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Mycobacterium chimaera was identified as a species within the Mycobacterium avium complex in 2004. Until recently, it was predominantly seen in immunocompromised patients. In 2015, an outbreak of disseminated M. chimaera disease was described in European patients after undergoing open-heart surgery in which contaminated heater-cooler water units were used. Using whole genomic sequencing and phylogenetic analysis, investigators found a highly clonal outbreak from the German manufacturing site of the heater-cooler water units. This outbreak has now proven to be world-wide. Patients present with fever, fatigue, and weight loss months to many years after surgery. They are found to have systemic manifestations, including endocarditis, pancytopenia, renal dysfunction, chorioretinitis, and hepatitis. Preliminary reports suggest a high mortality rate despite aggressive treatment. In some patients, the predominant laboratory abnormalities are elevations in liver function tests, leading to diagnostic hepatobiliary work-ups, including liver biopsy. The pathologic changes in the liver have not yet been described. Herein, we report the clinicopathologic findings of the largest series of M. chimaera liver disease in the United States to date: 7 cases within a large, multihospital health care network. Five (71%) patients died of disease, despite aggressive treatment. Liver function test abnormalities were predominantly biliary: mean values of alkaline phosphate 288 U/L, aspartate aminotransferase 79 U/L, alanine aminotransferase 64 U/L. All 7 biopsies showed a consistent and characteristic dual pattern of injury: small, ill-formed collections of sinusoidal histiocytes with rare multinucleated giant cells, and scattered architectural changes of venous outflow obstruction. Two (29%) cases showed mild pericellular fibrosis. Nodular regenerative hyperplasia was seen in 2 (29%) cases, consistent with a sinusoidal/venous obstructive pattern of injury. We postulate that the sinusoidal location of the granulomas contributes to the venous obstructive changes. Recognition of this characteristic dual pattern of injury can allow pathologists to suggest the diagnosis and prompt the appropriate diagnostic and therapeutic interventions.

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BACKGROUND: Despite colorectal cancer (CRC) screening and survival rates exceeding national averages in the United States, Kaiser Permanente Southern California (KPSC) aimed to identify system-level improvement opportunities to further reduce mortality from CRC. METHODS: To examine modifiable factors contributing to CRC mortality, a structured hybrid electronic/manual mor- tality review was used to examine 50 randomly selected cases among 524 individuals aged 25-75 years diagnosed with stage II, III, or IV CRC after July 2008 who subsequently died. Physicians conducted chart reviews using a standardized data extraction tool based on evidence-based best practices. RESULTS: Eighty-six percent (43) of the 50 decedents were initially diagnosed with stage III or IV CRC; two cases of appendiceal cancer were excluded. Thirty-one percent (15) of the remaining 48 cases presented with no history of screening; 15% (7) had documented iron deficiency anemia and abdominal pain or rectal bleeding; and 6% (3) had no follow-up colonoscopy after positive screening. Eleven (52%) of the 21 patients with initial stage II-III CRC received appropriate surveillance after curative surgery; 57% (12) developed metastases. Adjuvant chemotherapy was offered to 88% (14/16) of patients with stage III (node-positive) CRC; chemotherapy initiation was delayed in 6 patients. Missed opportunities for surgical oncology evaluation occurred among 61% (11/18) of patients with liver metastases at diagnosis. Failure to report clinically significant features on pathology occurred in 2 patients; they received appropriate treatment for other reasons. CONCLUSIONS: Improvement opportunities existed at multiple stages of care, including screening, evaluation of symp toms, timeliness of care, use of adjuvant chemotherapy, and surgical oncology practices.

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Prior studies have shown that young patient age at diagnosis is associated with an increased risk of local recurrence among women with ductal carcinoma in situ (DCIS) treated with breast-conserving therapy. Whether this can be explained by differences in clinical or pathologic features of DCIS according to age is an unresolved issue. We compared clinical and pathologic features of DCIS among 657 women in 4 age groups: <45 years (n=111), 45 to 54 years (n=191), 55 to 64 years (n=160), and 65+ years (n=195). DCIS presented as a mammographic abnormality less often in younger than in older women (68%, 82%, 81%, and 86% for women <45, 45 to 54, 55 to 64, and 65+ y, respectively; P=0.003). Among the pathologic features analyzed, DCIS extent as determined by the number of low power fields was greater in younger than in older women (mean number of low power fields were 18.6, 14.2, 10.8, and 11.3 in women <45, 45 to 54, 55 to 64 and 65+ y; P<0.001). In addition, cancerization of lobules was present more often in younger than in older women (77%, 73%, 66%, and 50% for women <45, 45 to 54, 55 to 64 and 65+ y, respectively; P<0.0001). Of note, we found no statistically significant relationship between age and DCIS architectural pattern, nuclear grade, comedo necrosis or expression of estrogen receptor, progesterone receptor or human epidermal growth factor receptor 2. We conclude that DCIS in younger women is more often symptomatic, is more extensive, and more often shows cancerization of lobules than DCIS in older women. Whether these features contribute to the higher local recurrence risk in young women with DCIS treated with the breast-conserving therapy requires further study.

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Flat epithelial atypia is an alteration of mammary terminal duct lobular units that is considered to be a precursor to, or early stage in, the development of some forms of ductal carcinoma in situ. No prior study has systematically evaluated the relationship between various clinico-pathologic features of ductal carcinoma in situ and the presence of coexistent flat epithelial atypia. An understanding of such relationships could provide insight into the connection between flat epithelial atypia and ductal carcinoma in situ. We reviewed slides from 543 ductal carcinoma in situ patients enrolled in a case-control study assessing epidemiologic and pathologic risk factors for local recurrence. We examined the association between the presence of flat epithelial atypia and various clinical factors, pathologic features of the ductal carcinoma in situ, and the presence of coexistent atypical ductal hyperplasia, lobular neoplasia, and non-atypical columnar cell lesions. In univariate analysis, the presence of flat epithelial atypia was significantly related to ductal carcinoma in situ nuclear grade (most common in low grade, least common in high grade; P<0.0001), architectural pattern (most common in micropapillary and cribriform, least common in comedo; P<0.0001), absence of comedo necrosis (P<0.001), absence of stromal desmoplasia (P=0.02) and absence of stromal inflammation (P=0.03). In multivariable analysis, features of ductal carcinoma in situ independently associated with flat epithelial atypia were micropapillary and cribriform patterns and absence of comedo necrosis. Additionally, flat epithelial atypia was significantly associated with the presence of atypical ductal hyperplasia, lobular neoplasia, and columnar cell lesions in both univariate and multivariable analyses. These observations provide support for a precursor-product relationship between flat epithelial atypia and ductal carcinoma in situ lesions that exhibit particular features such as micropapillary and cribriform patterns and absence of comedo necrosis.

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We report a term male infant presenting on postnatal day 1 with fulminant hepatic failure. Described congenital infection, metabolic disorders, and cardiovascular etiologies of acute neonatal liver failure were assessed and eliminated. A liver biopsy on postnatal day 10 showed neonatal giant cell hepatitis (NGCH) with an unusual degree of fibrosis for this early postnatal age. NGCH is a clinical diagnosis of cholestatic disorders of unknown etiology in the newborn, and, to our knowledge, has not been previously associated with immediate neonatal hepatic failure. The giant cell transformation is a common response to a variety of insults and only rarely occurs beyond the neonatal period. Most cases present with cholestatic jaundice and varying degrees of coagulopathy, and, many, as in this case, show progressive resolution.

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