Katrine Hansen

Asplenic-hyposplenic Overwhelming Sepsis: Postsplenectomy Sepsis Revisited

Absence of the spleen or splenic function predisposes individuals to risk of overwhelming infection. These infections are most often due to encapsulated organisms, especially pneumococcus, Haemophilus influenzae type b, and meningococcus, but any bacterial agent may cause the rapid onset of septicemia, meningitis, pneumonia, and shock characteristic of the asplenic-hyposplenic condition. The risk is greatest in infants and young children, but asplenic-hyposplenic adults also have an increased risk of infection. Prophylactic antibiotics and immunization with polyvalent pneumococcal, H. influenzae type b, and meningococcal vaccines have reduced the incidence of infections in asplenic-hyposplenic individuals, but even these measures have not eliminated the risk. Surgeons have adopted techniques to save as much splenic tissue as possible and some splenic functions, such as pitting red cells, have been preserved, but conservative surgery has not provided total protection against overwhelming infection. Therapies designed to interrupt the cascade of overwhelming sepsis have not yet been successful.In those cases in which the spleen is surgically removed, the underlying disease or condition leading to splenectomy influences the risk of sepsis. Splenectomy incidental to other operations, such as gastrectomy, results in the lowest risk for overwhelming infection, but this is still some 35-fold greater than the risk for overwhelming infections in the general population. In increasing order of risk, the other main indications for surgical removal of the spleen are idiopathic thrombocytopenia purpura, trauma, transplantation procedures, hereditary spherocytosis, staging Hodgkins disease, portal hypertension with hypersplenism, and thalassemia. Pathologists should comment on the risk of overwhelming sepsis when spleens are processed as surgical specimens, and should carefully weigh all splenic tissue, including accessory spleens and splenic implants (splenosis), in autopsy cases with and without overwhelming sepsis.

Renal tubular apoptosis in twin-to-twin transfusion syndrome.

Twin-to-twin transfusion syndrome (TTTS) is caused by uneven shunting of blood between monochorionic twins, resulting in polycythemia in the recipient twin and growth restriction, anemia, and oliguria in the donor twin. Recent reports have described loss of proximal convoluted tubules in the kidneys of TTTS donor twins. In order to elucidate the pathogenesis of tubular deficiency in TTTS, we have reviewed the renal pathology in 25 twin pairs with autopsy-proven TTTS. Loss of differentiated proximal tubules, associated with atrophy of medullary tubules, was identified in 12/25 donor twins. In seven of these cases (all > 23-wk gestational age), the kidneys showed diffuse or partial tubular atrophy without evidence of cell death, similar to previously reported patterns. In five cases (all between 18- and 22-wk gestation), proximal and medullary tubules showed active injury characterized by markedly increased apoptosis, cell detachment, and intraluminal cell debris associated with calcifications. Tubular apoptosis tended to be more prevalent in donor fetuses with greater inter-twin body weight discordance, consistent with a more severe degree of TTTS. These results extend the spectrum of tubular alterations in TTTS to include an early stage of active apoptotic injury. The temporal distribution of injury patterns suggests that apoptotic injury of proximal and medullary tubules may be a precursor to partial or diffuse tubular atrophy. We speculate that the risk for development of tubular apoptosis in TTTS depends on the severity and timing of the hemodynamic imbalance, whereby early mid-trimester fetuses may be more vulnerable.Congenital diaphragmatic hernia (CDH) is a congenital disorder, complicated by pulmonary hypoplasia (PH) and pulmonary hypertension. Hypoplastic lungs have fewer and smaller airspaces than normal, with thicker interalveolar septa; the adventitia and media of pulmonary arteries are thickened, and the total size of the pulmonary vascular bed is decreased compared to normal. Although histological abnormalities in PH have been described, less is known about the underlying molecular mechanisms. Therefore, we have investigated a series of proteins, known to be involved in angiogenesis, including von Hippel-Lindau protein (pVHL), hypoxia-inducible factor-1a (HIF-1a), vascular endothelial growth factor (VEGF), fetal liver kinase 1 (Flk-1), and endothelial and inducible nitric oxide synthase (eNOS, iNOS) by immunohistochemistry on paraffin-embedded lung tissue of CDH patients (n = 13), patients with lung hypoplasia due to other causes (n = 20), and normal controls (n = 33). pVHL was expressed more frequently in the arterial smooth muscle cells of CDH lungs compared with both other groups. Furthermore, HIF-1a was expressed less frequently in the endothelium of arteries, veins, and capillaries of CDH lungs as compared with both other groups. No differences were observed in the expression patterns of VEGF, Flk-1, eNOS, and iNOS between the different groups. Our data suggest a role for pVHL and HIF-1a in normal and abnormal pulmonary angiogenesis. The differential expression of these proteins may provide a molecular basis for the histological differences observed in the lung vessels of patients with CDH.

Cystic dysplasia of the testis

Cystic dysplasia of the testis (CDT) is a rare congenital defect that results in the formation of numerous irregular cystic spaces within the mediastinum testis. We describe a 4-year-old boy with right testicular swelling who underwent orchiectomy for CDT after a preoperative ultrasound examination revealed a multicystic, anechoic lesion. Grossly, the lesion was 2 cm in size and was composed of multiple, irregularly shaped cystic spaces lined by flattened cuboidal epithelium. Immunohistochemical studies revealed that the epithelial cells expressed keratin, vimentin, and epithelial membrane antigen. Both the histologic appearance of the cyst lining and the immunohistochemical profile resembled the epithelium of rete testis. In our review of the literature 10 cases (including this lesion) of CDT have been described. A defect in the connection between the efferent ductules, derived from the mesonephric epithelium, and the rete testis and seminiferous tubules, derived from the gonadal blastema, is currently thought to be the most likely explanation of the pathogenesis of CDT.

Reference Values for Second Trimester Fetal and Neonatal Organ Weights and Measurements

To establish accurate reference ranges for the entire second trimester, we documented organ weights, body weight, and linear measurements for 597 fetuses and neonates with gestational ages ranging from 12 to 26 wk. We determined the mean and standard deviation for weights and measurements at each week of gestation using the StatView™ SE + Graphics statistical program. The analyses revealed a linear correlation between the gestational age and, respectively, the toe-heel length, crown-rump length, and crown-heel length. Body and organ weights increase at varying rates throughout the second trimester. The data correlate well with weights and measurements previously published for the latter half of the second trimester, and extend these reference ranges to encompass the entire second trimester.

CYSTIC DYSPLASIA OF THE RETE TESTIS: A BENIGN CONGENITAL LESION ASSOCIATED WITH IPSILATERAL UROLOGICAL ANOMALIES

PURPOSE Cystic dysplasia of the rete testis is a benign congenital lesion that can mimic testicular cancer. We report 6 cases, review the literature, discuss the embryological etiology and make management recommendations. MATERIALS AND METHODS The records and pathology reports of 6 boys presenting with cystic dysplasia of the rete testis at 5 institutions were reviewed, as was the relevant literature. RESULTS Of the 6 cases 5 presented as scrotal masses in previously healthy boys and 1 as an abdominal mass in a newborn with multiple congenital anomalies. One patient had been followed from birth for a multicystic dysplastic kidney and 4 were found to have an ipsilateral absent kidney during evaluation. Development of the contralateral side was normal in most cases. CONCLUSIONS Cystic dysplasia of the rete testis is an unusual, benign congenital lesion that can mimic testicular cancer in presentation. The presence of ipsilateral renal anomalies, particularly renal agenesis, can suggest cystic dysplasia of the rete testis in the differential diagnosis preoperatively. Even if cystic dysplasia of the rete testis is suspected, we recommend inguinal exploration and early control of the spermatic cord in the event that neoplasia is identified. If possible, the goal of preserving as much normal testicular parenchyma as possible is desirable. Long-term followup for possible recurrence is recommended, particularly after local excision.

Placental findings after laser ablation of communicating vessels in twin-to-twin transfusion syndrome.

As laser ablation of placental vascular communications gains acceptance as treatment option for severe twin-to-twin transfusion syndrome (TTTS), pathologists are increasingly confronted with the interpretation of laser-treated placentas. We present our preliminary institutional experience with the gross and microscopic analysis of these specimens. Patients underwent selective ablation for severe TTTS (Quintero stages II to V) between 16 and 25 wk gestation and the placentas were examined between < 24 h and 19 wk postoperatively. The placental vasculature was injected with gelatin-dye mixtures. The type and number of vascular anastomoses were recorded, followed by routine histopathological analysis of the placenta. Foci of laser impact were identified in all placentas examined within 1 month after laser coagulation. Located along the recipient side of the dividing membrane, the laser-treated vessels appeared hemorrhagic and showed a characteristic abrupt interruption of dye filling after vascular injection. In placentas examined more than 1 month after intervention, the most frequent gross finding was the absence or relative paucity of intertwin anastomoses, associated with subchorionic fibrin deposition. Microscopically, laser-treated vessels showed varying degrees of necrosis, associated with focal hemorrhage, avascular villi, and fibrin deposition in the underlying parenchyma. In some cases of intrauterine fetal demise or placental disruption, no definite laser scars were identified. As expected, the number of residual anastomoses (all types) was significantly smaller in laser-treated placentas than in control monochorionic placentas (2.4 ± 2.2 [n = 10] vs. 6.2 ± 3.2 [n = 70], P < 0.01). Velamentous cord insertion was noted in 50% of cases; markedly uneven placental sharing in 60%. Detailed analysis of laser-treated placentas and clinicopathological correlation may lead to a better understanding of the pathophysiology of TTTS and continued refinement of therapeutic approaches for this often lethal condition.

Postmortem RNA and protein stability in perinatal human lungs.

The availability of fetal and neonatal lung tissue is an invaluable resource to elucidate the molecular regulation of human lung development. In this study, we have investigated the mRNA and protein stability of perinatal lung tissues treated with RNA later (Ambion Inc., Austin, TX) or snap frozen in liquid nitrogen (LN2). Lung samples were obtained from 25 consecutive perinatal autopsies of live-born and stillborn infants (median gestational age, 23 weeks) with various clinical presentations. Treatment of lung tissue with RNA later yielded more total RNA and protein than LN2 freezing. The integrity of RNA, assessed by spectrophotometry and gel electrophoresis, was equivalent between both tissue preservation methods, and both methods produced RNA suitable for reverse transcriptase–polymerase chain reaction analysis of representative genes (&bgr;-actin and surfactant protein-B [SP-B]). Similarly, the protein integrity of RNA later-treated tissues was equivalent to that of LN2-frozen tissues, as judged by Western blot analysis of SP-B/actin protein expression. Although the total yield was similar in live-born, nonmacerated stillborn and macerated stillborn infants, only RNA and protein from live-born or nonmacerated stillborn infants was suitable for subsequent molecular analyses. Within the 41-hour range studied, the duration of the postmortem interval did not affect the yield or integrity of RNA and protein with either tissue preservation method. In summary, high-quality RNA and protein, suitable for routine molecular analyses, can be obtained from postmortem lung tissue from live-born and nonmacerated stillborn infants, even with prolonged postmortem intervals. RNA later is equivalent, if not superior, to LN2 for preservation of postmortem RNA and protein in developing human lungs.

Hsal 1 is related to kidney and gonad development and is expressed in Wilms tumor.

Abstract. Townes-Brocks syndrome (TBS) is a human genetic disorder with features including urogenital, limb, anal and cardiac malformations associated with mutations of the TBS gene, Hsal 1. To begin to understand the role of the Hsal 1 protein (p140) in both normal development and disease pathogenesis, both message and protein expression were evaluated in specific tissues associated with TBS. DNA sequence information for Hsal 1 predicts that this homeotic, Drosophila homologue (Sal) encodes a zinc-finger protein consistent with a transcription factor. mRNA for Hsal 1 was highly expressed in fetal kidney and brain, with detectable production in thymus and heart. p140 was found in fetal ureteric bud, fetal and postnatal renal tubular epithelium, and renal blastema. In the 14-week fetal testis, the Hsal 1 protein was specifically expressed in the testosterone producing Leydig cells while in adult gonads Hsal 1 was also found in both Leydig and Sertoli cells, spermatogonia of the testis, and granulosa cells of the ovary. Evaluation of Wilms tumor revealed consistently high expression of the gene product in the epithelial and blastemal components. These spatial and temporal patterns of expression for Hsal 1, and the phenotypic effects associated with TBS, suggest that Hsal 1 plays an important role in the development and functional maintenance of the kidney and gonads. Furthermore, the Hsal 1 gene product may play a part in the pathogenesis of specific neoplasms occurring in these organs in addition to its specific role in Townes-Brocks syndrome.

High-grade serous carcinoma arising in a low-grade serous carcinoma and micropapillary serous borderline tumour of the ovary in a 23-year-old woman.

but so far no data about this transcriptional factor have been published for malignant plasma cells. FOXP1 is considered a potential therapeutic target in a variety of cancers. Koon et al. wrote a review in 2007 about FOXP1 changes in gastrointestinal, lung, head, neck and breast cancer, genitourinary malignancies and B-cell lymphomas. They stated that FOXP1-directed therapy could have significant potential, but that many data about FOXP1 function are still missing. It is still not clear whether FOXP1 acts as an oncogene or tumour suppressor, or if there are other, as yet uninvestigated malignancies in which it has prognostic value. Our data describe a case of MM with hyperploidy, multiple IgH translocations and FOXP1 expression; to our knowledge this is the first reported case with six translocated genes as well as the first reported case of FOXP1 expression in malignant plasma cells. It demonstrates the need for further investigation into the prognostic value of FOXP1 protein expression in MM.

Relevance of the Pap Test: A Report of HPV-DNA Test-Negative High-Grade Squamous Intraepithelial Lesions of the Female Lower Genital Tract.

Objective: A vast majority of cervicovaginal intraepithelial lesions are caused by high-risk human papillomaviruses (HPVs). The Pap test has been the sole method used for the screening of cervicovaginal squamous intraepithelial lesions (SIL). Recently, the FDA approved an HPV-DNA assay as a method of primary screening. We report on a series of FDA-approved HPV-DNA test-negative SIL with HPV genotyping, using an alternative method on the corresponding surgical biopsy specimens. Study Design: A retrospective review identified cytology-positive HPV-negative cases over a 15-month period at a tertiary care gynecologic oncology institution. Corresponding biopsies were reviewed and genotyped for high-risk HPVs. Results: Of the 18,200 total cases, 17 patients meeting the study criteria were selected with 27 surgical specimens corresponding to their cytologic diagnoses. Four patients with high-grade lesions were identified, 3 of whom (75%) were positive for HPV. One of these 4 patients (25%) showed high-grade SIL on biopsies from 4 separate sites in the cervix and vagina. Multiviral HPV infections were frequent. Conclusions: We discuss the relevance of cotesting for screening cervical SILs and emphasize that false-negative results are possible with the FDA-approved HPV screening assay, also in patients with high-grade SIL. These cases may be detectable by cytologic examination and this suggests that the Pap test remains an important diagnostic tool.