Insulin-like Growth Factor II mRNA-binding Protein 3 is a Highly Sensitive Marker for Intravascular Large B-cell Lymphoma: Immunohistochemical Analysis of 152 Pathology Specimens From 88 Patients.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of aggressive extranodal large B-cell lymphoma characterized by the selective growth of lymphoma cells within the lumina of blood vessels, particularly capillaries. IVLBCL lacks mass formation, and its diagnosis can be challenging. We analyzed the utility of insulin-like growth factor II mRNA-binding protein 3 (IMP3) immunohistochemistry for IVLBCL diagnosis in various organs. Double staining with paired box 5 (PAX5) was performed for validation. Overall, 152 pathological specimens (111 positive and 41 negative for IVLBCL) obtained from 88 patients with a diagnosis of IVLBCL were stained for IMP3 and IMP3/PAX5. As negative controls, 40 pathology specimens from 38 patients with no history of IVLBCL or other B-cell lymphomas were stained for IMP3, which comprised 31 benign pathological specimens from 29 patients in whom malignancy was suspected, 7 cases of appendicitis with intravascular and/or intralymphatic lymphoid proliferations, and 2 cases of intravascular natural killer/T-cell lymphoma. All mononuclear cells with cytoplasmic staining were considered positive for IMP3 expression, but expression restricted to germinal center B cells was excluded from evaluation. All 111 IVLBCL pathological specimens were positive for IMP3 and IMP3/PAX5. In addition, 11 of the 41 specimens originally diagnosed as IVLBCL-negative showed IMP3/PAX5 double-positive cells, raising the suspicion of IVLBCL. However, of the 40 negative control samples, IMP3-positive non-germinal center B cells were detected in only 2 samples ( P = 0.0131) and no intravascular IMP3-positive B cells suspicious for IVLBCL were identified. Altogether, IMP3 immunohistochemistry is a highly sensitive marker of IVLBCL and can be a helpful adjunct for IVLBCL diagnosis.

Immunohistochemistry of the oncofetal protein IMP3 is helpful in the diagnosis of intravascular large B-cell lymphoma using skin biopsy.

BACKGROUND: The oncofetal protein insulin-like growth factor 2 mRNA binding protein-3 (IMP3) is expressed in various cancers. In this study, we examined the diagnostic utility of IMP3 immunohistochemistry in the context of intravascular large B-cell lymphoma (IVL). METHODS: We obtained 25 skin biopsy (SB) specimens diagnosed as IVL and nine IVL-negative SB specimens from 27 IVL patients. Additionally, 27 negative SB specimens from 26 non-IVL patients were obtained from our pathology archives. We performed IMP3 immunohistochemistry on these 61 SB specimens, considering IMP3 expression in any mononuclear cell as positive. In selected cases, triple immunostaining for IMP3, PAX5, and CD34 was performed to analyze the origin and location of IMP3-positive cells. RESULTS: IMP3 was expressed in most intravascular lymphoma cells in all the 25 SB specimens diagnosed as IVL. Furthermore, our evaluation revealed the presence of intravascular IMP3-positive B-cells in five of the nine negative SB specimens from IVL patients; however, this was not observed in the 27 SB specimens from non-IVL patients. CONCLUSION: IMP3 was expressed in most IVL cells, and IMP3 immunohistochemistry could serve as a sensitive diagnostic aid for detecting IVL cells in SB.

Late relapse of IgM nephropathy-associated nephrotic syndrome after repeated administration of immune checkpoint inhibitor against pulmonary adenocarcinoma.

ICPIs were effective for primary and metastatic foci of lung adenocarcinoma, but their repeated use provoked a late relapse of IgM nephropathy and lethal lesions in pancreas and lung. ICPIs should be used carefully in cases of immune-related disease.

Cutaneous Coinfection of Cytomegalovirus and Mycobacterium chelonae Accelerated by Immunosuppression.

A mildly diabetic 58-year-old male had traumatic ulceration on the left popliteal fossa, and the lesion progressed to a painful 6 cm deep ulcer. After surgical debridement and skin grafting, ulceration recurred. Pyoderma gangrenosum was clinically diagnosed after the first biopsy, indicating a noninfective ulcer. Immunosuppressive therapy (prednisolone and cyclosporine A) induced complete epithelialization in three months. Four months later, subcutaneous nonulcerated nodules appeared on the anterior area of the left lower leg. Subcutaneous induration progressed and ulceration recurred, so that immunosuppressive therapy continued for one year. Cytomegalovirus (CMV) viremia was detected, and the second biopsy demonstrated CMV inclusions of endothelial and perivascular cells in fibrosing septolobular panniculitis. Cyclosporine A was cancelled, prednisolone was tapered, and ganciclovir started. Viremia soon disappeared, but the lesion progressed to large induration with multiple ulcers measuring up to 3 cm. The third biopsy disclosed infection of Gram-positive mycobacteria, accompanying fat droplet-centered suppurative granulomas without CMV infection. Microbial culture identified Mycobacterium chelonae. Clarithromycin with thermotherapy was effective. A review of the second biopsy confirmed coinfection of CMV and Gram-positive mycobacteria. Immunostaining using a panel of anti-bacterial antibodies visualized the mycobacteria in the lesion. Positive findings were obtained with antibodies to Bacillus Calmette-Guérin, Bacillus cereus, MPT64 (Mycobacterium tuberculosis-specific 24 kDa secretory antigen), LAM (Mycobacterium tuberculosis-related lipoarabinomannan), and PAB (Propionibacterium acnes-specific lipoteichoic acid).

Acute Coronary Syndrome in Acute Myeloid Leukemia with Maturation Accompanying Megakaryocytic Differentiation.

An autopsy case (85-year-old Japanese male) of myeloperoxidase- (MPO-) positive acute myeloid leukemia with maturation (M1) accompanying megakaryocytic differentiation is presented. The patient manifested acute coronary syndrome. Even after emergent percutaneous coronary intervention, his performance status remained poor, so no chemotherapy against leukemia was given. The final white blood cell count reached 291,700/µL, and the platelet count was elevated to 510,000/µL. No cytogenetic studies were performed. He died at the 25th day of hospitalization. Autopsy revealed marked leukemic infiltration to the endocardium and subendocardial myocardium. Subendocardial myonecrosis was surrounded or replaced by the leukemic blasts, and neither granulation tissue reaction nor fibrosis was observed. In the cardiovascular lumen, lard-like blood clots were formed and microscopically consisted of leukemic blasts and platelets (leukemic thrombi). Infiltration of leukemic blasts was seen in the body cavities and systemic organs including the lung. The MPO-positive blasts lacked azurophilic granules and expressed the stem cell markers, CD34 and CD117 (c-kit). No features of myelofibrosis were seen in the 100% cellular marrow. In the endocardium, liver, lymph nodes, and bone marrow, megakaryocytic cells (CD42b/CD61+, MPO-) were distributed, while the small-sized blastic cells in the blood and tissues predominantly expressed MPO. The blasts lacked expression of CD42b/CD61. Megakaryocytic differentiation might be stimulated by certain tissue factors. AML accompanying megakaryocytic differentiation in certain tissues and organs should be distinguished from acute megakaryoblastic leukemia. The mechanisms provoking acute coronary syndrome in acute myeloid leukemia are discussed.

Paraneoplastic Pemphigus Involving the Respiratory and Gastrointestinal Mucosae.

Paraneoplastic pemphigus (PNP), an autoimmune mucocutaneous disorder involving the oral and bronchial mucosae, is a rare complication of hematologic malignancy. Serologically, serum autoantibodies against varied desmosome-related proteins are of notice. PNP is often lethal due to bronchiolitis obliterans and opportunistic infection. A 70-year-old Japanese male complained of dry cough, stomatitis, and sore throat. The lips and oral mucosa were severely eroded, and skin eruptions were seen on the chest and abdomen. The biopsy features were consistent with PNP, and the deposition of IgG and IgM was shown on the plasma membrane of the involved keratinocytes. Serological studies demonstrated autoantibodies to desmoglein-3, desmocollins-2 and -3, bullous pemphigoid antigen-1, envoplakin and periplakin. Systemic evaluation disclosed mantle cell lymphoma, stage 4B. After chemotherapy, partial remission was reached. PNP was treated with methylprednisolone and intravenous immunoglobulins, and the oral lesion only temporarily responded. He died of respiratory failure two months after onset. Autopsy revealed residual indolent lymphoma and systemic opportunistic infections. Aspergillus colonized the eroded bronchial/bronchiolar mucosa, associated with extensive vascular invasion. Coinfection of cytomegalovirus (CMV) and Pneumocystis jirovecii caused interstitial pneumonia. The oropharyngeal, respiratory, esophageal, and gastrointestinal mucosae were diffusely infected by CMV. Bronchiolitis obliterans was observed in the peripheral lung. PNP-related acantholysis-like lesions were microscopically identified in the bronchial and gastrointestinal mucosa. IgG deposition and cleaved caspase-3-immunoreactive apoptotic cell death were proven in the involved mucosal columnar cells. Pathogenesis of the mucosal involvement is discussed.

IGF2BP3 (IMP3) expression in angiosarcoma, epithelioid hemangioendothelioma, and benign vascular lesions.

BACKGROUND: Insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3 or IMP3) is an oncofetal protein that is expressed in various cancer types, and its expression is often associated with poor prognosis. IGF2BP3 expression has not been fully settled in vascular lesions. METHODS: We evaluated the expression of IGF2BP3 in malignant (angiosarcoma and epithelioid hemangioendothelioma [EHE]) and benign (hemangioma, granulation tissue cappilaries, and pyogenic granuloma) vascular lesions using immunohistochemistry. IGF2BP3 expression was scored as negative (0% of endothelial/neoplastic cells), equivocal (1-25%), or positive (> 26%). RESULTS: Eight of 30 (26.7%) cases of angiosarcoma and two of five (40%) cases of epithelioid hemangioendothelioma were positive for IGF2BP3. In contrast, hemangiomas (10 cases) and granulation tissue capillaries (12 cases) were all negative for IGF2BP3, and some cases of pyogenic granuloma (six of 14 cases) was scored as equivocal. In angiosarcoma, IGF2BP3 expression was independent of age, gender, location, morphological pattern, prognosis, presence of metastatic foci, and PD-L1 expression. CONCLUSIONS: IGF2BP3 is a useful marker to distinguish between malignant and benign vascular lesions.

Herpes Simplex Virus Pneumonia: Importance of Aspiration Etiology.

Herpes simplex virus (HSV) pneumonia caused by aspiration from the oropharyngeal exudates is described. An 89-year-old Japanese male in a poor performance state complained of appetite loss followed by difficulty in swallowing, and bilateral pulmonary infiltrates with interstitial reactions were radiologically pointed out. Antibiotics administration was ineffective, and he died on the 6th day of hospitalization. At autopsy, HSV-induced multiple mucosal erosions were observed on the tongue, pharynx, epiglottis, and trachea. In bilateral lower lobes of the lung, HSV infected bronchiolar and type-II alveolar cells in association with acute interstitial reactions. The infected cells with intranuclear inclusion bodies were immunoreactive with HSV antiserum. HSV-1 infection was confirmed by immunostaining with monospecific monoclonal antibodies and by type-specific real-time polymerase chain reaction. It is very likely that HSV pneumonia was provoked by aspiration of infected exudates from the upper airway (namely, sequential infection from the tongue, epiglottis, and trachea to lung). Oropharyngeal herpes might cause anorexia and difficulty in swallowing, probably accelerating aspiration. The medical staff did not recognize the oropharyngeal lesions of this aged patient. We must realize again the importance of oral care for hospitalized patients to avoid aspiration pneumonia, including herpetic pneumonia.