ANATOMIC PATHOLOGY

Penile Clear Cell Carcinoma: A Report of 5 Cases of a Distinct Entity

Liegl, Bernadette and Regauer, Sigrid

Authors present a series of 5 penile clear cell carcinomas, which arose in middle-aged men at the inner side of the foreskin. They were large, exophytic, partly ulcerated, and widely invasive tumors with sharp demarcation to the surrounding normal skin/mucosa. Histologically, they were composed of large clear cells with intracytoplasmic PAS/d-PAS-positive material and showed extensive lymphatic and blood vessel invasion. Strong staining with antibodies to Muc-1, EMA, and CEA was typical. All carcinomas harbored HPV16 DNA, although only one carcinoma revealed HPV-related cytologic cell changes. All 5 patients had extensive, partly cystic inguinal lymph node metastases with a striking clear cell differentiation and focal dense sclerotic basement membrane material, either at or within several months after initial diagnosis. Two patients are alive without disease after 7 and 10 years. One patient died after 9 months of widespread disease and 2 patients are presently alive at 7 and 17 months follow-up with widespread lymphatic and hematogenous metastases despite adjuvant chemo- and radiation therapy. In contrast to squamous cell carcinoma, penile clear cell carcinomas show extensive blood and lymph vessel invasion and early metastases to regional lymph nodes. Clear cell carcinomas represent a distinct group of penile cancers that may have a different clinical behavior than usual penile squamous cell carcinomas.

American Journal of Surgical Pathology. 28(11):1513-1517, November 2004

Postmortem diagnosis of Parkinson's disease
[Article in German]
Sandmann-Keil D and Braak H.

Parkinson's disease is a continuously progressive degenerative disorder of the central, peripheral and enteric human nervous systems. Not only the substantia nigra, but also a number of other components of the motor and limbic systems, as well as the autonomic regulation, suffer heavy damages. Only a few of the many types of nerve cells in the human central nervous system develop the characteristic Lewy bodies and Lewy neurites. They are composed primarily of aggregated alpha-synuclein and lead to the premature destruction of the affected neurons. Due to the selective neuronal vulnerability, a distinctive distribution of changes occurs within the central nervous system, leading to a corresponding loss of functionality in many systems. The changes occur in an ordered timely fashion. The ascending pathological process begins within the brain at the glossopharyngeal and vagal areas, nearly destroys the substantia nigra, and reaches the mesocortex of the gray matter. From here it expands to further areas of the neocortex, thereby marking the end phase of the disease.

Pathologe. 2004 Nov 6

 

Pituicytoma

Kowalski RJ, Prayson RA, Mayberg MR.

Pituicytoma is a rare, low-grade neoplasm that originates in the neurohypophysis of the pituitary gland. Authors report the clinicopathologic features of a pituicytoma arising in a 52-year-old man who presented with a mass and panhypopituitarism, clinically suggestive of a pituitary adenoma. The tumor was marked by a proliferation of elongated cells arranged in bundles and interlacing fascicles. The tumor demonstrated positive staining with S-100 protein and glial fibrillary acid protein antibodies. The tumor did not stain with antibodies to cytokeratin, synaptophysin, chromogranin, anterior pituitary hormones, or p53. An MIB-1 labeling index of 1.1% was observed. The tumor was subtotally resected and recurred 11 months after the initial surgery.

Ann Diagn Pathol. 2004 Oct;8(5):290-4

 

Ki-67 expression in patients with uterine leiomyomas, uterine smooth muscle tumors of uncertain malignant potential (STUMP) and uterine leiomyosarcomas (LMS)

Mayerhofer K, Lozanov P, Bodner K, et al

The aim of this study was to evaluate the expression of Ki-67 in uterine smooth muscle tumors, comparing leiomyomas, uterine smooth muscle tumors of uncertain malignant potential (STUMP) and uterine leiomyosarcomas (LMS) and to prove the accuracy of a Ki-67 expression as a useful parameter in the diagnosis of LMS.

METHODS: Ki-67 was assessed using immunohistochemistry from paraffin-embedded tissue in 20 patients with uterine LMS, 22 cases of STUMP and 25 cases of leiomyomas. RESULTS: Ki-67 was present in 10/20 (50%) LMS, in 0/22 (0%) STUMP and in 2/25 (8%) leiomyomas. Significant differences regarding the frequency of Ki-67 expression were observed between LMS and STUMP (p = 0.0001) as well as between LMS and leiomyomas (p = 0.002), but not between STUMP and leiomyomas (p = 0.491). Likewise, the staining intensity differed significantly between LMS and leiomyomas (p = 0.018) as well as between LMS and STUMP (p = 0.002), but not between STUMP and leiomyomas (p = 0.368).

CONCLUSIONS: The results demonstrate that the significantly elevated Ki-67 antigen expression in LMS, which correlates well with the rapid growth of these malignant tumors, may be a useful immunohistochemical parameter to distinguish between cases of malignant smooth muscle tumors and those of uncertain or borderline histology.

Acta Obstet Gynecol Scand. 2004 Nov;83(11):1085-8

 

Carcinomas with micropapillary morphology: clinical significance and current concepts

Nassar H.

Invasive micropapillary carcinoma has been recently recognized as a rare but distinctive variant of carcinoma in various anatomic sites, including breast, urinary bladder, lung, and major salivary glands. Morphologically, it is characterized by small tight clusters of neoplastic cells floating in clear spaces resembling lymphatic channels. Most often this growth pattern is mixed with a variable component of conventional carcinoma or other variants. In addition to a unique morphology, tumors with invasive micropapillary growth share a high propensity for lymphovascular invasion and lymph node metastases. Patients have typically high-stage disease at presentation and a poor clinical outcome compared with that of patients with conventional carcinoma arising in the same organ site. In this article the author reviews the available literature on tumors displaying a micropapillary component.

Adv Anat Pathol. 2004 Nov;11(6):297-303

 

Concentrated Smear Technique for Examining Sentinel Lymph Nodes of the Breast at the Time of Frozen Section

Andrew A. Renshaw and Edwin W. Gould

Examination of sentinel lymph nodes for breast carcinoma in the frozen section room at the time of surgery is useful and, if positive, can result in completion axillary dissection at that time. To avoid wasting tissue, many pathologists use direct smears to examine these specimens. The authors sought to determine whether a concentrated smear technique that was subjectively easier to screen was as sensitive as standard direct and imprint smears. Eighty-five histologically positive lymph nodes were examined in the frozen section room by intraoperative cytology during the study period (35 using routine direct or imprint smears and 50 with a concentrated technique in which cells are spread in an area of 1 cm²); 44 (52%) were identified as positive. Positive cytologic results correlated strongly with the size of the metastatic focus (P < .0001). The sampling sensitivity of the concentrated technique was 60% vs 39% for routine direct or imprint smears (P = .08). There were 3 screening errors in the routine smears and none in the concentrated smears (P = .08). The concentrated technique is as sensitive as routine direct smears for sampling sentinel nodes for breast carcinoma and may be associated with a lower screening error rate.

Anatomic Pathology, November 12, 2004

 

CLINICAL PATHOLOGY

Thrombocytopenia in malaria

Patel U, Gandhi G, Friedman S, Niranjan S.

Malaria continues to be a cause of high mortality and morbidity. Imported cases of malaria are increasing in New York City. Yet, New York physicians, when evaluating patients for fever, frequently missed the diagnosis of malaria. Authors evaluated the role of platelet count for predicting malarial infection. The study included patients seen between 1996 and 2000 in a New York community hospital for fever who had traveled to a malaria-endemic area. Forty patients with malaria were identified. The study found the sensitivity of platelet count for diagnosing malaria was 100%, and the specificity was 70%. The negative predictive value was 100% and the positive predictive valve was 86%. Hence, the authors propose that in any patient with fever and recent travel history, platelet count is an important clue to the diagnosis of malaria. A finding of thrombocytopenia should increase the suspicion of malaria and lead to performance of more specific tests, including multiple peripheral smears and ELISA for parasite-specific antigen, etc.

J Natl Med Assoc. 2004 Sep;96(9):1212-4

 

Standardisation of glycated haemoglobin

Is a scientific advance, but it could worsen overall blood glucose control

The detection of sugars in the urine of people with diabetes usually is attributed to Matthew Dobson. However, first attempts at quantification of urine sugars seem to have been made by Francis Home, an Edinburgh physician. Estimation of urine sugar as a measure of severity of diabetes had two major problems that, until recently, were shared with its contemporary equivalent, estimation of glycated haemoglobin. Firstly, both are surrogate measures of the average concentration of plasma glucose that is responsible for the microvascular and arterial damage that manifests itself in later years. Secondly, both also included in their measurement non-specific (nonglucose) substances when using available assays. Very recently, the glycated haemoglobin assay has been standardised by the scientific community to remove this non-specificity, but switching to this more accurate method for everyday reporting of results could lead to confusion and worsening of the control of diabetes.

Urine glucose remains of value only where the cost of self-monitored blood glucose control is out of reach, but glycated haemoglobin (as HbA_1c) has become central to any level of diabetes care. In the diabetes control and complications trial (DCCT) and the UK prospective diabetes study (UKPDS), HbA_1c was the measure used to define the relation between glucose control and outcomes such as retinopathy. As a result, HbA_1c is the measure by which clinicians can relate blood glucose control to the microvascular and arterial risk in any patient with diabetes. Jeffcoate usefully reminds us, in a recent issue of Diabetic Medicine, of some of the many caveats that underlie interpretation of a series of HbA_1c results in an individual. However, taken together with self-monitored blood glucose profiles and assessment of hypoglycaemia (both of which also have problems related to reliability), HbA_1c is likely to remain a cornerstone of management of diabetes for some decades.

In the 1980s, difficulties with assays in the Kroc study (the feasibility study for the diabetes control and complications trial) led to urgent and successful attempts to standardise the assay, anchored on methods in David Goldstein's laboratory in Minneapolis. The assay of the UK prospective diabetes study was subsequently aligned with this. With the success of the two studies, the clinical and biochemical communities sought to harmonise clinical laboratory assays to that standard, an exercise that remains a remarkable example of informal international cooperation.

Such harmonisation served the needs of people with diabetes and their healthcare advisers to near perfection, but unfortunately the ultimate reference standard being used included a fixed non-specific element amounting to approximately 2.0% (HbA_1c units) of total haemoglobin, and thus around one third of the measured HbA_1c at the upper end of the quoted reference range (6.1% (HbA_1c units)). Thanks to the commendable efforts of the International Federation of Clinical Chemists, which has developed a reference standard based on mass spectrographic analysis of a glycated peptide fragment of haemoglobin the extent of the error is now securely described. With the cooperation of diagnostics' manufacturers (mandated in the European Union), specific results could be available to all people with diabetes, clinicians, and researchers.

But is this desirable? Nearly every guideline for diabetes has based its intervention and target levels on the standard of the diabetes control and complications trial, and the curves describing the relation between HbA_1c and complications from that trial and the UK prospective diabetes study are widely recognised. A further problem, incompletely understood, is that higher numbers of a pathological entity lead to greater clinical action independent of true clinical importa quirk of human numeracy. Accordingly, a study from Sweden shows that changes in HbA_1c standardisation leading to smaller numbers lead to a worsening of overall blood glucose control. As a result, adoption of the International Federation of Clinical Chemists' standard in reporting of HbA_1c might not only risk losing the benefits of years of professional education on the quantitative relation between overall blood glucose control and complications, but might also risk increasing blindness and cardiovascular events through higher attained blood glucose concentrations.

 

Is there a way out? Not to make use of the advance introduced by the International Federation of Clinical Chemists would be unreasonable. Alternatives considered at a recent meeting convened by the International Diabetes Federation included continued reporting to the diabetes control and complications trial's standard (using the defined relation between the two standards), a coordinated global switch to reporting to the new, lower standard of the International Federation of Clinical Chemists, reporting in absolute units (such as g/kg rather than percentage), or reporting in average blood glucose equivalents. As people with diabetes already measure their own glucose concentrations by self-monitoring, the last of these has some attraction. However, even this approach would still need a major global education initiative, and whether the globally influential North American community would be prepared to carry through any such change is unclear at present.

Meanwhile one message seems clear. Piecemeal switching of the reporting standard by individual laboratories or even countries is likely to lead to confusion and ignorance among patients and healthcare professionals that could seriously damage individual health outcomes in people with diabetes. Therefore, individual practitioners need to remain sensitive to these risks, while requiring the international diabetes community to continue to move forward in achieving a coordinated programme, which makes use of the new standard.

Editorial, BMJ  2004;329:1196-1197 (20 November)

 

MOLECULAR PATHOLOGY

Molecular Basis of Proteinuria

Akhtar M, Al Mana H.

The glomerular filtration barrier is composed of endothelial cells, basement membrane, and podocytes. In recent years, remarkable progress has been made in our understanding of the molecular structure of the filtration barrier and its relation to the effectiveness of the barrier function. The glomerular basement membrane is composed of a multitude of proteins, including collagen IV, heparan sulfate proteoglycans, and laminin, among others. The slit diaphragm, which is seen as a membrane covering the space between adjacent foot processes close to the basement membrane, is an extremely important structure with a crucial role in permselectivity of the filtration barrier. Its composition is now understood to consist primarily of a unique protein called nephrin. Mutations in the gene-encoding nephrin are known to result in the Finnish type of nephrotic syndrome. The exact mechanism by which nephrin controls permselectivity is not yet clear, but it is known to interact with several podocyte proteins including CD2AP, podocin, and alpha-actinin-4. Abnormalities of any of these proteins may result in proteinuria. The role of nephrin and its associated proteins in the pathogenesis of common acquired glomerulopathies in humans is still under investigation. Normal function of podocyte also depends upon maintaining a fully mature and terminally differentiated phenotype. A host of transcription factors, especially WT1 and PAX2, play a significant role in modulating podocyte function.

Adv Anat Pathol. 2004 Nov;11(6):304-309