Metastatic adenocarcinoma of unknown primary site: diagnostic electron microscopy to determine the site of tumor origin

Poorly differentiated malignant tumors and metastatic adenocarcinomas have been studied by electron microscopy. Rapid ultrastructural analysis allows the accurate diagnosis of the cell of tumor origin to be reported in conjunction with the routine surgical signout of paraffin sections. The identification of specialized intracellular structures is useful for determining the site of origin of metastatic tumors. Particularly useful in this material was the presence of lamellar (surfactant) bodies, typical of alveolar cell carcinoma of the lung, as well as the presence of apical terminal webs, diagnostic of gut epithelial cells.     

Diagnosis and management of metastatic neoplasms with unknown primary

In cancer of unknown primary (CUP), metastases are clinically and histologically confirmed, but the primary tumor site remains elusive after extensive work-up. CUPs make up for 2–3% of all epithelial malignancies. The two prevailing histologies are adenocarcinomas and undifferentiated carcinomas, whereas squamous cell carcinomas, neuroendocrine carcinomas and rare histologies account for the remaining 10%.The diagnostic work-up in CUP relies strongly on a detailed immunohistological (IHC) analysis in order to characterize the tumor type, nowadays aided by molecular techniques. Diagnostics also include a thorough clinical examination, a basic lab draw with the most relevant tumor markers, and cross sectional imaging. Additional PET-CT is recommended in cervical lymph nodes suggestive of head and neck cancer and in limited metastases potentially treatable in curative intent.As for treatment, it is paramount to identify patients who fall into one of the six well defined “favorable” subset categories, namely extragonadal germ cell tumors, adenocarcinoma with isolated unilateral axillary lymph nodes in female patients, squamous cell carcinoma with neck lymph nodes, squamous cell carcinoma with inguinal lymph nodes, serous papillary peritoneal carcinomatosis in females and blastic bone metastasis in males with elevated PSA. These subsets are distinct both regarding the required treatment and the comparably favorable prognosis. Within the remaining “unfavorable” group, patients of colon and renal cancer type should be identified based on IHC and clinical picture, since the prognosis of these patients seems to improve with the use of therapy tailored to the presumed primary as well. For the few patients with limited metastases it should be assessed whether they are candidates for surgery, radiotherapy or surgery followed by irradiation in curative intent. The remaining majority of patients are treated with empiric palliative chemotherapy, typically a platinum – paclitaxel combination, though the level of evidence for this therapy recommendation is low. Gemcitabine alone or in combination can be used as an alternative.Decoding of the molecular profiles in CUP offers the prospect of targeted therapy with novel agents. However, there appears to be no uniform molecular pattern for CUP, and the observed molecular diversity thus poses a challenge to respective clinical trials.     

Intraductal tubular neoplasms of the pancreas: an overview

Intraductal lesions of the pancreas are an uncommon but increasingly recognized group of entities mainly because of advances in imaging technology. In the past, precise categorization and understanding of true pancreatic intraduct neoplasms were hampered not only by their relative rarity but also because of the plethora of terminology and criteria used in nomenclature and diagnosis. Although significant progress has been made in the characterization of some of these lesions, as exemplified by intraductal papillary mucinous neoplasms, understanding of the rare intraductal tubular adenoma (ITA) and intraduct tubular carcinoma (ITC) continues to evolve. By definition, these are a group of intraductal, radiologically detectable neoplasms that can progress to or be associated with invasive adenocarcinoma and, as such, are precursor lesions to pancreatic ductal adenocarcinoma. Their often shared clinical and radiological features make precise histological diagnosis essential for appropriate management and optimal outcome. We provide an overview of these neoplasms and highlight recent developments in the understanding of ITA and ITC which have led to ITA being considered a variant of gastric-type intraductal papillary mucinous neoplasms and ITC being encompassed within the intraductal tubulopapillary neoplasm category. We also emphasize the distinguishing histological features to aid diagnosis of these rare lesions.     

Metastatic vs primary malignant neoplasms affecting the umbilicus: clinicopathologic features of 77 tumors

Periumbilical skin is unique due to its proximity to intra-abdominal and pelvic structures. In addition to primary skin malignancies, it is a site often involved with metastatic disease. We reviewed the clinical and pathologic features of 77 umbilical malignancies occurring at our institution since 1988. Seventy-seven patients were identified (female/male ratio, 4.1:1.0) with the average age for women being 63 years and 55 years for men. Eighty-eight percent of malignancies originated outside the umbilicus and 12% were primary skin tumors. Fifty-eight (85%) patients with metastatic tumors had umbilical involvement from a known primary vs 10 (15%) with unknown primaries. Nine patients with metastatic tumors to the umbilicus would present with solitary umbilical involvement. Of these patients, 56% would not have a primary site assigned to their metastatic disease. In women, the 3 most common primary sites were the ovary, endometrium, and pancreatobiliary tree, whereas for men, it was the genitourinary tract, pancreatobiliary tree, and the gastrointestinal tract. Of the primary umbilical malignancies, 44% of patients were male and 56% female. Malignant melanoma was the most common primary umbilical malignancy. In summary, women are more likely than men to have malignant tumors affecting the umbilicus. Overall, the most likely primary site of a metastatic tumor to the umbilicus is the genitourinary tract. Rarely, patients present with metastatic tumors to the umbilicus, and most of these patients will not have a primary site of tumor origin assigned.     

Desmosomes and microvilli mean a lot: diagnosis of neoplasms of unknown origin using electron microscopy

Neoplasms of unknown origin present a difficult diagnostic dilemma, particularly if they are very poorly differentiated. Adenocarcinomas, squamous cell carcinomas, melanomas, lymphomas, and sarcomas can all be very difficult to diagnose if the light microscopic cytomorphology is sufficiently undifferentiated. Electron microscopy (EM) can either demonstrate differentiation or narrow the range of differential diagnoses. The authors report the case of a 64-year-old male who has been HIV positive for several years and was found to have expansile lytic lesions in several ribs and a thumb fracture associated with a soft tissue mass which was biopsied. The tumor was composed of very pleomorphic malignant cells without specific differentiation. The malignant cells stained positive for pancytokeratin (AE 1/3), EMA, CEA, CK20, and CK7. Rare cells had mucicarmine-positive intracytoplasmic droplets. They were negative for S-100, calretinin, CD45, MART-1, and vimentin. EM revealed intracytoplasmic lumina with long microvilli and many well-formed desmosomal junctions. The diagnosis was initially very broad. Immunohistochemistry narrowed the diagnosis to carcinoma, but EM alone was able to narrow the diagnosis to poorly differentiated adenocarcinoma. In a neoplasm of unknown origin, EM can either narrow the differential significantly or, in the case of limited material, provide information that otherwise may not be attainable.     

MET mutations in cancers of unknown primary origin (CUPs)

Cancer of unknown primary origin (CUP) defines metastatic disease of unknown origin, accounting for 3-5% of all cancers. Growing evidence demonstrates that inappropriate execution of a genetic program named "invasive growth," driven by the MET oncogene, is implicated in the metastatic process. MET activation in cancers is mainly consequent to overexpression, whereas mutations are rarely found. We reasoned that the occurrence of MET somatic mutations might sustain premature occult dissemination of cancer cells, such as that observed in CUPs. We sequenced MET in genomic DNA obtained from 47 early metastatic cancers. By extensive immunohistochemical analysis a primary site was afterward postulated in 24 patients, whereas 23 cases remained of unknown primary (CUPs). MET somatic mutations were found in seven cases, all belonging to the CUP cohort. Mutational incidence (30%) was thus significantly higher than the expected one (4%), in the absence of high mutational background. Several nucleotide changes were novel and clustered either in the kinase domain or in the extracellular semaphorin domain. Mutated receptors were functional and sustained the transformed phenotype, suggesting that MET activating mutations are genetic markers associated with the CUP syndrome.     

Immunohistologic evaluation of metastatic carcinomas of unknown origin: an algorithmic approach

Pathologists are now asked frequently to determine the primary site for metastatic carcinomas of unknown origin (MCUO), using adjunctive morphological techniques such as electron microscopy, immunohistology, and other modalities. The authors present an algorithmic immunohistochemical approach to this problem that is based on their experience with over 2,800 routinely-processed epithelial malignancies of various types. These have been studied with antibodies to keratins, vimentin, epithelial membrane antigen, MOC-31, tumor associated-glycoprotein-72 (recognized by monoclonal antibody B72.3), prostate-specific antigen, thyroglobulin, gross cystic disease fluid protein-15, carcinoembryonic antigen, CA-125, CA19-9, placental alkaline phosphatase, S100 protein, and estrogen receptor protein. The algorithm that is structured around these 14 analytes is based on the relative predictive value of each marker, which in turn, determines its place in the sequence of interpretation. The authors' experience with this approach shows 67% accuracy with regard to the ultimately determined site of origin for MCUO, a figure which is similar to that reported by other investigators.     

Interstitial 9q deletion. A primary change in a case with splenomegaly of unknown origin.

In a case with splenomegaly of unknown origin and features of hypersplenism, an interstitial 9q deletion was identified as a sole clonal abnormality of bone marrow cells. The meaning of 9q deletion as a primary change, as well as its clinical significance, are considered.     

Fever of unknown origin

This is a case study of a 26-year-old Hispanic male who presented with an initial complaint of fevers, chills and generalized weakness for three weeks. Patient reported a classical history of diurnal fever with temperature spikes as high as 105.8F after returning from a trip to Guatemala. His symptoms had waxed and waned for 3 weeks. This case study will focus on the initial presentation, value of complete history and physical exam, use of laboratory data and use of specialized diagnostic procedures in the outpatient setting. This case proves to be highly relevant to primary care in the context of treating patients with fevers of unknown etiology. Primary care physicians should be alert for unusual diseases in patients who are returning from foreign travel. Malaria is a potentially fatal disease that can be acquired by travelers to certain areas of the world, primarily developing nations. Transmitted through the bite of the Anopheles mosquito, malaria usually presents with fever and a vague systemic illness. The disease is diagnosed by demonstration of Plasmodium organisms on a specially prepared blood film. This case study speaks to the importance of prompt work up and treatment of fever of unknown origin that presents in an unusual clinical picture or that is not readily explainable.     

Immunohistological studies in five patients with unknown primary carcinomas and poorly differentiated neoplasms

In the evaluation of five patients with unknown primary carcinomas or poorly differentiated neoplasms, the most critical step was to obtain an accurate histological diagnosis upon which to base therapeutic options and prognosis. This required a thorough pathological examination which included histochemical and immunohistological staining of a properly prepared biopsy specimen of ample size. Two cases of lymphoma, two of carcinoma, and one of melanoma are presented in which the correct pathological diagnosis was made with immunohistological techniques permitting the institution of appropriate therapy. The value of a simple antibody panel employed with properly prepared tissue is clearly demonstrated by these cases.     

Psychodermatology: an overview.

As the skin is an organ that has a primary function in tactile receptivity and reacts directly upon emotional stimuli, dermatological practice involves a psychosomatic dimension. It is, however, the high visibility of dermatoses and their easy accessibility which make the skin a direct target for behavioural problems. Furthermore, self-destructive tendencies and hypochondriacal features often express themselves through dermatological symptoms: dermatitis artefacta and skin hypochondriasis are among the specific psychocutaneous disorders discussed here. In view of the clinical interface between dermatology and psychiatry, general guidelines are formulated and specific aspects of psychotherapy, behavioural treatment and psychotropic drug treatment are discussed.     

Cytokines: an overview.

Cytokines are a broad, heterogeneous group of proteins and polypeptides that regulate intercellular communication. Examples of cytokines include interleukins, interferons, colony-stimulating factors, and a variety of growth factors. The preparation of large quantities of highly purified recombinant cytokines has provided a basis for their biological and physicochemical characterization. The pleiotropic biological effects of these factors are expressed through binding to specific, high-affinity cell-surface receptors. Although they are different in amino acid sequence, cytokines have a number of biological and physicochemical properties in common.