N-Methyl Protoporphyrin IX: An Understudied Porphyrin.

N-Methyl protoporphyrin IX (NmePPIX) is a derivative of protoporphyrin IX (PPIX) and the lattice of heme. Certain xenobiotics strongly induce NmePPIX production in the liver. The existence of endogenous NmePPIX in untreated animal liver has also been reported. The detailed mechanisms of NmePPIX biosynthesis remain unclear, but cytochrome P450 enzymes are thought to be critical in xenobiotic-induced NmePPIX production. High levels of NmePPIX cause PPIX accumulation because NmePPIX is a potent inhibitor (Ki = 7 nM) of ferrochelatase, the last enzyme in the heme biosynthesis pathway that converts PPIX to heme. NmePPIX is also involved in several other physiological processes, including inhibition of nitric oxide production and promotion of lamin aggregation. Compared to the two well-characterized porphyrins, PPIX and heme, NmePPIX is understudied regarding the mechanism of formation, fate, and physiological functions. This Review summarizes the current understanding of NmePPIX and provides perspectives on areas of future research on NmePPIX.

Increased macrophage density of cardiac allograft biopsies is associated with antibody-mediated rejection and alloantibodies to HLA antigens.

BACKGROUND: Antibody-mediated rejection (AMR) is characterized histologically by intracapillary macrophages. Macrophage density may be an alternative method of determining inflammatory changes in AMR. METHODS: We identified 118 heart transplant patients with serologic testing for HLA alloantibodies. Macrophage density was graded as 1+ (<45/mm(2)), 2+ (46-90/mm(2)), and 3+ (>90/mm(2)). Maximal macrophage density and complement staining over multiple biopsies were correlated with peak panel reactive antibodies (PRA), donor-specific antibodies (DSA), and the clinical diagnosis of AMR. RESULTS: The presence of PRA correlated with macrophage score (p = 0.001). Macrophage density correlated with any DSA (p < 0.0001), class I DSA (p < 0.0001), class II DSA (p < 0.0001), and class II DQ (p < 0.0001). Nine patients had clinical AMR. Among patients with AMR, 89% had a biopsy over the period of AMR with ≥3+ macrophage density (89% sensitivity); among patients without AMR, 93% of patients had no biopsy at any time with ≥3+ macrophage density (specificity). There was perfect concordance between the scores of C4d positivity and macrophage density in 61% and only partial concordance in 20%, with complete discordance in 19% in biopsies taken during clinical episodes of AMR. CONCLUSIONS: Macrophage density in allograft endomyocardial biopsies is frequently elevated during clinical episodes of AMR and correlates well with alloantibodies.

Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing.

PURPOSE: Pathologic examination of prostate glands removed from patients with prostate cancer commonly reveals infiltrating CD4+ and CD8+ T cells. Little is known about the phenotype of these cells, despite accumulating evidence suggesting a potential role for chronic inflammation in the etiology of prostate cancer. EXPERIMENTAL DESIGN: We developed a technique that samples the majority of the peripheral prostate through serial needle aspirates. CD4+ prostate-infiltrating lymphocytes (PIL) were isolated using magnetic beads and analyzed for subset skewing using both flow cytometry and quantitative reverse transcription-PCR. The transcriptional profile of fluorescence-activated cell sorted prostate-infiltrating regulatory T cells (CD4+, CD25+, GITR+) was compared with naïve, peripheral blood T cells using microarray analysis. RESULTS: CD4+ PIL showed a paucity of TH2 (interleukin-4-secreting) cells, a surprising finding given the generally accepted association of these cells with chronic, smoldering inflammation. Instead, CD4+ PIL seemed to be skewed towards a regulatory Treg phenotype (FoxP3+) as well as towards the TH17 phenotype (interleukin-17+). We also found that a preponderance of TH17-mediated inflammation was associated with a lower pathologic Gleason score. These protein level data were reflected at the message level, as analyzed by quantitative reverse transcription-PCR. Microarray analysis of pooled prostate-infiltrating T(reg) revealed expected Treg-associated transcripts (FoxP3, CTLA-4, GITR, LAG-3) as well as a number of unique cell surface markers that may serve as additional Treg markers. CONCLUSION: Taken together, these data suggest that TH17 and/or Treg CD4+ T cells (rather than TH2 T cells) may be involved in the development or progression of prostate cancer.

A comparative study of honeycombing on high resolution computed tomography with histologic lung remodeling in explants with usual interstitial pneumonia.

BACKGROUND: There is little information comparing high-resolution computed tomography (HRCT) findings in UIP with different components that make up remodeling histologically. DESIGN: We compared histologic features with HRCT scans from 69 explants with UIP. The extent of 7 histologic features were semi-quantitated: respiratory-lined cysts, bronchiolectasis, pulmonary interstitial emphysema (PIE), lobular remodeling, areas resembling non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP)-like pattern, and mucus pooling within cysts extending into surrounding parenchyma. Subpleural cystic spaces and areas of lobular remodeling were measured morphometrically. Histologic features were compared to three findings on HRCT: diagnostic pattern (UIP, probable UIP, or inconsistent with UIP pattern), degree of honeycombing, and degree of ground-glass opacities. RESULTS: Histologically, respiratory-lined cysts were observed in 78%, bronchiolectasis in 83%, interstitial emphysema in 22%, lobular remodeling in 96%, NSIP-like areas in 87%, DIP-like reaction in 10%, and mucin extravasation in 78%. Morphometrically, cysts of PIE measured 6.2±2.9 mm, respiratory-lined cysts 3.5±2.4 mm, and bronchiolectatic cysts 3.3±1.5 mm. Remodeled lobules measured 3.6±1.1 mm. UIP pattern on CT correlated strongly with histologic extent of bronchiolectasis (p=0.001). HRCT honeycombing showed a positive correlation with histologic bronchiolectasis (p=0.001) and respiratory-lined cysts (p=0.001). GGO was positively associated with NSIP-like areas (p=0.02) and extravasated mucus (p=0.05). CONCLUSIONS: HRCT findings typical of UIP and HRCT honeycombing correlate best with bronchiolectasis histologically. NSIP pattern is common, and is associated with CT finding of GGO.

Ascending aortitis: a clinicopathological study of 21 cases in a series of 300 aortic repairs.

There are few single-institution clinicopathological series of aortitis. In this study, all ascending aneurysms were prospectively evaluated pathologically with ≥6 aortic sections over a 6-year period.Of 300 ascending aortic resections, there were 21 cases of aortitis (7%), in 11 women and 10 men (mean 67, range 41-88 years). There were 19 patients with aneurysms, and two patients with sclerosing periaortitis, clinically suspected to have intramural haematoma. Of the 19 patients with aneurysms (11 women), two had prior temporal arteritis, one ankylosing spondylitis, one IgA nephropathy, one undifferentiated autoimmune disease, one Lyme disease, and one fibromyalgia. In only two patients was aortitis suspected before surgery as the cause of aneurysm. Four patients developed distal aortic aneurysm requiring repeat surgery. Valve replacement or repair was necessary in nine patients, and two patients died after surgery. There were no significant differences between patients with and without autoimmune disease. The histological features were necrotising aortitis in 18 of 19 patients with aneurysmal aortitis, and there was one case of non-necrotising aortitis. One valve showed autoimmune valvulitis, congenitally bicuspid associated with ankylosing spondylitis. Necrotising aortitis was classified as acute (n = 5), healing (n = 9), and healed (n = 4). Acute necrotising aortitis was associated with need for valve replacement (p = 0.01) and younger age (p = 0.01). The healed phase had subtle histological features, sparse medial inflammation, marked medial attenuation, and chronic adventitial inflammation. Two patients with periaortitis demonstrated marked fibroinflammatory thickening of the adventitia with histological features typical of IgG4-related disease; neither had systemic symptoms. Ascending aortitis is histologically diverse, most frequently of the medial necrotising type, and is usually not suspected pre-operatively. Awareness of the histological spectrum is necessary for pathological diagnosis.

Acute medial dissection of the ascending aorta: evolution of reactive histologic changes.

BACKGROUND: The histologic reaction in the adventitia to aortic dissections may be relevant to dating the onset of symptoms and to providing insight into pathogenesis. DESIGN: We prospectively studied 43 surgically excised acute ascending aortic dissections before false-lumen rupture, with emphasis on inflammatory reaction in the false-lumen wall in relation to duration of symptoms. RESULTS: A total of 31 men and 13 women were included in the study. Duration of symptoms was <12 hours (n=9), 12 to 24 hours (n=12), 1 to 2 days (n=8), 2 to 7 days (n=11), and >1 week (n=3). Medial inflammation was predominantly lymphohistiocytic and was marked in 3 cases but limited to the region adjacent to the dissection plane, unlike aortitis. Adventitial neutrophils occurred before 12 hours, peaked between 12 and 24 hours, and were rare after 2 days. Eosinophils occurred after 1 day, peaked between 2 and 7 days, and were predominant between 2 and 4 days. Macrophages were present after 1 day and peaked between 2 and 7 days. Mesothelial reaction occurred only after 1 day. Apoptosis and mitotic figures involving stromal cells occurred after 12 hours and peaked between 1 and 2 days; mitotic figures persisted up to 7 days. CONCLUSIONS: Adventitial inflammation is prominent soon after intimal injury in aortic dissections before rupture of the false lumen. The pattern of inflammation is distinct from aortitis and can be used to date early aortic dissections.

End-stage sarcoid lung disease is distinct from usual interstitial pneumonia.

Sarcoid lung disease may result in progressive lung failure, necessitating transplant. There is a debate on whether the scarring is similar to or distinct from that seen in other fibrotic lung disease such as usual interstitial pneumonia (UIP). We prospectively evaluated histologic sections from 9 lung explants with end-stage sarcoid lung disease diagnosed clinically and by chest computed tomographic scans. The study included 7 women and 2 men. Four lungs showed active granulomatous disease, with nonfibrotic nodular granulomas in the interstitium; the other 5 were predominantly fibrotic, of which 3 had areas of honeycombing (cysts lined by respiratory epithelium with surrounding scar). Chest computed tomographs of 8 cases were all read as either probable or definite sarcoid. Patients in the fibrotic phase were significantly older (P=0.016). All cases showed dense acellular collagen, which was more extensive in the fibrotic phase. Granulomas were present in a lymphatic distribution (along bronchi, the lobular septa, and the pleura) and were predominantly small clusters of macrophages or giant cells embedded in scar in the fibrotic phase. Granulomas were not identified in 2 lungs in the fibrotic phase. In contrast to the honeycombing of UIP, the honeycombing was predominantly central, with prominent bronchiectasis. These end-stage sarcoid lungs were characterized by a fibrotic and active granulomatous pattern, both of which are very distinct from that seen in UIP.

Histologic features associated with metastatic potential in invasive adenocarcinomas of the lung.

INTRODUCTION: The International Association for the Study of Lung Cancer (IASLC) recently reclassified adenocarcinomas of the lung on the basis of histologic patterns. However, there is lack of consensus about a grading system for these tumors. We studied a series of invasive lung adenocarcinomas and correlated histologic features with lymph node and distant metastases. A series of invasive lung carcinomas resected over a 5-year period were retrospectively reviewed and classified by the IASLC system. The proportion of each histologic subtype was estimated at 5% increments, and cytologic features were blindly recorded and subsequently correlated with lymph node and distant metastases. The 125 tumors were classified on the basis of the predominant pattern as lepidic predominant (LPA) (n=9), acinar (n=71), solid (n=23), papillary (n=11), and mucinous (n=11). The acinar pattern was heterogeneous, in that a cribriform subgroup (n=34) was significantly more likely to demonstrate lymph node metastases compared with a tubular subgroup (n=37) and had a higher mitotic rate, rate of necrosis, vascular invasion, and prominent nucleoli. Mucinous tumors were LPA (n=3), tubular (n=4), and cribriform predominant (n=4). The rate of lymph node metastasis was greatest in the solid type (P=0.02). The rate of distant metastasis was greatest in the mucinous and solid groups (P<0.02). Mitotic activity (≥ 1/HPF), desmoplasia >20% of the tumor, prominent nucleoli, and vascular invasion, along with a solid growth pattern ≥ 20%, were independently associated with metastatic potential and considered poor prognostic histologic features. A 3-tiered grading system separated tumors into well differentiated (predominantly LPA, papillary, and tubular patterns), moderately differentiated (predominantly cribriform tumors), and poorly differentiated (≥ 20% solid growth pattern). Tumors in the well-differentiated group were elevated to moderately differentiated if there were poor prognostic histologic features. Using this system, there was a stepwise increase in the rate of lymph node metastasis (P<0.0001) and distant metastasis (P=0.0004) from well-differentiated, moderately differentiated, to poorly differentiated tumors, the rate being 40, 46, and 39, respectively. Application of the IASLC classification in this series resulted in a predominance of acinar adenocarcinomas. To stratify tumors into clinically relevant grades, grading by pattern (tubular, cribriform, solid), mitotic activity, and nuclear features is useful.

Isolated pulmonary amyloidomas: report of 3 cases with histologic and imaging findings.

Amyloid tumors presenting as lung masses are rare. We report 3 patients seen over a 2-year period with multiple lung masses, 2 that were suspicious for metastasis, and one in a patient with chest pain. Pathologic evaluation demonstrated amyloid tumor in each case. Two demonstrated a prominent macrophage giant cell reaction; scattered polyclonal plasma cells were present in two of the cases. PET scanning of 2 of the patients revealed an SUV of 1.9 and 4.0, respectively. Short-term follow-up revealed that none of the 3 cases were associated with lymphoproliferative disorders. This small series and a literature review suggest that pulmonary amyloidomas are usually isolated lesions, and that PET may show increased uptake simulating a neoplasm.

Histologic findings in lung biopsies in patients with suspected graft-versus-host disease.

The histopathologic features of pulmonary graft-versus-host disease (GVHD) status post-bone marrow transplant are not well described. Lung biopsies from patients with clinically suspected GVHD were studied. There were 17 biopsies from 9 men and 5 women. Alveolar changes were classified as acute lung injury with intra-alveolar fibrin, organizing pneumonia (OP), and chronic interstitial pneumonia (CIP). Intraepithelial bronchiolar T cells were increased in 16 of 17 biopsies within bronchiolar mucosa (56 ± 30 per 100 epithelial cells). Atypical pneumocytes were present in 10 biopsies, and atypia was marked in 2 biopsies. Reactive bronchiolar cells were also seen in all 3 groups and showed mild atypia in 5 and marked atypia in 1, mimicking viral cytopathic effect. Apoptosis of bronchiolar epithelium and interstitium was seen in all but 1 case and was most marked in the acute injury and OP patterns. Perivenular cuffing was present in 11 of 17 biopsies. All 3 patients with acute injury died of acute respiratory distress syndrome; 1 patient with OP died of systemic GVHD; and 1 patient with CIP pattern died of opportunistic infection. Obstructive lung disease with obliterative bronchiolitis developed in 3 patients, all of whom stabilized with treatment and were alive at last follow-up (mean, 25 months). All 3 histologic patterns of pulmonary GVHD are characterized by intrabronchiolar T cells, apoptosis, and perivenulitis, which help to distinguish GVHD from infections. The acute lung injury pattern has a poor prognosis, and bronchiolitis obliterans syndrome develops in a subset of patients with CIP histologic pattern.

Pulmonary oligometastases: histological features and difficulties in determining site of origin.

INTRODUCTION: Pulmonary oligometastases are resected both for diagnostic and therapeutic reasons. The histological features may be nonspecific, resulting in diagnostic difficulties. DESIGN: The authors retrospectively studied the clinical and pathological features of 73 open resections of lung metastases from 64 patients to determine the frequency and types of problems in establishing site of origin. RESULTS: There were 18 primary organ sites, the most frequent being colon (n = 10), head and neck (9 squamous and 6 salivary gland), kidney (n = 7), and soft tissue (n = 7). Unusual histological features included detached alveolar tumor clusters at the periphery (83% of adenocarcinomas), lepidic spread (2 metastatic pancreatic tumors), and entrapped pneumocyte-lined cysts (6 tumors). A majority of squamous carcinomas from the head and neck presented difficulties in regard to excluding a second primary, especially 4 with basaloid features that mimicked primary basaloid lung carcinoma. Other tumors mimicking lung primaries included pancreatic, endometrial, and breast metastases. Germ-cell tumors, sarcomas, melanomas, and sarcomatoid carcinomas presented diagnostic difficulties. Overall, comparison with the primary tumor with or without immunohistochemical studies was performed in 38 of 73 cases (52%). CONCLUSIONS: Pulmonary oligometastases comprise a wide range of histological types and often require careful pathological evaluation to determine primary site of origin.

Ectopic hepatic tissue presenting as right atrial mass.

A 52-year-old woman had a well-circumscribed, mobile mass (1.8 × 1.7 cm) in the right atrium detected by echocardiography and confirmed by magnetic resonance imaging. Subsequent histologic evaluation of the mass revealed benign, ectopic hepatic tissue. Ectopic liver is a rare occurrence, and most frequent anatomical distribution of ectopic hepatic tissue is the region around the gallbladder. In exceptional cases, ectopic liver can be found within the thorax. The reported case demonstrates that ectopic liver should be included in the differential diagnosis of right atrial masses removed surgically.

'Bronchioloalveolar carcinoma': is the term really dead? A critical review of a new classification system for pulmonary adenocarcinomas.

'Bronchioloalveolar carcinoma' (BAC) is a designation that has been in use for over 50 years. Recently, the International Association for the Study of Lung Cancer, in association with the American Thoracic Society and the European Respiratory Society (IASLC/ATS/ERS) has recommended dropping the term altogether. It is argued that 'BAC' has no clear conceptual meaning, has been used in conjunction with invasive tumours of various types, and was applied to mucinous and non-mucinous tumours that are pathogenetically distinct. In addition to replacing 'BAC' with the standard pathological 'adenocarcinoma in situ', the IASLC/ATS/ERS panel also attempted to tackle the more substantial problem of standardising the terminology of lung adenocarcinomas that are not clearly invasive. By identifying 'minimally invasive adenocarcinomas' with <5 mm invasion, the IASLC/ATS/ERS has attempted to classify invasive tumours with little metastatic potential. Problems remaining with the new classification include use of the term 'lepidic predominant adenocarcinoma' (LPA), which replaces BAC with invasive components, and lack of clarity regarding what constitutes true invasion in well-differentiated lung adenocarcinomas. Specifically, the distinction between acinar growth pattern and in situ growth is not standardised. The basis for the new classification, as well as the plethora of previous attempts at classifying lung adenocarcinomas that are neither clearly invasive nor clearly in situ, are reviewed. Time will determine if the use of a 5 mm limit is workable or if the term 'LPA' has traction.

Adenocarcinomas with prominent lepidic spread: retrospective review applying new classification of the American Thoracic Society.

BACKGROUND: Recently, a new classification of lung adenocarcinomas has been proposed for tumors with lepidic spread. The greatest diameter of the invasive component determines minimally invasive cancers, and the term bronchioloalveolar carcinoma is no longer used. METHODS: We retrospectively reviewed 87 resected adenocarcinomas of the lung; 30 tumors with lepidic growth and without high-grade invasive areas were identified, and the invasive component was measured morphometrically and categorized. A dimension of 5 mm was the cutoff for invasion. Regional lymph node involvement and short-term follow-up were compared among subtypes of these well-differentiated and moderately differentiated adenocarcinomas. RESULTS: There were 11 well-differentiated adenocarcinomas with lepidic growth: 3 adenocarcinomas in situ (nonmucinous) and 8 minimally invasive adenocarcinomas (MIAs) (4 mucinous and 4 nonmucinous). There were 19 invasive moderately differentiated adenocarcinomas with a prominent lepidic growth pattern (LPAs). The mean size of the 3 adenocarcinomas in situ cases was 0.9±0.7 mm; the total size of the 8 MIA cases was 1.4±1.8 cm and that of the 19 LPA cases was 3.2±2.1 cm. The invasive size of the MIA was 0.3±0.6 and that of the LPA was 2.2±0.3. The invasive pattern of the LPAs was papillary and acinar without desmoplasia (n=3) and acinar with desmoplasia (n=16). Seven of the invasive desmoplastic tumors showed complex single-cell invasion or lymphatic invasion. Identification of the transition from lepidic to invasive acinar was straightforward because of the presence of elastotic desmoplasia. The transition between complex acinar papillary invasion and lepidic growth was often difficult to discern. Lymph node metastases were present in 5 cases (26%), all in tumors with an acinar, desmoplastic invasive component of >1 cm, with areas of single-cell invasion. With follow-up, progressive nodal involvement or distant metastases occurred in 4 patients, all with complex invasive patterns; 3 with invasion >1 cm and 1 with lymphatic invasion in smaller invasive tumors. Recurrent lung nodules occurred in 5 patients, including 1 patient with MIA, 1 with nondesmoplastic invasion, 2 with desmoplastic invasion, and 1 with complex desmoplastic invasion. CONCLUSIONS: Approximately one third of lung adenocarcinomas have significant lepidic spread, and of these nearly one third are minimally invasive. Measurement of the invasive component may be difficult without elastotic desmoplasia. In this small series, lymph node and distant metastases occurred only in those with complex invasive patterns, but lung recurrence occurred in all subtypes, including MIAs.

Adenomatoid tumor of the testis with intratesticular growth: a case report and review of the literature.

Adenomatoid tumor of the male genitourinary tract is a rare benign neoplasm thought to be of mesothelial origin. In exceptional cases, these lesions may involve the testicular parenchyma, of which there are only 9 published cases in the literature. The authors describe a rare case of a testicular tumor in a 41-year-old male with normal tumor markers. Histopathology and immunohistochemical studies revealed an adenomatoid tumor with intratesticular growth. No involvement of the epididymis or testicular membranes was identified. The morphological clues leading to the correct diagnosis of adenomatoid tumor and the possible histogenesis and differential diagnosis are discussed.