Lefkowitch Flashcards
1
Q
Diagnosis?
Inheritance pattern?
Gene?
Most common mutation?
Pathophysiology?
Symptoms?
A
Hereditary Hemochromatosis
- homozygous autosomal recessive
- HFE gene
- C282Y
- HFE protein in small intestinal cells, regulation of iron uptake. Mutation –> unregulated uptake of iron regardless of need
- liver, pancreas, heart, pituitary, and skin –> hepatomegaly, diabetes, cardiomyopathy, amenorrhea, and hyperpigmentation
2
Q
Diagnosis?
2 types of bodies?
Most common?
A
Cardiac Sarcoidosis
Schaumann bodies are found with much higher frequency in sarcoidosis and berylliosis than in infective granulomatous diseases.
• Asteroid bodies are stellate inclusions that stain with antiubiquitin antibodies. They are less common than Schaumann bodies but do occur frequently.
3
Q
Giant Cell Myocarditis v. Cardiac Sarcoid
Histiocytes?
Inflammatory cells?
Myocardium?
CD4/CD8?
A
Giant Cell Myocarditis
- Giant cells
- Eos, +/- neuts
- Myocardial necrosis
- CD8+
Cardiac Sarcoid
- Epithelioid granulomas and giant cells
- +/- Eos, if neuts look for infection
- Myocardial fibrosis
- CD4+
4
Q
Diagnosis?
Symptoms?
Radiology?
Histology?
Causes?
Treatment?
A
Chronic eosinophilic pneumonia
- symptoms mimic infectious pneumonia
- radiology –> migratory infiltrates with the reverse pulmonary edema sign
- more dense infiltrates at the periphery with central sparing
- intraalveolar fibrin and small vessels +/- eosinophilic transmural inflammation
- idiopathic, parasitic infections, medication reactions, Churg-Strauss syndrome, and allergic bronchopulmonary aspergillosis
- steroids –> most patients respond with complete resolution
5
Q
Diagnosis?
Histology?
Age?
Prognosis?
A
Müllerian Adenosarcoma
- benign glands cuffed by malignant stroma
- may look like phyllodes tumor
- mostly 50’s +
- predominately polypoid growths that fill the entire uterine cavity
- +/- deeply invasive
- can undergo sarcomatous overgrowth
- higher histologic grade
- aggressive with metastatic potential
- less aggressive than MMMT
6
Q
Differential diagnosis of Ewing sarcoma?
A
Differential diagnosis of Ewing sarcoma
- Lymphoma
- Metastatic neuroblastoma
- Mesenchymal chondrosarcoma
- Embryonal rhabdomyosarcoma
7
Q
Diagnosis?
Genetic/molecular (most common}?
Stains?
Histology patterns?
A
Ewing sarcoma/PNET
- t(11;22) (q24;q12)
- fusion of the EWS and Fli-1 genes –> EWS/Fli-1 fusion transcript
- diagnostic of Ewing sarcoma/PNET
- Stains
- CD99+ >90%
- PAS & PAS-D+ for glycogen
- Histology
- Mitotic figures frequent (5-50/10 HPF)
- Undifferentiated appearance
- Small cells
- Round to oval nuclei
- Smooth nuclear membrane
- Fine chromatin
- Small nucleoli
- Small amount of clear to amphophilic cytoplasm
- Cell borders may be distinct
- Differentiated appearance
- Medium sized cells
- Moderate sized nuclei with moderate atypia
- Irregular nuclei
- Small to medium sized nucleoli
- Moderately abundant eosinophilic or amphophilic cytoplasm
- Homer-Wright rosettes
- Radiating fibrillar material surrounded by a ring of nuclei
- Pseudorosettes
- central blood vessel
- Other patterns
- alveolar or angiomatoid
- Metaplastic cartilage or bone
- Skeletal muscle in ectomesenchymoma variant
8
Q
Diagnosis?
Histology?
Stains?
Genetics?
Serum studies?
A
Neuroblastoma
- Histology
- Small round nuclei with stippled (“salt and pepper”) chromatin
- Ganglion cells
- Schwannian stroma resembles collagen
- Neuropil
- +/- Dense lymphoid infiltrate
- Homer-Wright rosettes of tumor cells surrounding neurofibrillary tangles
- 7 subtypes according to the degree of neuroblastic maturation and the amount of background schwannian stroma
- Positive stains
- Synaptophysin, NB84, Tyrosine hydroxylase, NSE, Chromogranin
- S100 in Schwannian stroma
- MYCN oncogene amplification
- PCR or FISH
- MYCN amplified tumors worse prognosis
- Serum catecholamines elevated
9
Q
A
Embryonal rhabdomyosarcoma
- uniform population of small round and spindle cells with frequent formation of pseudorosettes around small blood vessels and can mimic Ewing sarcoma/PNET. Although this tumor has many useful immunohistochemical markers (myosin, myogenin, sarcomeric actin, insulinlike growth factor II), it lacks a specific molecular marker, in contrast to Ewing sarcoma/PNET.
10
Q
A
Mesenchymal chondrosarcoma
- sheets and clusters of uniform, small round cells
- multiple foci of well-differentiated cartilage
- t(11;33) (q24;q12) translocation
- expression of Sox9
- master regulator of cartilage differentiation
11
Q
A
Acute atherothrombotic occlusion of the middle cerebral artery
- Coronal section showing brain swelling in the lateral aspect of the frontal lobe and the basal ganglia.
12
Q
Cerebral ischemic infarction
A
Cerebral ischemic infarction
- Inadequate perfusion of a brain territory due to arterial occlusion (e.g., thrombosis or embolism) leads to an ischemic infarction. Different gross and microscopic findings can be seen in an infarct at different times.
- Changes seen in acute infarction (8 to 36 hours) include blurring of the gray/white matter junction, a dusky discoloration of the gray matter, and slight softening. Microscopically, vacuolation of the neuropil and shrunken hypereosinophilic neurons are seen. Neutrophilic infiltration begins around 24 hours.
- In subacute infarction (5 to 30 days), cerebral edema is the most prominent abnormality; dusky gray discoloration and blurring of the gray/white matter junction are also present. Microscopic pathologic examination includes necrotic tissue, anecrotic and reactive microvessels, reactive astrocytes, and microglial activation with the presence of macrophages.
- Chronic infarction (months to years) is characterized by cavitation. The cystic cavity is surrounded by reactive astrocytes and may contain residual macrophages.
- The anterior cerebral artery (ACA) supplies the most medial parts of the frontal lobes and superomedial parietal lobes. The middle cerebral artery (MCA) supplies the lateral surface of the hemispheres as well as the basal ganglia and the internal capsule. The posterior cerebral artery (PCA) supplies the occipital lobe.
13
Q
Fanconi’s anemia
A
Fanconi’s anemia
- markedly increased risk for developing MDS and AML
- autosomal recessive disorder
- associated with skin, skeletal, and renal abnormalities, as well as mental retardation
- All cases eventually progress to pancytopenia and marrow failure
14
Q
Pap test in pregnancy
A
Pap test in pregnancy
- a shift towards lower maturation (atrophic) suggests progesterone deficiency and may indicate intrauterine fetal demise or infection
- corpus luteum of pregnancy and the placenta produce progesterone, resulting in a predominance of intermediate squamous cells
- Cytolysis may be marked due to lactobacilli
- “Navicular” cells are boat-shaped intermediate cells containing abundant glycogen. This is not a specific finding in pregnancy. Navicular cells also may be seen during administration of progesterone or androgen-containing hormones.
- Postpartum smears show a predominantly atrophic pattern in approximately one-third of nonlactating and two-thirds of lactating mothers.
15
Q
A
Chondromyxoid fibroma
- Histology
- pseudolobules of cellular myxoid and chondroid tissue separated by stalks of vascularized connective tissue
- stalks contain blood vessels, mononuclear cells, and scattered giant cells
- periphery of the lobules is comprised of a dense population of small spindle, often stellate cells in a myxoid stroma containing microcysts
- toward the center of the lobules, differentiation to immature cartilage is represented by round chondrocytes in a focally chondroid stroma
- chondrocytes often show hyperchromasia and double-nucleation but no mitoses
- immaturity of the cartilage and the presence of atypia may lead to misinterpretation as chondrosarcoma
- Extremely rare benign bone tumor arising in young adults
- Age 15-25 years, no gender preference
- Presents with dull, achy pain
- Site: metaphysis of long tubular bones, small bones of feet or any bone, skull base (clivus)
- Xray: Extremely well circumscribed, lytic defect with scalloped, sclerotic margin similar to metaphyseal fibrous defect
16
Q
A
Common Variable Immunodeficiency (CVID)
- genetic immune defect
- decreased levels of immunoglobulins
- poor or absent antibody production
- exclusion of other causes of hypogammaglobulinemia
- recurrent bacterial infections, increased autoimmune and neoplastic diseases
- white, M = W, teens - twenties
- GI
- decreased plasma cells in the lamina propria
- plasmacytoid lymphocytes present,
- lymphocytes increased
- atrophic gastritis
- reduced serum gastrin
- achlorhydria, decreased intrinsic factor, vitamin B12 malabsorption
- Lymphoma
- EBV
17
Q
Antibodies against M-type phospholipase A2 receptor (PLA2R) are central to the pathogenesis of?
A
Membranous Nephropathy
18
Q
Most common PTLD T/natural killer (NK)-cell lymphomas?
A
Most common T/NK-cell posttransplant lymphoproliferative disorders (PTLD)
- Hepatosplenic T-cell lymphoma
- Peripheral T-cell lymphoma NOS
19
Q
A
Congenital cystic adenomatoid malformation
- It is commonly found in neonates and young children but may be diagnosed by prenatal ultrasound.
- Usually unilateral but can be bilateral.
- Subcategorization depends on size of cysts, type of lining epithelium, and presence/absence of cartilage or skeletal muscle.
- Associated malformations: renal anomalies (cystic renal disease, agenesis, dysgenesis), intestinal atresias, and cardiac malformations.
- Fetal hydrops is common.
20
Q
Fire-Related Injuries
A
Fire-Related Injuries
- death results from the delayed complications of the burn with the resultant effects on the entire body (systemic inflammatory response) and the increased susceptibility to opportunistic infection.
- Fire death –> smoke inhalation
- The extensive burns and charring seen on a dead body recovered after a fire are often postmortem occurrences.
- postmortem thermal artifacts
- pugilistic posture
- epidermal hematoma
- corneal clouding
- A subdural hematoma detected in a burned body occurred before death.
21
Q
Immunohistochemistry to Detect Transforming Mutations?
A
Immunohistochemistry to Detect Transforming Mutations
- The point mutation from arginine to histidine in codon 132 (R132H) of isocitrate dehydrogenase 1 (IDH1) is commonly found in astrogliomas and is not present in gliosis. The test can be performed with an antibody specific to the mutant IDH1.
- Mutations of TP53 commonly lead to a protein with a longer half-life than the short-lived wild type p53 protein; thus accumulation of this protein can be studied by IHC.
- Integrase interactor 1 (INI-1) is deleted in rhabdoid tumors and epitheloid sarcomas; thus absence of the protein aids making the diagnosis of these entities.
- HER-2/NEU amplification is studied by Herceptest assessed according to ASCO-CAP or treatment of gastric cancer (ToG) guidelines for breast and gastric carcinoma, respectively
22
Q
Luminal A/B tumors
A
Luminal A tumors
- high expression of estrogen receptor and progesterone receptor positivity
- low proliferation, primarily low grade
- good prognosis
- show low benefit from chemotherapy (pathologic complete response of 0% to 5%)
Luminal B tumors
- lower level of estrogen receptor expression
- high proliferation
- possible HER2 positivity
- intermediate to poor prognosis
- intermediate benefit from chemotherapy (pathologic complete response of 10% to 20%).
23
Q
Basallike breast cancers
A
Basallike breast cancers
- typically triple-negative
- by IHC 10% may be ER/PR+
- highly proliferating, high-grade tumors
- 80% of BRCA1 germline–associated tumors with poor outcome but with associated benefit from chemotherapy (pathologic complete response of 40%).
24
Q
HER2-positive tumors by gene expression profiling
A
HER2-positive tumors by gene expression profiling
- 70% to 80% HER2+ by IHC and FISH
- high proliferation, high grade, and poor outcome
- benefit from chemotherapy (pathologic complete response of 25% to 40%) but not as much as basal tumors
- may express estrogen receptor–related or progesterone receptor–related genes
25
Q
Molecular apocrine–type breast cancers
A
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
26
Q
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 (?)
A
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 (+)
27
Q
Claudin-low breast cancers
A
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
28
Q
Gene Expression Profiling–Based Breast Cancer Classification
A
Gene Expression Profiling–Based Breast Cancer Classification
- Luminal A
- Luminal B
- Molecular apocrine-type
- Claudin-low
- Basallike
- HER2-positive
29
Q
Most common site?
Population?
What do they produce and how is it tested?
4 poor prognostic indicators?
A
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
30
Q
What is the most common solid tumor in children, excluding CNS tumors?
A
Neuroblastoma
31
Q
Clinical presentation?
Gross?
Histologic hallmark?
Stains?
A
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
- hallmark: presence of all three trophoblast cell types
- 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+)
32
Q
Arising in ovary
A
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
33
Q
5 artifacts of tissue processing?
A
Artifacts of tissue processing
- The “fried egg” appearance of oligodendroglioma
- Stromal retraction in basal cell carcinoma
- Clefting in salivary gland adenoid cystic carcinoma
- Retraction in micropapillary carcinoma of the breast
- nuclear clearing that characterizes papillary thyroid carcinoma
34
Q
A
tall cell variant of papillary carcinoma
35
Q
5 aggressive forms of PTC?
A
Aggressive forms of PTC
- tall cell variant
- diffuse sclerosing
- columnar cell
- solid
- PTC with prominent hobnail features
36
Q
Thyroid, diagnosis?
A
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.
37
Q
Intraabdominal mass in a patient with AIDS
DDx?
Stains?
A
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
38
Q
Thyroid Mutations
A
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).
39
Q
Thyroid Mutations
A
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
40
Q
Mutations in PTC
Most common -> least common?
Pathway?
Associations?
A
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%
41
Q
Follicular Thyroid Mutations
A
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
42
Q
Medullary Thyroid Carcinoma Mutations
A
Medullary Thyroid Carcinoma Mutations
- Activating RET mutations
- Germ line mutations un > 95% of familial cases
- MEN2
- familial medullary thyroid carcinoma
43
Q
Thyroid FNA
A
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
- BRAF V600E mutation or RET/PTC translocationhas a high PPV for malignancy
- 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
44
Q
- rash and worsening renal function
- Palpable purpuric lesionson the buttocks and feet, including the soles
- skin biopsy
- leukocytoclastic vasculitis
- Direct immunofluorescence staining showed granular deposits consisting primarily of IgM and C3 in a vascular pattern in the papillary dermis.
- anemia and renal insufficiency, with microscopic hematuria and proteinuria in the nephrotic range
- Serum complement levels markedly decreased for C4 and were borderline decreased for C3.
- antistreptolysin O, antinuclear antibody, antineutrophilic cytoplasmic antibody (ANCA) antibodies
- +/- hepatitis C and cryoglobulins
- Rheumatoid factor was elevated
- renal biopsy
- immune complex–mediated diffuse proliferative glomerulonephritis
- immunofluorescence studies showed mesangial and focal capillary loop deposits of IgG, C3, and IgM
- MPGN
A
Cryoglobulinemic Vasculitis
45
Q
Cryoglobulinemic Vasculitis
A
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.
46
Q
Testing for Cryoglobulinemia
A
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.
47
Q
A
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.
48
Q
Special Subtypes of Invasive Breast Cancer
Prognosis?
A
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
49
Q
A
Sclerosing adenosis
50
Q
Location of Lesions in the Breast
Skin (1)
The terminal duct lobular unit
Nipple (4)
Subareolar (4)
A
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.
51
Q
A
Paget disease
- nipple and subareolar region
- DCIS arising in lactiferous ducts and extending into the epidermis
52
Q
A
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
53
Q
A
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
54
Q
A
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
55
Q
Breast Cancer Staging by American Joint Committee on Cancer
Microinvasive breast cancer
Stage pN0(ITC) i
Stage pN1mi
Inflammatory breast carcinoma
T4a
A
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.
56
Q
A
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.
57
Q
Translocations in MALT lymphoma
A
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
58
Q
Helicobacter pylori and Gastric Carcinoma
A
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.
59
Q
Comparison of Monoclonal and Polyclonal Antibodies
A
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).
60
Q
The strong, widespread, linear staining of the capillary endothelium with complement component C4d is consistent with which type of allograft rejection?
A
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.
61
Q
What is Amyloidosis?
5 non-hereditary types and association?
5 hereditary forms?
Bonus: amyloidogenic protein?
EM?
A
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
62
Q
- In Western countries, most cases with systemic or generalized amyloid deposits (involving the kidneys) are due to the deposition of ___-amyloid, mostly secondary to the secretion of abnormal __.
- The most common presentation of AL and AA amyloidosis is ___, which is associated with __.
- Patients with vascular deposits present with __.
A
- 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.
63
Q
- __ testing has now become the serologic test of choice for evaluation of celiac disease, largely replacing the __ for initial testing.
- Genetic testing for __ is utilized in selected cases as part of the clinical evaluation of celiac disease.
- __ is present in approximately 95% of patients with celiac disease and most of the remaining 5% are positive for __.
- __testing is not diagnostic of celiac disease (present in approximately __ of the Caucasian population), but absence of these haplotypes virtually excludes celiac disease.
A
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.
64
Q
In typical cases of celiac disease, intraepithelial lymphocytes are CD__+/CD__+.
Abnormal lymphocyte populations (with __ phenotype) may be seen in cases of refractory celiac disease and these patients are at increased risk for development of __.
- Histopathologic features of celiac disease include )__, and variable architectural abnormalities, including __.
- Most or all features of celiac disease, including intraepithelial lymphocytosis and variable amount of villous atrophy, may be present in cases of __.
A
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.
65
Q
- The prevalence of celiac disease is higher in __ and __ than in the general population.
- Patients with celiac disease (also known as gluten-sensitive enteropathy) are at risk for developing __.
A
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.
66
Q
What is it?
A
Pauciimmune Crescentic Glomerulonephritis
67
Q
At least 80% of patients with pauciimmune crescentic glomerulonephritis test seropositive for __.
__ has specificity for __ or __ on enzyme-linked immunosorbent assay.
- By definition, in pauciimmune crescentic glomerulonephritis, immunofluorescence reveals __.
- The pathogenesis of pauciimmune crescentic glomerulonephritis involves __ leading to vasculitis and crescentic glomerulonephritis.
A
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.
68
Q
Alternative causes of crescentic glomerulonephritis include:
- __, which shows __
- immune complex–mediated forms of crescentic glomerulonephritis (e.g., __), which show __on immunofluorescence and electron
A
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.
69
Q
On testicular surface….
Most common tumor of the epidymis?
Treatment?
Age?
Cell of origin?
Gross?
Histology?
Stains?
A
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.
70
Q
A
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.
71
Q
A
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.
72
Q
Classic presentation?
Prognosis?
Cell of origin?
Histology?
DDx?
Stains?
A
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.
73
Q
A
Hashimoto thyroiditis
74
Q
Several studies have demonstrated __ deposition within the context of Hashimoto thyroiditis.
- Laboratory work-up of patients with Hashimoto thyroiditis may reveal __ antibodies.
- These autoantibodies likely mediate thyrocyte dysfunction as follows: deposition of__ on the __ of follicular epithelial cells leads to __ and thyrocyte necrosis.
- Hashimoto thyroiditis is associated with several human leukocyte antigen (HLA) alleles including __.
- The incidence of Hashimoto thyroiditis is increased among individuals with __.
A
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.
75
Q
A
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.
76
Q
5 Salivary gland cribriform lesions?
A
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.
77
Q
A
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.
78
Q
- Prognosis?
- Location?
- Age?
- Clinical presentation?
- Frequency of recurrence?
- Cell of origin?
- Genetics?
- Most helpful diagnostic marker? caveat?
- Best way to detect mutation?
DDx:
A
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
79
Q
Stains?
EM?
Mutation?
Acute disseminated form?
2 other types?
A
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
80
Q
Located in lateral ventricle
a/w?
grade?
histology?
A
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
82
Q
Tuberous sclerosis
CNS lesions?
Gross?
Histology?
Most common?
Genes?
A
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
83
Q
Tuberous sclerosis cutaneous lesions
A
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
84
Q
Incidence?
Age?
Location?
Presentation?
Gross?
Histology?
Treatment?
Prognosis?
A
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
85
Q
Clinical finding?
Caused by?
A
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.
86
Q
A
Radiation changes
87
Q
4 forms?
Virus?
Stain?
A
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
89
Q
A
MMMT gross
90
Q
A
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.
92
Q
aka?
Presentation?
Location?
Time?
Age?
Histology?
DDx?
A
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
93
Q
Age?
Gender?
Location?
Presentation (early and late)?
Prognosis?
Tx?
What reduces recurrence?
Gross?
Histology?
Stain?
What counts as fibrosarcomatous transformation?
Most common site of dissemination?
Mutation?
A
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 (< 2%)
- 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
94
Q
DDx in pleura?
Best panel of stains?
A
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.
98
Q
Location?
Presentation?
Prognosis?
Imaging?
Gross?
Histology?
Other forms?
A
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).
99
Q
What is the most common parasitic infection?
Infective form?
Histology?
A
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
104
Q
What is the most common renal tumor in newborns?
3 types?
mutation?
Tx?
A
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.
105
Q
Presentation?
Age?
Location?
Radiology?
Tx?
Prognosis?
A
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
106
Q
Where are the lesions?
What are the antibodies agains?
Tests?
A
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.
107
Q
Location?
Age?
Histology?
Stains?
Genetics?
Prognosis?
A
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
110
Q
A
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.
112
Q
A
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.
113
Q
A
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
114
Q
A
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).
115
Q
A
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.
116
Q
A
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
117
Q
p190
p210
p230
p16
p53
A
- 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.
118
Q
A
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
120
Q
Southern blot of a B-cell lesion showing a single sharp band with a probe for Epstein–Barr virus (EBV) termini. A single sharp band is seen.
A
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.
121
Q
A
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.
122
Q
What causes pipestem fibrosis in the liver?
A
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.
123
Q
DDx?
A
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.
124
Q
A
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.
125
Q
Dx?
Cause?
Result?
HLA?
Causes of primary hyperthyroidism?
Causes of secondary hyperthyroidism?
A
- 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
126
Q
Dx in infant?
Increased risks?
Tx?
A
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).
127
Q
Dx?
Weight < ___?
Timeline?
Deficiency in?
Tx?
Complications of Tx?
A
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
130
Q
Who gets it?
Endoscopy?
Histology?
DDx?
A
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.
131
Q
Dx?
Histology?
Subtypes?
Stains?
Children and young adults with multiple__ and diabetes?
Most likely to progress an special staining?
A
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.
132
Q
Adult Dx?
DDx?
Icreased prevalence in what population?
Histology?
A
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
134
Q
Dx criteria?
A
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.
135
Q
Dx?
Cell type?
A/W?
A
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.
136
Q
Dx?
Where do they most commonly occur?
Age?
A
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.
137
Q
A
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.
138
Q
A
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.
139
Q
A
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
141
Q
A
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.
143
Q
Dx?
Age?
Gender?
Prognosis?
Staining?
Genetics?
A
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
144
Q
A
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.
146
Q
A
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.
149
Q
Dx?
Age?
Gender?
Prognosis?
A
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.
150
Q
Dx?
Age?
Gender?
Location?
A
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.
151
Q
A
152
Q
Dx?
Radiology?
Histology?
Stains?
Prognosis?
A
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.
153
Q
A
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.
154
Q
A
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).
156
Q
Dx?
Stains?
Genetics?
A
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.
157
Q
DDx?
A
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).
159
Q
A
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.
163
Q
Inclusion Bodies
- __
- ___ inclusions
- inside multinucleated giant cells
- may be found in several granulomatous conditions
- __
- yellow-brown structures of __significance
- associated with histiocytes
- resemble fungi
- __
- eosinophilic inclusion bodies with radiating lines
- made of ___
- in the cytoplasm of multinucleated giant cells
- __
- concentrically laminated small calcifications
- most commonly seen in __
- may also occur in association with __
A
- 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
