Lefkowitch Flashcards

Question

Molecular apocrine–type breast cancers

Answer 1

Molecular apocrine–type breast cancers * some histologic apocrine features * gross cystic disease fluid protein (GCDFP-15) positive * estrogen receptor negative * androgen receptor positive * high proliferation and grade * poor prognosis

Answer 2

Based on estrogen receptor and androgen receptor, cancer can be divided into: Luminal * estrogen receptor (+), androgen receptor (+) Basallike * estrogen receptor (-), androgen receptor (-) Molecular apocrine * estrogen receptor (-), androgen receptor (+)

Answer 3

Claudin-low breast cancers * poorly differentiated * frequently metaplastic, show epithelial mesenchymal transition * have a stem cell–like expression profile that appears less differentiated than basal cancers * may show basal markers and low estrogen receptor expression * prognosis is slightly better than basallike tumors * slightly lower pathologic complete response (25% to 40%) than basal cancers

Answer 4

Gene Expression Profiling–Based Breast Cancer Classification 1. Luminal A 2. Luminal B 3. Molecular apocrine-type 4. Claudin-low 5. Basallike 6. HER2-positive

Answer 5

Neuroblastoma * abdomen, adrenal \> extra-adrenal sites, * most common solid tumors in children, excluding CNS tumors * produce catecholamines, tested in the urine, elevated levels of their derivatives, homovanillic acid (HVA) or vanillyl mandelic acid (VMA) * poor prognosis * MYCN amplification * A mitosis karyorrhexis index (MKI) \>200 * Age at diagnosis \>2 yo * 1 p deletion in children \<1 yo

Answer 6

Neuroblastoma

Answer 7

Choriocarcinoma * presents as vaginal bleeding or mets * Gross: hemorrhagic tumor mass, extensive necrosis * Histology: * hallmark: presence of all three trophoblast cell types * cytotrophoblasts * intermediate trophoblasts * syncytiotrophoblasts * Chorionic villi are absent * Hemorrhage and necrosis * Mitotic activity is brisk * does not make its own blood vessels or tumor stroma --\> extensive necrosis * Chemo most effective in chorio arising from complete hydatidiform moles, best prognosis * Intraplacental choriocarcinomas are usually small and are most commonly identified on gross examination as a blood clot or an area that appears to surround an infarct * Stains * trophoblasts: CK+ * Intermediate trophoblasts: hPL+(strong), β-hCG+(weak) * Syncytiotrophoblasts: hPL+(weak), β-hCG+(strong) * absence of nuclear β-catenin (normal POC+)

Answer 8

Papillary Thyroid Carcinoma Arising in Struma Ovarii * rare, no current consensus as to how to treat * Struma ovarii is a specialized monodermal teratoma that is composed predominately of thyroid tissue * hyperthyroidism in 5% to 8% * 5% to 10% are malignant (ID'd post surgery) * PTC most common carcinoma * same BRAF mutation

Answer 9

Artifacts of tissue processing 1. The “fried egg” appearance of oligodendroglioma 2. Stromal retraction in basal cell carcinoma 3. Clefting in salivary gland adenoid cystic carcinoma 4. Retraction in micropapillary carcinoma of the breast 5. nuclear clearing that characterizes papillary thyroid carcinoma

Answer 10

tall cell variant of papillary carcinoma

Answer 11

Aggressive forms of PTC * tall cell variant * diffuse sclerosing * columnar cell * solid * PTC with prominent hobnail features

Answer 12

Radioactive iodine treatment * Nuclear changes occur in thyroid follicular epithelial cells following administration of radioactive iodine. * Propylthiouracil, potassium iodide, and β-blockers do not usually produce nuclear abnormalities. * Nuclear abnormalities may be found in Hashimoto thyroiditis. * Histologic features of Hashimoto thyroiditis, such as oxyphil metaplasia, fibrosis, and significant/destructive chronic inflammation, are not characteristic of radioactive iodine treatment. * Optically clear nuclei, which characterize papillary thyroid carcinoma, are not a feature of radioactive iodine treatment.

Answer 13

Mycobacterial Pseudotumor * Mycobacterial pseudotumors are a rare manifestation of tuberculosis and nontuberculous mycobacterial infection reported exclusively in immunosuppressed individuals, typically patients with AIDS. * Histologically, mycobacterial pseudotumors are spindle cell lesions that closely resemble mesenchymal tumors, especially Kaposi sarcoma. Proper distinction between these entities is of paramount importance because both therapy and prognosis are affected. * Members of Mycobacterium avium complex (MAC), but not M. tuberculosis, may stain positively for desmin, actin, and cytokeratin. Lesions with this immunoprofile could potentially be misinterpreted as smooth muscle tumors. For this reason, acid-fast stains are essential in evaluation of any spindle cell lesion in patients with AIDS. * Mycobacterial pseudotumors more commonly occur in lymph nodes, but have also been described in the appendix, bone marrow, and brain. * Spindle cells typically stain positively for macrophage markers, such as CD68. * AFB * Gomori-methenamine-silver (GMS) * PAS * Antidesmin immunoperoxidase * Antiactin immunoperoxidase

Answer 14

PTC * BRAF (BRAFV600E) * RAS genes (HRAS and NRAS) * RET/PTC translocations (RET/PTC1 and RET/PTC3) * TRK translocations (\<5%) Follicular thyroid carcinomas * RAS (HRAS and NRAS codon61) * PAX8/PPAR gamma translocations Follicular adenomas * RAS mutations Medullary thyroid carcinoma * Activating RET mutations * Germ line mutations are seen in \>95% of familial cases (MEN2 or familial medullary thyroid carcinoma).

Answer 15

BRAF * PTC RAS * PTC * Follicular carcinoma * Follicular adenoma RET * PTC * Medullary (MEN2 & familial medullary thyroid carcinoma) TRK translocations * PTC PAX8/PPAR gamma translocations * Follicular thyroid carcinomas

Answer 16

Mutations in PTC Activate the mitogen-activated protein kinase (MAPK) pathway * BRAF point mutations * 40-50% * mainly BRAFV600E * a/w classical and tall cell * predict more aggressive behavior even in pT1 tumors * only in 10% of follicular variant PTC * RAS genes * 10% to 20% * mainly HRAS and NRAS codon 61 mutations * mainly in the follicular variant * RET/PTC translocations * 10% to 20% * fusions of RET with 11 different partners * mainly RET/PTC1 [fusion partner CCDC6] and RET/PTC3 [fusion partner NCOA4] * a/w classical histologic appearance, a younger age at diagnosis, lymph node metastasis, and radiation exposure (RET/PTC2) * TRK translocations * \<5%

Answer 17

Follicular Thyroid Mutions RAS mutations * up to 50% follicual carcinoma * HRAS and NRAS codon61 * +/- follicular adenomas (precuresor?) PAX8/PPAR gamma translocations * 30-35% follicular carcinoma

Answer 18

Medullary Thyroid Carcinoma Mutations * Activating RET mutations * Germ line mutations un \> 95% of familial cases * MEN2 * familial medullary thyroid carcinoma

Answer 19

Testing of thyroid fine needle aspirates * **BRAF V600E** mutations, **NRAS** and **HRAS** **codon 61** mutations, and **RET/PTC** translocations help manage thyroid nodules * + BRAF V600E mutation or RET/PTC translocationhas a high PPV for malignancy * provided the LOD of the test is not \<1% mutant in normal or 1% lesional cell in normal * + PAX8-PPAR gamma translocation is strongly a/w invasion in a follicular neoplasm * In specimens with indeterminate cytology, having 1 mutations is a/w an increased risk of malignancy * 88% follicular lesion of uncertain significance * 87% follicular neoplasm * 95% suspicious for malignancy * versus no mutation: 6%, 14%, and 28% * the high PPV can allow total thyroidectomy instead of lobectomy in positive cases

Answer 20

Cryoglobulinemic Vasculitis

Answer 21

Cryoglobulinemic Vasculitis With mixed cryoglobulinemia * serum complement activation results in selective depression of the C4 level, often below LOD; most frequently in patients with type II cryoglobulins. Type II cryoglobulins * a monoclonal component, often an IgM rheumatoid factor, and polyclonal IgG * Renal involvement is 3x more prevalent than type III mixed cryoglobulinemia Type III cryoglobulins * polyclonal IgM rheumatoid factor and polyclonal IgG Hepatitis C antibodies are positive in 80% Whenever a pathologic diagnosis of MPGN type I is made * must rule out mixed cryoglobulins, HCV, other infectious agents s * If the clinical and histopathologic findings are highly supportive of a cryoglobulinemic vasculitis and a negative cryoglobulin test is obtained, repeat testing at a reputable laboratory should be performed.

Answer 22

Testing for Cryoglobulinemia * specimen must be maintained between 37° C and 41° C from the time of its withdrawal until the serum is isolated in the laboratory. * After centrifugation at 37° C to remove RBCs and fibrin, the serum is transferred at room temperature to a cryocrit tube, which is stored at 4° C for 1 week and observed daily for 7 days. * If the serum becomes cloudy, the cryocrit tube is centrifuged in the cold, and the cryocrit is measured. * The cryoglobulin is washed and assessed for monoclonality by immunofixation and for the presence of rheumatoid factor. * If the specimen is exposed to temperatures \<37° C at any time before the serum is obtained or improper processing in the laboratory can result in a false-negative cryoglobulin test.

Answer 23

Special Subtypes of Invasive Breast Cancer: Inflammatory Breast Carcinoma Associated with a bad prognosis defined primarily on clinical grounds—having an erythematous or peau d’orange skin appearance and carcinoma anywhere in the breast.

Answer 24

Special Subtypes of Invasive Breast Cancer: a/w good prognosis * luminal A, mucinous, tubular, cribriform, and medullary * Better prognosis than NST a/w bad prognosis * inflammatory carcinoma, which currently is defined primarily on clinical grounds * having an erythematous or peau d’orange skin appearance and carcinoma anywhere in the breast Invasive micropapillary carcinoma * aggressive tumor, a/w high lymphatic and lymph node metastasis rate (75%) regardless of tumor size, even for T1a lesions central fibrotic focus a/w poor prognosis Worse prognosis than invasive ductal NST * luminal B * HER2 amplified * most basal-type Basal-type a/w good prognosis * Pure medullary carcinoma * secretory carcinoma * adenoid cystic carcinoma

Answer 25

Sclerosing adenosis

Answer 26

Location of Lesions in the Breast Skin * Angiosarcoma (anywhere radiation/obstruction) The terminal duct lobular unit * cystic disease * usual ductal hyperplasia * adenosis and sclerosing adenosis * atypical ductal or lobular hyperplasia * lobular and ductal carcinoma in situ * invasive lobular/ductal carcinoma * peripheral papilloma Nipple * Paget disease representing ductal carcinoma in situ arising in lactiferous ducts and extending into the epidermis * florid papillomatosis of the nipple (nipple adenoma) * Solitary intraductal papillomas * syringomatous adenoma of the nipple Subareolar * Solitary intraductal papillomas * abscess formation * lactiferous ducts with squamous metaplasia * Terminal duct obstruction leads to duct rupture proximally * Duct ectasia * subareolar sclerosing duct hyperplasia.

Answer 27

Paget disease * nipple and subareolar region * DCIS arising in lactiferous ducts and extending into the epidermis

Answer 28

Florid papillomatosis of the nipple * potentially mass-forming lesion * aka nipple adenoma * characterized by ductular proliferation arising from lactiferous ducts and florid intraductal epithelial hyperplasia, varying degrees of atypia * may be a/w cancer

Answer 29

Subareolar sclerosing duct hyperplasia * characterized by a geographic area of duct sclerosis and stromal elastosis with florid epithelial proliferation * looks like nipple adenoma but nipple isn't involved * this lesion is in the family of radial sclerosing lesions but tends to show less cyst formation * may be a/w carcinoma * myoepithelial cells surround the intraductal epithelial proliferation * highlighted with a smooth muscle actin, smooth muscle myosin heavy chain, or p63 immunostain

Answer 30

Syringomatous adenoma of the nipple * benign, locally infiltrating neoplasm histologically similar to the tumor of the skin * does not appear to arise from skin, and it is not typically associated with intraductal epithelial proliferation * should be distinguished from florid papillomatosis of the nipple (nipple adenoma). * small tubular and ductular structures with elongated architecture in a teardrop shape * infiltrative pattern that should not be confused with an invasive carcinoma * ducts are lined by one or more layers of small uniform cells

Answer 31

Breast Cancer Staging by American Joint Committee on Cancer Microinvasive breast cancer * \< or = 1 mm in greatest dimension Stage pN0(ITC) i * finding tumor cells that show no malignant activity (i.e., stromal reaction or mitotic activity spanning \<0.2 mm or \<200 cells) Stage pN1mi * Lymph node micrometastasis that spans 0.2 to 2 mm * If multiple lymph nodes show micrometastases but none shows a regular metastasis (i.e., \>2 mm) * if one of the metastases is greater than 2 mm, the pN(1-3) status corresponds to the total number of nodes that are positive regardless of their micrometastatic status The definition of inflammatory breast carcinoma (T4d) by AJCC criteria is largely a clinical definition. * Most of the skin is involved, showing diffuse erythema and edema (peau d’orange). * The presence of carcinoma in the skin or dermal lymphatics, although closely associated with inflammatory breast cancer, is insufficient for the diagnosis. * If no clinical evidence of inflammatory breast cancer is present, the staging of tumor involving the skin is based on its overall size or whether there is skin ulceration or satellite skin nodules (T4b). * Conversely, any amount of tumor anywhere in the breast, whether or not involving the skin, in the presence of clinical evidence of inflammatory breast cancer is inflammatory breast carcinoma. T4a * carcinoma extension to chest wall (includes ribs, intercostal muscle, and serratus anterior muscle) but does not include invasion of pectoralis muscle only.

Answer 32

Transmissible spongiform encephalopathies * Prion diseases or transmissible spongiform encephalopathies are caused by the accumulation of an abnormal form of a normal cellular protein (prion). In the brain, neuronal death, gliosis, synaptic loss, and microvacuolation, or spongiform change, are present. Prion diseases display transmissibility to humans and other mammalian species. * The molecular pathologic process of prion diseases involves the conversion of a normal cellular protein, called prion protein (PrP), into an abnormal configuration. The gene PRNP for PrP is located on chromosome 20. * Four different human prion diseases have been identified: Creutzfeldt-Jakob disease (CJD) and variant Creutzfeldt-Jakob diseases (vCJD), Gerstmann-Strӓussler-Scheinker disease (GSS), fatal familial insomnia (FFI), and kuru. GSS and FFI are inherited forms of the disease caused by mutations in the PRNP gene. vCJD and kuru are contracted by eating prion-containing tissues (bovine in the former, and human brain tissue in the latter). * The annual incidence of sporadic CJD is one to two cases/million population. Clinical presentation includes rapidly progressive dementia with ataxia and myoclonus. Pseudoperiodic synchronous discharges (PSDs) can be seen on the electroencephalogram (EEG). CT and MRI studies may show variable cerebral and cerebellar atrophy. * Histologically, neuronal loss (especially in cortical layers III to V), gliosis, and vacuolation of the neuropil are seen in affected areas. The vacuoles are diffuse or focally clustered and are typically round and small. The vacuoles are intracellular and mainly occur in gray matter. The most common affected areas are the cerebral and cerebellar cortices, but basal ganglia and thalamus can also be involved. * Decontamination procedures should take place after conduction of autopsies of suspected prion disease. Instruments and surfaces can be decontaminated by immersion in or application of 2N sodium hydroxide for one hour. Tissue for histologic examination should be treated with formic acid before processing.

Answer 33

Translocations in MALT lymphoma t(11;18) * API2 and MALT1 genes * gastric and pulmonary t(14;18) * IgH and MALT1 genes * ocular adnexa/orbit and salivary gland Trisomy 3 * nonspecific abnormality frequently detected in MALT lymphomas t(3;14) * IgH and FOXP1 genes * thyroid, ocular adnexa/orbit, and skin Trisomy 18 * nonspecific abnormality frequently detected in MALT lymphomas

Answer 34

Helicobacter pylori and Gastric Carcinoma * sixfold increased risk of gastric carcinoma in individuals infected with H. pylori. * Infection and gastric cancer risk are high in Japan and Colombia. * Africa, where the infection rate is also high, the gastric cancer rate is very low. * This so-called African enigma remains unexplained. * CagA and VacA genes are being studied as possible oncogenes. CagA-positive H. pylori strains are associated with alterations in the gastric epithelial cell cycle and apoptosis, more severe mononuclear and neutrophilic infiltrates, and more severe glandular atrophy and intestinal metaplasia. VacA-positive strains are frequently isolated from distal gastric cancers. * Host factors include certain interleukin-1β subtypes, tumor necrosis factor-α expression, and genetic polymorphisms of mucin (MUC-1) and human leukocyte antigens (HLA). * Known environmental risk factors are excessive dietary salt and inadequate intake of fruits and vegetables.

Answer 35

Comparison of Monoclonal and Polyclonal Antibodies * Monoclonal antibodies are obtained using hybridoma technologies. * They bind to a single epitope on an antigen. If the antigen shares the epitope with other substances, cross-reactivity will be complete and cannot be reduced by affinity purification or adsorption. * Polyclonal antibodies, which actually consist of a mixture of various antibodies, reactive against various epitopes on an antigen with varying affinities, can be made more specific by adsorption with cross-reacting antigen, to remove cross-reacting antibodies and more avid by adsorption with the relevant antigen to select higher affinity antibodies. * Although each monoclonal antibody is of a single type or isotype, both IgG and IgM antibodies are used. In recent years there has been increasing use of nonmurine monoclonal antibodies (e.g., AMACR is a rabbit monoclonal).

Answer 36

Allograft Rejection * Morphologically humoral rejection is defined by margination of leukocytes (macrophages) toward the endothelial lining and activation of endothelial cells. * Highlighting the macrophages with anti-CD68, endothelial cells (anti-CD31), and adhesion molecules (anti-CD62E) and demonstrating activation of complement (C3d) or binding of immunoglobulin along the endothelial lining of capillaries all favor humoral rejection. * Demonstrating CD8 positive T lymphocytes is a feature of cellular rejection. * Both forms of rejection may occur concurrently.

Answer 37

Amyloidosis comprises a group of diseases characterized by extracellular deposition of β sheet fibrils. In the systemic forms, the amyloid causes progressive organ dysfunction leading to death. Non-hereditary forms * immunoglobulin light chains in primary systemic amyloidosis (AL) * heavy chain (AH) * amyloid A in secondary amyloidosis (AA) * β2-microglobulin in dialysis-associated arthropathy (Aβ2M) * amyloid β protein (Aβ) in Alzheimer disease and Down syndrome Hereditary forms include: * transthyretin (ATTR) * apolipoprotein A-I (AApoAI) and A-II (AApoAII) * gelsolin (AGel) * lysozyme (ALys) * fbrinogen A-alpha chain (AFib) Another amyloidogenic protein is leukocyte chemotactic factor 2 (LECT2) EM: 7.5-10 nm in diameter fibrils with randomly dispersed, non-branching arrangement in mesangium and subendothelium

Answer 38

* In Western countries, most cases with systemic or generalized amyloid deposits (involving the kidneys) are due to the deposition of AL-amyloid, mostly secondary to the secretion of abnormal lambda light chains in the setting of a plasmacytoma. * Although patients with AL amyloidosis have a monoclonal gammopathy, not all patients with renal disease and a monoclonal gammopathy have AL amyloidosis. * The most common presentation of AL and AA amyloidosis is heavy proteinuria, which is associated with glomerular deposits. * Patients with vascular deposits present with slowly progressive chronic kidney disease with less proteinuria secondary to less glomerular involvement.

Answer 39

Celiac disease * IgA antitissue transglutaminase (tTG) testing has now become the serologic test of choice for evaluation of celiac disease, largely replacing the more labor-intensive (although similarly accurate) antiendomysium antibody for initial testing. * Genetic testing for HLA DQ2 and DQ8 is utilized in selected cases as part of the clinical evaluation of celiac disease. HLA DQ2 is present in approximately 95% of patients with celiac disease and most of the remaining 5% are positive for HLA DQ8. Although positive DQ2/DQ8 testing is not diagnostic of celiac disease (present in approximately one-third of the Caucasian population), absence of these haplotypes virtually excludes celiac disease.

Answer 40

Celiac disease * In typical cases of celiac disease, intraepithelial lymphocytes are CD3+/CD8+. Abnormal lymphocyte populations (with CD3+/CD8- phenotype) may be seen in cases of refractory celiac disease and these patients are at increased risk for development of enteropathy-associated T cell lymphoma. * Histopathologic features of celiac disease include intraepithelial lymphocytosis (characteristically showing a “tip-heavy” distribution), and variable architectural abnormalities, including villous atrophy (ranging from none to total) with variable crypt hyperplasia and expansion of the lamina propria by chronic inflammatory cells, especially plasma cells. None of the previous findings, however, are specific for celiac disease and clinical correlation is required to establish this diagnosis. * Most or all features of celiac disease, including intraepithelial lymphocytosis and variable amount of villous atrophy, may be present in cases of tropical sprue. Correlation with clinical (i.e., traveling to tropical regions) and laboratory findings (negative celiac disease workup) are generally required to establish this diagnosis.

Answer 41

Celiac disease * The prevalence of celiac disease is higher in patients with Down’s syndrome and diabetes mellitus than in the general population. * Patients with celiac disease (also known as gluten-sensitive enteropathy) are at risk for developing enteropathy-associated T-cell lymphoma.

Answer 42

Pauciimmune Crescentic Glomerulonephritis

Answer 43

Pauciimmune Crescentic Glomerulonephritis * At least 80% of patients with pauciimmune crescentic glomerulonephritis test seropositive for antineutrophilic cytoplasmic antibody (ANCA). * ANCA has specificity for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA) on enzyme-linked immunosorbent assay. * By definition, in pauciimmune crescentic glomerulonephritis, immunofluorescence reveals minimal to absent positivity for immunoglobulins and complement. * The pathogenesis of pauciimmune crescentic glomerulonephritis involves ANCA-mediated neutrophil activation, causing neutrophil degranulation on endothelial surfaces and leading to vasculitis and crescentic glomerulonephritis.

Answer 44

Pauciimmune Crescentic Glomerulonephritis • Alternative causes of crescentic glomerulonephritis include * anti-glomerular basement membrane (GBM) disease, which shows linearstaining for IgG, kappa, and lambda along the GBM * immune complex–mediated forms of crescentic glomerulonephritis (e.g., lupus nephritis (LN) and IgA nephropathy), which show granular deposits of immunoglobulins and complement on immunofluorescence and electron microscopy.

Answer 45

Adenomatoid tumor situated on the testicular surface * benign neoplasm, curable by local resection * mesothelial cell origin * can present in any age group from adolescence to senescence * most common tumor of the epididymis and can also occur in the spermatic cord and paratestes * Grossly they are often firm white well-circumscribed nodules * Histology can vary * some lesions containing spaces resembling vascular channels, and others having more glandular or tubular structures suggesting an epithelial neoplasm * sometimes, signet ringlike cells are present, simulated by the presence of cytoplasmic vacuoles * cells have abundant eosinophilic cytoplasm and the nuclei are small with occasional inconspicuous nucleoli * can be infiltrative microscopically and are present in a fibrotic background * some are associated with abundant smooth muscle; these are known as adenomatoid leiomyomas * muscle cells will be positive for smooth muscle actin (SMA), but not the cells lining the channels and spaces * Positive: calretinin and epithelial markers, such as AE1AE3, epithelial membrane antigen (EMA), Cam5.2, CK5/6, and CK7 * Negative: CD31 and CD34 * In difficult cases, in which the differential diagnosis is metastatic adenocarcinoma, a panel to include markers that are positive in carcinoma and not in mesothelial proliferation may include carcinoembryonic antigen (CEA), factor VIII-related antigen, HBME-1,MOC31, BER-EP4, B72.3, and CD15.

Answer 46

Differentiated Vulvar Intraepithelial Neoplasia accounts for 2% to 10% of all cases of VIN, making it the least common of the VIN subtypes. occurs in postmenopausal women, with the mean age at presentation being 67 years, 2 to 3 decades later than what is seen with the more common warty and basaloid variants. • One quarter of patients have a history of cigarette use. Multifocal disease is infrequent because of the lack of association with HPV. Lichen sclerosus is often associated with differentiated VIN. Differentiated VIN may be seen adjacent to squamous cell carcinoma. * Clinically, the lesions of differentiated VIN are small, ranging in size from 0.5 to 3.5 cm in greatest dimension. They often manifest as focal gray-white discolorations with a roughened surface or an ill-defined raised, thickened white plaque. Some lesions manifest as discrete elevated nodules. * Histologically, these lesions can be extremely difficult to identify because they demonstrate a high degree of cellular maturation with a lack of widespread architectural abnormality, nuclear pleomorphism, and cellular atypia. When atypia is present, it tends to be confined to the basal layer. * The differential diagnostic pitfall for differentiated VIN is the benign mimic squamous cell hyperplasia, especially in superficial biopsy specimens. However, close inspection of differentiated VIN reveals abnormal squamous cells in the epithelium. They are conspicuously enlarged with large vesicular nuclei, usually with macronucleoli. Rare cells may be binucleated. The cytoplasm is abundant and brightly eosinophilic, indicative of premature differentiation or keratinization. Intercellular bridges typically are very prominent. These findings are the hallmark of differentiated VIN.

Answer 47

Endometrioid Adenocarcinoma of the Ovary * Endometrioid adenocarcinoma is one of the most common subtypes of epithelial ovarian carcinoma. It is recognized histologically by glands or tubules that are lined by stratified columnar cells. Luminal mucin is present, whereas cytoplasmic mucin is commonly absent. It is histologically similar to its counterpart in the uterine corpus. * Cases may or may not be associated with endometriosis. However, in cases in which endometriosis is an associated risk factor, patients present 5 to 10 years earlier than patients without concurrent endometriosis. * In one study, interleukin-1 receptor II was identified both in the cells of endometriosis and in ovarian endometrioid adenocarcinoma, which may provide a link between the two entities. * More recent immunohistochemical and molecular studies have separated ovarian epithelial tumors into two groups: type I tumors, which are of lower histologic grade (e.g., low-grade endometrioid adenocarcinomas), and type II tumors, which are of higher histologic grade (e.g., high-grade endometrioid adenocarcinomas). Type II tumors often harbor p53 mutations not identified in type I tumors and have a much more aggressive course. * A frequent mimic of ovarian endometrioid adenocarcinoma is metastatic colon adenocarcinoma. However, a carefully selected immunohistochemical panel can aid in differentiation. Ovarian endometrioid adenocarcinoma is positive for cytokeratin 7 and CA 125 in most cases; this panel is negative in colon adenocarcinoma. Colon adenocarcinoma is strongly positive for cytokeratin 20 and CDX-2 in most cases; this panel is negative in endometrioid adenocarcinoma. * A morphologic mimic of microglandular ovarian endometrioid adenocarcinoma is the microfollicular variant of adult granulosa cell tumor. The inhibin positivity identified in adult granulosa cell tumor is not seen in ovarian endometrioid adenocarcinoma.

Answer 48

Microcystic Adnexal Carcinoma * Microcystic adnexal carcinoma classically manifests as a papule or nodule on the upper lip but can occur in other areas of the face. They are aggressive neoplasms that invade deeply and have a high tendency for local recurrence. * Microcystic adnexal carcinomas are eccrine carcinomas that histologically demonstrate infiltrative epithelial cords associated with a sclerotic stroma. Horn cysts, ducts, and glandlike structures may be seen. Tumors cells may extend into the subcutis and skeletal muscle. * The main histologic differential diagnoses are desmoplastic trichoepithelioma, morpheaform basal cell carcinoma, and syringoma. Perineural invasion, deep dermal involvement, and poor circumscription are histologic clues suggestive of microcystic adnexal carcinoma. A desmoplastic trichoepithelioma is a well-circumscribed tumor in the upper to middle dermis exhibiting cords of basaloid islands and horn cysts. * Immunohistochemistry shows glandular structures that stain positively for carcinoembryonic antigen (CEA). * Ber-EP4 staining may helpful in differentiating an infiltrative or morpheaform basal cell carcinoma from a microcystic adnexal carcinoma because basal cell carcinomas stain almost universally with Ber-EP4, whereas microcystic adnexal carcinomas are usually negative.

Answer 49

Hashimoto thyroiditis

Answer 50

Hashimoto thyroiditis * Several studies have demonstrated immune complex deposition within the context of Hashimoto thyroiditis. * Laboratory work-up of patients with Hashimoto thyroiditis may reveal antithyroglobulin, antithyroid peroxidase, and antimicrosomal antibodies. * These autoantibodies likely mediate thyrocyte dysfunction as follows: deposition of immune complexes (as immune complexes) on the basement membranes of follicular epithelial cells leads to complement activation and thyrocyte necrosis. * Hashimoto thyroiditis is associated with several human leukocyte antigen (HLA) alleles including HLA-DR3, HLA-DR4, and HLA-DR5. * The incidence of Hashimoto thyroiditis is increased among individuals with Turner syndrome and Down syndrome.

Answer 51

Follicular Lymphoma * The hallmark translocation of follicular lymphomas, t(14;18)(q32;q21), places the BCL2 gene— normally on chromosome 18—under the influence of the IgH enhancer on chromosome 14. The resultant overexpression of the antiapoptotic BCL2 protein is associated with resistance of follicular lymphomas to chemotherapy. This translocation may also be seen in up to 20% to 30% of de novo diffuse large B-cell lymphomas (DLBCL). * The majority of these have a germinal center B-cell (GCB) phenotype, although it may rarely be seen in activated B-cell (ABC) phenotype DLBCL. Although nonneoplastic follicular center cells do not express BCL2 protein, normal mantle cells, B cells in hyperplastic marginal zones, and normal plasma cells express BCL2, as do normal T cells. In addition to follicular lymphomas, most MALT lymphomas, mantle cell lymphomas, chronic lymphocytic leukemias, and acute lymphoblastic leukemias express BCL2 protein 2. Cyclin D1 overexpression associated with t(11;14) is a hallmark of mantle cell lymphomas. * Because of wide variability of chromosome 18 breakpoints, standard polymerase chain reaction (PCR) – using primers that bind to the JH region, and recurrent breakpoints on chromosome 18 (major breakpoint region and minor cluster region)—detects the translocation in only approximately 35% to 65% of cases in which it is demonstrable by FISH. * Although the BCL2/JH translocation is believed to have oncogenic properties, the translocation is detectable at a low level in some reactive lymphoid proliferations. * An interesting recent finding in follicular B-cell lymphomas has been the demonstration of activating mutations of the polycomb complex member histone methyltransferase EZH2 in up to 20% of GCB-DLBCL, mainly those with BCL2 rearrangements. The mutation, which alters tyrosine 641 (Y641), results in increased activity in converting dimethylated to trimethylated H3K27. With wild type (WT) EZH2 on the other allele, this leads to increased trimethylation of H3K27: a repressive modification of histones, with chromatin condensation and reduced gene expression. Wild type EZH2 is also increased in the remaining GCB-DLCBL. This presents a potential target for small molecule inhibitors of EZH2. * Some B-cell lymphomas may harbor both IgH-BCL2 and MYC rearrangements on 8q24 (with IgH or non-IgH partners). These “double-hit” lymphomas tend to behave in a more aggressive manner; however, in GCB-DLBCL, the presence of a BCL2 translocation identifies a group with poor treatment outcome with rituximab-CHOP treatment, independent of the MYC status.

Answer 52

Basal cell adenocarcinoma * Basal cell adenocarcinoma (which represents the correct diagnosis in this case, based on the information provided as well as other findings) sometimes shows cribriform architecture. * Adenoid cystic carcinoma characteristically shows cribriform architecture. The pseudocysts within cribriform areas of adenoid cystic carcinoma show either mucoid basophilic material (glycosaminoglycans), or hyaline eosinophilic material (reduplicated basal lamina). * Low-grade salivary duct carcinoma is alternatively named low-grade cribriform carcinoma. * Mammary analogue secretory carcinoma characteristically shows lobular cribriform or microcystic architecture, with mucin in the microcysts/pseudocysts. * Benign lesions such as basal cell adenoma and pleomorphic adenoma may also display cribriform patterns.

Answer 53

Carcinosarcoma (Malignant Mixed Müllerian Tumor) * Endometrial biopsy specimens can present a difficult diagnostic challenge in the diagnosis of mixed tumor types depending on what has been sampled by the clinician. Sometimes the carcinoma might be the only area sampled. In other scenarios, only sarcomatous elements may be sampled. It is necessary to submit and examine all biopsy material fully to have the best opportunity to make the correct diagnosis; in some cases, this will be impossible because of sampling error. * Mixed müllerian neoplasms are composed of neoplastic epithelium and neoplastic mesenchymal elements. Tumors in this family are represented by benign and malignant components. Carcinosarcomas are composed of both malignant epithelium and malignant mesenchyme. * Carcinosarcomas are composed of obvious carcinoma, which may be squamous, endometrial, mucinous, serous, clear cell, or undifferentiated, with a sarcomatous component that may be homologous or heterologous. When undifferentiated elements are present, it can be difficult to tell whether the undifferentiated areas are carcinoma or sarcoma. Keratin stains are often not helpful because they can stain the sarcomatous elements as well as the carcinomatous elements. These undifferentiated elements have led some experts to consider these tumors as metaplastic carcinomas. * Although tumors were separated into heterologous and homologous carcinosarcomas in the past, there are few data to suggest this distinction is useful. * Although features of the stromal component of the tumors, including mitotic index, presence and type of heterologous elements, and grade, have no predictive value of the presence of metastasis on presentation, high-grade, serous, and clear cell carcinoma histology can be predictive of the presence of metastasis on presentation.

Answer 54

Dermatofibrosarcoma Protuberans * slow-growing dermal spindle cell tumor of intermediate malignancy * typically occurs on the trunk and proximal extremities of young and middle-aged adults * solitary lesion or multiple polypoid nodules arising in an indurated plaque * Local recurrence is common, occurring in one third of all cases. * immunohistochemical and ultrastructural evidence indicates a fibroblastic origin * t(17;22) translocation in \> 90% --\> pathogenic COL1A1-PDGFB fusion gene * most helpful diagnostic marker is CD34, which stains 50% to 100% of the cells * CD34 is negative or focally positive in dermatofibromas * PCR may be used to identify the COL1A1-PDGFB fusion gene DDx: Giant cell fibroblastoma * considered a variant of dermatofibrosarcoma protuberans that often manifests in childhood * may exhibit the same immunogenetic and cytogenetic profile as DFSP Fibrosarcomatous change in DFSP * characterized by a fascicular or herringbone growth pattern, represents malignant transformation * fibrosarcomatous areas express CD34 in less than 50% of cases

Answer 55

Langerhans Cell Histiocytosis * Langerhans cell histiocytosis previously was divided into multiple clinical subtypes, but there is much overlap. The different forms of Langerhans cell histiocytosis have similar pathology in that there is a proliferation of Langerhans cells, which can be identified by the distinctive reniform, or kidney-shaped, nuclei. * Langerhans cells stain positively with S-100 protein and CD1a immunohistochemical stains. Langerhans cells do not stain with CD68. * With electron microscopy, characteristic Birbeck granules are seen within Langerhans cells. The Birbeck granules resemble a tennis racquet. * BRAF V600Emutation Letterer-Siwe disease * acute disseminated form of Langerhans cell histiocytosis * usually seen in infants and has many systemic manifestations * skin lesions are characterized by hyperpigmented scaly patches, which can coalesce and form a seborrheic dermatitis–like eruption * unresponsive dermatitis in the diaper area * hyperpigmented papules with associated hemorrhage at the periphery of the dermatitis area Hand-Schüller-Christian disease * a form of Langerhans cell histiocytosis that is characterized by the triad of bone lesions, exophthalmos, and diabetes insipidus Eosinophilic granuloma * a form of Langerhans cell histiocytosis that usually consists of either a few lesions or one lesion and most commonly affects the bone * skin and oral mucosa occasionally can be involved. Congenital self-healing reticulohistiocytosis * also known as Hashimoto-Pritzker disease * a variant of Langerhans cell histiocytosis with a very good prognosis * lesions are often present at birth but can manifest within the first few weeks of life as well * most commonly, there are scattered papules and nodules over the skin * occasionally, only a single lesion is present

Answer 56

Subependymal giant cell astrocytoma (SEGA) * Associated with Tuberous Sclerosis * most common CNS neoplasm in TS patients * typically present in the wall of the lateral ventricles and are predominantly exophytic * benign, slow-growing, discrete neoplasms and are graded as WHO grade I tumors * many large plump cells with abundant glassy eosinophilic cytoplasm and large eccentric nuclei are present accompanied by elongated cells with smaller nuclei and fibrillar processes, forming a nodular appearance

Answer 57

Tuberous sclerosis * autosomal dominant * lesions in the CNS * cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas * patients can present with seizures, mental retardation, behavioral problems and raised intracranial pressure * cutaneous lesions * hypomelanic macules, facial angiofibromas, periungal or subungal fibromas, and shagreen patches or fibrous hamartomas * cardiac rhabdomyomas * pulmonary lymphagioleiomyomatosis * renal angiomyolipomas, and renal cysts * Two different genes are associated with tuberous sclerosis: * TSC1 gene: hamartin located in chromosome 9q34 * TSC2 gene: tuberin located in chromosome 16p13.3

Answer 58

Tuberous sclerosis lesions in CNS * cortical tubers, subependymal nodules, and subependymal giant cell astrocytomas * patients can present with seizures, mental retardation, behavioral problems and raised intracranial pressure Cortical tubers * effacement of the neocortex with collections of large, bizarre cells and extensive fibrillary gliosis beneath the pia * Grossly, the cortical tubers are firm and scattered over the brain blurring the gray-white matter junction Subependymal nodules * firm or calcified protrusions, single or in rows, more commonly in the walls of the lateral ventricles Subependymal giant cell astrocytomas (SEGA) * most common CNS neoplasm in TS patients * typically present in the wall of the lateral ventricles and are predominantly exophytic * benign, slow-growing, discrete neoplasms * WHO grade I tumors * many large plump cells with abundant glassy eosinophilic cytoplasm and large eccentric nuclei are present accompanied by elongated cells with smaller nuclei and fibrillar processes, forming a nodular appearance TSC1 gene: hamartin, 9q34 TSC2 gene: tuberin, 16p13.3

Answer 59

Tuberous sclerosis cutaneous lesions * hypomelanic macules (ash-leaf) * facial angiofibromas * periungal or subungal fibromas * shagreen patches * fibrous hamartomas Two different genes are associated with tuberous sclerosis: * TSC1 gene: hamartin, 9q34 * TSC2 gene: tuberin, 16p13.3

Answer 60

Acral myxoinflammatory fibroblastic sarcoma * rare mesenchymal neoplasm of low malignant potential * adults in the fourth and fifth decade * slow growth and paucity of symptoms * distal extremities * subcutis of fingers and hand 60% \> toes, foot, and ankle 30% \> forearm and arm \> rare in the trunk * Gross: superficial, multinodular, average 3 cm * Histology: * mixture of inflammatory cells and epithelioid or spindle tumor cells, embedded in poorly vascularized and variably myxoid stroma +/- large mucin pools * characteristic cells with abundant cytoplasm and large nuclei with vesicular chromatin and large virocytelike eosinophilic macronucleoli (Reed-Sternberg like) * multivacuolated lipoblastlike tumor cells +/- * low-grade sarcoma, frequent local recurrences following surgery * no proven distant metastases or tumor deaths * surgery is the treatment of choice

Answer 61

Battle Sign * Battle sign (named after a British surgeon) is a sign of a basilar skull fracture (fracture of the base of the skull). * Battle sign is due to blood tracking down behind the ear from the fracture. * The area of hemorrhage is not always the site of impact. * Battle sign is analogous to “spectacle hemorrhages” (raccoon eyes) around the eyes, which are caused by orbital plate fractures.

Answer 62

Radiation changes

Answer 63

Kaposi sarcoma involving stomach Four forms of Kaposi sarcoma (KS) are described: (1) classic form, an indolent, primarily cutaneous disease typically affecting older men of Mediterranean ancestry (2) endemic form, primarily affecting HIV-negative children in Africa (3) iatrogenic form, affecting organ transplantation patients on immunosuppressive therapy (4) HIV-associated cases. * Human herpesvirus-8 (HHV-8) is thought to play a major role in all forms of KS. * Histology * proliferation of relatively bland spindle to epithelioid cells forming slitlike spaces containing red blood cells * +/- eosinophilic, PAS-positive hyaline inclusions within tumor cells * monoclonal antibody to HHV-8 latent nuclear antigen (LANA) is a highly sensitive and specific marker of HHV-8 infection in paraffin-embedded tissue sections of KS * other spindle cell lesions, such as spindle cell hemangioma, dermatofibrosarcoma protuberans, and pyogenic granuloma, are LANA negative

Answer 64

Secondary tumors involving the penis * In spite of the rich vascularity of the penis, it is a rare site for metastatic carcinoma. * All of the carcinomas listed have been reported to metastasize to the penis; however, genitourinary tumors, particularly of **prostatic and urinary bladder origin, are the most common primary site for tumors metastasizing to the penis**. * In the penis, most metastases are within the vascular channels of the erectile tissues of the penis. This is usually manifested as multiple painless subcutaneous nodules. Rarely, malignant priapism can occur. * The distinction between metastatic urothelial carcinoma of the urinary bladder and primary penile urethral carcinoma can be difficult. Demonstration of in situ urothelial carcinoma at the site in the penile urethra can be a helpful clue that it is a primary carcinoma.

Answer 65

MMMT gross

Answer 66

Lichen Amyloidosis * Amyloidosis refers to a group of disorders characterized by abnormal extracellular deposition of β-pleated amyloid protein, either systemically or localized to a specific organ. There are approximately 25 distinct forms of amyloid fibril proteins. * Primary localized cutaneous amyloidosis is associated with the deposition of amyloid in the skin without associated deposits in internal organs. The most common variants are macular amyloidosis and lichen amyloidosis. * The amyloid in macular amyloidosis and lichen amyloidosis is believed to be keratinocyte-derived. This belief has been supported by ultrastructural studies demonstrating transitional forms between viable keratinocytes and amyloid and by positive reactions with monoclonal antibodies directed against keratin. * Lichen amyloidosis usually manifests as persistent, pruritic plaques on the shins or other extensor surfaces of the extremities, particularly the anterior thighs or forearms. Macular amyloidosis manifests as pruritic, hyperpigmented macules that form a rippled pattern, most commonly on the upper back. * On histopathologic examination, macular amyloidosis and lichen amyloidosis demonstrate amorphous, eosinophilic deposits of amyloid limited to the papillary dermis. Pigment incontinence within melanophages and a sparse perivascular lymphohistiocytic infiltrate are often seen. In lichen amyloidosis, the deposits may expand the papillae and displace the elongated rete ridges laterally. The overlying epidermis is acanthotic and hyperkeratotic. * Congo red stains amyloid protein a brick-red color, and amyloid exhibits positive “apple-green” birefringence under polarized light. Other histochemical stains that can be used to detect amyloid deposits include crystal violet, methyl violet, PAS, Sirius red, pagoda red, and thioflavine T.

Answer 67

AL type: * Also called primary amyloidosis * Most common cause of renal amyloidosis in US * Due to plasma cell dyscrasias with systemic deposition of amyloid and mild increase in bone marrow plasma cells that are monoclonal * 20% have myeloma or other lymphoproliferative disorders * Deposits are more likely lambda (75%) light chains or fragments than kappa type, often from amino-terminal fragment of variable region of light chain * Either vascular-limited or diffuse patterns * 40% develop nephrotic syndrome * Urinary exosomes may be useful to identify patients with AL amyloidosis * Poor prognosis; patients may develop acute leukemia after alkylating agents, secondary malignancies after autologous transplantation AA type: * Also called secondary amyloidosis * Associated with chronic inflammatory conditions such as osteomyelitis, bronchiectasis, decubitus ulcers, Crohn’s disease, rheumatoid arthritis, tuberculosis * Main amyloid component is protein A, derived from proteolytic cleavage of serum amyloid A protein, an acute phase reactant * 90% have renal insufficiency or nephrotic syndrome at diagnosis * Renal function is associated with amount of amyloid deposition * Treatment: treat the underlying inflammatory condition Beta 2 microglobulin type: * Associated with long-term hemodialysis or peritoneal dialysis; also renal failure between treatments; increases with duration of dialysis * Amyloid protein composed of intact and modified beta 2 microglobulin, an integral part of HLA class I antigen complex, that is usually eliminated by the kidney * Amyloid deposits occur in blood vessel walls, perineural and periarterial tissue, bone, joint, skin, subcutaneous tissue, heart, GI and lungs * May cause carpal tunnel syndrome, joint disease and bone cysts ATTR type: * Amyloid fibrils consist of transthyretin * Associated with familial amyloidosis Familial Mediterranean fever: * Autosomal recessive, deposits consist of AA amyloid AH type: * Due to heavy chains * Very rare (predominantly lambda)

Answer 68

Pernio * aka chilblains * inflammatory skin condition * pruritic, painful, or pruritic and painful violaceous papules and nodules that occur on acral surfaces, most commonly the dorsum of the fingers and toes, but the nose, ears, and thighs also can be affected * A clue to the diagnosis is the anatomic distribution and cyclic nature of the lesions * develops in patients exposed to nonfreezing cold in damp conditions * lesions develop with a change of weather going into winter and resolve during spring and summer * most commonly, occurs in young women * Histology * superficial and deep perivascular land periadnexal ymphocytic dermal inflammatory infiltrates t * perieccrine accentuation of the infiltrate is characteristic * varying amount of interface change can be seen * Pernio and chilblains lupus erythematosus have overlapping clinical and histologic features, evaluate for SLE * should not be confused with lupus pernio, which refers to a form of cutaneous sarcoidosis

Answer 69

Dermatofibrosarcoma protuberans * young adults * male predominance * trunk and the proximal extremities * early lesions have a plaquelike appearance and late lesions are multinodular with skin ulceration * low-grade sarcoma with a high propensity for local recurrence if incompletely excised * complete excision requires wide margins because of infiltration beyond the grossly visible margins * recurrence rate of 20% within 2 years of surgery * Mohs surgery significantly reduces the rate of recurrence ( * Gross: the lesion is firm and fibrous and varies from a small dermis based plaquelike area or nodule to a large multinodular lesion that ulcerates the overlying skin and deeply involves the underlying adipose tissue * occasionally may be purely subcutaneous * Histology: * proliferation of uniform, mildly atypical spindle cells, arranged in a tight, repetitive storiform pattern * infiltrates the dermis surrounding the epidermal appendages and infiltrates the fat in a checkerboard or beaded pattern * lesional cells are uniformly CD34 positive * may contain fascicular areas that are indistinguishable from fibrosarcoma * composed of intersecting fascicles of spindle cells with increased atypia and mitotic activity (\>10 mitoses per 10 HPFs) * to be considered fibrosarcomatous, must represent \> 5% of the entire lesion * DFSP with fibrosarcomatous transformation has a small but definite metastatic potential 5% to 10% * lung is the most common site of dissemination * t(17;22) *COL1A1-PDGFB*

Answer 70

Immunohistochemistry of Thoracic Neoplasm * CD34, BCL2, Calretinin, CK, S100, SMA Solitary fibrous tumor of the pleura (SFTP) * positive for anti-CD34 and anti-BCL2. mesothelioma * anticalretinin and anticytokeratin (anti-CK) staining nerve sheath tumors * anti-S100 staining myofibroblastic and smooth muscle proliferations * smooth muscle markers, SMA The pleural location essentially excludes any primary gastrointestinal stromal tumor, and thus, CD117 and DOG-1 staining are not a primary concern. * Similarly, negative anti-CK staining excludes virtually all primary pulmonary carcinomas, thus staining for anti- thyroid transcription factor (anti-TTF-1) is a low priority. * Antidesmin may be added to the panel to distinguish SFTP from other spindle cell neoplasms, but antismooth muscle actin (anti-SMA) is a better choice, because it covers both neoplastic and nonneoplastic smooth muscle and myofibroblastic proliferations. Both are negative in solitary fibrous tumor of pleura.

Answer 71

Antigen Retrieval * The introduction of heat induced epitope retrieval in the mid-1990s revolutionized diagnostic immunohistochemistry, allowing staining of morphologically superior paraffin sections for antigens hitherto detectable only on frozen sections. * Various buffers have been used for antigen retrieval, and although its mechanism is not known, **buffer pH, temperature, and duration appear to be the most important determinants of efficacy of antigen retrieval**. * Antigen retrieval protocols may need to be varied, depending on the antigen detected, tissue processing method, etc. * Although the specific buffer per se may not be important, one simple fact that is often overlooked is that **buffer-pH is generally measured at room temperature, and temperature-pH relationships vary for different buffers.**

Answer 72

Gliomas codeletion of 1p and 19q is a favorable prognostic marker in ologodendrogliomas unbalanced translocation between chromosomes 1 and 19, with loss of the derivative that contains the long arm of chromosome 1 and the short arm of chromosome 19 deletion of 1p and 19q is evaluated either by FISH using 1p36 and 19q13 probes, with control probes on the long and short arms of chromosomes 1 and 19, respectively; or by LOH analysis using polymorphic microsatellite markers on the chromosomes 1p and 19q. * Although the codeletion is virtually diagnostic of oligodendrogliomas, not all oligodendrogliomas harbor these deletions. They are rarely, if ever, seen in pediatric oligodendrogliomas. * 1p and 19q deletions are associated with MGMT promoter methylation and IDH1 or IDH2 mutations. * IDH1 or IDH2 mutations are seen in 70% to 80% of grades II and III astrocytomas and oligodendrigliomas, and virtually all 1p/19q deleted oligodendrogliomas. They are also seen in glioblastomas that arose from low grade gliomas, but virtually never in de novo glioblastomas. IDH1/2 mutated gliomas are either 1p/19q deleted or carry p53 mutations. * MGMT is a DNA repair enzyme that removes alkly groups from DNA. Promoter hypermethylation of MGMT is associated with loss of expression of MGMT and sensitivity of gliomas to alklylating agents.

Answer 73

Secretory Breast Cancer * median age of 25 years * young men with a median age of 19 years * eosinophilic secretions in intracellular and extracellular vacuoles * vacuoles are positive on PAS-D * positive for S-100 and α-lactalbumin * basallike tumor by gene expression profiling * triple negative and basal marker positive * t(12;15) resulting in a fusion transcript ETV6-NTRK3 * results in activation of both the Ras-Mek1 and pI3k-Akt pathways * activation of mammary growth factor (also known as signal transducer and activator of transcription 5A) which is thought to be mechanistically linked to the observed secretory change. * Excellent prognosis * if the tumor is large or metastatic, it demonstrates unfavorable behavior * prognosis is better in children and adolescents and is noted to be slightly worse in adults

Answer 74

Pigmented Villonodular Synovitis * aggressive, proliferative lesion * large joints * causes erosion of adjacent bones * joint is usually swollen, not painful or only slightly painful, and there may be +/-symptoms of internal derangement * no systemic symptoms * Xray: swelling in and around the joint, joint narrowing, erosion of the articular margins, and lytic defects of the bone * MRI and CT: punctate signal voids in the lesion * Gross: rusty brown color of the joint fluid and synovial surfaces, which have both a fernlike villous and nodular appearance * Histology: * striking villous hypertrophy of the synovial surface lined by hyperplastic cells that are heavily laden with hemosiderin pigment * large nodules formed by coalescence of the villi * membrane is hypervascular and is crowded with aggregates of lipid-laden macrophages, scattered giant cells, and occasional lymphocytes * surgical excision * recurrences are common because of the difficulty of complete surgical removal * A nodular form (diffuse nodular synovitis) may involve the large joints with the knees much more frequently affected than the hips and ankles. * A single nodule may occur in a large joint such as the knee (localized nodular synovitis) but is very common in the tendon sheaths around the finger joints (localized nodular tenosynovitis).

Answer 75

Neurocysticercosis * Cysticercosis is the most common parasitic infection. * clinical presentation can include seizures, papilledema, headache, vomiting and ataxia, focal motor and sensory deficits, dementia and acute hydrocephalus. * most common in the developing world * caused by infection with the larval form of the pork tapeworm, Taenia solium * can present two months to 30 years after infection * One or multiple cysts can occur in the parenchyma, meninges or ventricles. * A viable intraparenchymal cysticercus contains a single invaginated scolex. * After degeneration, they become fibrotic and present as a firm white nodule (a calcified lesion on imaging). * Histology: * cyst wall is sparsely cellular and consists of three distinct layers: an outer, eosinophilic layer with microvilli; a middle cellular layer; and an inner reticular layer * encysted larvae can be visible with minimal surrounding parenchymal reaction. * during degeneration of the cyst, an inflammatory response is initiated, predominantly composed of neutrophils with variable amounts of granulation tissue, eosinophils, and fibrosis * when the cysticercus dies, it calcifies and the inflammation diminishes

Answer 76

Mycosis fungoides * no specific cytogenetic abnormalities * most common type of T-cell lymphoma skin primary, 50% of all primary cutaneous lymphomas * confined to the skin for a protracted period of time * extracutaneous dissemination may occur in advanced stages, mainly to lymph nodes, liver, spleen, lungs, and blood * postitive: CD3, CD5, CD4 * negative: CD7, CD8

Answer 77

Inversion of chromosome 14 is seen in 80% of T-cell prolymphocytic leukemia cases.

Answer 78

Fungal Infection in Transplant Patients * tend to occur early, usually within 2 months * Candida infection is a major complication in patients after intraabdominal solid organ transplantation because of surgical manipulation of the bowel. It is particularly prevalent among liver transplant recipients. * Aspergillosis is associated with a nearly 100% mortality rate and more commonly infects the lungs and surgical wounds. * Cryptococcal infections and Pneumocystis pneumonia 3% to 10%

Answer 79

Langerhan’s Cell Histiocytosis * aka histiocytosis X, eosinophilic granuloma, Hand-Schuller-Christian disease, Letterer-Siwe disease * clinically diverse and can have local or generalized symptoms * Histology * proliferation of Langerhan-type histiocytes accompanied by a mixed inflammatory component * Approximately 85% of cases occur before age 30 and 60% occur before age 10 * Prognosis is excellent for single-focus disease * Common sites include skin, bone, liver, and lung

Answer 80

Mesoblastic nephroma * Congenital mesoblastic nephroma is the most common renal tumor in newborns. * Microscopically, it is divided into three subtypes: (1) Classic: less common, resembles infantile fibromatosis or leiomyoma with fascicles and whorls of bland spindled myofibroblasts and thin collagen fibers; tumor surrounds tubules and glomeruli, has irregular borders; chondroid metaplasia / dysplasia of the entrapped tubules is common; mitoses are rare; necrosis / desmoplasia are not present (2) Cellular: resembles infantile fibrosarcoma with a sheet-like proliferation of plump, atypical spindle cells with abundant cytoplasm, vesicular nuclei and nucleoli; frequent mitotic figures (25-30 / 10 HPF) and necrosis; the tumor has a pushing border * t(12;15), which results in ETV6-NTRK3 gene fusion, which is similar to the translocation seen in infantile fibromatosis (3) the mixed subtype, which is a combination of both types • Most cases, including the cellular variant, are cured by surgical excision.

Answer 81

Reparative Granuloma (Formerly Giant Cell Reparative Granuloma) * benign, reactive lesion of bone of unknown cause * 10 to 25 years * predilection for facial bones such as the mandible and maxilla * second most common site is the bones of the hands and feet * local swelling secondary to the expansion of the contour of the underlying bone * Xray: * round or oval lucency with fine trabeculations and well-defined margins * may expand the contours of the bone and cause cortical thinning * usually no cortical destruction or periosteal new bone formation * surgical curettage is the treatment of choice * recurrence rate is high (33% to 50%) in the lesions of the hands and feet * in these locations, reparative granulomas that show destructive behavior are best treated by amputation or ray resection

Answer 82

Pemphigus Vulgaris autoimmune blistering disorder autoantibodies directed against desmoglein 3 and desmoglein 1, desmosomal proteins that are part of the cadherin family flaccid blisters can develop both in the oral mucosa and on the skin lesions tend to appear in the oral cavity and proceed to involve the skin blisters commonly break and leave erosions on the skin Histology: * intraepidermal blister, acantholysis and “tombstone” pattern of basal layer keratinocytes Direct immunofluorescence testing * perilesional skin adjacent to a blister, distinct pattern of intercellular deposition of IgG and C3 (vulgar fishnet stockings) Indirect immunofluorescence * testing a patient’s serum on monkey esophagus, pemphigus vulgaris has a distinct pattern of intercellular deposition of IgG. ELISA testing can be employed as an additional technique to evaluate a patient’s serum for the presence of antibodies to desmoglein 3 and desmoglein 1. The presence of antibodies to desmoglein 3 is correlated with oral involvement, and the presence of antibodies to desmoglein 1 is correlated with skin involvement. • The disease activity of pemphigus vulgaris correlates with antibody titers.

Answer 83

Angiomatoid fibrous histiocytoma * soft tissue neoplasm that involves the deep dermis and subcutaneous tissue * generally small (1-3 cm) * children and young adults (mean age 20 years) * extremities \> trunk \> head and neck * Histiology * thick fibrous pseudocapsule * lymphoplasmacytic infiltrate with germinal centers * a center with epithelioid and spindle fibrohistiocytic cells * large blood-filled spaces * +(var) for desmin in 50% to 80% of the cases * originates from myoid cells of lymphoid tissue * t(2; 22) (q34; q12), EWSR1 and CREB1 genes * indolent clinical course, local recurrences in \<10% * rare mets reported

Answer 84

CDX-2 * CDX-2, a homeobox transcription factor involved in gastrointestinal development, is a useful marker for tumors of gastrointestinal origin. * Poorly differentiated colonic carcinomas are often CDX-2 negative. * Gastric carcinomas are usually positive, although normal gastric surface epithelium is CDX-2 negative. * Pancreato-biliary neoplasms stain weakly or not at all with anti-CDX-2. * Intestinal type adenocarcinomas arising in the genitourinary tract are usually positive; Barrett’s epithelium may be positive; mucinous adenocarcinomas of the ovary show patchy, but often strong, CDX-2 staining. * A subset of mucinous and large cell neuroendocrine lung carcinomas may show patchy, but strong, staining for CDX-2.

Answer 85

Breast Cancer—Her2/neu * Amplification of the HER2/Neu (ERBB2) gene, with associated HER2 protein overexpression and constitutive activation of its tyrosine kinase activity, is more frequent in ER/PR-negative breast cancers and is an independent indicator of poor prognosis. * More importantly, ERBB2 is a target of, and ERBB2 amplification is a marker of, sensitivity to treatment with trastuzumab (Herceptin). In addition, the small tyrosine kinase inhibitor (TKI) lapatinib, and the new anti-HER2 antibody, pertuzumab, which targets a different HER2 epitope, have been shown to be effective in HER2 amplified breast cancer. The latter has been shown to improve progression-free survival rate by almost 50% in patients with advanced breast cancer, when added to docetaxel and trastuzumab. * Although semiquantitative immunohistochemical tests for protein expression, such as Herceptest, are convenient, variability of antigen preservation and retrieval, as well as interobserver variability in interpretation, make immunohistochemistry a less reliable predictor of response than FISH. The American Society of Clinical Oncology and College of American Pathologists have issued guidelines for evaluating the HER2 status of breast tumors. * Resistance to trastuzumab is poorly understood, and many mechanisms may be involved, including loss of the ERBB2 external domain, overexpression of MUC4, increased transcription of ERBB2, and bypassing EGFR signaling by activation of downstream pathways, especially the PI3-kinase/mTOR pathway, including activating PIK3CA mutations and loss of PTEN. * One means of overcoming resistance is treatment with mTOR pathway inhibitors, such as everolimus. Although modest responses have been shown in pretreated patients, clinical trials to evaluate the drug in combination with chemotherapy and trastuzumab are underway. * Trastuzumab has also been shown to be active in HER2 amplified/overexpressing adenocarcinoma of the stomach and distal esophagus. The criteria for immunohistochemical and FISH evaluation from the ToGA trial that showed this benefit differed from the CAP/ASCO criteria, although a recent publication from Memorial Sloan Kettering shows that the CAP/ASCO criteria may be adequate.

Answer 86

Ileal urine * These degenerated cells with pyknotic nuclei resemble histiocytes, but are degenerated ileal glandular epithelial cells in ileal urine. They usually lack a columnar appearance because epithelial cells tend to “round up” in fluid, and they frequently resemble macrophages. * Ileal urine commonly has a granular background containing bacteria, cellular debris, and inflammatory cells. This background debris may make it difficult to identify neoplastic cells from a recurrent or metachronous tumor; however, the malignant cells actually may be better preserved than the degenerated intestinal cells, and will show cytologic features characteristic of malignant urothelial cells. * Cytologic changes due to radiation of urothelium are similar to its effects on other types of epithelial cells; features include marked cell enlargement (cytomegaly; enlargement of both the nucleus and the cell itself), vacuolization of the cytoplasmic and nucleus, “smudged” nuclei, and polychromatic or two-tone cytoplasmic staining. * Radiation changes may persist for years following treatment. Examination of voided urine is not a primary method of diagnosing prostatic diseases. In fact, it is very uncommon to find normal prostatic cells or evidence of benign disorders of the prostate in voided urine. * Neutrophils, lymphocytes, and histiocytes almost always are present in ileal urine specimens and do not necessarily indicate an infectious process.

Answer 87

Mesothelioma in pleural fluid * Most pleural mesotheliomas produce bloody pleural effusions. Symptoms may include chest pain and shortness of breath. * Pleural fluid samples containing malignant mesothelioma usually are very cellular. In addition to single tumor cells, there may be large, complex clusters with scalloped or “knobby” borders and composed of thousands of neoplastic cells. Binucleated and multinucleated neoplastic cells are common. In contrast to carcinomas, in mesotheliomas, there is no second cell population of tumor cells with features different from benign mesothelial cells. On the contrary, there is a spectrum of cytologic atypia, with cells ranging from almost normal-looking mesothelial cells to cells with obviously malignant features;however, the cells that appear benign and relatively bland actually are larger than benign mesothelial cells. Some of the overtly malignant appearing cells retain mesothelial features, e.g., intercellular windows and cell-in-cell formations. In some cases, however, the malignant cells are only minimally atypical and diagnosis based on cytologic features alone may not be possible. * The long microvilli on the surfaces of mesothelial cells are responsible for the so-called “lacy skirt” appearance of the periphery of these cells as well as the presence of a space or “window” between adjacent mesothelial cells. * Ancillary studies that may be helpful in distinguishing mesothelioma from adenocarcinoma include mucin stains (mucicarmine, PAS with and without diastase, and Alcian blue or colloidal iron with hyaluronidase), immunocytochemical stains (including carcinoembryonic antigen [CEA], B72.3, EMA, LeuM1, CK5/6, WT1, D2-40, and calretinin, among others), and electron microscopy. * Some studies have shown that EMA and desmin immunostains are helpful in distinguishing between mesothelioma and nonneoplastic/reactive mesothelial cells. The combination of EMA positivity and negative desmin staining reportedly favors malignant mesothelioma, while a combination of negative EMA and positive desmin favors a reactive process. * The wide reported sensitivity of cytologic examination for the diagnosis of malignant mesothelioma reported in literature (from 4% to 77%) may be due to variations in sampling, specimen preparation, and the use of ancillary testing. * Although cytologic findings may be consistent with a diagnosis of mesothelioma in the proper clinical setting (e.g., pleural thickening in a patient with asbestos exposure), confirmatory pleural tissue biopsy is usually warranted prior to treatment.

Answer 88

Spirochetosis. * Intestinal spirochetosis is a noninvasive infection by spirochetes, most commonly Brachyspira pilosicoli and Brachyspira aalborgi, which proliferate along the colonic epithelial surface. * Although thought to represent an incidental finding in some cases, spirochetosis has been associated with diarrhea, anal discharge, and abdominal pain in immunosuppressed individuals, especially in the setting of HIV/AIDS (definite cause-effect relationship still uncertain because of the concomitant infections and other confounding factors in these cases). * Prevalence of 2% to 16% in Western countries, being significantly higher in developing countries. Most commonly seen in homosexual men with HIV/AIDS. * Gross/endoscopic appearance of the mucosa is usually normal. * This infection must be suspected and a “fringed,” basophilic line is seen along the apical border of colonicytes (including colonocytes within crypts). Organisms along the epithelial surface are highlighted by silver stains (Warthin-Starry and Steinter stains). Alcial blue pH 2.5 and PAS stains can also be used, while Gram stains usually fails to highlight these organisms.

Answer 89

Sclerosing hemangioma * related to pneumocytes at different stages of maturation * lesional cells are cytokeratin positive in lining areas and diffusely TTF-1 positive * generally benign although rare cases have been shown to have lymph node metastasis (do not appear to affect prognosis) * 4 typical patterns * papillary, solid, sclerotic, and angiomatoid * not always all present in the same tumor

Answer 90

Gynecomastia * intraductal epithelial hyperplasia and periductal increased cellularity and edema * 3 stages * early florid, intermediate, and late inactive or fibrotic * may be seen in the female breast * most common lesion of the male breast * bimodal distribution but may be seen at any age * affects 30% to 60% of boys and 30% of adults * most are ER positive * occasionally, breast lobules may be seen * a/w hyperthyroidism; cirrhosis; chronic renal failure; use of hormones; and use of numerous common drugs (digitalis, cimetidine, and spironolactone) * NO increased incidence of breast carcinoma * Pseudogynecomastia may be seen in obese males because of lipomastia (i.e., fat in the breast, lacking glandular proliferation).

Answer 91

Porokeratosis (Disseminated Superficial Actinic Type) * **The key histopathologic feature is a cornoid lamella, which is a column of parakeratotic cells beneath which there is absence or diminution of the granular layer as well as dyskeratotic or vacuolated keratinocytes.** * **The linear type of porokeratosis has the greatest risk of malignant transformation to squamous cell carcinoma.** * genetic condition with many clinical forms * solitary or multiple * Porokeratosis of Mibelli is characterized by one or more round plaques with an atrophic center and a thin, elevated, keratotic border. * Disseminated superficial actinic porokeratosis manifests as multiple, annular lesions with a hyperkeratotic, threadlike border on sun-exposed areas. * Other variants include linear porokeratosis and punctate porokeratosis. * The cornoid lamella corresponds clinically to the raised, keratotic or threadlike rim that is seen in lesions of porokeratosis. * • Two cornoid lamellae may be present, often in disseminated superficial actinic porokeratosis type, and the intervening epidermis is often atrophic and hyperkeratotic. The dermis may demonstrate a bandlike, lichenoid inflammatory infiltrate, mimicking a lichenoid keratosis. Solar elastosis may be present. * Multiple cornoid lamellae may be present in the linear and reticulated forms as well as in porokeratosis ptychotropica. Porokeratosis ptychotropica is a rare variant that manifests as verrucous papules in the perianal area.

Answer 92

Epithelioid hemangioendothelioma * peak incidence in the fifth decade of life * deep soft tissue \> subcutis and skin * lower and upper extremities \> trunk, head and neck, mediastinum, and abdominal cavity * solitary, slightly painful mass ~3 cm * most originate within vessels * gross appearance of an organizing thrombus with a variegated white-red cut surface, or it may be an ill-defined pale and firm lesion * cords and nests of round to spindled endothelial cells embedded in myxohyaline matrix resembling cartilage * tumor cells have uniform round nuclei and abundant eosinophilic cytoplasm that is often vacuolated, giving the cell the appearance of a “blister” cell * mitotic activity is low (\<3 mitoses per 20 HPF) and tumor necrosis is infrequent (less than 10%) * increased cytologic atypia and mitotic activity are usually associated with a more aggressive behavior * Positive: CD31, CD34, FLI1, and Factor VIII * recurrent t(1; 3) (p36.3; q25) translocation * unpredictable behavior, high-risk tumors are usually * \> 3 cm and have \>3 mitoses per 50 * high risk patients may benefit from adjuvant chemotherapy, in the same way of patients with hepatic and pulmonary EHE

Answer 93

* p190 is the most common protein isoform seen in acute B-lymphoblastic leukemia (B-ALL) patients with bcr-abl rearrangement. * p190 is the most common isoform seen in pediatric B-ALL patients. In contrast, in adult B-ALL patients (much less common than in pediatric B-ALL), about half of patients have the p190 isoform and the other half have the p210 isoform. * p210 is the most common protein isoform seen in chronic myeloid leukemia. * p230 is the second most common protein isoform seen in chronic myeloid leukemia (CML). The p230 isoform is associated with a prominent neutrophil maturation in CML. * p16 is a tumor suppressor gene and is not a protein encoded by the bcr-abl rearrangement. In acute lymphoblastic leukemia p16 can show homozygous deletion and is associated with a poor prognosis. * p53 is a tumor suppressor gene and is not a protein encoded by the bcr-abl rearrangement. p53 mutation is associated with a poor prognosis in many malignancies, including hematolymphoid malignancies.

Answer 94

Listeria villitis * placenta and fetus are infected with Listeria via the hematogenous route * important cause of second trimester abortion * acquired by the mother from consumption of contaminated meat or unpasteurized dairy * premature delivery or stillbirth * most common in pregnant women, immunocompromised hosts, the elderly, and newborns

Answer 95

DiGeorge’s syndrome * cardiac anomalies, abnormal facies, thymic aplasia, cleft palate, and hypocalcemia/hypoparathyroidism * CATCH-22; the 22 is for the abnormal chromosome * deficiency of PTH --\> hypocalcemia, often severe enough to cause tetany and seizures * includes velo-cardiofacial syndrome, Schprintzen syndrome, and conotruncal anomaly face syndrome * 1 in 4,000 * The genes that contribute to the phenotype have not yet been identified.

Answer 96

Lymphoma – EBV associated * Epstein–Barr virus (EBV) infections of B cells are characterized by latency with long-term persistence in these cells. * Each cell is infected once. During infection the virus forms a circular episome, incorporating a variable number of terminal repeats. EBV DNA in progeny cells has the same number of repeats as the “parent” cell. * EBV DNA in progeny cells has the same number of repeats as the “parent” cell. Southern blotting, following BamH1 digestion to cut sequences flanking the termini, using a probe that binds to the terminal repeats, reveals multiple bands in polyclonal populations of cells with separate circularization events, and a single band in DNA from clonal B-cell samples. * Length of termini is not an indication of strain or of duration of infection * Although clonal EBV infection is characteristic of posttransplant B-cell lymphomas, it is seen in other lymphomas, including endemic Burkitt’s lymphoma, immunoblastic B-cell lymphomas in acquired immunodeficiency syndrome, EVB associated T/NK cell lymphomas, and rarely, in posttransplant T-cell lymphomas. * Southern blotting is no longer widely used for diagnosis of EBV-associated conditions; however, in situ hybridization for EBVearly RNA (EBER) and viral load testing for EBV DNA are now widely used in diagnosis of EBV-associated lesions and management of patients in the posttransplant setting.

Answer 97

Sarcoidosis * Sarcoidosis is an idiopathic disease characterized by nonnecrotizing granulomas. Although typically involving mediastinal lymph nodes and the lung, sarcoidosis can be a systemic process. Cardiac involvement, central nervous system involvement, skin involvement, and ocular involvement are well described. * The yield on transbronchial biopsy is excellent in pulmonary sarcoid, and especially high if an airway abnormality is seen during bronchoscopy. Four to six negative biopsy fragments have a high negative predictive value. Ruling out sarcoidosis remains one of the major nonneoplastic uses of transbronchial biopsy. * When open lung biopsies are performed, sarcoidal granulomas are observed to follow lymphatic routes. * The disease can be found incidentally and often resolves spontaneously. It may require steroid therapy. However, a subset of patients will progress to pulmonary fibrosis despite therapy, requiring lung transplantation. * Sarcoidosis can be nodular. Vascular involvement can be seen as well, especially in areas of confluent granulomas. * A variety of inclusions can be seen in granulomatous disease including sarcoidosis. These inclusions are notsufficiently specific to attribute a granulomatous process to sarcoidosis;however, calcium oxalate, asteroid bodies (stellate), Schaumann bodies (concentric lamellated bodies), and least frequently Hamazaki-Wesenberg bodies (minute oval bodies) can be seen. Their recognition is important as cautionary advice to not mistake them for yeast forms.

Answer 98

Schistosomiasis and Pipestem Fibrosis * Symmers fibrosis refers to the dense, rounded, and fibrotic portal tracts that are seen on the cut surface of the liver in late schistosomiasis. * Early changes in schistosomiasis include schistosomal granulomas within portal vein branches, sometimes with an extensive surrounding eosinophil infiltrate and corona of degranulated bright red eosinophil granules (Hoeppli-Splendore effect). * Later changes in schistosomiasis include portal tract fibrosis, loss of portal vein lumina, and acquisition of schistosomal finely granular black pigment in Kupffer cells and portal macrophages. * Acid-fast stain is useful to apply to suspected schistosomal granulomas or other suspicious areas because the outer cuticle and lateral spike of Schistosoma mansoni and other species are positive on acid-fast bacilli.

Answer 99

Fibrin Ring Granulomas and Q Fever * Fibrin ring granulomas (also called “donut granulomas”) are lobular granulomas that are distinguished from other types of granulomas by their central, seemingly empty space (a lipid vacuole) surrounded by strands of fibrin with outer lymphocytes and macrophages. * Fibrin ring granulomas are chiefly formed as a result of infections, the most frequent association being with Q fever (C. burnetii infection). * The histologic differential diagnosis of fibrin ring granulomas includes cytomegalovirus, Leishmania spp., hepatitis A virus infection, and allopurinol toxicity. These granulomas have been considered a nonspecific reaction, chiefly to infections. * Fibrin ring granulomas are typically located within the lobular parenchyma and are not within portal tracts. Their central empty hole and surrounding strands of fibrin are histologically distinct from sarcoid granulomas, which are usually fibrosing and often clustered adjacent to portal tracts, and drug-related granulomas, which lack the central vacuole and sometimes contain eosinophils.

Answer 100

Thin Basement Membrane Nephropathy * The clinical presentation of microscopic hematuria, in the absence of significant proteinuria or renal insufficiency, is most commonly encountered in the following three renal conditions: thin basement membrane nephropathy (TBMN), hereditary nephritis (i.e., Alport syndrome), and IgA nephropathy. * Before a patient with microscopic hematuria undergoes renal biopsy, possible urologic causes for hematuria must be excluded. * The glomeruli in TBMN usually appear unremarkable on light microscopy. The normal glomerular basement membrane (GBM) thickness averages approximately 320 nm in women and 350 nm in men. Diagnostic criteria for TBMN are diffuse GBM thinning, with mean thickness less than 225 nm in women and less than 250 nm in men. * The main clinical finding in TBMN is isolated microscopic hematuria. Many patients have a family history of isolated hematuria with autosomal dominant transmission. * TBMN results from a heterozygous mutation in either COL4A3 or COL4A4; these genes encode the alpha-3 (COL4A3) and alpha-4 (COL4A4) chains of collagen IV. * TBMN is a nonprogressive condition that is often referred to clinically as benign essential hematuria.

Answer 101

* Graves disease * antithyroid-stimulating hormone receptor (anti-TSHR) antibodies, which cause constitutive activation of follicular epithelial cells * overproduction of triiodothyronine (T3) and thyroxine (T4) * Histologic features * papillary hyperplasia * “scalloping” of colloid * follicles containing little or no colloid * columnar morphologic appearance * HLA-B8 has been associated with an increased risk for development of Graves disease * HLA-Bw35 has been associated with an increased risk for development of subacute thyroiditis. * Causes of primary hyperthyroidism * Graves disease, “toxic” goiter, and “toxic” adenoma * Causes of secondary hyperthyroidism * pituitary adenoma and gestational thyrotoxicosis

Answer 102

Infant of a diabetic mother * 3-10% of all pregnancies are affected by abnormal glucose regulation * increased risk of growth abnormalities, respiratory distress, hypoglycemia, and congenital anomalies * If maternal blood glucose is tightly controlled, the risk of adverse events is markedly decreased (but is still increased over baseline). * Nesidioblastosis generally refers to congenital hyperinsulinism with an abnormal microscopic appearance of the pancreas. * If severe, near-total pancreatectomy may be needed (rare).

Answer 103

Hyaline membrane disease * Hyaline membrane disease (HMD) is most commonly seen in white male infants weighing less than 2500 grams. * Besides prematurity, other predisposing conditions include maternal diabetes, twin gestation, and caesarean section without trial of labor. * Hyaline membranes form in about 2 to 3 hours after onset of respiratory distress (won’t be seen in stillborns or in infants who died within an hour of birth). * HMD is caused by deficiency in surfactant protein B, caused either by prematurity or genetic mutation. * Bronchopulmonary dysplasia (chronic lung disease of infancy) is a complication of the treatment of HMD. * Exogenous surfactant administration significantly improves morbidity and mortality

Answer 104

PCR optimization • Amplification of templates with a high GC content is complicated by the high melting temperature (Tm) of the template, and, therefore, its greater tendency to re-anneal during the primer-annealing step. Organic additives, such as Betaine (N,N,N-trimethylglycine), DMSO (dimethylsulfoxide), dihydroxy alcohols (pentanediol, hexanediol), or glycerol may increase yields of GC-rich PCR templates * All the reagents mentioned appear to act by reducing the difference between primer and product/template Tm. Proprietary reagents that improve amplification of GC-rich templates often contain one or more of these additives. * Another method to improve amplification of GC-rich templates is to add analogs of minor-groove binding drugs to the 5′ end of the primer, increasing the Tm of the primer without increasing primer length. * Commercial kits that are optimized for templates with high GC content often use one of the additives above. * Sequences with a high GC and high AT content may also be underrepresented in high throughput sequencing approaches that use capture, and may require the use of additional probes.

Answer 105

Bubonic plague—Yersinia pesitis Q fever—Coxiella burnetii Tularemia—Francisella tularensis Botryomycosis—Staphylococcus aureus Pontiac fever—Legionella species Bacterial pneumonias * Plague is caused by Yersina pestis, and can cause lymph node enlargement (bubos), sepsis, and pneumonia. It is flea borne, but can be contracted from animal carcasses and severely infected animals. * Tularemia can also cause severe pneumonia and is caused by exposure to infected rodents including rabbits. It can be tick transmitted, and this causes skin ulcers and node enlargement. Bacterial inhalation can cause severe pneumonia. * Botryomycosis is a term for bacterial accumulations/cluster in tissue. Heart valve vegetations with gram positive coci are an example, but they can be seen in severe infections including abscess formation. * Legionella causes a severe fibrinopurulent pneumonia often leading to multilobar involvement and diffuse alveolar damage when most severe. * Q fever is an infection by Coxiella burnettii, which can result in high fever, headaches, cough, pneumonia, and hepatitis. Blood from infected animals whether during slaughter or parturition is the source. The ring granuloma in bone marrow or liver can strongly suggest the diagnosis.

Answer 106

Gastric antral valscular ectasia (GAVE) * older women, history of autoimmune conditions * presents with anemia due to chronic blood loss * Endoscopically,(“watermelon stomach”) longitudinal raised red mucosal stripes along the antrum and pylorus * Microscopically, thrombi within dilated mucosal vessels * Associated less specific histologic features include regenerative epithelial changes and fibromuscular hyperplasia of the lamina propria. * spare the gastric body (in contrast with portal hypertensive gastropathy, which also involves the gastric body). * Abnormal antral motility and mucosal prolapse are thought to be involved in the pathogenesis of this disease.

Answer 107

Hepatocellular Adenoma (Liver Cell Adenoma) * benign tumor of hepatocytes * Histology * thickened cords of hepatocytes * interspersed blood vessels (thin venous and arterial profiles are seen) * NO bile ducts * subclassified into four groups based on genomic classification: * type 1, HNF-1α mutations, with large droplet steatosis and without atypia * type 2, β-catenin mutations, with atypia and features that may transition to hepatocellular carcinoma * type 3, interleukin-6 ST mutations, including inflammatory or telangiectatic adenoma * type 4, no known mutation, with no specific features * to distinguish it from carcinoma * reticulin (which should show preserved reticulin framework throughout, in contrast to the “paucireticulin” pattern seen in hepatocellular carcinoma * possibly CD34 (should show limited expression near pseudo–portal tracts). * immunostains can be added * trio of glypican-3, glutamine synthetase, and heat shock protein 70 (which all should be negative) * Children and young adults with multiple adenomas (adenomatosis is defined as ≥10 adenomas) and diabetes are very likely to haveHNF-1α mutation and maturity-onset diabetes of the young type 3. * Adenomas with suspicious features for the development of or transition to hepatocellular carcinoma (nuclear atypia, pseudoglandular growth, increased mitotic activity, focal loss of reticulin) and harboring β-catenin mutations should demonstrate glutamine synthetase expression and nuclear overexpression of β-catenin on immunohistochemical staining.

Answer 108

Postinfantile Giant Cell Hepatitis * rare in adults (in contrast to multinucleated giant hepatocytes in a neonatal liver biopsy specimen, a frequent change). * affects only centrilobular hepatocytes * Histologic DDx: * autoimmune hepatitis * HCV infection with or without HIV coinfection * drug hepatotoxicity * primary sclerosing cholangitis (less common) * prevalence is slightly more than 2% in chronic hepatitis C

Answer 109

Dysproteinemic Renal Disease * The particular amino acid sequence of a monoclonal light chain dictates its biochemical properties, which determine the propensity of the light chain to form light chain amyloidosis, light chain deposition disease (LCDD), or light chain cast nephropathy (i.e., myeloma cast nephropathy). * The lambda light chain isotype is seen in most cases of primary amyloidosis. In contrast, the kappa isotype predominates in myeloma cast nephropathy and LCDD. * In approximately 90% of cases of LCDD, the deposits stain solely for kappa light chain. A monoclonal lambda light chain is responsible for the remaining 10%. By definition, Congo red staining for amyloid is negative. * In approximately 75% of cases of light chain amyloidosis, the deposits stain for lambda light chain. A monoclonal kappa light chain is responsible for the remaining 25%. By definition, Congo red staining reveals apple-green birefringence when viewed under polarized light. * Myeloma cast nephropathy or light chain cast nephropathy is the most common pattern of renal involvement in patients with multiple myeloma, and the usual manifestation is acute renal failure. The light microscopy findings in myeloma cast nephropathy include distinctive tubular casts and widespread tubular injury. Immunofluorescence microscopy demonstrates intense staining of the casts for either kappa or lambda light chain; staining for the reciprocal light chain is typically weak or negative. Kappa staining is seen in most cases.

Answer 110

Mastocytosis A diagnosis of systemic mastocytosis requires the major criterion: * presence of multifocal compact mast cell clusters that exceed 15 cells in either bone marrow or any extracutaneous organs 4 minor criteria of which 3 must be fulfilled for a diagnosis of systemic mastocytosis. * Spindled morphology in 25% or more of mast cells * Aberrant CD2 and/or CD25 expression in mast cells * A persistently elevated serum tryptase level of 20ng/mL or higher * The presence of a KIT mutation involving codon 816.

Answer 111

Progressive transformation of germinal centers (PTGC) * expanded germinal center with infiltrating small lymphoid cells, predominance of small mantle cell B-lymphocytes resulting in disruption and eventual replacement of the germinal center * can be seen in reactive lymphadenopathy, especially in a background of florid follicular hyperplasia * can also be seen simultaneously in the lymph node with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) * It is uncertain whether these lesions (PTGC) are truly a precursor lesion for NLPHL.

Answer 112

Lymphangioma of the small intestine and mesentery * Lymphangiomas occur most commonly in the head and neck area of young children. They can, however, occur in the gastrointestinal tract of children and adults. Although they are often asymptomatic, it can present with symptoms of intestinal obstruction. * The cystic spaces represent dilated lymphatic vessels lined by endothelial cells that are positive for CD31 and factor VIII-related antigen. Cystic lymphangiomas are benign lesions that are usually cured by surgical excision * Intestinal lymphangiectasia may be primary or secondary. Patients present with protein-losing enteropathy and malabsorption, hypoalbuminemia, hypogammaglobulinemia, and lymphopenia, resulting in secondary immunodeficiency. Primary disorders, which result from congenital obstruction to lymph flow or abnormal lymphatic structures, may be limited to intestinal lymphatics or may involve multiple organs. Secondary lymphangiectasia may be central, resulting from cardiac disease or from local obstruction to lymphatics due to a wide variety of causes.

Answer 113

Primary Sclerosing Cholangitis with Ductopenia * A young adult with cholestatic serum liver tests (particularly isolated alkaline phosphatase elevation) should be investigated for primary sclerosing cholangitis (PSC) and its frequently accompanying background of inflammatory bowel disease. * The most diagnostic lesions found in PSC include periductal “onion-skin” fibrosis and fibroobliterative lesions (i.e., fibroobliterative cholangitis—round or ovoid scars that replace former bile ducts). * The presence of chronic portal and periportal inflammation in PSC underscores the point that PSC sometimes may resemble chronic hepatitis, including the presence of interface hepatitis. * Alternative differential diagnoses of ductopenia include primary biliary cirrhosis (PBC), usually seen in middle-aged women; drug-induced liver injury (e.g., amoxicillin and clavulanic acid); and syndromic and nonsyndromic paucity of intrahepatic bile ducts in infants and children. * A definitive diagnosis of PSC should be rendered by radiologic assessment of the extrahepatic and intrahepatic bile ducts. Serum perinuclear antineutrophilic cytoplasmic antibody is often elevated in patients with PSC. * In a liver specimen that otherwise appears to be consistent with PSC because there is periductal fibrosis and other seemingly diagnostic features, if plasma cells are unusually prominent and the periductal inflammation is particularly dense, an important additional consideration is IgG4-associated cholangitis. IgG4-associated cholangitis should be excluded by immunostaining with antibody to IgG4 and by evaluation of the individual’s serum IgG4 level.

Answer 114

Embryonal Carcinoma of the Ovary * Embryonal carcinomas are composed histologically of disorganized sheets of large primitive cells that may form papillae. The nuclei often contain large, prominent nucleoli. Mitotic activity is brisk, and necrosis is commonly seen. * Embryonal carcinoma as a pure ovarian neoplasm is rare. It is more commonly seen as a component of mixed germ cell tumor. * OCT 4 is a transcription factor that regulates and maintains pluripotency in embryonic germ and stem cells. It is highly sensitive and specific for embryonal carcinoma as well as dysgerminoma/seminoma. It has a nuclear immunohistochemical staining pattern. * CD30 staining is common in embryonal carcinoma, although it should not be used as the sole diagnostic marker. It has a membranous staining pattern. * Most embryonal carcinomas demonstrate positivity for CD30, OCT 4, cytokeratin AE1/AE3, and AFP. CD117, epithelial membrane antigen (EMA), and CD45 are consistently negative.

Answer 115

Cherubism * autosomal dominant trait with high penetrance but variable expressivity * bilateral, painless, symmetric swelling of the posterior mandible, resulting in an expansion of the lower part of the face, and upward gaze of the eyes (Renaissance angel face) * ages of 2 and 5 years, progresses until puberty, stabilizes * multilocular expansile radiolucencies * Histology * clusters of multinucleated giant cells * fibroblastic stroma * small blood vessels * focally associated with bone formation

Answer 116

Neurodegenerative diseases, genetic abnormalities * A large number of neurodegenerative diseases can be caused by genetic mutations or abnormalities. Genetic abnormalities can include single gene mutations and microsatellite repeat instability leading to expansion of tandem triplet repeats. * Mutations in the gene for α-synuclein, SNCA, cause some familial cases of Parkinson’s disease. α-synuclein is a protein that forms the pathologic inclusions (Lewy body) in Parkinson’s disease, diffuse Lewy bodies, and multiple system atrophy. * In Huntington disease, an increase in the number of repeats of the CAG sequence is seen in the HTT gene localized in the short arm of chromosome 4 and coding for the protein huntingtin. * Mutations in the APP gene have been associated with autosomal dominant forms of Alzheimer disease. The APP gene is located on chromosome 21 (thus, the association of Alzheimer disease and Down syndrome) and codes for the amyloid-β precursor protein (APP). * The tau gene, MAPT, is located on chromosome 17 and codes for the microtubule-associated protein, tau. Mutations in this gene are associated with chromosome 17-linked frontotemporal lobar dementia. * In X-linked bulbospinal neuronopathy (like Kennedy disease), a CAG repeat region in the first exon of the androgen receptor gene on the X chromosome causes slowly progressive lower motor neuron weakness of facial, bulbar, and proximal limb muscles.

Answer 117

Epithelioid sarcoma * Epithelioid sarcoma (ES) mainly occurs in the distal extremities of young adults and shows a male predominance. The most commonly affected sites are the fingers, hands, and forearms. * The neoplasm tends to spread along the aponeuroses in a centripetal pattern and may involve and ulcerate the skin. * ES appears as a single or multiple well-circumscribed nodules, which occasionally may ulcerate. * The tumor nodules are composed of a mixture of epithelioid and spindle cells with nuclei that have complex outlines and generally inconspicuous nucleoli. The center of the nodules may undergo necrosis, giving it a pseudo-granulomatous appearance. * ES is positive for vimentin, cytokeratin, and EMA and for CD34 in more than 50% of the cases. HHF-35, desmin, and S100 may be focally positive. * ES may recur locally in 30% to 80% of the cases, and it metastasizes in up to 40% of cases, mainly to lung, lymph nodes, soft tissues, and central nervous system. Metastases may occur late, with a survival rate of less than 70% at 5 years and 50% at 10 years.

Answer 118

Special Stains for Microorganisms * A combination of PAS and GMS stains can be helpful in differentiating small budding yeast forms. Organisms showing weak PAS and strong GMS staining suggest a diagnosis of Histoplasma over Candida and Blastomyces, which show strong PAS positivity. * More specific methods can be used to stain a narrower number of organisms, such as alcian blue, which stains the mucoid capsule of C. neoformans. * Acid-fast stains detect long-chain fatty acids in the microorganism wall. These are present in only certain bacteria (e.g., most mycobacteria, Legionella, and Nocardia), protozoa (e.g., Cryptosporidium, Isospora), and the shell of some Schistosoma eggs (S. mansoniand S. japonicum). * Warthin-Starry and Dieterle stains are silver-based methods used to identify spirochetes but are also known to stain some fungi, Donovan bodies, and Legionella. Dieterle stain is used for Bartonella henselae, syphilis (Treponema pallidu), mycobacterium tuberculosis

Answer 119

Salivary duct carcinoma * \> 50 yo * M \> W * most aggressive salivary gland malignancies * perineural invasion and lymph node involvement occur in the majority * occurs de novo and/or within preexisting pleomorphic adenoma (i.e., as a manifestation of carcinoma ex pleomorphic adenoma) * positive nuclear immunohistochemical staining for androgen receptor, and positive membranous staining for Her-2/neu * 17q21.1 amplification, involving the gene ERBB2, 40% of salivary duct carcinoma

Answer 120

Cryoglobulinemic Glomerulonephritis * Hepatitis C virus (HCV) infection is associated with membranoproliferative glomerulonephritis (MPGN), cryoglobulinemic glomerulonephritis (which frequently has overlapping findings with MPGN), and membranous nephropathy. * Among patients with mixed cryoglobulinemic glomerulonephritis, the most common underlying condition is HCV infection. * In HCV-associated cryoglobulinemic glomerulonephritis, light microscopy typically reveals diffuse proliferative glomerulonephritis with large intracapillary deposits that occlude capillary lumina. The deposits are eosinophilic on hematoxylin-eosin stain and red on trichrome stain. Similar-appearing deposits may be seen in intrarenal arteries or arterioles, where they can produce a cryoglobulinemic vasculitis. * Immunofluorescence staining reflects the composition of the cryoglobulin in the circulation. In HCV-associated cryoglobulinemic glomerulonephritis, the cryoglobulin is mixed (type 2), usually consisting of monoclonal IgM and kappa light chains complexed to polyclonal IgG. The deposits typically stain dominantly for IgM and kappa chains, with less intense staining for IgG and lambda light chains. Staining for complement components C3 and C1 also is typically present. * In the skin, cryoglobulinemic vasculitis manifests as a palpable purpuric rash.

Answer 121

Leprosy * Histopathologically, tuberculoid leprosy is characterized by epithelioid cell granulomas with Langhans giant cells surrounded by lymphocytes and plasma cells. Eosinophils are not characteristic. Granulomas develop in and around cutaneous nerves and are often elongated rather than round, which is a helpful feature to distinguish them from sarcoidosis. * With the worldwide implementation of supervised multidrug therapy, there has been a significant reduction in the case detection rate of leprosy. * M. leprae and Mycobacterium lepromatosis are the two causative agents of leprosy. M. lepromatosis was discovered more recently and has been implicated in cases of diffuse lepromatous leprosy. * In tuberculoid leprosy, M. leprae bacilli are few and require patient examination of Fite-Faraco–stained sections. The organisms stain only weakly (or not at all) with standard acid-fast stains, such as Ziehl-Neelsen. By contrast, the lepromatous form of leprosy is characterized by numerous bacilli that are easily identifiable in the foamy histiocytes characteristic of this entity. * Worldwide, the number of new cases of leprosy has decreased approximately 44% in the past 6 years. In the United States, the prevalence rate of leprosy is less than 1 case per 10,000, and leprosy occurs mainly in the southern states. It was reported in a heart transplant patient in 2003.

Answer 122

Follicular neoplasm of thyroid • The photomicrograph shows a highly cellular specimen containing follicular cells arranged in a microfollicular pattern. This appearance combined with finding scanty or no colloid is suggestive of a follicular neoplasm. Rosette-like microfollicles may not appear as well formed as those in the photomicrograph. Clusters or small, tight aggregates of follicular cells may be seen.

Answer 123

Autosomal Dominant Polycystic Kidney Disease (ADPKD) * one of the most common human heritable diseases, affecting approximately 1:500 to 1:1000 individuals * bilateral renal cyst formation, leading to massively enlarged kidneys * expanded renal parenchyma comprises a massive aggregate of cysts lined by flattened-to-cuboidal epithelium * presentation * 20-40 yrs * renal insufficiency, hypertension, hematuria, and renal colic * slowly progressive, most develop ESRD (8-10% of all patients with ESRD in the US) * most common extrarenal manifestations * hepatic cysts, 50% of patients, may cause pain, not a/w functional impairmen * complications that reflect the expression of polycystin in vascular smooth muscle * Cardiac valve abnormalities, mitral valve prolapse, 25% of patients * Intracranial berry aneurysms, 5% to 8% of patients * 85% mutation in the gene PKD1 (chromosome 16) * 13% mutation in the gene PKD2 (chromosome 4) * gene products, polycystin-1 and polycystin-2, are proteins that regulate renal epithelial cell proliferation and differentiation * mechanism of cyst formation requires an inherited (autosomal dominant) mutation of one allele and the development of a somatic mutation (second hit) in the second allele

Answer 124

Nephrotic Syndrome * The most common cause of nephrotic syndrome varies depending on age and ethnic group. * The most common cause of primary nephrotic syndrome in children is minimal change disease. * Different sources differ with respect to whether the most common cause of nephrotic syndrome in nondiabetic adults is membranous nephropathy or focal segmental glomerulosclerosis. * Focal segmental glomerulosclerosis (FSGS) is the most common cause of nephrotic syndrome in African American adults. * Patients with IgA nephropathy typically present with hematuria and subnephrotic proteinuria; full nephrotic syndrome is unusual in IgA nephropathy.

Answer 125

Myxoid Chondrosarcoma * rare variant of chondrosarcoma that may occur in soft tissue or bone * 40s to 50s * men are affected twice as often as women * Histology * monotonous proliferation of uniform, relatively small cells, deeply acidophilic cytoplasm and vesicular nuclei * sheets and cords in a very myxoid stroma * Wide surgical excision is the treatment of choice. * Despite a slow, protracted course, late recurrences and metastases occur commonly.

Answer 126

Langerhans Cell Histiocytosis * Langerhans cell histiocytosis is a neoplastic proliferation of large specialized dendritic cells (Langerhans cells) admixed with a mixed inflammatory population composed of an abundance of eosinophils, neutrophils, lymphocytes, and plasma cells. The disease may be present as a single lesion (monostotic) or as a few or multiple lesions involving several bones and may be associated with involvement of other tissues. * Individuals of any age may be affected, but 80% to 85% of patients are younger than age 30, and 60% are younger than 10 years. There is a male predilection. * Langerhans cell histiocytosis most commonly involves the femur, the bones of the pelvis, and the mandible. In the long bones, it is most often diaphyseal. In adults, the ribs are the most common site. The monostotic form is much more common (80% of cases) than the polyostotic form. * Histology is characterized by the presence of proliferating Langerhans cells intermixed with inflammatory cells, such as lymphocytes, neutrophils, plasma cells, and frequently many eosinophils. The morphologic hallmark of this lesion is a large histiocyte with abundant cytoplasm and a longitudinal nuclear groove imparting a “coffee bean” appearance to the nucleus. Despite the previous name eosinophilic granuloma, eosinophils are not an essential component of the lesion. * The Langerhans cell typically expresses S100 and CD1a. The typical finding on electron microscopy is the cytoplasmic racket-shaped Birbeck granule.

Answer 127

Chondroblastoma * Chondroblastoma is a tumor of immature cartilage, accounting for 1% of bone tumors. It occurs in skeletally immature individuals (first and second decades) and favors the epiphyses of long bones, being typically located in the distal femur, proximal tibia, and proximal humerus. It may involve less frequently the axial bones, vertebrae, and talus and calcaneus. * Clinically, pain—present for several months to several years—is a consistent symptom. There may be associated joint effusion in lesions that reach up to the subarticular endplate. * Radiographically, chondroblastoma is a small lesion (2.5 to 6.0 cm) that causes a sharply demarcated radiolucency circumscribed by a sclerotic rim of bone. Irregular calcifications may be seen. * Chondroblastoma is characterized by cohesive sheets of uniform, small cells with well-defined margins (chondroblasts) that often show a pavementlike architecture. Ill-defined nodules of fluffy acidophilic matrix representing immature cartilage (chondroid) are associated with the cells. Not unusually, chondroblasts may show mitoses (one to two in 10 high-power fields) without atypical figures. Giant cells of various sizes are arranged in clusters distributed throughout the tumor. Calcifications of the chondroid matrix around the chondroblasts form a basophilic mesh (“chicken-wire” calcifications); although these “chicken-wire” calcifications are characteristic of this lesion, they are not always present. The tumor frequently undergoes aneurysmal transformation. The tumor consistently expresses vimentin and S100 and is reported to show positivity for cytokeratins. * In most cases, the tumor has a limited growth potential and follows a benign course. Recurrences occur in about 10% of cases. Benign lung implants (rather than true metastases) can occur and are successfully treated by resection. Aggressive behavior may rarely occur.

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Reactive Perforating Collagenosis * Reactive perforating collagenosis is a rare perforating disorder characterized by transepidermal elimination of altered collagen. * Classic reactive perforating collagenosis is a genodermatosis inherited in an autosomal dominant or recessive manner, in which lesions are precipitated by trauma. The adult-onset, acquired type of reactive perforating collagenosis is associated with diabetes mellitus and chronic renal failure, especially in patients on dialysis, and is considered a type of acquired perforating dermatosis. * Reactive perforating collagenosis is clinically characterized by papulonodules that have a central keratotic dell and resemble lesions of molluscum contagiosum or prurigo nodularis. The histologic combination of a saucer-shaped invagination containing neutrophilic debris and vertically oriented strands of collagen that have perforated through the epidermis is characteristic. * Masson trichrome stain can be performed to confirm that the perforating fibers represent collagen. The collagen stains blue-green. * Other forms of perforating disorders in the differential diagnosis of reactive perforating collagenosis include Kyrle disease, perforating folliculitis, and elastosis perforans serpiginosa. Kyrle diseases results in a cornified plug within an invaginated epidermis without follicular involvement. Perforating folliculitis shows a hyperkeratotic plug with basophilic debris associated with a follicular unit. Elastosis perforans serpiginosa demonstrates perforation of van Gieson-positive elastic fibers through the epidermis.

Answer 129

Parkinson disease * Parkinson disease (PD) is a neurodegenerative disorder with a clinical picture that includes bradykinesia or akinesia, resting tremors, rigidity, and postural instability. Also associated are autonomic dysfunction, cognitive disturbances, and dysphagia. It has a mean age of onset of 61 years. * Pallor of the substantia nigra and locus ceruleus is seen in brains of patients with PD, due to the loss of pigmented neurons. Cerebral atrophy and ventricular enlargement can also be present. * The histopathologic features of PD includes widespread α-synuclein accumulations in neurons and dystrophic neurites throughout the CNS. Lewy body accumulation in isocortical neurons is a hallmark of diffuse Lewy body disease. In addition, variable neuronal loss occurs in many nuclei, in particular the substantia nigra, locus coeruleus, nucleus basalis of Meynert, and dorsal motor nucleus of the vagus nerve. * The prominent lesions of PD are α-synuclein-positive Lewy bodies. Lewy bodies are spherical, cytoplasmic, intraneuronal inclusions with a hyaline eosinophilic core, concentric lamellar bands, and a narrow pale-stained halo. * Mutations in the gene for α-synuclein, SNCA, have been associated with some familial cases of PD. * There are patients with dementia whose brains contain both Parkinson pathology (Lewy bodies) and Alzheimer pathology (amyloid plaques and neurofibrillary tangles).

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Enzyme deficiencies in hereditary erythrocyte disorders * Pyruvate kinase is the most common hereditary erythrocyte enzyme deficiency in the glycolytic pathway and accounts for up to 90% of cases. * Hexokinase, aldolase, and phosphofructokinase deficiencies are extremely rare. * Glucose-6-phosphate dehydrogenase is not an enzyme of the glycolytic pathway, but of the pentose phosphate pathway (hexose monophosphate shunt)

Answer 131

Mesothelioma * Immunohistochemistry * positive: calretinin, cytokeratin 5/6, and WT-1 * negative: CD15, B72.3, CEA, and BerEP4 * Loss of a p16 tumor suppressor gene appears to be an important event in the development of malignant mesothelioma * In pleural mesothelioma, loss of p16 expression is often due to homozygous deletion of the p16 gene on chromosome 9. * Malignant mesothelioma is an aggressive malignancy that arises from mesothelial-lined serosal spaces. This includes pleura, peritoneum, and, less commonly, tunica vaginalis. * This malignancy is associated with asbestos exposure and occurs decades after exposure. Lung fibrosis can also occur from asbestos exposure, but lung fibrosis need not be present for mesothelioma to occur. * Histologically, malignant mesothelioma can be epitheloid, biphasic or sarcomatoid. Epitheloid patterns of growth are quite varied, although many cases have papillary, tubule-papillary or solid growth. * Immunohistochemistry panels are required for accurate diagnosis. These include a mixture of markers positive in mesothelial cells/mesothelioma and those positive in epithelial cells/carcinoma. * Invasion, including invasion of adipose tissue, is an important criterion in determining malignancy. Reactive mesothelial cells can be quite atypical, making the distinction of reactive mesothelial proliferations from malignant ones difficult.

Answer 132

Acute Hepatitis * Acute hepatitis (either viral or drug-related) is characterized by diffuse lobular necroinflammation, with ballooning and apoptosis of hepatocytes, disarray of liver cell plates, and diffuse portal and sinusoidal inflammation (chiefly lymphocytes). * The major causes of acute hepatitis include hepatitis viruses (A through E) and drugs (usually idiosyncratic or unpredictable agents); alternative, herbal, and recreational agents should be considered. * Histologic determination of the cause is often difficult. Helpful additional features favoring drug-induced liver injury include abundant eosinophils, bile duct damage, granulomas, and otherwise atypical histologic features for acute hepatitis. * Autoimmune hepatitis may rarely appear on histology as acute hepatitis. Features that may raise suspicion for autoimmune liver disease include prominence of central perivenulitis (inflammation and liver cell dropout around central veins, with inflammation prominently lymphocytes and plasma cells), plasma cell prominence within the portal and periportal inflammatory infiltrates, and the presence of bridging necrosis (central-to-portal bridging necrosis).

Answer 133

Mucoepidermoid carcinoma * According to series that include both major and minor salivary glands, mucoepidermoid carcinoma (MEC) is the most common malignant salivary gland tumor overall. * MEC is by far the most common malignant tumor of the parotid gland. * Different series list either MEC or adenoid cystic carcinoma as the most common carcinoma of oral cavity salivary glands. * Most series identify adenoid cystic carcinoma as the most common malignancy of the submandibular gland, sublingual gland, lacrimal gland, and salivary glands of the nasal cavity and paranasal sinuses. * Primary tumors of tracheal salivary glands are rare. Of these, adenoid cystic carcinoma is the most common.

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Isospora * I. belli is a protozoan known to infect only humans. Ingestion of contaminated food or water containing oocysts causes disease, which is usually self-limited in healthy individuals. * I. belli infection is rare among immunocompetent individuals. Immunocompromised patients are susceptible to more severe infections.Isospora organisms have been detected in the stool of 0.2% to 3% of patients with AIDS. * The differential diagnosis includes other protozoan infections such as Microsporida and Cryptosporidium. Morphologic features are used to differentiate such organisms. * Histologically, Isospora infection of the small bowel is characterized by mucosal atrophy with shortening of villi and crypt hypertrophy. Lamina propria eosinophilia is a distinct feature that is not usually present in other protozoan infections. I. belli organisms measure approximately 30 μm and are identified in and beneath enterocytes.

Answer 135

Normal fetal lung * The lung at this stage has just made a transition (at around 16 weeks) from the earlier “pseudoglandular” stage to the “canalicular” stage. In the canalicular stage there are tubular airspaces with a developing network of capillaries in the intervening mesenchyme. * The next stage of lung development is known as the “saccular” stage (28 to 34 weeks) when discrete acini with secondary crests are seen. * The final stage is the fully developed “alveolar” stage when thin-walled alveoli are present. * Alveoli are apparent at about 35 weeks gestation. The number of alveoli at birth increases tenfold by the age of 2 years. * It is important to recognize normal fetal histology so as not to confuse it with a pathologic entity, such ascongenital cystic adenomatoid malformation(CCAM).

Answer 136

Tumors with nuclear grooves * PTC * Solid pseudopapillary, pancreas * Chondroblastoma * Granulosa cell tumor * +/- Lepidic adenocarcinoma, lung

Answer 137

ERBB2 Testing * Standardization of testing and reporting is critical, ERBB2 as a therapeutic target * Fixation in neutral buffered formalin for 6-72 hours. (cytology specimens also) * IHC/ISH used, samples equivocal by one test are reflexed to another method HER2 IHC * 3+ * \>10% dark, circumferential staining * 2+ * \>10% noncircumferential staining or moderate staining * \<10% dark, circumferential staining * reflexed to ISH or FISH * 1+ * \>10% faint or barely perceptible staining * 0 * no staining or staining of \<10% * reported as negative * If the pathologist suspects a discordance with histopathologic findings, the test should be reflexed to ISH or FISH. ERBB2 ISH/FISH * Positive * \>6 avg ERBB2 copy number (single probe ISH, dual probe ISH, FISH) * \>2 ERBB2 to CEP17 ratio * Equivocal * 4-5 copy number by single probe ISH * +/- \<2 ERBB2:CEP17, by dual probe ISH and FISH * retest by IHC or test a different sample * Negative * \<4 ERBB2 copy number (single probe ISH) * +/- \<2 ERBB2:CEP 17 (dual probe ISH or FISH) Retest HER2 on excision if needle bx: * HER2 negative in grade 3 tumors * showed a small amount of invasive carcinoma * different histologic pattern is seen on the excision * question of the handling of the needle biopsy * original result was “equivocal”

Answer 138

* Schaumann bodies * calcium and protein inclusions * inside multinucleated giant cells * may be found in several granulomatous conditions * Hamazaki-Wesenberg bodies * yellow-brown structures of unknown significance * associated with histiocytes * resemble fungi * Asteroid bodies * eosinophilic inclusion bodies with radiating lines * lipids arranged into bilayer membranes * in the cytoplasm of multinucleated giant cells * Birefringent calcium oxalate and calcium carbonate microcalcifications * may be found in sarcoidosis * Psammoma bodies * concentrically laminated small calcifications * most commonly seen in papillary neoplasms * may also occur in association with benign mesothelial hyperplasia

Lefkowitch Flashcards

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