant lymphoma, is diagnosed by observation of intravascular proliferation of tumor cells in samples taken from affected organs. However, diagnosis of IVLBCL is usually difficult due to the lack of mass formation. IVLBCL may be fatal when the diagnosis is delayed, so an accurate early diagnosis is the key to successful treatment. Random skin biopsy (RSB), in which specimens are sampled from normal-appearing skin, has been reported as useful. However, the specific method of RSB remains controversial, with individual institutions using either the punch method or the incisional method. Research has shown that the incisional method has higher sensitivity than the punch method. We discuss whether this difference might owe to the collection of punch specimens from an insufficient depth and whether the punch method might result in false negatives. For RSB, we recommend taking specimens not only from normal-appearing skin, but also from any lesional skin, because lesions may reflect micro IVLBCL lesions. To ensure accurate diagnosis, both dermatologists and hematologists should know the proper method of RSB. This review summarizes the appropriate biopsy method and sites for RSB.

Clinical utility of positron emission tomography leading to rapid and accurate diagnosis of intravascular large B-cell lymphoma presenting with the central nervous system symptoms alone: A case report and review of the literature.

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare entity among large B-cell non-Hodgkin lymphomas and is often difficult to diagnose. We report the case of a patient with IVLBCL who presented with central nervous system (CNS) symptoms alone, in which positron emission tomography (PET) enabled a rapid and accurate diagnosis. Case Description: An 81-year-old woman was admitted to our hospital with a 3-month history of gradually progressive dementia and declining spontaneity. Magnetic resonance imaging revealed multiple hyperintense lesions bilaterally on diffusion-weighted imaging without enhancement on gadolinium-enhanced T1-weighted imaging. Laboratory findings showed elevated serum lactate dehydrogenase (626 U/L) and soluble interleukin-2 receptor (sIL-2R) (4692 U/mL). Cerebrospinal fluid (CSF) analysis showed slightly elevated levels of protein (166 mg/dL) and lymphocytic cells (29/µL), and ß2-microglobulin (ß2-MG) (4.6 mg/L) was highly elevated. Whole-body computed tomography revealed faint ground-glass opacities in the upper and middle lung fields and diffuse enlargement of both kidneys without lymph node swelling. 18F-fluorodeoxyglucose (FDG)-PET showed diffuse and remarkably high FDG uptake in both upper lungs and kidneys without uptake by lymph nodes, suggesting a malignant hematological disease. IVLBCL was confirmed histologically by incisional random skin biopsy from the abdomen. Chemotherapy using R-CHOP regimen in combination with intrathecal methotrexate injection was started on day 5 after admission and follow-up neuroimaging showed no signs of recurrence. Conclusion: IVLBCL presenting with CNS symptoms alone is rare and often has a poor prognosis associated with delayed diagnosis, and various evaluations (including systemic analysis) are therefore necessary for early diagnosis. FDG-PET, in addition to identification of clinical symptoms and evaluation of serum sIL-2R and CSF ß2-MG, enables rapid therapeutic intervention in IVLBCL presenting with CNS symptoms.

Early Diagnosis of Intravascular Large B-Cell Lymphoma by Random Skin Biopsy.

Introduction: Delayed diagnosis of intravascular large B-cell lymphoma (IVLBCL) is associated with a poor prognosis, making early diagnosis and treatment essential. However, early diagnosis remains challenging. Case description: Here we present the case of a 75-year-old man with fever of unknown origin, in whom random skin biopsy (RSB) allowed early diagnosis of IVLBCL. Discussion: The usefulness of RSB, which involves incisional skin biopsies of three or more sites that contain subcutaneous fatty tissue, such as the thighs, abdomen and upper arms, has been debated. In cases of suspected IVLBCL, RSB is less invasive than a biopsy of the internal organs. Conclusion: We suggest that combining RSB with bone marrow examination may facilitate the diagnosis of IVLBCL. LEARNING POINTS: Delayed diagnosis of intravascular large B-cell lymphoma (IVLBCL) is associated with a poor prognosis, but early diagnosis is difficult due to its diverse, non-specific presentation.This case report illustrates the value of random skin biopsy in the early diagnosis of IVLBCL in a man with fever of unknown origin and haematological abnormalities without lymphadenopathy, splenomegaly or bone marrow abnormalities.The diagnostic accuracy of random skin biopsy depends on several factors, including the location and number of sites biopsied, and the depth and width of the biopsy.

Rapid deterioration of intravascular large B-cell lymphoma with mass formation in the trigeminal nerve and multiple organ infiltration: An autopsy case report.

Intravascular large B-cell lymphoma (IVLBCL) is a rare lymphoma characterized by the selective growth of lymphoma cells within the lumen of vessels. We describe the case of a 69-year-old male who presented with marked pain in the left facial region. Gadolinium-enhanced magnetic resonance imaging revealed a swollen left trigeminal nerve (TN) and positron emission tomography/computed tomography demonstrated fluorodeoxyglucose-only uptake at the same site. The patient had high serum lactate dehydrogenase and soluble interleukin-2 receptor levels. As random skin biopsy and bone marrow biopsy detected no abnormal pathogenesis, open biopsy of the TN was performed, revealing diffuse large B-cell lymphoma (DLBCL). However, ground glass opacities rapidly developed in both lung fields with severe respiratory failure. The patient died of progressive disease before the initiation of chemotherapy. Postmortem examination revealed widespread lymphoma cells in the lumen of vessels in multiple organs, including the lungs, excluding the bone marrow and skin. Lymphoma cells formed a mass in the TN and left lumbar plexus. A diagnosis of IVLBCL was made based on the postmortem pathological analysis. DLBCL of abnormal sites, such as the peripheral nervous system, should be considered in cases of IVLBCL as a differential diagnosis.

[A case of intravascular large B-cell lymphoma manifested as lacunar infarction].

A 79-year-old man was admitted to our hospital because of sudden onset of left ataxic hemiparesis. Brain MRI diffusion weighted images showed typical lacunar infarction on the right internal capsule. He had no risk factors of cerebrovascular disorder such as hypertension, diabetes mellitus, hyperlipidemia and arrhythmia. On admission, he had a slight fever and his laboratory data showed anemia, thrombocytopenia and elevation of CRP and LDH. Intravascular large B-cell lymphoma (IVLBCL) was suspected because the serum level of soluble IL-2 receptor was also elevated. Pathological diagnosis of IVLBCL was underwent by the skin biopsy from his senile hemangiomas. Although IVLBCL was known to demonstrate various CNS lesions, it is extremely rare to be manifested as a single lacunar infarction, and this case must be important for the differential diagnosis.

Probability scoring system of intravascular large B-cell lymphoma for the application of random skin biopsy: A retrospective cohort study.

Background: Intravascular large B-cell lymphoma (IVLBCL) is rare and fatal when diagnosed late in the disease course. Random skin biopsy (RSB) is useful for early diagnosis, but criteria for its application are not well established. Objective: To develop an IVLBCL-probability scoring system for stratifying patients and investigate its feasibility and capability for RSB application. Methods: A retrospective cohort of 77 consecutive patients with suspected IVLBCL who underwent RSB was included in this study. All patients were classified into 3 IVLBCL-probability groups according to the IVLBCL-probability scoring system comprising the following 4 components: general symptoms, organ-specific symptoms, serum soluble-interleukin-2 receptor levels, and serum lactate-dehydrogenase levels. Results: The high (score 7-10), intermediate (score 4-6) and low (score 1-3) IVLBCL-probability groups contained 32, 30, and 15 patients, respectively. All 5 patients with IVLBCL were stratified into the high IVLBCL probability group. Accuracies in the diagnosis of IVLBCL were 100%, 100%, and 93.8% for the low, intermediate, and high IVLBCL-probability groups. The positive detection rate in the high IVLBCL-probability group increased to 9.4% from 3.9% across all groups. Conclusions: The newly-developed IVLBCL-probability scoring system has good capability for stratification of patients and could allow limiting application of RSB for diagnosis only to high-probability groups.

A Case of Intravascular Diffuse Large B-Cell Lymphoma Initially Suspected as Interstitial Pneumonia Associated With Systemic Scleroderma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse LBCL. The patient was a 71-year-old female admitted to our hospital with hypoxia. On admission, chest computed tomography revealed a ground-glass opacity. Interstitial pneumonia associated with systemic scleroderma was suspected because of positive anti-centromere antibody. Thereafter, steroid pulse therapy and plasma exchange were performed. Although ground-glass opacity improved, bilateral pleural effusion appeared, so we performed a random skin biopsy because of her elevated serum lactate dehydrogenase and soluble interleukin-2 receptor levels. The patient was diagnosed with IVLBCL with symptoms improving after 6 cycles of rituximab plus chemotherapy treatment.

Bone marrow infiltration pattern in patients with intravascular large B-cell lymphoma diagnosed by random skin biopsy.

We retrospectively analyzed bone marrow (BM) infiltration pattern in consecutive 30 intravascular large B-cell lymphoma (IVLBCL) patients diagnosed by random skin biopsy (RSB). BM infiltration of lymphoma was observed in 18 patients (60.0%), including five patients with the intrasinusoidal pattern with minimal extravasation, eight patients with the mixed of intrasinusoidal and scattered/interstitial or nodular infiltration, and five patients with the nodular/diffuse pattern. Twelve patients were negative for lymphoma infiltration. BM histology of patients with IVLBCL were diverse and frequently discordant with those of other site of IVLBCL lesions. BM biopsy had a poorer diagnostic performance for detecting intravascular features.

Intravascular lymphoma with hypopituitarism: A case report.

BACKGROUND: Intravascular lymphoma (IVL) is a rare subtype of lymphoma involving the growth of lymphoma cells within the vessel lumina without lymphadenopathy. Because of various modes of presentation and its rarity, IVL is often diagnosed postmortem. Herein, we report a case of intravascular B-cell lymphoma with hypopituitarism, an extremely rare complication, that was successfully treated with chemotherapy. CASE SUMMARY: An 80-year-old Japanese woman presented with a 7-mo history of a tingling sensation in the lower limbs. She also presented with various other symptoms such as pancytopenia, high fever daily, and unconsciousness with hypoglycemia. Although the doctor who previously treated her diagnosed hypoglycemia as being due to hypopituitarism, the cause of the other symptoms remained uncertain despite a 7-mo evaluation period. We performed bone marrow aspiration to evaluate pancytopenia and found that she had hemophagocytic lymphohistiocytosis (HLH). On the basis of a random skin biopsy for assessing the cause of HLH, she was diagnosed with intravascular B-cell lymphoma. HLH and hypopituitarism were considered secondary to IVL. All her clinical findings matched the presentations of IVL. She was immediately treated with chemotherapy and achieved complete response. She was relapse free two years after treatment. CONCLUSION: IVL should be included in the differential diagnosis of hypopituitarism, which although life-threatening, is treatable through prompt diagnosis and appropriate chemotherapy.

Concomitant subcutaneous intravascular lymphoma lesions in a patient with cardiac diffuse large B-cell lymphoma: is intravascular lymphoma a distinct clinical entity?

We describe a patient who presented with large cardiac diffuse large B-cell lymphoma (DLBCL) and adrenal masses. The patient also had subcutaneous intravascular lymphoma lesions which were detected by random skin biopsy. Although ambiguous, minimal extravascular location of lymphoma cells is permitted for the diagnosis of intravascular large B-cell lymphoma (IVLBCL) in the WHO definition, a number of rare cases have been reported as having concomitant tumours in other organs, such as the adrenal gland, brain, and penis. We assume that IVLBCL might be a peculiar feature of DLBCL characterised by preferential localisation of lymphoma cells within the capillaries rather than a distinct disease entity of DLBCL.

Pure intravascular recurrence of CD5-positive diffuse large B-cell lymphoma primarily arising from the nasal cavities.

BACKGROUND: CD5-positive diffuse large B-cell lymphoma (DLBCL) and intravascular large B-cell lymphoma (IVL) are recognized as rare subsets of large B-cell lymphoma with poor prognosis. These two categories have similar clinicopathological features suggesting that they might overlap. CASE PRESENTATION: We present a case of a 72-year-old man with submental tumors. Positron emission tomography/computed tomography (PET/CT) showed tumors in the nasal and paranasal region and multiple submental and jugular swollen lymph nodes with abnormal uptake of 18F-fluorodeoxyglucose (FDG). Histology of biopsy from nasal tumors showed diffuse infiltration of large lymphoid cells, which showed positive expressions for CD20, CD79a, CD5 and negative for CD3 on immunohistochemistry. Thus, a CD5-positive DLBCL was diagnosed. After administration of 8 cycles of R-THPCOP (rituximab, pirarubicin, cyclophosphamide, vincristine and prednisolone), complete remission was achieved. Eight months after the first chemotherapy dose, local recurrence occurred. After salvage chemotherapy, nasal and paranasal tumors and lymph node swelling disappeared on PET/CT images, although the patient suffered from respiratory disturbance. A random skin biopsy revealed IVL, which was consistent with intravascular recurrence of CD5-positive DLBCL. Bone marrow smears showed hemophagocytosis. CONCLUSION: We present a rare case of primary CD5-positive DLBCL that relapsed as pure IVL after chemotherapy. Our case suggests that CD5-positive DLBCL is closely related to IVL.

A Case of Recurrent Ischemic Stroke due to Intravascular Lymphomatosis, Undiagnosed by Random Skin Biopsy and Brain Imaging.

Intravascular lymphoma (IVL) is a rare disease characterized by the proliferation of lymphoma cells in the lumen of the small blood vessels. Although early diagnosis of IVL is important to prolong survival of the patients, its atypical symptoms and clinical course often delay its diagnosis. More than half of the patients are diagnosed at autopsy. We report a 68-year-old man who presented with transient ideomotor apraxia and mildly elevated soluble interleukin-2 receptor levels. He was initially diagnosed with aortogenic embolic stroke. He developed rapidly progressive neurological manifestations with enlargement of brain lesions on brain computed tomography and magnetic resonance imaging and died 3 months after symptom onset. The diagnosis of IVL could not be made by random skin biopsy, but was finally made at autopsy. For the early diagnosis, sufficient random skin biopsy or brain biopsy should be planned when suspected.

Random skin biopsy of patients with intravascular large B-cell lymphoma associated with thrombocytopenia and coagulation abnormalities: proposal of a modified biopsy method.

Intravascular large B-cell lymphoma (IVLBCL) is classified as a rare type of non-Hodgkin's B-cell lymphoma by the World Health Organization. It is characterized by the presence of lymphoma cells in the lumens of the small vessels of several organs, most notably the skin. Diagnosis of IVLBCL is difficult because of the lack of lymphadenopathy and because lesions need to be histologically confirmed via a biopsy of the affected organs. Random skin biopsy (RSB) of normal-appearing skin is a useful and apparently safe means of evaluating IVLBCL. However, patients with IVLBCL often exhibit thrombocytopenia, and we describe a case in which a patient with thrombocytopenia experienced hemorrhagic shock and died shortly after RSB. For this reason, we reviewed cases of RSB performed at our hospital and found that the middle adipose tissue contained a higher percentage of atypical lymphoid cells than other layers of the skin. On the basis of our findings, we propose a strategy for the safer performance of RSB in IVLBCL patients with thrombocytopenia and coagulation abnormalities.

Long-term complete remission in a patient with intravascular large B-cell lymphoma with central nervous system involvement.

This report describes a patient with intravascular large B-cell lymphoma (IVLBCL) with central nervous system involvement at the time of diagnosis who achieved complete remission for over 5 years in response to therapy. The patient, a 71 year-old woman, was previously healthy with the exception of taking verapamil for paroxysmal supraventricular tachycardia. She had presented with pyrexia and gradually progressive anemia. Brain magnetic resonance imaging revealed an infarct-like lesion in the pons, although no paralysis was observed. She was diagnosed with IVLBCL on the basis of random skin biopsy. After eight cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, abnormal laboratory data had normalized, and no pontine lesion was evident on magnetic resonance imaging without receiving any intrathecal chemotherapy. IVLBCL is associated with poor prognosis, particularly in patients with central nervous system involvement. Early initiation of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy and drug interactions between anticancer agents and verapamil as a p-glycoprotein inhibitor were considered the possible reasons for favorable outcome in the present case.