Brenda L. Waters

Maternal Vascular Underperfusion: Nosology and Reproducibility of Placental Reaction Patterns

Placental examination can be a useful tool for specifying the etiology, prognosis, and recurrence risk of pregnancy disorders. The purpose of this study was to test the reliability of a predetermined set of placental reaction patterns seen with maternal vascular underperfusion in the hope that this might provide a useful diagnostic framework for practicing pathologists. Study cases (14 with clinical and pathologic evidence of maternal underperfusion plus 6 controls) were evaluated for the presence or absence of 11 lesions by eight perinatal pathologists. After analysis of initial results, diagnostic criteria were refined and a second, overlapping set of cases was reviewed. The collective sensitivity, specificity, and efficiency of individual assessments for the 11 lesions relative to the group consensus ranged from 74–93% (22/33 > 90%). Reproducibility was measured by unweighted kappa-values and interpreted as follows: < 0.2 poor, 0.2–0.6 fair/moderate, > 0.6 substantial. Kappa values for lesions affecting villi and the intervillous space were increased syncytial knots (any −0.42, severe −0.50), villous agglutination (0.42), increased intervillous fibrin (0.25), and distal villous hypoplasia (0.57). Individual estimates of percent involvement for syncytial knots, intervillous fibrin, and distal villous hypoplasia were correlated with placental and fetal weight for gestational age. Extent of increased intervillous fibrin showed the strongest correlation with both placental weight (R = −0.64) and fetal weight (R = −0.45). Kappa values for lesions affecting maternal vessels and the implantation site were acute atherosis (0.50), mural hypertrophy of membrane arterioles (0.43), muscularized basal plate arteries (0.48), increased placental site giant cells (0.54), and immature intermediate trophoblast (0.36). Correlation of maternal vessel and implantation site lesions with the clinical diagnosis of preeclampsia showed that excessive placental site giant cells and immature intermediate trophoblast were more sensitive and efficient predictors, whereas atherosis and muscularized basal plate arteries were more specific. Kappa value for a thin umbilical cord, a possible indicator of fetal volume depletion, was 0.61. Reproducibility for a global impression of maternal vascular underperfusion, taking into account all of the above lesions, was moderate (kappa 0.54) and improved after inclusion of additional pathologic and clinical data (kappa 0.68). Adoption of this clearly defined, clinically relevant, and pathologically reproducible terminology could enhance clinicopathologic correlation and provide a more objective framework for future clinical research.

Genetic Characterization of Angiomatoid Fibrous Histiocytoma Identifies Fusion of the FUS and ATF-1 Genes Induced by a Chromosomal Translocation Involving Bands 12q13 and 16p11

This case report documents the first karyotypic, fluorescence in situ hybridization, and genetic analysis of an angiomatoid fibrous histiocytoma that arose and recurred in the arm of a 5.5-year-old girl. Complex rearrangements between chromosomes 2, 12, 16, and 17 were noted, as well as deletion in the long arm of chromosome 11. Flow cytometry revealed a normal cell population. The t(12;16) site was further investigated using reverse transcriptase-polymerase chain reaction. We found that the FUS (also known as TLS) gene from 16p11 combined with the ATF-1 gene from 12q13 to generate a chimeric FUS/ATF-1. The FUS gene is rearranged in the t(12;16)(q13;p11) that characterizes myxoid liposarcoma and in acute myeloid leukemia with t(16;21)(p11;q22), while the ATF-1 gene is rearranged in the t(12;22)(q13;q12) found recurrently in clear cell sarcomas (malignant melanoma of soft parts). Thus, the FUS/ATF-1 gene in angiomatoid fibrous histiocytoma is predicted to code for a protein that is very similar to the chimeric EWS/ATF-1 found in clear cell sarcoma.

Detection of occult sentinel lymph node micrometastases by immunohistochemistry in breast cancer. An NSABP protocol B-32 quality assurance study.

Occult metastases, by definition, are not detected on initial examination. They may be present on slides but missed during screening or may be present in paraffin embedded tissue blocks and undetected without additional levels. Anticytokeratin immunohistochemistry (CK IHC) enhances detection of occult metastases, particularly micrometastases (>0.2 mm but not larger than 2.0 mm) or isolated tumor cell clusters (≤0.2 mm). This study defines the rate at which pathologists miss metastases on CK IHC of sentinel lymph nodes (SLN).

Absent Pulmonary Valve with Tricuspid Atresia or Severe Tricuspid Stenosis: Report of Three Cases and Review of the Literature

Absence of the pulmonary valve occurs usually in association with tetralogy of Fallot and occasionally with an atrial septal defect or as an isolated lesion. Very rarely it occurs with tricuspid atresia, intact ventricular septum, and dysplasia of the right ventricular free wall and of the ventricular septum. We present the clinical, anatomic, and histologic findings of a new case, and for the first time, the data from two patients with absent pulmonary valve and severe tricuspid stenosis, who exhibited similar histologic findings. We also reviewed the clinical and anatomic data of 24 previously published cases and compared them with the new cases. In all three new cases, the myocardium of the right ventricle was very abnormal. In the two cases with tricuspid stenosis, large segments of myocardium were replaced with sinusoids and fibrous tissue. In the case with tricuspid atresia, the right ventricular free wall contained only fibroelastic tissue. The ventricular septum in all three patients showed asymmetric hypertrophy and in two of the three patients, multiple sinusoids had replaced large segments of myocardial cells. The left ventricular free wall myocardium and the walls of the great arteries were unremarkable. Our data indicate that myocardial depletion involving the right ventricular free wall and the ventricular septum and its replacement by sinusoids and fibroelastic tissue occur not only in cases of absent pulmonary valve with tricuspid atresia but also in cases of absent pulmonary valve with tricuspid stenosis. The degree of myocardial depletion varies and is more severe when the tricuspid valve is atretic.

Development of the Human Fetal Testis

We describe the histological features of the fetal testis, utilizing 68 fetuses ranging in gestational age from 10 to 41 weeks. During fetal life, the tunica albuginea progressively increases in thickness, and between 29 and 32 weeks it develops two layers. Beyond 25 to 28 weeks, septa are invariably present. Tubules begin as straight structures and become maximally coiled by 30 weeks. Tubular diameter reaches its maximum by 16 weeks and remains constant throughout the rest of gestation. Germ cell and Sertoli cell numbers per tubular diameter have a wide range, but the median number for each cell type remains constant after 13 to 16 weeks. Leydig cells are most numerous between 17 and 19 weeks and decline thereafter. They are infrequent but still present at term. Interstitial lipochrome pigment accumulates during the latter half of gestation and may represent breakdown products from Leydig cell degeneration.

Cystic fibrosis with fibrosing colonopathy in the absence of pancreatic enzymes.

ABSTRACT Fibrosing colonopathy, characterized by dense submucosal fibrosis in the large bowel, is a disorder associated with bowel dysfunction in patients with cystic fibrosis who receive pancreatic enzyme supplementation. Most commonly, patients present with a distended abdomen and abdominal pain. Radiographs frequently demonstrate colonic wall thickening and luminal narrowing. Here I describe a neonate with cystic fibrosis who presented with both clinical and histological features of fibrosing colonopathy who had not received pancreatic enzymes. This report expands our understanding of the pathogenesis of fibrosing colonopathy.

What is adequate sampling of extraplacental membranes?: a randomized, prospective analysis.

CONTEXT It is the generally accepted practice to submit 1 or 2 membrane rolls when examining placentas. OBJECTIVE To determine whether obtaining additional sections would increase diagnostic yield and, if so, to what degree. DESIGN A membrane roll section was prospectively procured from each quadrant of its respective singleton placenta. These placentas were submitted for routine pathologic examination, the process of which was entirely separate from this study. All study sections were randomized and assigned new numbers, thereby blinding the pathologist to the placenta of origin. We evaluated the incidence of acute chorionitis/chorioamnionitis (AC/A) and atherosis when 1, 2, 3, or 4 slides were examined. The diagnostic yield from all possible combinations of single, pairs, and triplets of sections was tabulated. When an additional slide identified more extensive acute inflammation than what was demonstrated initially, the AC/A was upstaged. RESULTS With 1 section examined, 7 to 10 placentas had AC/A. With 2 sections, 10 to 15 placentas had AC/A; with 3 sections, 16 to 18 cases; and with 4 sections, 19 cases. Additional sections upstaged the AC/A diagnosis infrequently. A total of 4 of 53 placentas had atherosis, based on review of all 4 slides. One slide identified 1 to 3 cases of atherosis. With a second and third section, the yield increased to 2 to 4 and 3 to 4, respectively. CONCLUSIONS Review of a single membrane roll identified, at most, 53% of cases of AC/A and 50% of cases of atherosis. Additional sections increased the yield for both diagnoses in a roughly linear manner.

Delayed human herpes virus 6 encephalitis in a patient with allogeneic stem cell transplant

Human herpes virus 6 (HHV-6) can become reactivated in immunosuppressed individuals typically within the first 50–100 days following an allogeneic stem cell transplant [1,2]. Invasion of neural tissue by HHV-6 5 months following hematopoietic stem cell transplant (HSCT) was first documented in 1994 [3]. HHV-6 encephalitis during HSCT is associated with a poor prognosis [4,5]. Routinely, patients in the post-engraftment period are put on chemoprophylaxis and undergo cytomegalovirus (CMV) monitoring, but it is not currently recommended to screen or actively provide prophylaxis for HHV-6 [6]. We present a case of HHV-6 encephalitis more than 200 days after a 7/8 unrelated allogeneic stem cell transplant. In our review of the literature, this is the first reported case of HHV-6 encephalitis more than 6 months after a stem cell transplant. The patient was a 58-year-old male with acute myelogenous leukemia (AML) who received a non-myeloablative 7/8 matched unrelated donor stem cell transplant. He received fludarabine and busulfan for conditioning and tacrolimus, methotrexate and bortezomib for prophylaxis against graft-versus-host disease (GVHD). The patient then presented five and a half months after his transplant with relapsed AML, and was admitted for chemotherapy with decitabine in the setting of neutropenic fever and pneumonia. The patient was continued on acyclovir along with weekly CMV testing. He was tapered off his immunosuppression, which resulted in grade 2 GVHD of the skin. Systemic immunosuppression was not reinstated for this, but supportive care with ointments and steroid lotions was pursued. At 223 days post-transplant, 31 days since the initiation of decitabine and 30 days after his current admission, he developed progressively worsening disorientation and hallucinations. He was afebrile. Cerebrospinal fluid (CSF) examination revealed glucose 67 mg/dL (49% of plasma glucose, normal range: 60–80%), protein 52 mg/dL (15–60 mg/dL) and 12 white blood cells/cm3 (upper limit of normal [ULN] 5 cells/cm3) with 91% lymphocytes (normal range: 40–80%). On cytological evaluation there was lymphocytic pleocytosis with a small component of atypical lymphocytes. All cerebrospinal and blood cultures for bacterial, fungal or viral organisms were negative. The CSF was also negative for enterovirus RNA, herpes simplex virus (HSV) type 1 or type 2, varizella zoster virus (VZV) DNA and JC virus by polymerase chain reaction (PCR). A cryptococcal antigen performed on the CSF was also negative. Computed tomography (CT) of the head was negative for acute intracranial pathology. He could not tolerate magnetic resonance imaging (MRI) because of his mental status, and an electroencephalogram was not done. Ganciclovir was initiated empirically without improvement after 24 h. The family decided to transition the patient to comfort care, and the patient died 6 days later. HHV-6 by reverse transcription (RT)-PCR was positive in qualitative assays on both the CSF and serum. Autopsy findings showed acute anoxic changes in the left hippocampus without demyelinating lesions of the limbic system. However, there were rare foci of perivascular lymphocytes present in the cortical ribbon in the inferior frontal cortex and in the left temporal cortex. The perivascular lymphocytic infiltration is consistent with HHV-6 encephalitis as seen in prior case reports (Figure 1) [3,7]. There were no signs of interstitial pneumonia or hepatitis, which can be seen with HHV-6 infection. The diagnosis of HHV-6 encephalitis was made on the basis of the qualitative PCR result (serum and CSF), a typical CSF profile and characteristic autopsy findings. Also, other etiologies were excluded by a thorough work-up on the serum and CSF as above. HHV-6 is documented to cause encephalitis in patients after allogeneic stem cell transplant [8]. However, most studies of HHV-6 reactivation and its role in encephalitis investigate the acute post-engraftment phase [1,2]. Our patient did not experience his encephalopathy until  200 days postengraftment. There is a known increased risk for HHV-6 reactivation in allelic mismatched donors. Cases reported have noted a peak in HHV-6 viral load in CSF and serum weeks prior to encephalopathy and death [3,9]. Although our patient was 200  days from transplant, perhaps the manipulation of Leukemia & Lymphoma, September 2015; 56(9): 2709–2710

Tubocutaneous fistula in a premature infant.

Fistulous tracts between the uterus and skin were more common in the preantibiotic era and most often occurred after pelvic surgery. Tubocutaneous fistulas constituted a subset of this form of operative complication. With the improvement of operative techniques and use of antibiotics, the incidence of these fistulas is greatly reduced. In cases reported since 1963, the youngest patient to develop a tubocutaneous fistula was 15 years old. Reported here is an infant delivered at 25 weeks’ gestation, who developed necrotizing enterocolitis requiring 2 surgical interventions. At the time of insertion of a tunneled central venous catheter, the surgeon noted a mass in the right lower quadrant, which he excised. A noninflamed tubocutaneous fistula was identified pathologically with only the distal portion of the tube present. The childs history is similar to other reports in that she had previous operations and had developed significant fibrous abdominal adhesions. Her history is unique in that she is the youngest reported case and hers is the 1st report of this complication following surgery for necrotizing enterocolitis.