Thirty-year overview of Japanese autopsy cases of Takayasu arteritis -Results of analysis of Japanese autopsy reports.

OBJECTIVE: To analyze the trends in Takayasu arteritis (TAK) in Japan during three recent decades based on autopsy reports. METHODS: We extracted TAK cases from the Japanese Pathological Autopsy Reports published during three decades (1991-2000, 2001-2010, 2011-2020) and compared the data for the number of cases, age, gender ratio, malignant tumor complication rate, and cause of death (COD). RESULTS: 322 TAK cases were reported during the 30 years. They represented 0.04-0.06% of the total autopsies, with little variation among the three decades. The peak age at autopsy increased over time: from the 60s for 1991-2010 to the 70s for 2011-2020. The malignant tumor complication rate increased to 12.2%, 18.5%, and 22.7% during the three decades. However, about half of those cases had no metastases, and malignant tumors were rarely directly involved in a TAK patient's death. TAK-associated cardiovascular lesions (ischemic heart disease, aortic lesions) accounted for most deaths. CONCLUSIONS: Although the age at TAK onset showed little change during the 30 years, the age at autopsy has increased, suggesting that the long-term prognosis has improved. Although the malignant tumor complication rate increased with age, the most common CODs were cardiovascular lesions, which are prognostic factors for TAK.

Expert perspectives on pathological findings in vasculitis.

Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large-vessel vasculitis, (2) medium-vessel vasculitis, (3) small-vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small-vessel vasculitis, (4) variable-vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable aetiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer to typical pathological findings of vasculitis in daily practice.

Myasthenia Gravis Complicated by Eosinophilic Granulomatosis with Polyangiitis: A Case Report.

A 55-year-old woman with a history of allergic sinusitis was being administered cyclosporine for ptosis and diplopia due to myasthenia gravis since age 46 years. She developed painful dysesthesia that began in her feet and later spread to her palms, leading to difficulty in walking. Eosinophils were markedly increased in the peripheral blood. Nerve conduction studies revealed mononeuritis multiplex. Nerve biopsy showed the infiltration of eosinophils in the superior neurovasculature. Based on these findings, eosinophilic granulomatous polyangiitis was diagnosed. Methylprednisolone pulse therapy was followed by oral prednisolone. Two weeks after treatment, the patient could do normal daily activities without assistance. In patients with myasthenia gravis having a history of allergic diseases, considering EGPA as a complication and monitoring prior changes in blood data are necessary for early detection before apparent tissue damage.

Histological studies shed new light on the initiation and characteristics of calcification of coronary artery aneurysms in Kawasaki disease.

BACKGROUND: Calcification of coronary artery aneurysms (CAAs) is common in the remote phase of Kawasaki disease (KD), but the detailed features of its development remain unclear. This study aimed to elucidate the histological characteristics of calcification in KD CAAs. MATERIALS AND METHODS: The study materials consisted of 24 coronary artery branches with aneurysms that were obtained from 14 Japanese patients who died during the period from 40 days to 3 years after the onset of KD. We first examined the CAAs for the presence of thrombi and calcification. When calcifications were observed, we determined their location and shape, and investigated the time-course of the changes based on the time-interval from KD onset until death. Then we measured the area of each calcification and examined for correlations between the calcified area, and (1) the disease duration, and (2) the aneurysm diameter. RESULTS: Calcification was observed in 14 of 24 CAAs (in 7 of 13 LCA and 7 of 11 RCA). Thrombi were also seen in 13 of 14 CAAs with calcification. Calcification showed two localizations: in the organized portion of the thrombus (seen in 12 CAAs) and deep in the thickened tunica of the intima (3 CAAs). The earliest observation of calcification was in an infant who died on the 49th disease day: it was a small, band-shaped calcified lesion in granulation tissue that had formed at the boundary between the thrombus and the blood vessel wall. As the duration of KD increased, the calcified lesion increased in size, and nodular shapes were formed. Moreover, the calcified area tended to increase as the diameter of the aneurysm increased. CONCLUSION: Histologically, CAA calcification starts early in the remote phase of KD, and it is closely related to organization of thrombi.

Mammary Paget's Disease Presenting as an Annular Plaque.

Dear Editor,Mammary Paget's disease (MPD) is an adenocarcinoma localized within the epidermis of the nipple and/or the areola of the breast, and it is as a rule associated with a carcinoma of the underlying lactiferous ducts, where it usually starts. MPD is relatively rare, observed in 0.7-4.3% of all breast cancers (1). We present a patient with MPD and atypical clinical finding as an annular plaque. A 74-year-old Japanese woman with a past medical history of hypothyroidism presented with a 6-month history of an itching plaque on the left areola. The patient had been treated with the application of topical steroids for a duration of approximately 5 months, and showed no clinical improvement. Physical examination showed a pink plaque encircling the nipple on the left areola (Figure 1, a). The right nipple and areola appeared normal (Figure 1, b). No palpable masses were detected within either breast. A 3.5 mm punch biopsy of the skin at the 6 o'clock position of the left areola was performed. Histological examination showed single and small aggregations of atypical cells with large hyperchromatic nuclei and pale-staining, ample cytoplasm throughout the epidermis. There was a lymphocytic infiltration in the dermis (Figure 1, c). Immunohistochemical studies were positive for CK7 and negative for S-100 and HMB45. With the diagnosis of MPD, the patient underwent a partial mastectomy of the left breast center area, consisting of surgical excision of the left nipple, the adjacent surrounding areolar skin, and subcutaneous tissues. Subsequently, radiation therapy for the residual breast was prepared. As has been described in detail by Kanitakis, the skin lesion develops insidiously as a scaly, fissured, or oozing erythema of the nipple and, more rarely, the areola. Advanced lesions present as a well-demarcated, round, ovoid, or polycyclic eczema-like plaque with a pink or red hue. It is occasionally slightly infiltrated and has an erosive, oozing, scaly, or crusted surface. The lesions are almost invariably unilateral, showing centrifugal spread. Retraction or ulceration of the nipple are often noted (1). The present case exhibited a very rare clinical finding of a plaque encircling the nipple, which has not been reported previously. It was initially difficult to establish the diagnosis of MPD, and biopsy was needed to obtain a definitive diagnosis. Differential diagnosis of MPD comprises eczema as atopic dermatitis or contact dermatitis, erosive adenomatosis, and malignant skin condition such as Bowen's disease, superficial basal cell carcinoma, or superficially spreading melanoma. As in the present case, individuals presenting with an annular plaque are often considered to have sebaceous hyperplasia. Sebaceous hyperplasia is a common, benign skin condition involving hypertrophy of the sebaceous glands, common in middle-aged or older adults (2). These lesions can be single or multiple and manifest as yellow, soft, small papules. These papules are occasionally seen around the nipple, forming an annular plaque. In general, sebaceous hyperplasia is described as yellow-colored papules among Caucasians. However, caution is needed, since it is characterized by skin-colored papules among some Asians.In the present case, some pigmentation (2 to 3 mm in diameter) was observed on the left nipple. Pigmented MPD have been reported, and the mechanism underlying the pigmentation is not yet fully understood, but it has been proposed that Paget cells may release melanocytic chemoattractants or basic fibroblast growth factors that stimulate the proliferation of melanocytes within the tumor nests (3). The possibility of physiological pigmentation cannot be ruled out in the present case; on the other hand, the possibility of pigmented MPD cannot be ruled out either, since no pigmentation was observed on the right nipple.

The pathology of Kawasaki disease aortitis: a study of 37 cases.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis syndrome that occurs most frequently in children. Most clinical and pathological studies have focused on its coronary artery lesions. To date, no detailed studies of the aorta have been conducted. We studied KD autopsy cases with the aims of clarifying the time-course of changes in aortic lesions, the differences in the inflammatory cells and degree of inflammation at various aortic sites, and the progression of the inflammation. MATERIALS AND METHODS: The study materials were aortic specimens taken from 37 KD autopsy cases (acute phase: 19; remote phase: 18). Twenty-seven of the cases also had coronary aneurysms. We chose 3 aortic sites, i.e., the thoracic aorta, aortic root and aortic bifurcation, and we histologically observed and compared those sites in regard to the changes with time, the kinds of infiltrating cells and the number of inflammatory cells. We also observed the relationship between the vasa vasorum and inflammatory cell localization in the tunica media, and examined the progression of inflammation in the tunica media. RESULTS: Destruction of the vascular architecture was not seen in any of the 37 cases, but inflammatory cell infiltration was observed in 90% of the acute-phase cases. The inflammatory cell infiltration involved the tunica intima and tunica adventitia of the aorta on the 6th disease-day, and all layers of the aorta on the 13th disease-day; the infiltration peaked on the 18th disease-day. The infiltration gradually disappeared thereafter, and no significant infiltration was seen in the remote phase. The infiltrating inflammatory cells consisted mainly of CD163-positive macrophages. Comparison of the 3 sites of the aorta showed that the inflammatory cell infiltration was more severe in the aortic root and aortic bifurcation than in the thoracic aorta. The progression of inflammation to the aortic tunica media from the adventitia showed 2 patterns: 1 in which macrophages were aggregated around the vasa vasorum; and a second in which there was no such aggregation around the vasa vasorum, but there was diffuse inflammatory cell infiltration of the tunica media. In addition to this, there were findings of direct infiltration of cells from the tunica intima into the tunica media. CONCLUSION: Inflammation in KD occurs in the aorta. The changes with time and the kinds of infiltrating cells were the same as reported to date for coronary arteries in KD. There were differences in the degree of inflammation among the 3 aortic sites. It can be thought that the inflammation from the adventitia to the media progresses via the vas vasorum, and also, there is a possibility of spreading directly. From the intima to the media, inflammation spreads directly. However, formation of aneurysms and destruction of the vascular architecture of the aorta were absent in this study, unlike in coronary arteries.

Recognition of alpha-mannan by dectin 2 is essential for onset of Kawasaki disease-like murine vasculitis induced by Candida albicans cell-wall polysaccharide.

Objectives: Using a murine model of systemic Kawasaki disease (KD)-like vasculitis induced by Candida albicans cell-wall-derived mannan · ß-glucan · protein complexes, the objective was to elucidate the relationships of ß-glucan receptor dectin-1 (D1) and α-mannan receptor dectin-2 (D2) to the onset of that vasculitis.Methods: The incidence and histological severity of vasculitis were compared among mice lacking the genes for D1 or D2 (i.e. D1-/- and D2-/-) and wild-type (WT) mice.Results: The incidences of vasculitis in the three animal groups were 100% (18/18) in the WT group, 100% (18/18) in the D1-/- group, and 0% (0/18) in the D2-/- group. In the WT and D1-/- mice, severe inflammatory cell infiltration, consisting mainly of neutrophils and macrophages, was seen in the aortic root and the coronary arteries. On the other hand, in the D2-/- mice, not even mild vascular lesions such as endoarteritis were seen.Conclusion: Recognition of α-mannan by D2 played an important role in the onset of vasculitis in the studied murine model.

Expression of tenascin C in cardiovascular lesions of Kawasaki disease.

BACKGROUND/OBJECTIVE: To examine tenascin C (TN-C) expression in coronary artery lesions (CALs) and myocardial lesions (MLs) in Kawasaki disease (KD). METHODS AND RESULTS: Twenty-five KD autopsy cases (post-KD-onset range of 6 days to 17 years) were examined in this study. Time-course analysis based on the disease day was performed of the histological findings for the CALs and MLs, as well as the localization and intensity of expression of TN-C. TN-C expression was observed to coincide with the areas where inflammatory cell infiltration was present in both coronary arteries and myocardium during the acute stage of KD, and the intensity of its expression correlated with the degree of inflammation. Obvious TN-C expression persisted in the thickened intima and media of CALs even after Disease Day 27. However, in spite of the presence of inflammatory cell infiltration, TN-C expression became weaker in the adventitia and surrounding connective tissue. After 8 months or more, TN-C was not expressed in the vasculitis scars of most cases, but expression was observed around newly formed vessels in the thickened intima and around recanalized vessels after thrombotic occlusion. CONCLUSIONS: The findings suggest a correlation between the degree of inflammation and TN-C expression in the cardiovascular lesions of acute-stage Kawasaki disease.

Histopathological aspects of cardiovascular lesions in Kawasaki disease.

Kawasaki disease (KD) is the commonest vasculitic syndrome. It affects medium-sized arteries, principally the coronary arteries. Histologically, coronary arteritis begins at 6 to 8 days after the onset of KD and the inflammation rapidly involves all layers of the artery. This results in severe damage to the structural components of the artery leading to arterial dilation. The inflammatory infiltrate in KD arteritis is characterized predominantly by infiltration of monocytes and macrophages. Activated neutrophils, monocytes and macrophages are believed to be involved in the initial stage of coronary arteritis. Inflammatory cell infiltration may continue for up to 25 days of disease following which the inflammatory cells gradually decline in number. Inflammatory lesions in the arteries are relatively synchronous as they evolve from an acute to the chronic stage. If a giant aneurysm remains or vessel recanalization occurs after thrombotic occlusion of an aneurysm, the remodeling of vascular structures may continue for a much longer time.

Spontaneously Ruptured Paraovarian Tumor of Borderline Malignancy with Extremely Elevated Serum Carbohydrate Antigen 125 (CA125) Levels: A Comparison of the Imaging and Pathological Features.

BACKGROUND Paraovarian cysts are common and are generally benign; however, they are frequently misdiagnosed as being of ovarian origin. Conversely, paraovarian tumors of borderline malignancy are extremely rare. Especially, no cases of spontaneous rupture have been reported, and all previous reports had normal serum carbohydrate antigen (CA) 125 level. As for imaging findings, the presence of papillary projections in the lumen of paraovarian tumors does not always indicate malignancy or benignancy, which makes the preoperative distinction difficult. CASE REPORT We report a case involving a 22-year-old Asian woman with a spontaneously ruptured paraovarian tumor of borderline malignancy. The serum CA125 concentration was extremely elevated, at 28,831 U/mL. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a collapsed unilocular cystic lesion with multiple papillary projections. On MRI, the papillary projections showed two different patterns, which corresponded to the pathological findings. CONCLUSIONS Ruptured paraovarian tumors of borderline malignancy may show extremely high serum CA125 values. Furthermore, specific MRI findings may be useful in evaluating the malignancy of paraovarian tumors.

Internal Jugular and Subclavian Vein Thrombosis in a Case of Ovarian Cancer.

Central venous catheter insertion and cancer represent some of the important predisposing factors for deep venous thrombosis (DVT). DVT usually develops in the lower extremities, and venous thrombosis of the upper extremities is uncommon. Early diagnosis and treatment of deep venous thrombosis are of importance, because it is a precursor of complications such as pulmonary embolism and postthrombotic syndrome. A 47-year-old woman visited our department with painful swelling on the left side of her neck. Initial examination revealed swelling of the region extending from the left neck to the shoulder without any redness of the overlying skin. Laboratory tests showed a white blood cell count of 5,800/mm3 and an elevated serum C-reactive protein of 4.51 mg/dL. Computed tomography (CT) of the neck revealed a vascular filling defect in the left internal jugular vein to left subclavian vein region, with the venous lumina completely occluded with dense soft tissue. On the basis of the findings, we made the diagnosis of thrombosis of the left internal jugular and left subclavian veins. The patient was begun on treatment with oral rivaroxaban, but the left shoulder pain worsened. She was then admitted to the hospital and treated by balloon thrombectomy and thrombolytic therapy, which led to improvement of the left subclavian venous occlusion. Histopathologic examination of the removed thrombus revealed adenocarcinoma cells, indicating hematogenous dissemination of malignant cells.

Giant Hidroacanthoma Simplex Mimicking Bowen's Disease.

Hidroacanthoma simplex is a benign tumor of the skin, macroscopically resembling seborrheic keratosis or Bowen's disease and histologically mimicking clonal-type seborrheic keratosis. We observed a plaque of 70 × 50 mm on the right flank part. From clinical appearance, we suspected Bowen's disease; however, based on immunohistochemical findings, we made a diagnosis of hidroacanthoma simplex.

[Association between Proposed Cancer Foci from the Results of Systematic 12-Core Transrectal Needle Biopsies and Actual Cancer Foci from Radical Prostatectomy Specimens].

We investigated the diagnostic yield for systematic 12-core transrectal prostate needle biopsies. Subjects were 56 prostatic cancer patients who were diagnosed with transrectal ultrasound-guided 12 core prostate needle biopsies and who underwent open retropubic radical prostatectomy. Pathological findings were compared between needle biopsy specimens and total prostatectomy specimens in terms of the presence or absence of cancer foci. For the comparison, the prostate was divided into 5 regions : the apical, middle, basal, far lateral and transitional regions. Then, based on the pathological findings of the biopsies, the sensitivity, specificity, positive predictive value and negative predictive value were calculated for each region. As a result, the sensitivity and the specificity in the transitional region tended to be lower than in other regions, and six of ten false positive lesions were located in the transitional region on the biopsy specimens. Also, the negative predictive value tended to be lower in the apical and far lateral regions. In conclusion, thorough punctures in the apical, transitional, and far lateral regions of the prostate at the systematic transrectal biopsy were paramount important for improving the detection of cancer foci in these regions.

Role of TGF-ß Signaling in Remodeling of Noncoronary Artery Aneurysms in Kawasaki Disease.

Coronary artery aneurysms (CAA) remain an important complication of Kawasaki disease (KD), the most common form of pediatric acquired heart disease in developed countries. Potentially life-threatening CAA develop in 25% of untreated children and 5% of children treated with high-dose intravenous immunoglobulin during the acute phase of the self-limited vasculitis. Noncoronary artery aneurysms (NCAA) in extraparenchymal, muscular arteries occur in a minority of patients with KD who also have CAA, yet little is understood about their formation and remodeling. We postulated that activation of the transforming growth factor-ß (TGF-ß) pathway in KD may influence formation and remodeling of aneurysms in iliac, femoral, and axillary arteries, the most common sites for NCAA. We studied a resected axillary artery from one adult and endarterectomy tissue from the femoral artery from a second adult, both with a history of CAA and NCAA following KD in infancy. Histology of the axillary artery aneurysm revealed destruction of the internal elastic lamina and recanalization of organized thrombus, while the endarterectomy specimen showed dense calcification and luminal myofibroblastic proliferation. Immunohistochemistry for molecules in the TGF-ß signaling pathway revealed increased expression of TGF-ß2, TGF-ß receptor 2, and phosphorylated SMAD3. These findings suggest ongoing tissue remodeling of the aneurysms decades after the acute injury and demonstrate the importance of the TGF-ß signaling pathway in this process.

Multiple primary syphilis on the lip, nipple-areola and penis: An immunohistochemical examination of Treponema pallidum localization using an anti-T. pallidum antibody.

Primary syphilis caused by Treponema pallidum usually develops after sexual contact as an initial solitary sclerosis or hard chancre in the genital region. We describe a case of primary syphilis at three sites in genital and extragenital regions of a man who had sex with men. A 29-year-old man visited our hospital for skin lesions on his lower lip, nipple-areola and penis. A positive syphilis serological test for rapid plasma reagin had a titer of 1:16; the patient also tested positive for specific antibodies against T. pallidum, with a cut-off index of 39.0. Histopathological examination of a nipple-areola biopsy specimen revealed a thickened epidermis and dense infiltration of inflammatory cells extending from the upper dermal layers to the deep dermis. The inflammatory cells were composed of abundant lymphocytes, plasma cells, histiocytes and neutrophils. Immunohistochemical staining for T. pallidum using an anti-T. pallidum antibody showed numerous spirochetes in the lower portion of the epidermis, scattered inside inflammatory cell infiltrate and perivascular sites throughout the dermis. Based on these findings, the patient was diagnosed with primary syphilis. Treatment with oral amoxicillin hydrate was started. Five days after starting treatment, a diffuse maculopapular rash (syphilitic roseola) occurred on his trunk and extremities. Perivascular cuffing due to T. pallidum was present throughout the dermis in the biopsy specimen of a localized lesion of primary syphilis. Moreover, syphilitic roseola, which indicates generalized dissemination of T. pallidum, developed during the course of treatment for primary syphilis. Therefore, we considered perivascular cuffing to be indicative of the dissemination phase.

The role of TNF-α in a murine model of Kawasaki disease arteritis induced with a Candida albicans cell wall polysaccharide.

OBJECTIVES: Various inflammatory cytokines, including tumor necrosis factor-α (TNF-α), have been reported to play roles in Kawasaki disease (KD). Recently, anti-TNF-α therapy was reported to show efficacy in patients who do not respond to high-dose intravenous immunoglobulin therapy. However, there are many gaps in our understanding of the role that TNF-α plays in the development of KD arteritis as well as whether anti-TNF-α therapy causes any histological changes in the arteritis. Accordingly, the present histopathological study was carried out to elucidate the inhibitory effect of anti-TNF-α therapy on vasculitis as well as the role of TNF-α in the development of vasculitis in a murine model of KD vasculitis. METHODS: We used two anti-TNF-α drugs (etanercept and infliximab) to treat a Candida albicans-induced murine model of KD vasculitis. We investigated the histopathological changes in terms of the incidence of vasculitis, the scope of lesions and the degree of inflammation. RESULTS: Administration of etanercept to the mice reduced not only the incidence of vasculitis but also the scope of lesions and the degree of inflammation. CONCLUSION: Based on the histological findings, TNF-α is deeply involved in the development of vasculitis.

[A case of mixed epithelial and stromal tumor (MEST) of the kidney monitored as angiomyolipoma (AML) : a case report].

A 32-year-old woman presented with left abdominal pain. Intratumoral hemorrhage within a renal angiomyolipoma (AML) was suspected and embolization was performed. However, the patient declined surgery and was thus kept under observation. During the next 5 years, the tumor increased in size, and upper left abdominal pain appeared. Therefore, left radical nephrectomy was performed. The histopathological diagnosis was mixed epithelial and stromal tumor (MEST) of the kidney. A retrospective examination of imaging findings indicated that the fat which had been regarded as evidence of AML was actually either perinephric fat displaced by either the tumor or the renal sinus. In fact, the tumor consisted mainly of a cystic component containing a solid component. The possibility of MEST must be kept in mind when distinguishing renal tumors consisting mainly of cystic components in young to middle-aged women.

The role of TGF-ß and myofibroblasts in the arteritis of Kawasaki disease.

Inflammation of medium-sized, muscular arteries and coronary artery aneurysms are hallmarks of Kawasaki disease (KD), an acute, self-limited vasculitis of children. We previously reported that genetic variation in transforming growth factor (TGF)-ß pathway genes influences both susceptibility to KD and coronary artery aneurysm (CAA) formation. TGF-ß signaling has been implicated in the generation of myofibroblasts that influence collagen lattice contraction, antigen presentation, and recruitment of inflammatory cells as well as the generation of regulatory T-cells (Tregs). These processes could be involved in aneurysm formation and recovery in KD. Coronary artery tissues from 8 KD patient autopsies were stained to detect proteins in the TGF-ß pathway, to characterize myofibroblasts, and to detect Tregs. Expression of proteins in the TGF-ß pathway was noted in infiltrating mononuclear cells and spindle-shaped cells in the thickened intima and adventitia. Coronary arteries from an infant who died on Illness Day 12 showed α-smooth muscle actin (SMA)-positive, smoothelin-negative myofibroblasts in the thickened intima that co-expressed IL-17 and IL-6. CD8+ T-cells expressing HLA-DR+ (marker of activation and proliferation) were detected in the aneurysmal arterial wall. Forkhead box P3 (FOXP3), whose expression is essential for Tregs, was also detected in the nucleus of infiltrating mononuclear cells, suggesting a role for Tregs in recovery from KD arteritis.TGF-ß may contribute to aneurysm formation by promoting the generation of myofibroblasts that mediate damage to the arterial wall through recruitment of pro-inflammatory cells. This multi-functional growth factor may also be involved in the induction of Tregs in KD.