May 2007
ANATOMIC PATHOLOGY
Does
Immunohistochemistry Help in Distinguishing Atypical Lipomatous Tumors From
Benign Lipoma?
Atypical lipomatous tumors/well-differentiated liposarcoma (ALT/WDL) is presently classified as an intermediate (locally aggressive) tumor according to the WHO classification of soft tissue tumors, with the use of the term atypical lipomatous tumor determined entirely by tumor location and resectability. Karyotypically, ALT/WDL is characterized by supernumerary ring and/or giant chromosomes with amplification of the 12q14-15 region, including the murine double-minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) genes. Amplifications of MDM2 and CDK4 genes may be demonstrated by comparative genomic hybridization, quantitative polymerase chain reaction, and fluorescent in situ hybridization. Not surprisingly, amplification of these genes results in overexpression of the corresponding proteins detected through antibodies raised against both MDM2 and CDK4. To this effect, Dr Jean-Michel Coindre and a group of Swiss and Canadian collaborators extensively evaluated a group of ALT/WDL and benign adipocytic tumors, the latter being a major source of confusion in biopsy and resection specimens of lipomatous tumors. In a series of 44 ALT/WDL and 49 benign adipose tumors, these workers demonstrated MDM2 and CDK4 protein expression using immunohistochemistry as follows: ALT/WDL expressed MDM2 (100%) and CDK4 (91%), as opposed to benign adipose tumors (MDM, 5%; CDK4, 2%), the latter comprising spindle cell/pleomorphic lipomas. Hence, the sensitivity of ALT/WDL versus benign adipose tissue was 100% for MDM2 and 91% for CDK4, with a specificity of 96% for MDM2 and 98% for CDK4. A note of caution is that MDM2 immunostaining often presented as scattered positive nuclei, with a higher proportion of positive atypical spindle cells situated in the fibrous areas of ALT/WDL. CDK4 staining was often more diffuse and intensely stained than MDM2. In support of the immunohistochemistry data, a strong correlation was demonstrated between MDM2 and CDK4 immunostaining and gene amplification. Hence, when confronted with a well-differentiated adipocytic tumor, positive immunostaining for MDM2 and/or CDK4 strongly supports a diagnosis of ALT/WDL, even with very focal immunoreactivity with the former marker. In a parallel study supporting the immunohistochemical study, Shimada et al demonstrated MDM2 and CDK4 gene amplifications in all ALT/WDL with both real-time polymerase chain reaction and fluorescent in situ hybridization analysis.
In contrast, dedifferentiated liposarcoma (DDL), while karyotypically sharing the same chromosomal aberrations and gene amplifications as the ALT/WDL group, is characterized as malignant in the WHO 2002 classification on the basis of its increased metastatic potential. Again, not surprisingly, MDM2 and CDK4 immunohistochemistry highlighted 95% and 92% of DDL, respectively. However, in contrast to ALT/WDL, the simulators of DDL (eg, malignant peripheral nerve sheath tumors, myxofibrosarcoma, and embryonal rhabdomyosarcoma) also demonstrated immunoreactivity for MDM (18%) and CDK4 (7%) respectively, somewhat dampening the value of these immunomarkers in this differential diagnostic context. Nevertheless, it may still be of value in investigating MDM2 and CDK4 immunoreactivity in well-differentiated adipocytic components surrounding pleomorphic tumors of the retroperitoneum in an attempt to distinguish DDL from other pleomorphic sarcomas of the retroperitoneum or deep soft tissue.
Advances in Anatomic Pathology, Volume 14(3), May
2007, p 231
Gastritis on the Stage
[News in Brief]
Chronic gastritis is epidemiologically and biologically linked to the development of gastric cancer and Helicobacter pylori, its most important etiologic factor, is recognized as a class I carcinogen. However, the assessment of cancer risk in individual patients is difficult, in part because gastric carcinogenesis is modulated by yet undefined factors, including environment, bacterial strain, and host responses.
One potential way to predict the cancer risk is to assess the status of the gastric mucosa for inflammation and atrophy and place patients on approximate points of the natural history of chronic gastritis, from the reversible inflammatory lesions (often limited to the antrum) at the one end, to the extensive atrophic changes associated with high risk for gastric cancer at the other. The Houston-updated Sydney System and the subsequent modified guidelines for the evaluation of atrophy are now widely used for reporting gastritis. Yet, many clinicians are befuddled by a diagnosis like antrum-predominant H. pylori chronic active gastritis with moderate metaplastic atrophy, and would prefer a more cogent concluding message.
Building on our current understanding of the morphologic alterations of gastritis and their evolution, AUTHORS have suggested that, as in chronic hepatitis, it could be useful to report the phenotypes of gastritis in terms of grading and staging. Grading would express the cumulative intensity of the inflammatory components, whereas staging would convey information on the anatomic extent of the atrophic-metaplastic changes related to cancer risk.
This proposal was formally presented in March 2005 to an international group of gastric pathologists and other experts [the Operative Link for Gastritis Assessment (OLGA)] that agreed to test the validity of staging in a series of retrospective and prospective studies to be carried out independently in populations with different cancer risk. It was also agreed that, if such pilot studies yielded encouraging results, larger prospective studies would be designed.
The first such national study designed to test whether the OLGA-Staging consistently stratified patients according to their cancer risk and provided clear prognostic/therapeutic information has been published in December 2006. The study, conducted in a Northern Italian population with high risk for gastric cancer, included 439 dyspeptic patients who underwent endoscopy with standardized biopsy sampling. Incidental neoplastic lesions and peptic ulcers were recorded. Gastric biopsies were evaluated according to the Updated Sydney System and staging (atrophy, on a 0 to IV scale) and grading (overall inflammatory infiltrate, on a 0 to 4 scale) scores were applied according to the OLGA criteria.
The results of this study showed that benign conditions (including duodenal ulcers) consistently clustered in 0-II Stages (P<0.001), whereas all neoplastic (invasive and non-invasive) lesions clustered in Stages III-IV (P<0.001). The authors conclude that gastritis staging, combined with H. pylori status, provided clinically relevant information on the overall status of the gastric mucosa with implication regarding prognosis, therapy, and management.
Studies with similar aims are currently being conducted in several populations around the world and we may see the results within the next year or two. If either staging or grading (or the two combined, as I personally believe) will prove useful and reliable to state concisely a patient's cancer risk, pathologists might have to learn to attach the 2-word, 2-number set at the end of each gastric biopsy report as diligently as they already do with liver biopsies.
Advances in Anatomic Pathology, Volume 14(3), May
2007, p 233
Glassy Cell Carcinoma of the Endometrium:
A Case Report and Review of the Literature
Gabriella
Ferrandina, Gian Franco Zannoni, Marco Petrillo et al.
Glassy cell carcinomas are composed of malignant cells showing a “ground glass” cytoplasm, distinct cell membranes, and large nuclei with prominent nucleoli. To our knowledge, only 12 cases of glassy cell endometrial carcinomas (EGCC) have been reported until now.
A 63-year-old patient complaining of irregular vaginal bleeding underwent hysteroscopy-guided biopsy revealing a well-differentiated endometrial endometrioid adenocarcinoma. The patient underwent left salpingo-oophorectomy, total abdominal hysterectomy, and pelvic lymphadenectomy. The final diagnosis was FIGO stage IB poorly differentiated endometrial adenosquamous carcinoma with >90% of glassy tumor cells. The patient is alive, with no evidence of disease for 69 months after diagnosis.
Authors describe an additional case of EGCC and review the data of the literature, emphasizing the need to strictly define the criteria for the diagnosis and the potential usefulness of assessing biologic parameters for the prognostic characterization of this rare entity.
Pathology
- Research and Practice,
Volume 203, Issue 4,
Renal Cell
Carcinoma and the Renal Sinus
Grignon D, Paner GP.
Renal sinus fat invasion was incorporated as one of the parameters for pT stage definition of renal cell carcinoma (RCC) only in the latest 2002 American Joint Committee on Cancer/tumor-node-metastasis staging protocol. The current pT3a subcategory (in addition to adrenal gland involvement) groups 2 modes of extrarenal extension by RCC, either by peripheral perinephric fat extension or by renal sinus fat invasion. Recent prospective studies have shown that with more directed gross sampling and histologic evaluation, renal sinus invasion is actually more commonly diagnosed than previously reported, or when compared with retrospectively sampled RCC nephrectomy specimens. These studies have demonstrated that renal sinus invasion is the principal pathway for extrarenal extension for clear cell RCC; the incidence of which is related to size (tumors greater than 4 cm more frequently involve the renal sinus). More significantly, a recent retrospective study of pT3a clear cell RCC nephrectomy specimens showed that tumors invading the renal sinus fat portend a more aggressive outcome than tumors invading only the peripheral perinephric fat. Clear cell RCCs invading the renal sinus are more likely to have higher nuclear grade, regional lymph node involvement and sarcomatoid transformation than tumors invading only the perinephric fat. Given the importance of renal sinus invasion, sampling strategies for nephrectomy specimens should be modified to focus in this region as appropriate and pathologists should be familiar with the histologic criteria for staging renal sinus invasion.
Adv Anat
Pathol. 2007 Mar; 14(2): 63-8.
CYTOPATHOLOGY
Our Approach to
Squamous Intraepithelial Lesions of the Uterine Cervix
Morphological analysis remains the gold standard in the diagnosis and grading of CIN.
MORPHOLOGICAL DIAGNOSIS OF CIN
In our general surgical pathology practice at the University of Vermont, Fletcher Allen Health Care, Burlington, Vermont, USA, we see approximately 30 000 surgical cases a year, 3.3% of which are colposcopically guided cervical biopsies. Each cervical biopsy, initiated by an abnormal Papanicolaou smear with a diagnosis of low-grade squamous intraepithelial lesion (LG-SIL), high-grade squamous intraepithelial lesion (HG-SIL) or atypical squamous cells of undetermined significance, which cannot rule out HG-SIL, is reviewed in conjunction with the referring Papanicolao smear. Deeper levels are performed on the paraffin block if a lesion is not identified on the corresponding biopsy specimen.
General classification of CIN
A diagnosis of CIN is based primarily on the presence of nuclear atypia and loss of normal squamous maturation (polarity). Accurate grading of CIN lesions becomes important as we begin to understand the rates of regression, persistence and progression of the low-grade (CIN 1) and high-grade lesions (CIN 2 and 3), as their treatment and clinical follow-up algorithms are quite different.
Authors have
adopted a two-tiered approach for reporting cervical cytological specimens,
adapted from the
Summary
Morphological analysis remains the gold standard in the diagnosis and grading of CIN; however, recently, immunohistochemical markers such as p16INK4a and Ki-67 have emerged as helpful adjuncts to the diagnosis. They have proven beneficial in distinguishing high-grade cervical dysplasia from its benign mimics such as cervical atrophy, immature squamous metaplasia and reactive inflammatory lesions. As no ancillary test attains 100% sensitivity or specificity, we advocate the combined use of p16INK4a and Ki-67 in lesions that are morphologically suspicious for CIN. The utility of these markers in CIN screening has not been established. Their use in conjunction with possible ISH for HPV (episomal vs integrated signal patterns) has been shown to improve diagnostic accuracy and significantly reduce interobserver variability. Further large-scale studies are needed to examine the clinical usefulness of p16INK4a immunostaining and HPV ISH signal patterns, alone or in combination, in identifying CIN 1 lesions at higher risk of progression.
Take-home messages
Morphological analysis remains the gold standard in the grading of cervical intraepithelial neoplasia (CIN), but significant intraobserver and interobserver variability in the diagnosis of CIN still exists.
Potential benign mimics of high-grade cervical dysplasia (CIN 2 and 3) include basal-cell hyperplasia, immature squamous metaplasia, reactive/inflammatory lesions and squamous atrophy.
Surrogate markers such as immunohistochemistry for p16INK4a and Ki-67 have been shown to improve diagnostic accuracy and reduce interobserver variability.
Authors support the combined use of p16INK4a and Ki-67 immunohistochemistry in lesions that are morphologically suspicious for CIN.
Journal
of Clinical Pathology, Volume 60(5), May
2007, pp 449-455
CLINICAL PATHOLOGY
Rose Bengal Stain Helps Detect Malignant
Oral Lesions
Dr. Cheng-zhang Li of
To investigate whether rose bengal staining might also be useful in oral applications, the researchers studied the technique in 132 patients. Shading evaluation was based on a standardized 4-grade shade guide.
Following histological examination performed in 128 of the patients, it was found that staining detected epithelial dysplasia and oral squamous cell carcinoma with a sensitivity of 93.9% and a specificity of 73.7%.
In all, the technique allowed detection of 5 of 6 cases of epithelial dysplasia or squamous cell carcinoma before histological examination.
Given these findings, say the investigators, rose bengal staining "may be a valuable diagnostic test in detection or oral precancerous and malignant lesions."
Int J Cancer 2007;
120:1958-1963.
Serum Phosphorus linked to CVD
17 May 2007
MedWire News: High serum phosphorus levels are associated with an
increased risk of developing cardiovascular disease (CVD) in individuals free
of chronic kidney disease (CKD) or CVD, a community-based study suggests.
The association between phosphorus levels and CVD remained true even when
individuals with evidence of mild renal dysfunction were excluded.
Writing in the Archives of Internal Medicine, Ramachandran Vasan
(National Heart, Lung, and Blood Institute,
But recent data implicating elevated serum phosphorus in the pathogenesis of vascular
disease suggest that serum phosphorus levels within the reference range may
influence CVD risk in the general population, they say.
To investigate, the researchers studied information on phosphorus and calcium
levels and CVD data for 3368 participants of the Framingham Offspring study.
The baseline for the current study was taken as the second examination cycle
between 1979 and 1982, at which time these participants were aged on average 44
years and remained free of CKD and CVD.
Both serum phosphorus and calcium levels were normally distributed in the
population, Vasan et al report.
Phosphorus levels were associated with CVD risk factors, being positively
associated with age, high-sensitivity C-reactive protein level , and total to
high-density lipoprotein cholesterol ratio, and inversely related to body mass
index and systolic blood pressure.
Over an average follow-up period of 16 years, 524 participants experienced a
first CVD event.
There was a significant increase in the risk of CVD with increasing serum
phosphorus levels, at a hazard ratio (HR) for each 1-mg/dl increase in
phosphorus of 1.31.
Individuals in the highest quartile of phosphorus levels were 1.55 times more
likely to experience CVD than those in the lowest quartile.
Moreover, the graded association between serum phosphorus and CVD risk remained
robust when the multivariable analyses were restricted to those individuals
with an estimated glomerular filtration rate (eGFR) greater than 90
ml/min/1.73m2 and without proteinuria.
In contrast, serum calcium levels were not related to incident CVD.
“These observations emphasize the need for additional research to elucidate the
potential link between phosphorus homeostasis and vascular risk,” the
researchers conclude.
Arch Intern Med 2007; 167: 879-885
D-Dimer Identifies Stages in the
Progression of Diabetes Mellitus from Family History of Diabetes to
Cardiovascular Complications
Ezekiel U.
Nwose; Ross S. Richards; Herbert F. Jelinek et al
Aim: The aim of the study
was to ascertain whether there is variation in the fibrinolytic/coagulation
component of diabetes associated with disease progression to macrovascular
complications and whether D-dimer can discriminate such variation.
Methods: A total of 343 participants were selected based on clinical
status and divided into 7 groups: control, family history of diabetes,
pre-diabetes with/without CVD, diabetes with/without CVD and CVD only. Plasma
D-dimer was tested. Statistical analysis was performed on log normalised data
by ANOVA, Fisher's LSD post hoc test. After the initial analysis, data
were classified and re-analysed by quartiles, interquartile range and 95th
percentile.
Results: An overall significant difference between groups (p<0.002)
and a steady rise in D-dimer levels that became increasingly higher than
control as the disease progressed from pre-diabetes to cardiovascular
complications was observed. A statistically significant difference was observed
between control versus diabetes (p<0.0005). Analysis of data by quartiles
and percentiles gave qualitatively similar results, but a greater significant
difference between control versus pre-diabetes at 3rd quartile and
interquartile range (p<0.014).
Conclusion: Authors report
changes in D-dimer levels that may indicate diabetes disease progression to
macrovascular complications. Using D-dimer in conjunction with other biomarkers
to identify stages of disease progression, commencing from pre-diabetes and
continuing to development of asymptomatic and clinical cardiovascular disease
in diabetes mellitus, is worthy of consideration.
Pathology,
Volume 39, Issue
Best Practice in
Primary Care Pathology: Review 7
Abstract
This seventh best-practice review examines four series of common primary care questions in laboratory medicine: (1) blood count abnormalities 2; (2) cardiac troponins; (3) high-density lipoprotein cholesterol; and (4) viral diseases 2. The review is presented in a question answer format, with authorship attributed for each question series. The recommendations are a précis of guidance found using a standardised literature search of national and international guidance notes, consensus statements, health policy documents and evidence-based medicine reviews, supplemented by Medline Embase searches to identify relevant primary research documents. The recommendations are not standards, but form a guide to be set in the clinical context. Most are consensus based rather than evidence based. They will be updated periodically to take account of new information.
BLOOD COUNT ABNORMALITIES 2 (MJG, DB, WSAS, GS, PJC)
This second series of blood count scenarios examines selected abnormalities of white cell counts namely, lymphocytosis, neutropenia and eosinophilia.
As a typical full blood count report may contain >=10 results, values outside the quoted reference ranges occur frequently on a statistical basis. These questions and answers attempt to establish thresholds for clinical action or referral and identify situations that are likely to be of clinical importance. Some (eg, lymphocytosis) are extensively reviewed in existing guidelines, cited as the primary reference sources, whereas others, such as eosinophilia, draw guidance mostly from extrapolation from observational studies
When should I refer an adult patient with a lymphocytosis?
We recommend the following criteria for referral:
· a lymphocytosis (>5.0×109 cells/l), that is not explained clinically by acute, self-limiting viral illness.
· high lymphocyte count in patients previously diagnosed as having stage A chronic lymphocytic leukaemia (CLL) and followed up in primary care, if accompanied by anaemia and/or thrombocytopenia.
· development of any indications for treatment in a patient with grade A CLL being followed up in primary care.
The primary aim of this answer is to establish the need for referral of patients with possible leukaemia or lymphoma. Patients may be found to have a lymphocytosis in the course of routine investigations for unrelated symptoms or as part of health screening. The cause may be an increase in T lymphocytes that is often reactive to an acute illness and is rarely a reflection of malignancy. Alternatively, a B cell lymphocytosis may be present, which may be polyclonal but more often is the result of a clonal lymphoproliferative disorder, usually CLL. Other conditions presenting with a lymphocytosis, such as follicular lymphoma, marginal zone lymphoma, mantle-cell lymphoma or hairy-cell leukaemia, will often have clinical features, such as anaemia, splenomegaly or lymphadenopathy, and the blood film appearances may not be compatible with CLL. Although there is limited clear guidance, it would seem reasonable to wait for an acute viral illness to resolve and recheck the lymphocyte count when a lymphocytosis is associated with features of acute viral illness.
Diagnosis
A definitive diagnosis of CLL is based on the combination of a lymphocytosis >5.0×109 cells/l and a characteristic lymphocyte morphology and immunophenotype. Immunophenotyping is required to accurately classify the nature of the lymphocyte proliferation, thus enabling an appropriate treatment plan to be made. Although some morphological features are associated with the different types of lymphocyte proliferation, these are no longer acceptable as the only means of confirming the diagnosis that will influence the patient’s management. Immunophenotyping is always indicated in patients requiring treatment, in patients with lymphocytosis, that on morphological review is not typical of CLL, and in patients in whom it is thought important to exclude a reactive lymphocytosis. Blood films should be prepared for patients who have lymphocytosis >5×109 cells/l when reviewed for the first time.
When should I refer a patient with lymphocytosis to a haematologist?
Patients with lymphocytosis should be referred for a review by a haematologist if they have lymphadenopathy, splenomegaly, anaemia, thrombocytopenia, or when the blood film reports a lymphocytosis that is not consistent with CLL, or when the lymphocytosis is not explained clinically by an acute self-limiting viral illness.
Clinical follow-up of a patient with grade A CLL
The management of patients with early (stage A) CLL requires a collaborative approach between primary and secondary care. Some patients in stage A are regarded as having “smouldering CLL, characterised by haemoglobin >13 g/dl, lymphocyte count <30×109 cells/l, minimal or no lymphadenopathy and a lymphocyte doubling time >12 months, and these patients have a low progression rate (15% at 5 years, 80% 10-year survival). By contrast, patients with stage B or C disease have a 40% 5-year survival and require early treatment.
By extrapolation from the guidelines of the British Committee for Standards in Haematology, patients with indolent stage A CLL could be monitored in the primary care setting with a FBC every 6 months for the first 2 years. If the lymphocyte count doubles during this time, then the patient should be referred to a haematologist for an assessment. For patients whose lymphocyte count remains stable for this time, there is a low likelihood of the disease progressing, and monitoring can be reduced to an annual FBC. The follow-up of the patients seen initially in hospital who do not require treatment may be organised in primary care, in hospital outpatients or through a home-care service, depending on local resources and patient wishes. Before patients are discharged from the hospital follow-up, a clear management plan should be documented, which should include criteria for re-referral to the haematology service.
UK GMS contract indicator: none.
When should I refer a patient with a low neutrophil count?
Neutropenia is potentially associated with life-threatening infection and we recommend that the following situations are of significance and require referral to secondary care:
Neutrophils <1×109 cells/l and the patient is unwell/febrile: (especially if undergoing cancer chemotherapy): refer urgently for admission.
Neutrophils <1×109 cells/l and the patient is well/afebrile: repeat FBC with blood film examination within 48 h; if neutropenia persists, refer for urgent haematology outpatient department appointment.
Neutrophils 1-1.5×109 cells/l and the patient is well: refer to haematology or discuss with haematologist if neutropenia is progressively severe or persists on two occasions at least 6 weeks apart; or refer to haematology or discuss with haematologist if other blood count abnormality is present and persistent on two occasions at least 6 weeks apart.
Neutropenia is classified as
mild 1.0-1.5×109 cells/l
moderate 0.5 -1.0×109 cells/l
severe <0.5×109 cells/l.
Patients with neutrophil count <1×109 cells/l and fever require urgent, parenteral, broad-spectrum antibiotics, as infection may rapidly progress to established septic shock.
We found no published guidance for referral of patients with mild neutropenia. This guidance is drawn from a consensus of author and reviewer opinion.
Benign ethnic neutropenia is relatively common in individuals of African descent (neutrophil counts down to 1×109 cells/l) and is also seen in some of Middle Eastern extraction. Individuals are physically normal and lack a history of susceptibility to infection. Confirm neutropenia with repeat FBC and confirm normal morphology with blood film.
Transient neutropenia not lasting >2 weeks is usually related to viral infections and not associated with clinical problems. Occasionally, these infections may contribute to mild neutropenia for several months after the illness.
Most severe neutropenias are associated with fever, oral ulceration, and bacterial or fungal infections. The following areas should be reviewed:
History: Frequency and severity of infections, mouth ulcers, recent viral illness, exposure to drugs and toxins, and symptoms of malabsorption.
Drugs: Excluding cancer chemotherapy, the highest-risk categories are antithyroid drugs, trimethoprim sulfamethoxazole, sulfasalazine and neuropsychotropics. Many drugs may cause a chronic mild neutropenia for example, non-steroidal anti-inflammatory drugs, sodium valproate.
Examination: Notably mouth ulcers, fever, signs of infection.
Investigations: Notably whether the full blood count is otherwise normal.
Recurrent fever and oral ulcerations can be due to cyclical neutropenia: a rare autosomal dominant disorder in which neutrophil counts oscillate between 0.1×109 and 1.5×109 cells/l every 21 days. Neutropenic periods last 3-6 days, accompanied by malaise, anorexia, fever, lymphadenopathy and mucosal ulceration. The diagnosis is established by obtaining neutrophil counts twice weekly for a minimum of 6 weeks, but this should not hinder referral of severe neutropenia to secondary care.
UK GMS contract indicator: none.
How should I interpret a raised eosinophil count?
We recommend the following if a patient’s eosinophil count is (persistently) >0.35×109 cells/l or >1.5×109 cells/l:
Clinical history concentrating on allergy/atopy, gastrointestinal, skin, respiratory and joint symptoms, and any change in general health (malignancy) combined, depending on clinical context, with:
blood film (to examine for any morphological abnormality of the eosinophils),
stool parasite examination
urine analysis.
Non-specific allergy testing is not recommended
The upper limit of the reference range for the eosinophil count is >0.35×109 cells/l. Eosinophilia has been subdivided into mild (0.35-1.5), moderate (1.5-5) and severe (>5)×106 cells/l. In a review of 1862 cases studied in an Italian series, the most common causes and frequencies (which include potential drug reactions in several categories) can be summarised as follows:
atopic diseases including asthma 79.7%
parasitic infections 8.2%
haematological neoplasia 2.4%
allergic/atopic skin diseases 2.1%
solid tumours 1.9%
gastrointestinal disease 1.6% (mostly inflammatory bowel disease and coeliac disease)
lung disease 0.8%
connective tissue diseases 0.6%.
These patients were identified from detailed clinical history, and an escalating and extensive series of investigations were performed until a diagnosis was established. A further 2.7% of patients were defined as having eosinophilia of unknown significance.
An additional group of patients has been identified with idiopathic hypereosinophilic syndrome, which by definition excludes all patients with eosinophilia for which a cause can be found. A North American study of incidental eosinophilia (defined as eosinophil count of >5% or >0.7×109 cells/l in this study) in 195 300 automated haematology profiles found that of the 225 cases (0.1% of samples), almost all were attributable to either allergic processes or to known underlying diseases (advanced malignancy, connective tissues disease). Only two cases (patients receiving gold therapy) were both unanticipated and not associated with signs or symptoms of the cause of the eosinophilia. In 30% of cases, no cause was found by the patient’s doctor, although these patients were not subject to the same escalating investigations as in Rothenberg’s report. The authors concluded that repeat blood count and focused investigations (parasitology, skin prick testing depending on clinical context, foreign travel) are sufficient, and that extensive diagnostic testing is unnecessary. Although the great majority of cases will be attributable to common allergic or parasitic disease, a small proportion potentially reflect other serious lung, gastrointestinal, renal autoimmune or malignant disease, although these would be expected to exhibit other signs or symptoms of the disease. In addition, a small number of patients will present with either the hypereosinophilia syndrome or a haematological malignancy in which the only feature may be eosinophilia. Therefore, it would be reasonable to recommend that patients with persistent (>6 months) mild eosinophilia or a finding of moderate or increasing eosinophilia in which the above investigations do not reveal a cause should be referred for immediate assessment. In patients with moderate eosinophilia, if any signs of organ damage are present, as indicated by cardiac or pulmonary symptoms, then the referral should also not be delayed.
Journal of Clinical
Pathology, Volume 60(5), May 2007, pp
458-465
BOTTOM LINE
Mycobacterium
Tuberculosis at Autopsy Exposure and Protection: An Old Adversary Revisited
Abstract
Background: The risk of encountering tuberculosis (TB) has reduced with the decreased incidence of the disease; however, it still can be found at autopsy.
Aim: To assess the magnitude of exposure to Mycobacterium tuberculosis at autopsy in a large general hospital setting, in a country with low incidence.
Methods: Retrospective search of the autopsy records from 1991 to 2004. Patients’ records and histological slides were reviewed, and medical personnel interviewed.
Results: 15 cases of active TB were identified in the 14-year period, during which 4930 autopsies were performed (1 case per 329 autopsies); of these, 10 cases were unsuspected (67%). Five of these cases contained abundant acid-fast bacilli. Patients tended to be middle aged and males with complex clinical histories; two were HIV positive. Two patients were brought in dead to hospital, with no clinical indication of TB. Of 15 autopsy staff, 1 required chemoprophylaxis but none contracted TB.
Conclusion: The risk of unexpectedly encountering TB at autopsy continues even in a low-risk European setting. It has implications for the health of autopsy room staff, autopsy room design and ventilation, choice of protective equipment and for the public health service. Protective strategies include assessment of the risk of a case being infected, early recognition of gross lesions, use of methods for reducing the production of infected aerosols and protection against any aerosols created.
DISCUSSION
This study
indicates that, corresponding to its current lower population incidence in
Clinically
undiagnosed TB makes up a substantial proportion of active TB cases diagnosed
at autopsy. The 67% incidence in this study is similar to figures in older
studies. A total of 70% of cases of active TB were first diagnosed at autopsy
in an Italian study, 44% in a Swiss study and 75% in a Japanese study. A
similar study in
Our results
highlight that complex clinical histories may mask the underlying diagnosis of
TB. Cancers and a history of recent major operations were two major conditions
associated with active TB in a previous study. These were not features in the
current series, where only one unsuspected patient had carcinoma; by contrast,
five had severe ischaemic heart disease. Other reasons cited for both the
inability and delay in diagnosing TB include a low index of clinical suspicion,
clinicians’ inexperience, symptoms
masked by antibiotics, non-specific symptoms, atypical chest x ray findings and the increasing prevalence of
extrapulmonary TB. With the increasing incidence of HIV-associated TB, it is
likely that more cases will present at extrapulmonary sites and with both
atypical symptoms and non-specific chest x ray
findings. In our study, two of the suspected cases were HIV positive, with one
having miliary TB. Notably, both patients were >20 years younger than the
average patient in the study, and one had only recently immigrated to
This study contained three categories of subjects: (a) those suspected or diagnosed before autopsy (n = 5); (b) those first suspected or diagnosed during autopsy (n = 7); and (c) those unsuspected until later review of microscopy (n = 3). It is not possible to quantify the degree of exposure without the use of air sampling techniques, but intuitively the number of organisms seen on ZN staining might provide an approximate quantification. The finding of large numbers of organisms in half the unsuspected cases highlights the significant risk to autopsy personnel of acquiring the disease in the absence of protective measures.
It should be highlighted that for areas where BCG protection is not routinely used, Morbidity and Mortality Weekly Report guidelines, recently updated, suggest that autopsy personnel should have baseline TB screening on hire. Those with negative baseline test results should be screened annually for symptoms and evidence of infection. The recently available interferon gamma release assay tests may serve as a substitute for a skin test in this setting. These in vitro tests are expected to be more specific than tests that use tuberculin-purified protein derivatives.
When TB is unsuspected, early recognition of tuberculous lesions and minimising dissection will minimise aerosols. However, this has become more difficult in modern autopsy practice for several reasons. Prosectors perform fewer autopsies, they are less familiar with the gross appearance of TB because it has now become rare and the learning opportunities of diagnostic and teaching demonstrations on retained organs have virtually ceased because of the organ retention controversy. Previously, if there was even a moderate suspicion of TB, organs were retained for a period (ranging from at least 24 h to weeks) to be sterilised by immersion or perfusion fixation in formalin before dissection. Now, because of the difficulty in obtaining authorisation to retain organs, there is increased pressure to directly dissect suspected tissue, with consequent increased likelihood of infective aerosol production.
Any aerosol produced will be minimised by good autopsy room design and maintenance. Downdraft ventilation takes the infected aerosol away from the prosector face and extracts it from the floor area; negative pressure ensures that adjacent rooms are not contaminated and sufficient changes of air (12/h) is usually recommended to ensure that any dispersed aerosol is removed quickly. Filters for the externally discharged air must be changed regularly to ensure that the ventilation system continues to be effective. Contamination will be more contained (and easier to disinfect) and ventilation systems may be easier to regulate in smaller single-table rooms than in larger open-plan multi-table facilities. Systems that are noisy or produce uncomfortable draughts or variable ambient temperature are unsatisfactory and hazardous as they risk being shut down by staff.
No respirator is fully effective, respirators should be relied on only as a secondary means of protection against airborne toxic material after assessment of the possibility of TB. Simple surgical masks have little protective effect. N95 masks (so called because they exclude > 95% of aerosol particles) provide substantial protection and are reported by many autopsy personnel to be comfortable to wear routinely during all autopsies; (standard precautions suggest that they should be worn in all cases). N99 masks (>99.9% exclusion) are more effective at excluding aerosols, but are also more uncomfortable. Enclosed space-suit type masks give absolute protection but are heavy and hot, may produce fogging of visors or eyeglasses and cause difficulty in talking, factors that may lead to increased risk of cut injury or poor performance of the autopsy.
To prevent cutaneous TB, the Royal College of Pathologists Guidelines (http://www.rcpath.org ) include recommendations on standard autopsy clothing and appropriate gloves double-gloving with both latex and neoprene cut-resistant gloves), together with observation of standard precautions.
Older recommendations, that suggested retention and fixation of suspect organs before dissection have been replaced by recent guidelines (http://www.rcpath.org ), which indicate that dissection may continue with the use of respiratory protection. Although intuitively protective this is not evidence based; many pathologists, especially in the large number of facilities with suboptimal ventilation, would recommend organ retention/fixation (with appropriate consent) before completion of the dissection.
Prolonged stays in hospital with undiagnosed TB can be an important source of the disease for clinical healthcare workers; diagnosis at autopsy may identify this substantial health risk to hospital staff contacts (the average duration of stay in hospital in our study was 18.9 days for unsuspected cases) in addition to contacts in the community before admission. Naalsund et a found in their study of TB autopsies between 1977 and 1989 that 96 patients died from active pulmonary TB and that the median length of stay in hospital was 24 days before death in the untreated group, and 21 days before start of treatment in the treated group. An untreated positive patient is infectious for about 2 years on average, during which time a single patient can infect, on average, 20 contacts. Eight patients and two employees at a chronic care facility had a tuberculin skin test conversion that was ultimately traced to a cadaver diagnosed with TB 3 years previously. Two of the patients in our study arrived dead to the accident and emergency department, which presented challenges in contact tracing. These points emphasise the importance of reporting previously undiagnosed TB to public authorities.
Tuberculosis at autopsy, safety aspects
1. Awareness/risk assessment of deceased
Clinical findings or other suspicions of TB
High-risk group (HIV, steroids, etc)
History of TB:
Sensitive or resistant organism
Adequacy of therapy
2. Minimise aerosol creation
If gross lesions suspected:
Minimise dissection
Consider retaining organ; fix by perfusion or immersion
3. Reduce any aerosol created
Ventilation: downdraft, 12 changes/h, negative pressure
Maintenance: change filters regularly, test ventilation (use smoke test)
Autopsy room design (enclosed single-table room safer than open plan)
4. Protect personnel
Be Mantoux positive; if negative take BCG or frequent Mantoux tests
Personal protective devices: and protection
Routine use of N95 mask
N95, N99 masks or enclosed ventilators in high-risk/suspect cases
Gloves: 2 layers using both latex and neoprene cut-resistant gloves
Minimise number in room if TB suspected
5. Sterilise
Routine disinfection
Decontaminate autopsy room if TB suspected
6. Monitor health of personnel
Awareness/ risk assessment of any illness
Mantoux testing and chest imaging
Medication, prophylactic or therapeutic
Journal
of Clinical Pathology, Volume 60(5), May
2007, pp 487-491