November 2006
ANATOMIC PATHOLOGY
[Editorial]
This issue of Pathology Case Reviews is devoted to the topic of pathology of the thymus and mediastinum. Many advances have been made in recent years in our understanding of tumor processes that may involve this anatomic region. The development of newer monoclonal antibodies, as well as the advent of molecular techniques, has expanded our understanding of neoplastic processes and allowed us to gain insights into some of the diseases that can affect the mediastinum. In the present issue, a variety of different areas and disease processes affecting the thymus and mediastinum is covered, ranging from primary thymic epithelial tumors, neuroendocrine neoplasms, benign conditions that may simulate malignant tumors clinically, ectopic tissues that may give rise to tumors in the anterior mediastinum, unusual soft tissue neoplasms involving the mediastinal compartment, and malignant teratomatous lesions to neuroendocrine neoplasms.
Neuroendocrine carcinomas of the thymus have represented for many years a controversial topic. Although rare, these tumors are responsible for significant morbidity and mortality, and their biologic behavior and spectrum of differentiation in the mediastinum have been poorly understood. Additionally, the proper classification and nomenclature for these tumors in the mediastinal region continue to be controversial. We review the histopathologic spectrum of lesions that may be part of this family of tumors, as well as other related conditions that may enter in their histologic differential diagnosis.
The diagnostic criteria for the classification of primary thymic epithelial neoplasms have also been the subject of much discussion in recent years. In this issue, Drs Mahooti and Wakely discuss the cytologic differential diagnosis of thymoma, with special emphasis on the 2 major morphologic categories of these tumors presented in the new WHO classification. Marchevsky et al present a case of giant cystic hygroma in a child and discuss the clinical and pathologic differential diagnosis of cystic lesions in the mediastinum in the pediatric-age population. Pérez Montiel and DomÃnguez Malagón from the National Cancer Institute in Mexico City, a major referral center for germ cell tumors, share with us their experience with teratomatous lesions that undergo malignant transformation in the mediastinum. Controversies involving the current classification of these tumors are presented, along with a case showing rhabdomyoblastic transformation. The occurrence of tumors arising from ectopic tissues in the mediastinum is another difficult problem in mediastinal pathology. Tumors derived from ectopic thyroid and parathyroid tissue can often present as anterior mediastinal masses in the absence of any detectable pathology in the head and neck region. Identification of these tumors as arising from ectopic elements may be quite daunting, particularly on small biopsy samples. Daum, Mukesnabl, and Michal share with us a case of clear cell parathyroid hyperplasia in the mediastinum and discuss the importance of distinguishing this from a variety of primary and metastatic clear cell tumors in the mediastinum. Finally, rare soft tissue sarcomas can occasionally present as primary mediastinal masses. Seethala and Moran present a case of angiomatoid fibrous histiocytoma arising in the mediastinum and discuss the importance of considering the possibility of this condition in the interpretation of small mediastinoscopic biopsies.
Pathology
Case Reviews, Volume 11(5), September/October 2006, pp 197-198
Lipomatous Tumors as How We Have Reached Our Present Views, What
Controversies Remain and Why We Still Face Diagnostic Problems: A Tribute to Dr
Franz Enzinger
[Review Articles]
Abstract
The group of soft tissue lipomatous tumors constitutes an unusually complex clinical and morphologic mosaic. Over the last 4 decades, there has been great progress in identifying recognizable and reproducible patterns that are of great clinical significance. Through his sharp eyes, analytical and scientific mind, and didactic skills, Dr Franz Enzinger has played a key role in this development. Recent genetic discoveries in the field of lipomatous tumors have confirmed morphologically based theories and provided new insight into pathogenetic mechanisms.
Lipomatous tumors constitute one of the most complex areas of soft tissue pathology with an extremely wide spectrum in terms of incidence, clinical presentation, morphologic appearance, and behavior. This tumor group includes some of the most common human neoplasms as well as extreme rarities, ranging from minute superficial lesions indistinguishable from normal fat to deep-seated masses that are among the largest human tumors bearing no resemblance to normal or embryonal fat.
To a large extent, Dr Franz Enzinger's work over more than 4 decades has formed the current classification and concepts of lipomatous tumors (as in so many other areas). In addition to clearly defining the main subtypes of liposarcoma and their morphologic spectrum, he has identified several previously unknown entities that in the past led to overdiagnoses of malignancy.
This brief overview does not attempt to summarize all current views on lipomatous tumors, but rather highlight some of Dr Enzinger's important contributions, what has been learned since and what problems and controversies still remain.
The current World Health Organization (WHO) classification (2002) of adipocytic tumors includes 12 benign subtypes, 1 intermediate and 5 main types of malignant lipomatous tumors.
BENIGN ADIPOCYTIC TUMORS
These include the very common lipomas (with a very wide spectrum in terms of site, size, growth characteristics, and clinical significance), the relatively common angiolipomas, spindle cell lipomas, and pleomorphic lipomas as well as the more rare lipoblastomas, lipomatosis, myolipomas, chondroid lipomas, extrarenal angiomyolipomas, extra-adrenal myelolipomas, and hibernomas.
Of particular diagnostic importance has been Dr Enzinger's recognition of spindle cell and pleomorphic lipomas and chondroid lipomas, because they in the past were frequently misdiagnosed as liposarcoma or other sarcoma types. In addition, Dr Enzinger and coworkers have also defined the entities of abdominal myolipoma and the distinctive pediatric subgroup of lipofibromatosis and have reported some of the largest and best-defined series of lipoblastomatosis and fibrolipomatous hamartoma of nerve (lipomatosis of nerve).
Lipoblastoma (first reported and named in a case report by Vellios et al in 1958) and diffuse lipoblastomatosis were first truly defined in terms of clinical and morphologic spectrum in the large series (35 cases) reported by Chung and Enzinger in 1973. These lesion, that appear during infancy and typically involve upper and lower extremities, usually present as 3 to 5 cm well-circumscribed superficial masses but may more rarely be large, poorly defined, and diffusely infiltrating underlying skeletal muscle. Morphologically, they closely recapitulate various phases of the normal embryonal adipogenesis and may show a striking resemblance to myxoid liposarcoma that is, however, extremely rare in this age group (see below). A prominent histologic feature is the distinct lobulation with dividing fibrous septa, not usually seen in embryonal liposarcoma. Matured variants typically seen in older children and recurrent lesions may be difficult to distinguish from ordinary lipomas.
Spindle cell lipoma and pleomorphic lipoma, first defined by Enzinger and Harvey in 1975 and by Shmookler and Enzinger in 1981, are today recognized as one of the most common pseudosarcomas. Because of the overlapping morphologic features, the occurrence of hybrid forms and the very similar clinical presentation in terms of age, sex, and site distribution (typically middle-aged and elderly men, in the subcutis of neck, shoulders, and back) they are currently viewed as representing different ends of a continuous spectrum. Even for experienced soft tissue tumor pathologists these tumors sometimes continue to cause problems, particularly the entirely myxoid variants and very cellular, fascicular variants of spindle cell lipoma that may virtually lack any lipomatous component. Difficulties also arise in the pleomorphic lipomas that in addition to the characteristic floretlike giant cells may contain multivacuolated lipoblasts. Another problem are the tumors that have not read the book and occur at unusual, even deep-seated, sites. Both sporadic and familial cases of multicentric spindle cell lipomas have been reported.
Fibrolipomatous hamartoma of nerves (neural fibrolipoma), named lipomatosis of nerve in the current WHO classification, has been described under various names in case reports in the older literature. In 1985 Silverman and Enzinger reported the still largest series (26 cases) of these lesions that typically involve the median or ulnar nerves and digital branches in mostly young and middle aged adults (age range 11 to 39 y). In 1/3 of their cases there was an associated macrodactyly. The hamartomatous nature of the lesions is supported by the histologic features of the clinically enlarged nerves that include epineural and perineural diffuse infiltration of mature adipose tissue and fibrous tissue that tend to be concentrically arranged around the nerve bundles. Attempts to surgically remove these lesions are prone to cause severe nerve damage.
In 1993, Meis and Enzinger described and defined chondroid lipoma as a unique, benign lipomatous tumor simulating myxoid/round cell liposarcoma (MRCLS), or extraskeletal myxoid chondrosarcoma. These rare tumors can occur both superficially and deep and in particular tends to involve extremities and limb girdles. They may reach considerable size, adding to the risk of misdiagnosing them as sarcomas. There is a predilection for adult women but also pediatric cases do occur. Subsequent ultrastructural and immunohistochemical studies have shown that chondroid lipomas are truly biphenotypic with both lipoblastic differentiation and features of primitive cartilage
Myolipoma, first described by Meis and Enzinger in 1991, is a rare lesion predominantly seen in women and mostly in deep soft tissues, particularly within the abdomen and retroperitoneum, but occasionally also occurring more superficially in the abdominal wall and groins. This entirely benign lesion, composed of a usually dominating bland smooth muscle component intermingled with mature looking fat, should not be mistaken for angiomyolipoma, dedifferentiated liposarcoma with a smooth muscle component or the so-called lipoleiomyosarcoma
On the basis of a study of a large series (45 cases) from the AFIP lipofibromatosis, has been suggested as a unifying term for a group of pediatric lesions predominantly occurring in the hands and feet. These lesions, composed of adipose tissue and spindled fibroblastic elements, involving fibrous septa in fat and skeletal muscle, had previously been classified as various types of infantile or juvenile fibromatosis, fibrous hamartoma of infancy, or fibrosing variants of lipoblastoma. Recurrent or persistent tumor was seen in almost 3 quarters of the patients.
INTERMEDIATE AND MALIGNANT ADIPOCYTIC TUMORS
Traditionally, liposarcoma is defined as a malignant mesenchymal neoplasm exhibiting features of adipocytic differentiation usually in the form of tumor cells resembling embryonal fat cells, so-called lipoblasts (complications of this diagnostic approach are outlined below). However, the diversity and complexity of this group of sarcomas, being one of the most common among soft tissue sarcomas, is such that the term liposarcoma becomes meaningless unless qualified by subtype and indication of their malignant potential. In the early literature (starting with Virchow in 1857) the terminology for various subtypes are quite confusing (for a review see Kindblom et al. In the classic work of Enzinger and Winslow published in 1962, it is stated that among mesenchymal tumors, liposarcomas are probably unsurpassed by their wide range in structure and behavior and that they should rather be regarded as a group of related neoplasms than a well-defined entity. Their proposed classification of liposarcomas in 1 group of well-differentiated liposarcoma, 1 group of myxoid and round cell liposarcoma, and 1 group of pleomorphic liposarcoma, was shown to be of great prognostic significance and is largely unchanged since then. The so-called dedifferentiated liposarcoma, now added to the current WHO classification, is a variant of well-differentiated liposarcoma with progression to a usually high grade, nonlipogenic sarcoma.
Atypical lipoma, atypical lipomatous tumor, and well-differentiated liposarcoma are all terms that have been used for the most well-differentiated liposarcomas that without progression (differentiation) never metastasize. In the current WHO classification, these tumors have been grouped under the intermediate malignancy label. The terms atypical lipoma and atypical lipomatous tumor were originally introduced to emphasize their almost invariably nonaggressive behavior, as long as they occurred outside the abdomen/retroperitoneum. The striking tendency for the tumors occurring in the abdomen/retroperitoneum and groin areas to recur and not infrequently progress to higher grade sarcomas and eventually lead to the patients death, has motivated most soft tissue pathologists to retain the term well-differentiated liposarcoma. Also the deep-seated extremity tumors may, even if much less frequent, recur repeatedly and occasionally show dedifferentiation. It has therefore been suggested to use the term atypical lipomatous tumor only for the superficial, subcutaneous ones. In any case, irrespective of terminology, it is important for us as pathologists to convey to the clinicians the current knowledge of their behavior. Whether the dramatic difference in prognosis between the superficial atypical lipomatous tumors and the retroperitoneal tumors with an identical morphology is only a time-dependent phenomenon or indicate some true biologic differences remains unclear.
Four main subtypes of atypical lipomatous tumor/well-differentiated liposarcoma are recognized in the current WHO classification: the common lipomalike and sclerosing subtypes that frequently are mixed and the much rarer inflammatory and spindle cell variants. Such low-grade spindle cell variants may occasionally progress to higher grade fibrosarcomalike and malignant fibrous histiocytoma (MFH)-like sarcomas. Interestingly, Enzinger and Weiss in the third edition of their textbook on soft tissue tumors illustrate spindle cell liposarcomas (seemingly indistinguishable from those illustrated by Dei Tos et al as a part of the myxoid liposarcoma spectrum. Whether these spindle cell liposarcomas truly represents a distinct subgroup or only a pattern occurring in different liposarcoma settings remains somewhat unclear. We have also seen such low-grade spindle cell liposarcoma areas as part of both myxoid and pleomorphic liposarcomas as well as in low-grade areas of dedifferentiated liposarcomas with sometimes gradual transition to high-grade fibrosarcomatous areas.
Dedifferentiated liposarcoma (DDLS) was originally defined as a well-differentiated liposarcoma juxtaposed to a high-grade nonlipogenic sarcoma component. Such tumors had earlier been described in descriptive terms as well-differentiated liposarcomas mixed with various types of high-grade sarcoma patterns. DDLS are by far most commonly seen in the abdomen retroperitoneum, followed by deep soft tissues of the extremities, trunk, and head and neck areas; they are exceedingly rarely seen in the subcutis. In most cases, the high-grade areas are recognized from the onset; in some cases, however, they occur first in recurrences. Many times the high-grade areas dominate and the well-differentiated lipomalike areas can only be found after careful search (generous sampling is therefore important!). Particularly when diagnosing abdominal/retroperitoneal tumors in needle biopsies, close review of imaging studies is essential to detect the composite nature of these DDLS. The high-grade components can attain a wide range of appearances; MFH, myxofibrosacoma, and fibrosarcomalike features are the most common; both leiomyomatous and rhabdomyomatous differentiation can be seen as well as hemangiopericytomalike areas and cartilage and ostoid/bone matrix producing tumor components. A peculiar morphologic variant is the neural-like or meningothelial-like whirling pattern that can be seen associated with metaplastic bone formation. In rare instances, the dedifferentiated component has had features of so-called inflammatory MFH; such cases have presented with a leukemoid blood reaction.
More recently, the concept of DDLS has widened because it has been recognized that the dedifferentiated component may be of lower grade, resembling fibromatosis and low-grade fibrosarcoma. It is not always obvious where to draw the line between low-grade variants of DDLS and well-differentiated liposarcomas with focal progression to somewhat higher grade spindle type liposarcomas.
The outcome of DDLS depends largely on tumor site; the most common abdominal retroperitoneal tumors tend to recur repeatedly and often succumb from local complications. Extra-abdominal and retroperitoneal metastases are surprisingly rare for such high-grade sarcomas, suggesting a divergent biology. It has been argued, however, that this may partly be a time related phenomenon because many patients die relatively early in the course from local complications. The extremity located DDLS do significantly better.
The MRCLS group is the most common and represent close to half of all liposarcomas. As pointed out already in Enzinger's and Winslow's original work the purely myxoid and solid round cell patterns represent different ends of a continuous spectrum. That these tumors all belong to the same family is supported by their similar clinical characteristics, the frequent occurrence of intermediate and hybrid forms and more lately the unique karyotypic and molecular genetic findings (see below). Most of these tumors have features of classic myxoid liposarcoma or mixed/intermediate myxoid-round cell liposarcoma, whereas the purely round cell type is extremely rare.
In very rare instances MRCLS may present cartilage, osseous, and leiomyomatous and exceptionally even rhabdomyoblastic differentiation. Rarely, MRCLS may also contain dedifferentiated areas similar to that seen in well-differentiated liposarcoma.
A puzzling phenomenon described and discussed in detail already in Enzinger's and Winslow's original work, is the so-called multicentric MRCLS. In this condition, numerous tumors occur in various soft tissue sites and at other locations rarely affected by metastases. We have seen such patients develop up to 31 tumors over a 10-year period. Molecular genetic demonstration of monoclonality of such tumors in a single patient has confirmed that this indeed is an unusual presentation of metastatic disease.
There is an extensive literature testifying the adverse prognostic impact of increasing cellularity and occurrence of round cell components in these tumors. Enzinger and Winslow reported a 5-year survival of 77% for the purely myxoid subtype as opposed to 18% for the mixed myxoid-round cell and purely round cell types. We found 5-year survivals for purely myxoid, mixed myxoid/round cell, and purely round cell liposarcomas to be 80%, 40%, and 15%, respectively. Many have subsequently attempted to refine the prognostication of these tumors by introducing different criteria for where to draw the line between cellular myxoid liposarcoma and round cell liposarcoma and in particular a number of different percentage cut off points for the round cell component have been suggested. A worse prognosis has been seen in tumors with round cell components ranging from 5% to 25%. A disadvantage of simply applying a percentage approach is of course that this does not take into account the tumor size factor that is probably of great importance, as in most high-grade sarcomas.
Pleomorphic liposarcoma is the rarest type. They constitute probably less than 10% of liposarcomas. These typically deep-seated sarcomas occur predominantly in the extremities, more rarely in the trunk and retroperitoneum, and involve mostly elderly. Histologically, a number of patterns have been reported including the most common MFH-like, the lipoblastic type with numerous smaller or gigantic, multinucleated, bizarre lipoblasts, epitheloid type and myxofibrosarcomalike types. We have also seen an unusual small cell variant that may closely resemble round cell liposarcoma, but are clearly distinguished from these by the cytogenetic findings. Pleomorphic liposarcoma has an aggressive behavior with 5-year disease-free survival figures ranging from 40% to virtually 0%.
Liposarcoma occurring in children is extremely rare. In 1983, Shmookler and Enzinger reported the by far largest series of childhood (age range 8 mo to 15 y) liposarcomas (17 cases) and critically reviewed previous case reports in the literature, scoring their degree of belief or rather disbelief! Undoubtedly, true childhood liposarcomas are extreme rarities with probably in the past most reported cases having been misdiagnosed instances of lipoblastoma(tosis) and possibly chondroid lipoma that may be seen in children. The well-documented cases of true childhood liposarcoma occur mostly in children more than 10 years of age and are with very few exceptions of the myxoid-round cell type.
WHAT HAVE WE LEARNED FROM ADJUNCTIVE TECHNIQUES?
Over the years depending on the popularity and availability of different techniques, lipomatous tumors have been extensively studied with histochemistry (in particular to identify fat content and to characterize the nature of the myxoid matrix), electron-microscopy (eg. showing similarities with normal embryonal adipogenesis and documenting complex lines of differentiation) and immunohistochemistry (reporting among others the usefulness of S-100 protein and CD34 as markers). Overall, however, such techniques play a little role in the every day diagnosis of lipomatous tumors; traditional evaluation of histology combined with careful clinical correlation remains the basis for most diagnosis. The details of such adjunctive studies are not in the scope of this short summary.
In contrast, the more recent cytogenetic and molecular genetic studies of lipomatous tumors have been remarkably successful giving new insight into the biologic relationship between different morphologic variants, helped to support the correctness of morphologic classifications and have in some instances revealed pathogenetic mechanisms involved. Cytogenetic techniques have become useful diagnostic tools. For instance is the t(12;16)(q13;p11) causing the FUS/DDIT3 fusion highly sensitive and specific for myxoid-round cell liposarcomas.
WHY DO WE STILL FACE DIAGNOSTIC PROBLEMS?
The reasons for continuous diagnostic problems are many: the rarity and complexity of some of these lesions, the occurrence of lesions that do not fit well into our present ideas of tumor classification, the sometimes unpleasant feeling of being at the mercy of the surgeon that taken a biopsy of questionable representativity etc. From our experience of consultation cases the main reasons seems to be:
1. The belief that a liposarcoma diagnosis cannot be made without the demonstration of lipoblasts and that the finding of lipoblasts automatically indicates such a diagnosis has been difficult to eradicate. As we all know true lipoblasts (not lipoblastlike cells or pseudolipoblasts!) are seen in a number of benign lesions such as spindle cell/pleomorphic lipoma, chondroid lipoma, and of course lipoblastoma. Conversely, lipoblasts may be totally absent in well-differentiated liposarcomas, some myxoid liposarcomas, and occasional very primitive round cell liposarcomas (the true nature of which may be revealed by cytogenetic analysis). At times the MFH-like pleomorphic liposarcomas only reveal occasional bizarre lipoblasts after painstaking sampling suggesting that they are clearly underdiagnosed.
2. Lipoblastlike cells can occur in a number of neoplasms and reactive conditions. Particularly common is juicy looking areas with vacuolated macrophages in fat necrosis that may be seen in lipomas, reactions around ruptured silicone implants, and other injected compounds. Severely atrophic fat may get a worrisome appearance as may fat invaded by various neoplasms. Mucin containing cells in carcinomas and tumor cells of myxofibrosarcoma and acral myxoinflammatory fibroblastic sarcoma may very closely simulate lipoblasts. Fixation artifacts may lead to similar morphology. A number of these examples have been illustrated in detail in the latest edition of the Enzinger and Weiss's soft tissue tumor book.
3. To interpret biopsies from lipomatous tumors, particularly needle biopsies, is treacherous if not done in close conjunction with all pertinent clinical information, including imaging studies. To always think twice before making a liposarcoma diagnosis in children and in superficial lesions is a good rule, but it should be remembered that pediatric liposarcomas (almost exclusively MRCLS) occur as do superficial liposarcomas. Another good rule is to think twice before making a benign lipoma diagnosis in large fatty tumors of the abdomen retoperitoneum, groin, and perifunicular and paratesticular areas.
4. It can be seen as part of the spectrum of heterologous components of nonmesenchymal tumors such as carcinosarcoma and malignant mixed Mullerian tumors.
Advances in Anatomic Pathology, Volume
13(6), November 2006, pp 279-285
Histopathological outcome of 597
isolated soft tissue tumors suspected of soft tissue
sarcoma: A single-center 12-year experience
Leinung S, Mobius
C, Udelnow A, et al
BACKGROUND: The aim of this present report was to analyze the patients referred
to us with the presumptive diagnosis of soft tissue sarcoma (STS).
METHODS: Authors reviewed all patients referred to us with suspected soft tissue sarcoma (STS) of the extremities or trunk over a 12-year period.
RESULTS: Authors treated 597 patients with soft tissue tumors. Open biopsy revealed soft tissue sarcoma in 318 cases, benign mesenchymal tumor in 124 cases and isolated metastases (ISTM) from carcinomas in 98 patients; other pathologies were found in 57 patients. The primary carcinomas were lung cancer in 26 patients, breast cancer in 19 patients, renal carcinoma in 16 patients, carcinoma of the esophagus in 12 patients, colonic carcinoma in 5 patients, thyroid gland cancer in 6 patients, and in 14 patients carcinoma of unknown primary was diagnosed.
CONCLUSIONS: In authors collection of the
soft tissue tumors, 50% of the patients had the
diagnosis of soft tissue sarcoma, 20% presented with a metastasis of carcinoma
and 20% had a benign tumor. Referring to our results,
in patients with the presumptive diagnosis of soft tissue sarcomas, soft tissue
metastasis of a primary carcinoma was unexpectedly common, indicating that
greater consideration should be given to this differential diagnosis.
Eur J Surg Oncol. 2006 Oct 30; [Epub ahead of print]
True
smooth muscle neoplasms of the gastrointestinal
tract: morphological spectrum and classification in a series of 85 cases from a
single institute
Agaimy A, Wunsch
PH.
BACKGROUND AND AIM: True smooth-muscle neoplasms of the GI tract have been only rarely studied in the KIT era. Their incidence among other GI mesenchymal tumours and their clinicopathological spectrum have not been sufficiently analysed. MATERIALS AND METHODS: Authors reviewed all GI mesenchymal lesions at the Pathology Institute of the Nuremberg Clinic Centre from 1994 through 2005. RESULTS: Among 262 lesions, there were 142 GISTs (54%) and 85 true smooth muscle neoplasms (32%). Smooth muscle neoplasms comprised 72 polypoid leiomyomas (78%, 5 oesophageal and 67 colorectal), 10 intramural leiomyomas (11%, 5 oesophageal, 4 gastric and one ileal), two intramural leiomyosarcomas in the sigmoid colon and ileum (2%) and one polypoid leiomyosarcoma involving the stomach, descending colon and the retroperitoneum concurrently. None of the leiomyomas with available follow-up have recurred or metastasised.
CONCLUSION:
Smooth muscle neoplasms are the second most common mesenchymal neoplasms in the GI
tract after GISTs. They may arise either from the muscularis mucosae or proper
muscle layer forming polypoid and intramural lesions,
respectively. Polypoid leiomyomas
are more common in the rectosigmoid, while intramural
ones mainly arise in the vicinity of the oesophagogastric
junction. Polypoid leiomyomas
are sufficiently treated by endoscopic resection, and
local surgical excision is the treatment of choice for intramural leiomyomas. Intramural leiomyosarcomas
are rare high-grade sarcomas that commonly have infiltrated into the
surrounding tissue or metastasised by the time of diagnosis.
Langenbecks Arch Surg. 2006 Sep
21; [Epub ahead of print]
Histological assessment of
non-alcoholic fatty liver disease
Hübscher S G
Non-alcoholic fatty liver disease (NAFLD) is an important complication of the metabolic syndrome, which is becoming an increasingly common cause of chronic liver disease. Histological changes typically mainly affect perivenular regions of the liver parenchyma and include an overlapping spectrum of steatosis, steatohepatitis and persinusoidal or pericellular fibrosis, in some cases leading to cirrhosis. Once cirrhosis has developed, typical hepatocellular changes are often no longer conspicuous, leading to such cases being mistakenly diagnosed as 'cryptogenic'. Portal inflammation, ductular reaction and periportal fibrosis can also be seen as part of the morphological spectrum of NAFLD, particularly in the paediatric population. Hepatocellular carcinoma has also been described as a complication of NAFLD-associated cirrhosis. NAFLD is also an important cofactor in other chronic liver diseases, especially hepatitis C. Histological assessments have an important role to play in the diagnosis and management of NAFLD. These include making the potentially important distinction between simple steatosis and steatohepatitis and providing pointers to the aetiology, including cases where a dual pathology exists. A number of systems have been devised for grading and staging the severity of fatty liver disease. These require further evaluation, but have a potentially important role to play in determining prognosis and monitoring therapeutic responses.
Histopathology, Volume
49, Page 450 - November 2006
"In
situ-like" mantle cell lymphoma: a report of two cases
Richard P, Vassallo J, Valmary S et al
Mantle cell lymphoma (MCL) is a B cell neoplasm that most often shows a diffuse
growth pattern. Two cases of MCL are reported here, both with a previous
diagnosis of lymphoid hyperplasia. Morphologically, germinal centres are
hyperplasic with a normal or discretely enlarged mantle zone, where foci of
irregularly shaped small lymphocytes are seen. These are positive for CD20, CD5
and cyclin D1, confirming a diagnosis of in situ-like
MCL. This type differs from the mantle zone pattern in that the neoplastic mantle zone is very thin and there is very
little or no spread of tumour cells into interfollicular
areas. To the best of our knowledge, this is the first report on such a pattern
of MCL, which is important to recognise, as it can be confused with lymphoid
hyperplasia.
J Clin Pathol. 2006 Sep; 59(9):995-6.
An In-depth Look at Krukenberg
Tumor: An Overview
Osama M. Al-Agha, Anthony D. Nicastri
Krukenberg tumor is an uncommon metastatic tumor of the ovary. This article provides an overview of the major pathologic manifestations of Krukenberg tumor, patient characteristics, clinical and laboratory features of the disease, prognostic factors, and current knowledge about its pathogenesis. Pathologists have to be familiar with the diagnostic histopathologic features of the tumor and its principal differential diagnoses. Awareness of the diagnostic manifestations of the tumor leads to the correct diagnosis and prevents tumor misclassification, thus avoiding improper clinical management. The article also addresses the potential clinical utility of serum CA 125 in patients with Krukenberg tumors. Prognosis of Krukenberg tumor is still very poor but our review of the literature reveals several factors that appear to have an impact on survival. There is no established treatment for Krukenberg tumors. A national registry and prospective studies are needed to set a therapeutic approach for Krukenberg tumors in the hope of improving the survival rate.
PATHOLOGIC FEATURES
Gross
Features
Krukenberg tumors are bilateral in more than 80% of the reported cases. The ovaries are usually asymmetrically enlarged, with a bosselated contour. The sectioned surfaces are yellow or white; they are usually solid, although they are occasionally cystic. Importantly, the capsular surface of the ovaries with Krukenberg tumors is typically smooth and free of adhesions or peritoneal deposits. Of note, other metastatic tumors to the ovary tend to be associated with surface implants. This may explain why the gross morphology of Krukenberg tumor can deceptively appear as a primary ovarian tumor. However, bilateralism in Krukenberg tumor is consistent with its metastatic nature.
Microscopic Features
Microscopically, Krukenberg tumor has 2 components: epithelial and stromal. The epithelial component is composed chiefly of mucin-laden signet ring cells with eccentric hyperchromatic nuclei. The cytoplasm of the signet ring cells can be eosinophilic and granular, pale and vacuolated, or it can have a bull's eye (targetoid) appearance containing a large vacuole with a central to paracentral eosinophilic body composed of a droplet of mucin. Some tumor cells may lack a mucin vacuole. Mitotic activity is sparse. The signet ring cells can be single, clustered, nested, or they can be arranged in tubules, acini, trabeculae, or cords. Several different patterns can appear in one tumor. Krukenberg tumors displaying a predominantly tubular pattern have been subclassified as tubular Krukenberg to distinguish them from the classic type. In tubular Krukenberg tumors, the signet ring cells are present in tubules and intermingled with stromal cells. The histochemical identification of intracytoplasmic mucin in the signet ring cells is essential for Krukenberg tumor diagnosis. Because the intracytoplasmic mucins of the signet ring cells are neutral and acidic (mostly sialomucins), they stain with Mayer mucicarmine, periodic acid– Schiff with diastase digestion, and Alcian blue stains. Immunohistochemically, the tumor cells are immunoreactive to epithelial markers, such as cytokeratins (AE1/AE3), and epithelial membrane antigen, and they do not show immunoreactivity to vimentin and inhibin. The mesenchymal component of Krukenberg tumor is of ovarian stromal origin and is composed of plump and spindle-shaped cells with minimal cytologic atypia or mitotic activity. Stromal edema can be present focally but is sometimes diffuse and marked to the extent of forming pseudocysts. Sometimes the desmoplastic reaction in the stroma can be so intense that it obscures the signet ring pattern of the tumor, rendering its diagnosis challenging, and possibly confused with fibromas. Mucin-special stains can highlight the signet ring cells, facilitating the correct diagnosis
CA 125 IN KRUKENBERG TUMOR
Preoperative serum CA 125 levels in patients with
Krukenberg tumors can be elevated, though they
subsequently decrease after tumor resection. On the basis of this observation,
serum CA 125 level can be used for (1) postoperative follow-up of patients for
evaluation of complete resection of the tumor, and (2) follow-up of patients
with a history of primary adenocarcinomas
(gastrointestinal, in particular) for early detection of ovarian metastasis.
IMMUNOHISTOCHEMISTRY IN THE DISTINCTION OF METASTATIC CARCINOMAS FROM PRIMARY OVARIAN NEOPLASMS
Immunohistochemical evaluation may aid in distinguishing primary ovarian carcinomas from metastatic carcinomas. Cytokeratins 7 and 20 (CK7 and CK20) immunophenotype is the most commonly used analysis. Primary ovarian carcinomas are almost always immunoreactive to CK7 (90%–100%) but generally are not immunoreactive to CK20. By contrast, metastatic gastric carcinoma tends to be less frequently positive for CK7 (55%) but is positive for CK20 in approximately 70% of cases. Colorectal adenocarcinomas are usually negative for CK7 but positive for CK20 in most cases. Tumors metastasizing from the appendix are commonly positive for CK20 but positive also for CK7 in 50% of cases. Therefore, a CK7+/CK20− immunophenotype favors a primary ovarian carcinoma, whereas a CK7−/CK20+ or CK7+/CK20+ immunophenotype (CK20 positivity, in particular) favors a metastatic gastrointestinal carcinoma.
Use of source-specific antibodies can increase the diagnostic confidence. For example, immunoreactivity for carcinoembryonic antigen and CDX2 together with the immunoexpression pattern of CK7−/CK20+ increases the confidence in pointing toward the colorectal origin of the primary.
Archives of Pathology and Laboratory Medicine: Vol. 130, No. 11,
pp. 1725–1730.
MICROBIOLOGY
Nosocomial Tuberculosis in India
Madhukar Pai, Shriprakash Kalantri, Ashutosh Nath Aggarwal et al
Most high-income countries implement tuberculosis
(TB) infection control programs to reduce the risk for nosocomial
transmission. However, such control programs are not routinely implemented in
The risk that Mycobacterium tuberculosis can be transmitted from patients with active tuberculosis (TB) to other patients and healthcare workers has been recognized for many years. The level of risk varies by setting, occupation, patient population, and effectiveness of TB infection control measures but is higher in facilities that manage large numbers of smear-positive TB patients who do not receive rapid diagnosis, isolation, and treatment, particularly in the absence of other infection control measures). A hierarchy of control measures, including administrative, engineering, and environmental controls and personal protection measures, has been recommended to reduce nosocomial TB risk. These recommended measures are implemented by healthcare facilities in high-income countries, but given their high cost, few facilities in low-income countries can afford to implement them.
The World Health Organization (WHO) has proposed practical and low-cost interventions to reduce nosocomial transmission in settings where resources are limited. These recommendations emphasize prompt diagnosis and rapid treatment of TB rather than expensive technologies, such as isolation rooms and respirators. However, despite the widespread implementation of the directly observed therapy, short course (DOTS) strategy, which is internationally recommended, compliance with these simpler guidelines is generally poor in low-income countries.
In general, the primary focus of national TB
programs in high-prevalence, low-income countries is
to expand basic DOTS services. Typically, nosocomial
transmission is ignored, given countries' limited resources, but several
factors illustrate that nosocomial TB must be
addressed, even in such areas. First, nosocomial
transmission is of concern because it affects not only patients who are exposed
but also the healthcare workforce, which could adversely affect healthcare
services over time. Second, transmission of TB can have serious consequences,
particularly with multidrug-resistant TB (MDRTB).
Several outbreaks in the
These outbreaks can be explosive and associated with high death rates because
hospitalized patients are often immunocompromised.
Therefore, interventions to reduce nosocomial
transmission of TB are useful and cost-effective preventive measures to control
TB, including MDRTB, particularly in tertiary care settings.
Third, nosocomial TB
must be addressed because it can help the healthcare system, particularly the
private health sector, improve TB diagnosis and treatment and better align
practices with the DOTS strategy. For example, detecting smear-positive TB with
microscopy is a key component of the DOTS strategy and an important
administrative infection control measure. However, several studies have shown
that private practitioners in
Fourth, even though low-income countries have fewer resources, ignoring a potential hazard runs contrary to the principles of protecting human health, the cornerstone of health care in any country. Finally, the problem of controlling TB in hospitals is not a problem with TB alone but reflects a problem with infection control in general, which, if improved, could also prevent other infectious diseases (e.g., severe acute respiratory syndrome and avian influenza) that may be nosocomially transmitted. Thus, TB infection control programs can have secondary benefits. Ultimately, preventing outbreaks and protecting patients and staff are in the interests of healthcare facilities. TB infection control is a good starting point for such efforts.
In this article, we focus on
Nosocomial TB in India
Despite the prevalence of TB in
At a rural medical school hospital in Sevagram, Pai et al. performed
the tuberculin skin test (TST) and a whole-blood interferon-γ release
assay (IGRA) for 726 healthcare workers; 50% were positive by either TST or
IGRA. Nearly 70% of the participants reported direct contact with sputum
smear–positive TB patients. Exposure was particularly high among physicians in
training, attending physicians, and nurses. Increasing age and duration of
employment were risk factors for latent TB infection. Nurses, nursing students,
orderlies, and laboratory staff had higher prevalence of latent infection. A
repeat survey of 216 medical and nursing students in this cohort enabled
estimation of the annual risk for latent infection by using TST and IGRA. When
both tests were used, the annual risk for latent TB infection was estimated to
be 5%. The estimated community-based annual risk for infection in
At a tertiary care hospital in
In a retrospective review of healthcare workers who underwent anti-TB treatment in a tertiary care hospital in Vellore, Gopinath et al. identified 125 healthcare workers who had been treated for active TB between 1992 and 2001. The annual incidence of pulmonary TB was 0.35–1.80 per 1,000 persons during this period. The annual incidence of extrapulmonary TB was 0.34–1.57 per 1,000. These rates may have been underestimated because only healthcare workers who underwent TB treatment were counted. In this hospital, a case-control study showed that low body mass index and employment in medical wards were risk factors for TB disease among healthcare workers.
In a molecular epidemiologic study at a TB
hospital in
In summary, these studies suggest that nosocomial transmission of TB is a problem in
The predominance of extrapulmonary (mostly pleural) disease among healthcare workers may indicate progression to disease from newly acquired primary infection rather than reactivation of latent TB. Molecular epidemiologic studies suggest that pleural TB is different from other forms of extrapulmonary TB and is associated with the highest fingerprint clustering rate of all forms of TB, which suggests that pleural TB may be an early manifestation of recent infection. Lastly, although this assumption is based on limited data, nosocomial transmission of TB among hospitalized patients may occur in urban hospitals.
Factors That May Facilitate Nosocomial Transmission
Several factors may facilitate nosocomial transmission in Indian hospitals, although their
relative importance in facilitating transmission is unknown. The overwhelming
number of TB patients and repeated exposures to smear-positive TB patients are
likely to be critical factors. The RNTCP alone starts treatment for >100,000
patients every month, and thousands more are managed in the private sector.
Repeated exposure of trainees is particularly worrisome, given the lack of TB
infection control measures at most healthcare facilities. In
Delays in diagnosis and initiation of treatment
and failure to separate or isolate patients with smear-positive TB from other
patients also contribute to transmission risk. Previous studies in
Several factors might prolong infectiousness of TB patients and thereby facilitate nosocomial transmission. Poor adherence to treatment, lack of continuous drug supply, use of suboptimal treatment regimens, lack of adequate treatment support (e.g., direct observation of therapy [DOT]), and insufficient treatment duration have been reported, particularly in the private sector.
Few hospitals in
Previous surveys have identified gaps in
knowledge and awareness about TB in healthcare workers in
Other surveys have reported similar findings in
Call for Research and Action
Despite
After assessing the disease prevalence, risk
factors, and resources,
In conclusion, healthcare workers are essential
in the fight against TB, and their health needs to be protected.
EID Journal, Volume 12, Number 9–September 2006
CLINICAL
PATHOLOGY
Leukocyte count linked to reperfusion
success
Leukocyte count gives an indication of myocardial reperfusion success following
primary percutaneous coronary intervention (PCI)
treatment for acute myocardial infarction (AMI), Italian study findings
suggest.
Researchers found that low monocyte and neutrophil counts in the days after AMI were related to myocardial blush grade (MBG) and ST-segment resolution, both reliable markers of effective myocardial reperfusion, after primary PCI. The team therefore proposes that increases in these counts "may be used as a non-invasive marker of failed or incomplete myocardial reperfusion."
Matteo Mariani (Ospedale Civile di Legnano,
To investigate the established link between increased leukocyte counts and an
adverse outcome following AMI in more detail, the team studied total and
differential white blood cell counts in 238 patients with AMI, on their
admission to hospital, and then every 24 hours for at least 4 days after they
underwent primary PCI.
ST-segment resolution and MBG were evaluated immediately after the
procedure, and
The 162 (68%) patients with ST-segment resolution had a higher
frequency of MBG 2-3, a lower frequency of anterior MI, a lower peak creatinine kinase (CK), and lower
monocyte and neutrophil
peaks than those without ST-segment resolution.
Of note, linear regression analysis showed that the total white blood cell
(WBC) count was significantly inversely related to MBG 2-3 (p<0.001) and
6-month LV functional recovery (p=0.013), as well as being positively
associated with peak CK (p<0.001), and multivessel
coronary disease (p=0.0017).
Both monocyte and neutrophil
peaks were inversely related to MBG, (p=0.000 and p<0.001, respectively),
peak CK (both p<0.001), and 6-month
In multiple regression analysis, monocyte
count, along with MBG, CK peak, diabetes, and ischemic time were again
associated with 6-month
”In conclusion, the present study shows that neutrophil
and monocyte counts on the first days after acute MI
treated with successful primary PCI are related to markers of effective
myocardial reperfusion such as MBG and ST-segment resolution” the authors
write.
“However, only monocyte number and MBG are
significantly and independently associated with the contractile recovery of the
infarcted area at 6 months.”
Eur Heart J 2006; 27: 2511-2515
False Positive Cardiac
Troponin Results in Patients Without
Acute Myocardial Infarction
Gifford Lum, David E. Solarz,
Linda Farney
Cardiac troponin I (cTnI) and T (cTnT) are highly sensitive and specific biochemical markers for myocardial necrosis and are generally not elevated in cases other than acute myocardial infarction (AMI) and acute coronary syndrome (ACS). However, if the patient's clinical picture for AMI or ACS do not match an elevated troponin result, the laboratory should suspect a false positive troponin value caused by analytical interferences with this assay. These analytic interferences include fibrin clots, microparticles in sample, hetereophile and human anti-animal antibodies, rheumatoid factor, interference by bilirubin, hemolysis, lipemia, elevated alkaline phosphatase activity, macro immunocomplex formation, and analyzer malfunction. In general, analytical interferences resulting in false positive troponin results are associated with a specific manufacturer's troponin assay and are not encountered in all troponin assays. This review discusses steps which the laboratory should consider taking in the investigation of suspected analytical interference with the troponin assay. Awareness of the possibility of a false positive troponin result may assist the physician in the management of the patient without AMI or ACS and may spare the patient additional diagnostic procedures especially if the troponin result is not consistent with these diagnoses. A false positive troponin result is a reminder that although troponin plays an important role in the diagnosis of AMI and ACS, it should not be the only criterion for establishing these diagnoses.
A variety of clinical conditions other than myocardial infarction may be associated with elevated cardiac troponin levels; these conditions include acute pulmonary embolism, acute or severe heart failure, myocarditis, sepsis/critically ill patients, acute pericarditis, renal failure, hypovolemia, cerebrovascular accidents, tachyarrythmias, myocardial contusion, and takotsubo cardiomyopathy, reversible left ventricular dysfunction associated with emotional stress with evidence of exaggerated sympathetic activation. In addition, false elevations in patients without myocardial infarction may also occur because of analytical interferences with the troponin immunoassay.
Authors have encountered recently a case of a patient with a persistently elevated troponin I value without a clear clinical picture of myocardial infarction to illustrate a false positive troponin I result caused by analytical interference and to discuss the causes for the false positive troponin which may lead to unneeded clinical workup and intervention.
New Urine Test ID's Prostate Cancer
Genetic Test Finds Prostate Cancer, but
Can't Tell if It's Deadly
Daniel DeNoon
The test, from San Diego-based Gen-Probe, is
approved in some European countries but not in the
PCA3 (previously known as the DD3 gene) is found only in the prostate. When prostate cells become cancerous, their PCA3 genes go wild. Prostate cancer cells express 60 to 100 times more PCA3 RNA than normal cells.
That means the PCA3 test can do things the current PSA test can't do. The PSA test detects prostate-specific antigen, a protein given off by all prostate cells. If a man has an enlarged prostate -- a noncancerous condition called benign prostatic hyperplasia or BPH -- his PSA level can go up. This often triggers unnecessary biopsies and, sometimes, unnecessary surgery.
"The beauty of this test is it seems to be
independent of the BPH component," Mark Emberton,
MD, of the
Emberton, who has no
financial links to Gen-Probe, reported several studies of the PCA3 test at last
week's annual meeting of the British Association of Urological Surgeons in
The studies showed that the PCA3 test isn't influenced by the size of the prostate, even in people with BPH. And they showed that the test can help men decide whether they need a repeat prostate biopsy. Prostate biopsy involves multiple needle punctures into the walnut-sized prostate gland.
"This test is going to be of value in two currently problematic areas," Emberton tells WebMD. "It will help men with a [relatively] low PSA who need reassurance but don't want an invasive test. And it will help men with a negative biopsy but a rising PSA decide whether they need a second set of biopsies."