Adenocarcinoma of the urinary bladder.
Adenocarcinoma of the urinary bladder arising from the urothelial lining is an uncommon malignant neoplasm, accounting for 0.5-2.0% of all malignant vesical tumors. The histologic variants show a predominant colonic (enteric) type glandular morphology with varied histologic patterns. Based on the morphology they are clasified as follows: colonic (enteric) type, adenocarcinoma NOS, mucinous, signet ring cell (SRC), clear cell type, hepatoid, and mixed forms. These tumors are also grouped as urachal and nonurachal type (the following information is about the nonurachal type). Irrespective of the various histologic patterns, there is usually evidence of cystitis cystica et glandularis or surface glandular metaplasia in the adjacent benign urothelium. Patients usually are M and in their 6th decade. The most common clinical presentation is hematuria. ~90% of the tumors arising in exstrophied bladder are adenocarcinomas. They are also more prevalent in settings of vesical schistosomiasis. In most cases, they involve the trigone and posterior bladder wall, and tend to be unifocal. Grossly, they can have a papillary, nodular, flat, or ulcerated architecture. Some variants, especially SRC, tend to present with prominent bladder wall thickening (“linitis plastica” like) without apparent growth due to diffuse infiltration of the bladder wall by tumor cells. Microscopically, these tumors show pure glandular morphology, with well to moderately differentiated colonic-type infiltrating glands with or without abundant extracellular mucin. Bladder adenocarcinomas need to be distinguished from the more common metastatic adenocarcinoma (direct spread, lymphatic, and hematogenous). The principal primary organs to be considered include colon, prostate, female genital tract, appendix, stomach, and breast. The IHC panel used to distinguish primary vesical adenocarcinoma from metastatic colonic adenocarcinoma include: CK7 and CK20 (7 and 20 are positive in >50% of primary bladder adenos; colonic adenos are typically 7 negative and 20 positive), thrombomodulin (90% of urothelial carcinomas positive, 59% of bladder adenos positive, 0% colonic adenos positive), beta-catenin (nuclear staining in 81% of colonic adenos and 0% of bladder adenos, membranous staining in 100% of colonic adenos and 88% of bladder adenos), CDX-2 is positive in both.
Aggressive angiomyxoma.
Aggressive angiomyxoma is a rare mesenchymal tumor arising primarily in the soft tissue of the pelvis and perineum of adults. The term aggressive refers to its infiltrative nature and propensity for local recurrence, but it is an indolent tumor with low metastatic potential. F:M = 6.6:1. It occurs predominantly in women of reproductive age with a peak incidence in the 4th decade and an age range of 11 to 77. In women, it arises in the vulvovaginal region, perineum, and pelvis. In men, it arises in the inguinoscrotal region and perineum. AAM is often clinically mistaken for entities such as Bartholin cyst, vaginal or labial cyst, abscess, leiomyoma, lipoma, fibroepithelial polyp, and inguinal or perineal hernia. Grossly, AAM is unencapsulated, is poorly circumscribed, and may blend imperceptively with surrounding soft tissue. The tumor is tan-pink to tan-gray, bulky, and has a rubbery consistency with a glistening, gelatinous cut surface. Microscopically, AAM is a sparsely cellular tumor composed of pale to eosinophilic stroma studded with numerous haphazardly arranged blood vessels ranging in size from thin-walled capillaries and venules to larger muscular arteries. The stroma is myxoid with intermixed wispy collagen fibrils, scattered smooth muscle bundles, and extravasated RBCs. The tumor cells are cytologically bland and have a spindled, ovoid, or stellate appearance with ill-defined cytoplasmic borders. There is minimal to no cellular atypia and mitoses are rare. IHC shows diffuse positivity for ER, PR, vimentin, and desmin. DDx for AAM includes angiomyofibroblastoma, superficial angiomyxoma, fibroepithelial stromal polyps, myxoid lipomatous tumors, and myxoid leiomyoma.
Differential diagnosis of nephrogenic adenoma.
When the NA consists of surface lesions (papillary), the DDx includes urothelial papilloma, PUNLMP, and low-grade papillary urothelial carcinoma. When the NA involves deep lamina propria and/or superficial muscle, the DDx includes prostatic adenocarcinoma and urothelial carcinoma with bland histology. When the NA has hobnail cells or a solid growth of clear cells, the DDx includes clear cell carcinoma of the urinary bladder.
Epithelioid angiomyolipoma.
Originally believed to be a hamartomatous lesion, angiomyolipoma (AML) is currently defined as a benign mesenchymal tumor composed of a variable proportion of adipose tissue, spindle and epithelioid smooth muscle cells, and abnormal thick-walled blood vessels. AML is a member of the PEComa family. Although most AMLs arise in kidney, extrarenal AMLs are also described in various sites. The epithelioid variant of AML (EAML) is mainly characterized by a predominance of epithelioid cells. In contrast to their classical counterpart, EAMLs are now considered a potentially malignant neoplasm. EAMLs are more often associated with tuberous sclerosis complex than classical AMLs. EAMLs mimic morphologically a variety of neoplasms such as RCC, renal oncocytoma, adrenal cortical neoplasm, epithelioid smooth muscle tumor, epithelioid peripheral nerve sheath tumor, epithelioid GIST, epithelioid melanoma, hepatoblastoma, and HCC. Morphologic clues to diagnosis such as islands of mature fat and abnormal vessels should be diligently searched for in surgical specimens, and prudent use of IHC may be needed.
Examples of pseudoneoplastic lesions in the genitourinary tract (male and female) and their related neoplastic mimes.
Pseudocarcinomatous epithelial hyperplasia (adenocarcinoma and urothelial carcinoma). Postoperative spindle cell nodules (sarcomas; sarcomatoid carcinoma). Drug effects (eg, cytoxan cystitis mimicking carcinoma in situ) (urothelial carcinoma). Prostatic urethral (utricular) polyp (adenocarcinoma). Paratesticular mycobacterial pseudotumor (sarcomas). Xanthogranulomatous nephritis/cystitis/orchitis/endometritis/oophoritis (sarcomatoid carcinomas). Adenomatous and basal-cell prostatic hyperplasia (adenocarcinoma). Nodular stromal prostatic hyperplasia (low-grade sarcoma). Prostatic sclerosing adenosis (adenocarcinoma). Radiation effect on prostatic epithelium (residual adenocarcinoma). Granulomatous prostatitis/orchitis (sclerosing high-grade adenocarcinoma; sclerosing seminoma). Vaginal adenosis (adenocarcinoma). Uterine cervical mesonephric remnants (adenocarcinoma). Uterine cervical microglandular adenosis (adenocarcinoma). Ovarian stromal hyperplasia/hyperthecosis (ovarian stromal neoplasms). Nephrogenic metaplasia of bladder and urethra (adenocarcinoma). Endometriosis (adenocarcinoma).
Histologic features of nephrogenic adenoma?
A metaplastic response of urothelium to injury. Also associated with renal transplantation and intravesical bCG. Histologic features are tubules (96%) composed of a single layer of cuboidal or flattened cells with clear to eosinophilic cytoplasm, round nuclei, and fine chromatin. Other features are inflammation (95%), extension into muscle (77%), structures resembling vessels (73%), presence of adjacent urothelium (69%), peritubular sheaths (65%), prominent nucleoli (54%), cords and individual cells (46%), thyroidization of tubules (38%), blue-tinged mucinous secretions (32%), papillary configurations (19%), and signet ring-like tubules (12%). The adjacent urothelium, if present, often exhibits cuboidal metaplasia (61%) or squamous metaplasia (28%). Mitotic figures are not present.
IHC for adrenal cortical carcinoma vs pheochromocytoma?
Adrenal cortical carcinoma is synaptophysin +, chromogranin -, inhibin +, Melan-A +, calretinin +, S-100 -. Pheochromocytoma is synaptophysin +, chromogranin +, inhibin -, Melan-A -, calretinin -, S-100 reactive only in nuclei of sustentacular cells.
IHC staining of nephrogenic adenoma?
Strong and diffuse granular reactivity for P504S. Rarely shows focal PSA or PAP positivity. Frequently negative (44%) or only focally positive (44%) for CK903 (AKA 34betaE12). Positive for EMA, CK7, and PAX2. Negative for CD10 and p63.
Immunostain to distinguish muscularis mucosa from muscularis propria in urothelial CA of bladder?
Smoothelin, which is a marker of terminally differentiated smooth muscle cells, stains muscularis propria but not muscularis mucosa.
Nephrogenic adenoma.
Also called nephrogenic metaplasia. An uncommon benign lesion of the urothelial tract, characterized by a circumscribed proliferation of tubules (resembling renal tubules), cysts, and papillae lined by cells with low cuboidal to columnar epithelium. M:F = 2:1. Most occur in adults, but seen in age range 4-81 years. They commonly arise in the setting of prior urothelial injury, such as past surgery (60%), calculi (14%), or trauma (9%). Additionally, 8% of patients have a previous history of renal transplantation or BCG therapy for urothelial carcinoma of the bladder. They are most commonly seen in the urinary bladder (80%); however, urethra (12%) or ureter (8%) can also be involved.
Urachal carcinoma of the urinary bladder.
Urachal carcinoma is an uncommon tumor that can present as a bladder mass. It tends to occur in the dome and anterior bladder wall and has a male predominance. Adenocarcinoma with enteric features is the most common histologic subtype and can also show mucinous and signet ring cell variants. Diagnostic criteria for urachal carcinoma include (1) tumor in the dome; (2) absence of cystitis cystica and cystitis glandularis; (3) predominant invasion of the muscularis or deeper tissues with a sharp demarcation between the tumor and surface bladder urothelium that is free of glandular or polypoid proliferation; (4) urachal remnants within the tumor; (5) extension into the bladder wall with involvement of the space of Retzius, anterior abdominal wall, or umbilicus; and (6) no evidence of a primary neoplasm elsewhere. The previous criteria help in differentiating it from primary vesical adenocarcinomas. IHC profile is similar to primary vesical adenocarcinomas and hence is of no practical utility. The management of urachal carcinoma is typically a partial cystectomy as opposed to a radical cystectomy for primary bladder adenocarcinomas.
What are renal MESTs?
Mixed Epithelial and Stromal Tumors. Other names for this entity are: leiomyomatous renal hamartomas, congenital mesoblastic nephroma in an adult, cystic hamartoma of renal pelvis, solitary multilocular cysts of the kidney, multilocular renal cyst with mullerian-like stroma, and adult metanephric stromal tumor. Is a benign renal neoplasm of adults that has a variable admixture of epithelial and mesenchymal components. M:F = 1:10. Grossly, variably solid and cystic, tan to yellow, well-circumscribed but rarely encapsulated. Microscopically, the mesenchymal component is characterized by fascicles of spindle cells showing variable degrees of smooth muscle, fibroblastic, or myofibroblastic differentiation associated with interspersed bundles of collagen. The mesenchymal component resembling that of ovarian stroma, and focal changes of the stromal cells reminiscent of ovarian stromal cell luteinization have been described. The epithelial component is dispersed throughout the neoplasm and varies from round and regular tubules to more complex tubulopapillary structures with or without cystic dilatation. These are lined by cuboidal to flattened epithelium that may show clear cell change and a hobnail appearance. Malignant transformation, recurrence, and metastasis are rare in MESTs. For pathogenesis, the female preponderance of MEST and history of long-term estrogen replacement in females or long-term sex-steroid exposure in males, combined with frequent expression of ER and PR in the mesenchymal component suggest that steroid hormones may play a role in the evolution of these tumors. The major differential diagnosis is cystic nephroma. MESTs have a higher stromal to epithelial ratio, prominent ovarian stroma, smaller cysts with phyllodes glands pattern, and stromal luteinization. CN have a low stromal to epithelial ratio, large cysts, and thin septa. DDx also includes congenital mesoblastic nephroma and primary renal synovial sarcoma.
What are the average diameters for a normal glomerulus in newborns and adults?
Newborn, 100 um. Adult, 200-250 um. Glomeruli reach normal adult size by ~8 years of age.
What are typical staining patterns for CK7, CK20, CD10, and RCC in oncocytoma, chromophobe renal cell carcinoma, and clear cell renal cell carcinoma.
Oncocytoma: CK7 neg, ~25% are CK20 pos, ~30% are CD10 pos, RCC neg. Chromophobe renal cell carcinoma: CK7 pos, CK20 neg, 0 to 45% are CD10 pos, RCC neg. Clear cell renal cell carcinoma: CK7 neg, CK20 neg, CD10 pos, RCC pos.
What does CK AE1/AE3 cocktail stain, and what are it’s uses in prostate?
CK AE1/AE3 cocktail detects acidic (CK10, CK14-16, and CK19) and basic (CK1-CK6 and CK8) cytokeratins. Is useful in the DDx of nonspecific granulomatous prostatitis, crushed or marked inflammation, or xanthoma cells versus Gleason pattern 5 prostate carcinoma. Is also useful in diagnosing small cell proliferations in the prostate, such as small cell carcinoma, lymphoma, and rhabdomyosarcoma. In the posttreatment setting, is helpful in highlighting individual atrophic prostate cancer cells and is superior to PSA, which can be suppressed by therapy and is, therefore, not detectable by IHC posttreatment.
What is the PAX-2 marker?
The PAX-2 marker is a renal-restricted nuclear transcription factor expressed in 70-80% of metastatic clear cell RCC.
What is the RCC marker?
The RCC marker is a glycoprotein found in the brush border of the proximal tubules of the kidney. It is + in 47-85% of clear cell RCC and 60-90% of papillary RCC.
Will adrenal cortical carcinomas stain positive for cytokeratins?
Adrenal cortical carcinomas are negative for CKs in formalin-fixed tissue unless antigen retrieval techniques are utilized, and even then the tumors are only focally weakly positive.
Xanthogranulomatous pyelonephritis.
XGP is a chronic destructive granulomatous process of renal parenchyma in association with long-term urinary tract obstruction and infection. The 3 forms of XGP are diffuse, segmental, and focal. Segmental XGP is characterized by segmental involvement of the disease, and focal XGP is located within the cortex with no pelvic communication. Segmental and focal XGP can be associated with normal kidney function. F>M. Mean age is ~50, with a range of 2-84. Almost all patients are symptomatic, and the most common symptoms are flank or abdominal pain, lower urinary tract symptoms, fever, palpable mass, gross hematuria, and weight loss. The common laboratory findings are leukocytosis and anemia. Urine cultures most often reveal E. coli and P. mirabilis. On CT scan, the combination of a nonfunctioning enlarged kidney, a central calculus within a contracted renal pelvis, expansion of the calices, and inflammatory changes in the perinephric fat is strongly suggestive of XGP. Grossly, the kidney has single or multiple yellow to orange nodules, and there can be central necrosis with abscess formation, involvement of perinephric fat, diffuse cortical scarring with effacement of the normal renal architecture, and cortical atrophy. Microscopically, there is a granulomatous mixed inflammatory infiltrate with fibrosis and cholesterol clefts in the background. The inflammatory infiltrate is composed of a variable number of xanthomatous histiocytes with foamy cytoplasm, neutrophils, lymphocytes, plasma cells, and multinucleated giant cells. Also, a variable degree of renal tubular atrophy, tubular dilatation and focal squamous metaplasia of the urothelium, microabscesses, lymphoid aggregates with germinal center formation, and spindle cell proliferation can be seen. The lesion shows diffuse positivity for CD68 and vimentin, and negativity for SMA, desmin, and epithelial markers. DDx includes clear cell RCC, papillary RCC, sarcomatoid RCC, leiomyosarcoma, malakoplakia, and megalocytic interstitial nephritis.
The cytoplasm of the cells in renal oncocytomas are granular and deeply eosinophilic, reflecting the abundant, packed ___ seen at the ultrastructural level.
The cytoplasm of the cells in renal oncocytomas are granular and deeply eosinophilic, reflecting the abundant, packed mitochondria seen at the ultrastructural level. In some cases, areas of the tumor are composed of oncoblasts, which are identical to the cells of the usual oncocytoma, except that the cytoplasm is not as abundant. Focal areas of cytoplasmic clearing are not uncommon but should be focal and restricted to the areas of the central scar, representing degenerative clearing of the cytoplasm because of ischemic changes.
Can renal oncocytomas show infiltration into perinephric fat and microscopic lymphovascular invasion?
Yes. But make sure it really isn’t something else. Resample and reevaluate.
The perinuclear halos seen in chromophobe renal cell carcinoma reflect the presence of ___ around the nucleus at the ultrastructural level.
The perinuclear halos seen in chromophobe renal cell carcinoma reflect the presence of microvesicles around the nucleus at the ultrastructural level. The microvesicles, which do not have affinity to H&E staining, are thought to be related to defective mitochondriogenesis. They displace cytoplasmic organelles to the periphery of the cytoplasm, leading to prominent cell membranes.
What renal neoplasms are seen in patients with Birt-Hogg-Dube syndrome?
Patients with BHD syndrome have multifocal renal tumors that include hybrid tumors (renal oncocytoma + chromophobe RCC), oncocytomas, chromophobe RCCs, clear cell RCCs, and papillary RCCs.
Clear cell RCC arises from proximal/distal tubules, and chromophobe RCC and oncocytoma arise from proximal/distal tubules.
Clear cell RCC arises from proximal tubules, and chromophobe RCC and oncocytoma arise from distal tubules.
What are PAX2 and PAX8 and what can they be used for?
PAX2 and PAX8 are transcription factors that are essential for the development of kidney, mullerian, and other organs. They are expressed in normal kidney as well as in most of the renal neoplasms. PAX2 and PAX8 have very similar expression profiles in RCC and in ovarian and endometrial carcinoma. However, PAX8 is also expressed in thyroid follicular cells and thyroid carcinoma, but PAX2 is typically negative in thyroid tumors. This makes them useful for the workup of metastatic RCC.
Alpha-methylacyl coenzyme a racemase (AMACR).
AMACR is a mitochondrial enzyme mediating the expression of fatty acids and is commonly expressed in normal hepatocytes, the bronchus, and epithelium of the proximal renal tubules. It is a positive tumor marker for prostatic adenocarcinoma. Almost all papillary RCCs are positive for AMACR, but other types of RCC are rarely positive.
TFE3, TFEB, and cathepsin-K immunostains. What renal tumors do they stain?
TFE3 is a transcription factor that is overexpressed in a group of RCCs with translocation involving Xp11.2. TFEB is a transcription factor that is overexpressed in RCCs with t(6;11)(p21;q12). Cathepsin-K is overexpressed in most TFE3 translocation carcinomas and all TFEB translocation carcinomas.
What are 4 markers that are expressed in a high percentage of urothelial carcinomas but are not usually expressed in RCCs?
Uroplakin III, p63, thrombomodulin, and GATA3.
___ (an immunostain) is a useful marker for the diagnosis of metanephric adenoma.
CD57 (an immunostain) is a useful marker for the diagnosis of metanephric adenoma.
A specific feature that is seen in most cases of acquired cystic disease-associated RCC in the ACDK setting is ___.
A specific feature that is seen in most cases of acquired cystic disease-associated RCC in the ACDK setting is intratumoral oxalate crystals.
What renal tumors can develop in patients with acquired cystic disease of the kidney?
ACDK is often, but not always, associated with a history of dialysis. The tumor types seen in ESRD and ACDK encompass (1) the 3 common subtypes of RCC: papillary RCC, clear cell RCC, and chromophobe RCC; (2) the 2 other subtypes of RCC that are either exclusively or predominantly seen in the setting of ESRD: acquired cystic disease (ACD)-associated RCC, and clear cell papillary RCC.
For the following renal cystic diseases, give the cancer risk and the most common renal tumor types: ESRD and ACD of the kidney, von Hippel-Lindau disease, tuberous sclerosis complex, autosomal-dominant polycystic kidney disease.
ESRD and ACD of the kidney; cancer risk 3-7%; ACD-associated RCC, clear cell papillary RCC, usual types of RCC (papillary, clear cell, chromophobe). von Hippel-Lindau disease; cancer risk 45-60%; clear cell RCC. Tuberous sclerosis complex; cancer risk 2-3%; angiomyolipoma, clear cell RCC, oncocytoma, RCC unclassified/TSC-related. Autosomal-dominant polycystic kidney disease; cancer risk equivocal; clear cell RCC, papillary RCC.
What immunostain and pattern is characteristic of papillary clear cell RCC?
The tumor cells express carbonic anhydrase IX (CAIX) in a diffuse, membranous distribution but staining is absent along the luminal borders of the tumor cells (cup-shaped distribution).
What determines type 1 and type 2 von Hippel-Lindau syndrome?
The absence of pheochromocytoma (type 1) or the presence of pheochromocytoma (type 2). Certain genotype-phenotype correlations have been established; Type 1 disease is associated with loss of VHL protein through large deletions or nonsense mutations, while type 2 disease is associated with germline VHL missense mutations.
Multilocular cystic RCC.
Multilocular cystic RCC is a renal cortical neoplasm with a distinct, multilocular gross appearance, and is a variant of clear cell RCC. Microscopically, the tumor consists of numerous clear cell-lined cysts with small clusters of clear cells in the tumor septa. This entity accounts for approximately 4% of all clear cell RCCs and affects middle-aged adults with M:F = 1.2-2.1:1.
How are multilocular cystic RCCs and cystic clear cell RCCs different?
Multilocular cystic RCCs have cysts with small clusters of clear cells in the tumor septa. Cystic clear cell RCCs have expansile nodular growth within the septa.
What are the casts in light chain cast nephropathy AKA myeloma cast nephropathy composed of?
The are composed predominantly of a single monoclonal light chain, which is typically admixed with Tamm-Horsfall protein secreted by the thick ascending limb of Henle.
What are the 3 most common drugs associated with drug-induced cystalline nephropathy?
Sulfadiazine, acyclovir, and indinavir.
What conditions can lead to oxalate nephropathy?
Enteric hyperoxaluria, toxic exposures (such as ethylene glycol ingestion or excessive vitamin C intake (vitamin C is metabolized to oxalate)), excessive dietary intake of oxalate, and inborn errors of metabolism.
What is enteric hyperoxaluria?
It is the most common etiology of oxalate nephropathy and is caused by fat and/or bile acid malabsorption, leading to steatorrhea. Under normal conditions, calcium and oxalate complex with each other in the colonic lumen and are excreted in the feces. In the setting of fat malabsorption, high levels of free fatty acids are present in the intestinal lumen and bind calcium, thereby reducing the amount of free calcium available to bind oxalate. This results in high intestinal levels of free oxalate, which is readily absorbed by the colonic epithelium and ultimately precipitates as calcium oxalate crystals in the kidney. In addition, the presence of high levels of free fatty acids and bile salts enhances colonic mucosal permeability to oxalate, further promoting oxalate absorption. Enteric hyperoxaluria can be seen in patients with inflammatory bowel disease, pancreatic insufficiency, following bowel surgery (including jejunoileal bypass and rou-en-Y gastric bypass), and use of gastrointestinal lipase inhibitors such as orlistat.
Acute uric acid nephropathy typically presents as oliguric or anuric acute renal failure and is most frequently seen in the setting of ___.
Acute uric acid nephropathy typically presents as oliguric or anuric acute renal failure and is most frequently seen in the setting of massive tissue destruction because of tumor lysis syndrome. Histologically, there is diffuse acute tubular injury accompanied by uric acid crystals located predominantly in the collecting tubules. In formalin-fixed tissue, urate crystals are largely dissolved in processing, leaving behind empty lacunae. If frozen sections or alcohol-fixed specimens are examined, the urate crystals stain blue with hematoxylin and are birefringent under polarized light. The crystals are typically needle-shaped or rectangular and occasionally incite an interstitial inflammatory respone.
The most frequent cytogenetic abnormalities seen in these renal cell neoplasms (clear cell, papillary, chromophobe, oncocytoma)?
Clear cell -3p; papillary +7, +17, -Y; chromophobe -1, -Y; oncocytoma t(11q13).
What makes the distinction between a renal papillary adenoma and papillary carcinoma?
Carcinomas are equal to or greater than 5 mm in size.
Hemorrhagic cystitis due to adenoviruses, especially type 11, is most often seen in (type of patient).
Hemorrhagic cystitis due to adenoviruses, especially type 11, is most often seen in bone marrow transplant recipients.
What do the terms focal, diffuse, segmental, and global refer to when classifying glomerular diseases by distribution?
Classification of disease distribution when many glomeruli are considered: Focal - disease affecting only some of the glomeruli. Diffuse - disease affecting most or all glomeruli. Classification of disease distribution when single glomeruli are considered: Segmental - a lesion involving only a part of the glomerulus. Global - a lesion involving the entire glomerulus.
Although nodular glomerulosclerosis (or nodular mesangial sclerosis) is a characteristic feature for DM, this finding is not specific and should provoke consideration of other entities, including ___.
Although nodular glomerulosclerosis (or nodular mesangial sclerosis) is a characteristic feature for DM, this finding is not specific and should provoke consideration of other entities, including renal amyloidosis, monoclonal immunoglobulin deposition disease, fibrillary GN, and immunotactoid glomerulopathy.
Arterionephrosclerosis/Hypertensive nephropathy/Nephrosclerosis. Gross and histologic features?
The gross appearance of the kidney shows granularity of the capsular surface, which corresponds to the light microscopic glomerular and tubulointerstitial scarring due to this vascular injury. Microscopic features include proliferative and fibrotic intimal thickening with narrowing of the arteries that may be accompanied by replication of the internal elastic lamina. Subendothelial hyalinosis affecting primarily the afferent but not efferent glomerular arterioles is often observed. Early glomerular changes are initiated by ischemic injury to the glomerulus with thickening and wrinkling of the basement membranes, usually in a global distribution along with thickening and fraying of Bowman capsule. Collagen gradually accumulates in the urinary space and compresses the shrunken glomerular tufts until eventually the entire glomerulus is sclerotic. Globally sclerotic glomeruli (global glomerulosclerosis) may be arranged in wedge-shaped zones of chronic ischemic injury of the outer cortex if the blood flow of larger renal arteries is compromised. Global glomerulosclerosis is associated frequently with tubular atrophy and interstitial fibrosis of the surrounding parenchyma because the blood exiting the efferent glomerular arteriole supplies the adjacent peritubular capillaries. Progressively more glomeruli are involved until the process results in ESRD with few residual intact nephrons. In advanced arterionephrosclerosis, there may be glomerular enlargement and superimposed focal segmental glomerulosclerosis, which has been postulated to be secondary to overloading the decreasing numbers of functional nephrons.
Membranoproliferative glomerulonephritis is a well-known manifestation of hepatitis ___. In the setting of malignancies, MPGN is often associated with ___, and is less common observed with solid tumors.
Membranoproliferative glomerulonephritis is a well-known manifestation of hepatitis C. In the setting of malignancies, MPGN is often associated with non-Hodgkin lymphoma, and is less common observed with solid tumors.
Idiopathic or primary FSGS is caused by ___ and characteristically manifests with ___. Secondary FSGS arises because of ___.
Idiopathic or primary FSGS is caused by injury of the glomerular podocytes and characteristically manifests with nephrotic syndrome. Secondary FSGS arises because of structural or functional renal alterations, which can be categorized into 3 broad categories: (1) a response to reduction of functional nephron mass due to primary glomerular or tubulointerstitial disease of vascular, infectious, immunologic, hereditary, or congenital origin; (2) secondary to glomerulonephritis, with the consequence of postinflammatory segmental glomerular scarring; and (3) secondary to hereditary basement membrane defects, such as Alport syndrome.
In the bladder, how do you distinguish postoperative spindle cell nodule from inflammatory myofibroblastic tumor?
IMFTs tend to reach a larger size, have greater prominence of the myxoid stroma, lesser degree of cellularity, greater pleomorphism, and lesser tendency for keratin immmunoreactivity.
What tumors are seen in the subtypes of MEN syndrome?
MEN1: Pancreatic tumors (gastrinoma 50%, insulinoma 20-30%, VIPoma 12%, glucagonoma 33%. MEN 2B: Medullary thyroid carcinoma 85%, pheochromocytoma 50%, mucosal neuroma 100%, marfanoid body habitus 80%. FMTC: Medullary thyroid carcinoma 100%.
What is encrusted cystitis?
Encrusted cystitis is caused by bacterial infections associated with alkaline urine in a predisposed immunocompromised patient. Corynebacterium is frequently involved. Histologically, it si characterized by a necrotic surface containing encrusted calcifications and underlined by necrotic tissue with inflammatory cells and bacterial colonies.
What is emphysematous cystitis?
Emphysematous cystitis is a complication of urinary tract infection, characterized by the presence of air within the bladder wall, caused by gas-forming bacteria. It occurs more commonly in women, and particularly in immunocompromised patients, including those suffering from diabetes mellitus. It is usually suspected clinically or radiologically. Histologically, it shows a mixed inflammatory infiltrate, as well as clear air spaces in the lamina propria, which can be surrounded by a foreign bdy giant cell reaction.
What are von Hansemann cells?
Are also called Hansemann macrophages. These cells are modified macrophages found in malakoplakia of the urinary tract. Malakoplakia is the result of an acquired defect in macrophage function causing impairment of bactericidal activity. These large macrophages that are present at sites of infection (von Hansemann cells) exhibit numerous secondary lysosomes containing partially digested organisms. Fusion and calcification of these lysosomes results in the formation Michaelis-Gutmann bodies, considered pathognomonic of malakoplakia. The Michaelis-Gutmann bodies are one or several round basophilic structures measuring between 1µm and 10µm, can be extracytoplasmic or intracytoplasmic, some are laminated, others appear homogeneous, and others have a dense central core with a targetoid appearance. Michaelis–Gutmann bodies demonstrate positivity with PAS stain, von Kossa stain, and sometimes Perls Prussian blue stain.
What is the etiology of biliary atresia?
Biliary atresia is though to represent the end result of intrauterine or perinatal injury to bile ducts, leading to fibrous obliteration of these structures and severe cholestatic liver disease in the neonatal period. Various parts of the extrahepatic biliary system are initially affected, but intrahepatic bile ducts are subsequently involved in a significant proportion of patients, even in those who undergo an initially successful portoenterostomy/Kasai procedure. Histologic examination of bile duct remnants supports the contention that, in most cases, the observed fibro-obliterative cholangiopathy in biliary atresia results from destruction of a presumably well-formed biliary system rather than from primary failure of normal embryologic development of these structures. To date, however, no single agent or abnormality has consistently been implicated as a cause of biliary atresia in humans. Instead, multiple etiologic factors (including immunologic, viral, genetic/metabolic, vascular insult, and environmental/miscellaneous categories) have been postulated to be part of the pathogenesis of this complex disease.
What is the differential diagnosis in high-grade carcinoma involving the renal sinus?
Renal cell carcinomas (collecting duct carcinoma, renal medullary carcinoma, clear cell renal cell carcinoma, papillary renal cell carcinoma (usually type2)) vs. Invasive high-grade urothelial carcinoma of the upper urinary tract.
What genetic abnormality do mesoblastic nephroma, infantile fibrosarcoma, and secretory carcinoma of the breast share?
t(12;15).
In the bladder, does small cell carcinoma tend to be pure, or admixed with another histologic type?
SmCC of the urinary bladder accounts for only 0.3-0.7% of all primary bladder cancers. Compared with its pulmonary counterpart, which usually exhibits pure small cell growth, bladder SmCC is more frequently admixed with another histologic subtype (~40-50% of cases). The mixed epithelial component is most commonly conventional urothelial carcinoma, including CIS, followed by squamous cell carcinoma and adenocarcinoma and, rarely, even sarcomatoid (spindle cell) carcinoma. The frequent association of bladder SmCC with otherwise conventional UC has led to a proposed common origin for both tumors, suggesting that small cell appearance may represent dedifferentiation within urothelial cell neoplasms. Mixed tumors, even with only focal smal cell histology, show dismal prognosis that is more similar to that of pure SmCC than to UC or pure tumors consisting of other components, warranting, therefore, a diagnosis as SmCC.
How does small cell carcinoma of the bladder differ from small cell carcinoma in other body sites in regard to immunohistochemical staining?
Histomorphologically, bladder SmCC resembles its counterparts elsewhere in the body. Unlike SmCC of most other organs, however, the sensitivity of conventional neuroendocrine markers (such as synaptophysin, chromogranin A, NSE, and CD56) has been relatively low in bladder SmCC cases. Therefore, the WHO diagnostic criteria allow for the diagnosis of bladder SmCC to be made on morphologic grounds alone. CD56 stains 71% of bladder SmCC, synaptophysin stains 64%, and chromogranin A stains 29%. NSE stains 80% of bladder SmCC, but the specificity of NSE is very low.
What is the Vysis UroVysion test?
Vysis UroVysion is a molecular cytology test that detects aneuploidy of chromosomes 3, 7, and 17 and deletion of the 9p21 locus via fluorescence in situ hybridization (FISH) in urine specimens from persons with hematuria suspected of having bladder cancer.
The diffuse cytoplasmic positivity of chromophobe renal cell carcinoma with Hale’s colloidal iron stain is due to __.
The diffuse cytoplasmic positivity of chromophobe renal cell carcinoma with Hale’s colloidal iron stain is due to staining of acid mucopolysaccharides.
The granularity of oncocytes is due to __.
The granularity of oncocytes is due to an excessive amount of mitochondria, resulting in an abundant acidophilic, granular cytoplasm.
What are the PAX2 and PAX8 genes, what is their utility as immunostains?
PAX2 and PAX8 belong to the pair box gene family consisting of 9 members, PAX1 through PAX9, each of which encodes a transcription factor. These transcription factors are expressed in an orderly manner during fetal development. They play a critical role in the formation of tissues and organs during embryonic development and are also crucial for maintaining the normal function of certain cells after birth. Although these 9 transcription factors control the development of a wide range of organs, the roles of PAX2 and PAX8 in ontogenesis are distinctively similar. Both of them are known to control the development of the central nervous system, eye, kidney, thyroid gland, organs deriving from the mesonephric (wolffian) duct, and those related to the müllerian duct. Transcription factors are identified in the nuclei of the cell types that are under their developmental control during organogenesis, but they often disappear in mature tissue. These transcription factors, however, may reexpress in an organ-specific fashion during neoplastic transformation. For example, both PAX2 and PAX8 are abundantly expressed by renal blastemal cells during nephrogenesis, then are noted in only a few renal parenchymal cells in mature kidney, but are identified again in RCC. Tissue expression of transcription factor therefore has been used as a specific marker for tumor diagnosis.
Iatrogenic KS is associated with immunosuppression due to drugs or after transplantation. Kaposi sarcoma occurs mainly in ___ transplant recipients, and infrequently after other solid organ or bone marrow transplants.
Iatrogenic KS is associated with immunosuppression due to drugs or after transplantation. Kaposi sarcoma occurs mainly in renal transplant recipients, and infrequently after other solid organ or bone marrow transplants. Posttransplant KS may result from reactivation of latent HHV8 infection in recipients or from tumor cells contributed from organ donors. Transplant-associated KS has a protracted, but aggressive course. In transplant recipients, KS lesions may regress after discontinuation of immunosuppressive therapy.
What is a STUMP?
Stromal Tumor of Uncertain Malignant Potential (STUMP). STUMPs are rare prostatic tumors characterized by atypical stromal proliferation, that may resemble breast phyllodes tumors. They are characterized by hypercellular stroma or cytologic atypia, but without evidence of true sarcomatous transformation. The atypical stromal cells have enlarged nuclei with nuclear hyperchromasia and variable multinucleation. There are few/no mitotic figures, and no atypical mitotic figures. Tumors may be associated with benign prostatic glands that may including crowding, a prominent basal cell layer or prominent papillary infolding.
What entities are in the differential diagnosis of renal morphological lesions reminiscent of diabetic nephropathy?
Nodular, intercapillary glomerulosclerotic lesions resembling Kimmelstiel-Wilson nodules commonly observed in diabetic nephropathy can also be seen in patients without any clinical history or evidence of diabetes. The differential diagnosis includes: Monoclonal immunoglobulin deposition disease. Amyloidosis. Immunotactoid glomerulopathy (fibrillary glomerulonephritis). Fibronectin glomerulopathy. Collagen glomerulopathy. Membranoproliferative glomerulonephritis. Idiopathic nodular glomerulosclerosis. Nodular glomerulosclerosis secondary to chronic hypoxic or ischemic state. The well-formed, intercapillary, nodular mesangial lesions, along with thickened glomerular basement membranes and tubular basement membranes, and hyaline arteriolosclerosis are virtually pathognomic of diabetic nephropathy. However, the pathologist must exclude lesions reminiscent of diabetic nephropathy by performing special stains on histologic sections, IF, and EM studies.
What are common benign bladder lesions that exhibit glandular differentiation?
Cystitis cystica, cystitis glandularis, von Brunn nests, nephrogenic adenoma, intestinal metaplasia, urachal remnant, mesonephric remnant, endometriosis, and prostatic-type polyp. Also, be aware of pseudoglandular differentiation of reactive urothelium or in urothelial carcinoma; this is formation of small intraepithelial spaces due to degenerative changes rather than true glandular differentiation (there is no glandular epithelial lining).
The WHO defines primary adenocarcinoma of the bladder as ___.
The WHO defines primary adenocarcinoma of the bladder as an epithelial malignancy with pure glandular differentiation without evidence of typical urothelial carcinoma. In contrast, a tumor with both typical urothelial carcinoma and adenocarcinomatous components is classified as urothelial carcinoma with glandular differentiation.
What are urachal remnants?
Residual tissues from the embryonic allantoic stalk connecting the umbilicus and bladder.
What entities are in the differential diagnosis of HCC?
The differential diagnosis of HCC includes other hepatic lesions, such as focal nodular hyperplasia, angiomyolipoma, metastatic pancreatic or small bowel neuroendocrine tumors, and renal cell carcinoma.
What is the most common primary malignant tumor of the kidney in children?
Described by Max Wilms in 1899, Wilms tumor (nephroblastoma) is the most common primary malignant tumor of the kidney in children. While it rarely occurs in adults, the peak incidence is in young children (average age, 3-4 years). Approximately 500 cases are diagnosed annually in the United States.
Wilms tumor typically has a triphasic morphology. Describe.
Typically, Wilms tumors has a classic triphasic morphology: blastema, stroma, and epithelium, although in some cases only one or two of these components are present, for example in the “blastema-predominant” variant composed only of the primitive small round cell component, or in the “epithelial-predominant” variant mimicking metanephric adenoma. The epithelial component is typically formed by hyperchromatic primitive-appearing tubules and less commonly, small glomeruloid structures. Mesenchymal differentiation within Wilms tumors is prominent in some cases, particularly smooth muscle or skeletal muscle elements. Fat, cartilage, osteoid, squamous or glandular epithelium, and glial elements are also reported.
What are the unfavorable and favorable histologies of Wilms tumor?
Histologic classification of Wilms tumor is generally divided into two types: Unfavorable histology (tumors with focal or diffuse anaplasia) and Favorable histology (tumors with no anaplasia). Anaplasia is defined as presence of markedly enlarged hyperchromatic nuclei (3x greater in size than other tumor nuclei) and presence of atypical multipolar mitoses, both of which are changes typically seen at screening magnification. Diffuse anaplasia is defined as presence of anaplastic cells in multiple different fields of the primary tumor or in a metastatic site, whereas focal anaplasia refers to presence of anaplastic cells in one or only a few discretely localized foci. This distinction between focal and diffuse anaplasia warrants documentation or “mapping” of the site of sampling of tissue blocks in order to determine proximity of anaplastic fields submitted in separate blocks.
What are the variants of Wilms tumor?
Variants of Wilms tumor include the rhabdomyoblastic , blastemal-predominant, epithelial-predominant, teratoid, cystic variant, and cystic, partially differentiated nephroblastoma (CPDN). CPDN is characterized by microscopic foci of Wilms tumor within fibrous septations in a grossly cystic tumor. Gross identification of solid nodules within a cystic neoplasm warrants a diagnosis of cystic Wilms tumor rather than CPDN.
Approximately 90% of Wilms tumors are sporadic, while a minority are associated with syndromes and/or mutations in the tumor suppressor genes ___ or ___.
Approximately 90% of Wilms tumors are sporadic, while a minority are associated with syndromes and/or mutations in the tumor suppressor genes WT1 (chromosome 11p13) or WT2 (chromosome 11p15).
What are syndromes associated with Wilms tumor?
Syndromes associated with Wilms tumor include WAGR (Wilms tumor-Aniridia-Growth Retardation), Denys-Drash syndrome (Wilms tumor, mesangial sclerosis, gonadal dysgenesis), Beckwith-Wiedemann syndrome (Wilms tumor predilection, organomegaly, hemihypertrophy of extremities, omphalocele, and other anomalies), Simpson-Golabi-Behmel syndrome (Wilms tumor predilection, facial overgrowth, congenital anomalies), and isolated hemihypertrophy.
What are nephrogenic rests within Wilms tumors?
Nephrogenic rests are benign pre-neoplastic lesions associated with Wilms tumor in some cases. Detection of nephrogenic rests typically prompts screening and follow-up of the contralateral kidney due to the risk of multifocality and/or metachronous tumor formation. Hyperplastic nephrogenic rests are typically wedge-shaped and interdigitate microscopically with adjacent renal tubules, whereas incipient Wilms tumor nodules are typically spherical and have a capsule separating the tumor from the surrounding kidney. The difficulty in distinguishing a hyperplastic “adenomatous” nephrogenic rest from a small epithelial-predominant Wilms tumor is well-recognized. Accurate distinction requires examination of the edge of the lesion, and cannot be accurately distinguished by needle biopsy.
What entities are in the differential diagnosis of Wilms tumor?
The differential diagnosis of Wilms tumor includes other primary renal tumors of childhood, including malignant rhabdoid tumor, congenital mesoblastic nephroma (classic and cellular variants), clear cell sarcoma of the kidney, and renal cell carcinoma. Other diagnostic considerations include other small cell tumors of the kidney (synovial sarcoma, primitive neuroectodermal tumor of the kidney, desmoplastic small round cell tumor, neuroblastoma, lymphoma) and a variety of benign tumors (cystic nephroma, infantile ossifying tumor of the kidney, oncocytoma, and others).
What is clear cell oncocytosis?
Oncocytes are altered epithelial cells whose cytoplasm contains vast numbers of abnormal mitochondria. They are large, polygonal cells with well-defined borders and abundant finely granular acidophilic/eosinophilic cytoplasm. Cytoplasmic glycogen accumulation may peripheralize intracytoplasmic mitochondria, resulting in clear cytoplasm (clear cell oncocytosis). Or, it may be a fixation artifact.
Hypovolemic hyponatremia is often due to ___. Euvolemic hyponatremia is often due to ___. Hypervolemic hyponatremia is often due to ___.
Hypovolemic hyponatremia is often due to water loss either through the kidneys or GI tract. Euvolemic hyponatremia is often due to drugs. Hypervolemic hyponatremia is often due to CHF, nephrotic syndrome, or cirrhosis.
Type I renal tubular acidosis is due to ___. Type II renal tubular acidosis is due to ___. Type IV renal tubular acidosis is due to ___.
Type I, or distal renal tubular acidosis is due to the inability to produce an acid urine. Associated with hypokalemia. Type II, or proximal renal tubular acidosis is due to bicarbonate wasting. Associated with hypokalemia. Type IV renal tubular acidosis is due to aldosterone deficiency. Associated with hyperkalemia.
In which renal tubular acidosis is hyperkalemia seen?
Type IV. Type I and type II are associated with hypokalemia.
What is IMP3 gene and protein?
IMP3 protein is a member of the insulin-like growth factor II mRNA-binding proteins that consist of IMP1, IMP2, and IMP3. The IMP3 gene is located on band 7p11.2 and is identical to the KH domain–containing protein overexpressed in cancer (KOC) protein. IMP3 is an oncofetal protein involved in embryogenesis. Recent studies have shown that IMP3 is an important cancer-specific gene that is associated with many aggressive and advanced cancers and is specifically expressed in malignant tumors but is not found in benign tissues. Moreover, IMP3 promotes tumor cell proliferation, adhesion, invasion, and metastasis. IMP3 is an important prognostic biomarker for localized RCC (predicts metastasis and prognosis) and superficial urothelial carcinoma (predicts aggressive superficial UCs).
Xp11.2 translocation renal cell carcinoma is a subtype of renal cancer defined by a breakpoint at Xp11.2 with gene fusions between the transcription factor E3 (TFE3) gene and 6 other genes. The most common fusion partners are ___.
Xp11.2 translocation renal cell carcinoma is a subtype of renal cancer defined by a breakpoint at Xp11.2 with gene fusions between the transcription factor E3 (TFE3) gene and 6 other genes. The most common fusion partners are the papillary renal cell carcinoma (PRCC, 1q21) gene and alveolar soft part sarcoma chromosome region, candidate 1 (ASPSCR1, 17q25) gene. The same ASPSCR1-TFE3 gene fusion is seen in alveolar soft part sarcoma, a rare pediatric tumor. Another renal translocation carcinoma exhibits the t(6;11)(p21;q12) translocation with a gene fusion between the alpha gene and the transcription factor EB (TFEB) gene. Both TFEB and TFE3 are members of the MiTF/TFE family of transcription factors.
The only known predisposing risk factor for developing translocation RCC is ___.
The only known predisposing risk factor is cytotoxic chemotherapy treatment during childhood, which was found in about 15% of patients. The chemotherapeutic agents are thought to cause DNA damage, which then induces repair mechanisms that foster a translocation.
What are the FDA-approved criteria for a positive UroVysion FISH test result?
UroVysion is a multitarget multicolor FISH assay that examines 4 chromosomal abnormalities that commonly occur in UC. The assay is done on exfoliated urothelial cells using centromeric fluorescent denatured chromosome enumeration probes for chromosomes 3, 7, and 17, as well as a locus-specific identifier probe for 9p21. Normal cells are diploid or possess 2 copies of each chromosome. The types of genetic abnormalities observed by FISH include gains (3 or more copies) of one or more chromosomes, monosomy (1 copy), or deletions (no copies). The abnormalities that have been found to be associated with UC are polysomy (including tetrasomy), trisomy, and 9p21 deletion. The FDA-approved criteria for a positive FISH result are (1) 4 or more cells with polysomy (3 or more copies of 2 or more chromosomes), or (2) 9p21 deletion in 12 or more cells. A minimum of 25 morphologically abnormal cells need to be scanned.
What conditions is ACD associated with?
ACD appears to be due to defective iron utilization/metabolism and is associated with chronic nonhematologic disorders such as chronic infections, connective tissue disorders, malignancy, and renal, thyroid, and pituitary disorders.
How does renal failure cause anemia?
Another normocytic, hypoproliferative anemia is the anemia of chronic renal failure. Loss of the kidneys’ excretory function produces an increase in BUN and creatinine, as discussed later, as well as a buildup of metabolic byproducts. The resulting uremia appears to be responsible for changes in red cell shape, with burr cells (echinocytes) and ellipsoidal cells commonly present on peripheral blood films. Identification of burr cells on peripheral blood films during the course of illness may signal the development of renal dysfunction. In addition to decreased excretory function, the kidneys’ ability to produce erythropoietin is decreased, resulting in impaired erythropoiesis, such that the marrow’s response to hypoxia becomes inadequate. In contrast to aplastic anemia, white cell and platelet counts usually remain within normal limits.
70% of the total filtered sodium is reabsorbed in what part of the nephron?
Proximal convoluted tubule.
Epithelioid angiomyolipoma. Morphological DDx?
EAMLs mimic morphologically a variety of neoplasms such as RCC, renal oncocytoma, adrenal cortical neoplasm, epithelioid smooth muscle tumor, epithelioid peripheral nerve sheath tumor, epithelioid GIST, epithelioid melanoma, hepatoblastoma, and HCC. Morphologic clues to diagnosis such as islands of mature fat and abnormal vessels should be diligently searched for in surgical specimens, and prudent use of IHC may be needed.
What is BCG? What is it used for and what is the mechanism of action?
Bacille Calmette–Guerin is a live-attenuated strain of Mycobacterium bovis developed in 1921 as a vaccine for tuberculosis. The first published reports of its use in the bladder were in 1976. Intravesical BCG therapy has been demonstrated to reduce the recurrence rate and the risk of progression to muscle-invasive disease in patients with CIS (BCG is the gold standard for treatment of urothelial CIS), as well as superficial bladder tumors. High-risk patients treated with BCG following TURBT have lower cystectomy rates. The mechanism of action is induction of a massive influx of inflammatory cells and production of cytokines in the bladder mucosa and lumen that leads to an immune response against tumor cells. An intact immune system is a necessary prerequisite to successful BCG therapy.
Brief overview of low-grade myofibroblastic proliferations of the urinary bladder.
The low-grade myofibroblastic proliferations of the urinary bladder are rare lesions affecting males more often than they do females. The most-common signs and symptoms are hematuria and dysuria. Histopathologically, they are spindle cell proliferations in a loose myxoid stroma, even though compact proliferations or hypocellular fibrous patterns can be found. Typically, there are varying amounts of acute, chronic, or mixed inflammatory infiltrates. Necrosis is rare to absent. Muscularis propria infiltration is common, while perivesical soft tissue invasion is uncommon. IHC is nonspecific, except for ALK-1 positivity (20%–89%). FISH has demonstrated clonal genetic aberrations involving the ALK gene in 50% to 60% of cases. After surgery, only 6% of patients experience local recurrence, without metastases or deaths from the disease. Malignant transformation has been reported exceptionally. These myofibroblastic proliferations are probably part of a continuum with, at one end, benign pseudosarcomatous proliferations and, at the opposite end, more-aggressive lesions.
For renal allograft biopsies, what are requirements for minimum sample adequacy and optimal sample adequacy according to the Banff classification?
For minimum sample adequacy, a minimum of 7 glomeruli and one artery are required. For optimal sample adequacy, 10 glomeruli and two arteries are required.
Distinction between benign and malignant adrenal cortical tumors may be extremely difficult, and numerous authors have utilized various parameters in order to allow differentiation of these neoplasms. Medeiros and Weiss have proposed a system which utilizes histologic criteria only. What are the 9 features commonly associated with adrenal cortical carcinoma, according to these authors?
- High nuclear grade (Fuhrman criteria). 2. Mitotic rate exceeding 5 per 50 HPFs. 3. Atypical mitoses. 4. Eosinophilic tumor cell cytoplasm (>75% of tumor cells). 5. Diffuse architecture (>33% of tumor). 6. Necrosis. 7. Venous invasion (smooth muscle in wall). 8. Sinusoidal invasion (no muscle in wall). 9. Capsular invasion. The presence of two or fewer features portends low metastatic potential, while three or more features portend metastatic potential and/or recurrence. The three most important criteria according to Weiss are mitotic activity greater than 5 per 50 high-power field, atypical mitoses, and venous invasion.
Villin IHC stain. What is the target? In what normal and disease states is there positivity? What are some uses of the stain?
Villin is an actin binding protein present in cytoskeleton of intestinal microvilli; has critical role in maintaining brush border organization. It is relatively specific for GI epithelium with brush border microvilli or adenocarcinomas derived from them. Positive staining (normal): Digestive tract epithelium, proximal renal tubules, hepatic bile ducts. Positive staining (disease): Colonic adenocarcinoma, renal cell carcinoma, pulmonary adenocarcinomas. Negative staining: Renal distal tubules, bronchiolar epithelium, pulmonary alveolar cells, bronchial gland cells. Uses: Primary bladder adenocarcinoma (villin-, CDX2-) vs. colorectal carcinoma to bladder. Ovarian adenocarcinoma (villin-) vs. colorectal adenocarcinoma.
Congenital adrenal hyperplasia is a group of autosomal recessive disorders characterized by impairment of cortisol biosynthesis, with or without impairment of aldosterone biosynthesis, and ~95% of cases are due to ___ deficiency.
Congenital adrenal hyperplasia is a group of autosomal recessive disorders characterized by impairment of cortisol biosynthesis, with or without impairment of aldosterone biosynthesis, and ~95% of cases are due to 21-hydroxylase (21-OHD) deficiency. CAH is manifested in a variety of clinical severities comprised of three subtypes: i) classic salt wasting, ii) classic simple virilizing, and iii) nonclassic (mild or late onset) forms.
What entities are in the DDx of small round cell tumors of the kidney?
The differential diagnosis of small round cell tumors of the kidney includes blastema-predominant Wilms tumors, lymphoblastic lymphoma, clear cell sarcoma, small cell carcinoma, monophasic synovial sarcoma, neuroblastoma, rhabdomyosarcoma, desmoplastic round cell tumor, rhabdoid tumor and extraskeletal Ewing sarcoma/PNET.
Which type of azotemia (prerenal, renal, or postrenal) is most likely when the BUN/Cr ratio is maintained but the levels of both are elevated?
Renal azotemia. A maintained but elevated ratio is suggestive of an intrinsic renal defect, most commonly glomerulonephritis or tubulointerstitial nephritis. Deranged ratios, such as when BUN increases more than Cr, is suggestive of impaired renal perfusion, such as prerenal (insufficient volume to the kidney) and postrenal (insufficient volume out of the kidney).
What is the most common cause of renal failure in cirrhotic patients?
Spontaneous bacterial peritonitis.
What is the most common cause of secondary hyperparathyroidism?
Secondary hyperparathyroidism is due to increased physiological PTH as a response to increased resistance to PTH activity, most commonly in end-stage renal disease.
Which type of azotemia (prerenal, renal, or postrenal) is most likely when the BUN/Cr ratio is maintained but the levels of both are elevated?
Renal azotemia. A maintained but elevated ratio is suggestive of an intrinsic renal defect, most commonly glomerulonephritis or tubulointerstitial nephritis. Deranged ratios, such as when BUN increases more than Cr, is suggestive of impaired renal perfusion, such as prerenal (insufficient volume to the kidney) and postrenal (insufficient volume out of the kidney).
What is the most common cause of renal failure in cirrhotic patients?
Spontaneous bacterial peritonitis.
Bilirubinuria indicates (conjugated/unconjugated) hyperbilirubinemia.
Bilirubinuria indicates conjugated hyperbilirubinemia, because unconjugated bilirubin, even when quite elevated, does not appear in urine.
How can renal insufficiency spuriously elevate serum amylase?
Amylase is primarily cleared by glomerular filtration.
List non-pancreatic causes of hyperamylasemia.
Diabetic ketoacidosis, peptic ulcer disease, acute cholecystitis, ectopic pregnancy, salpingitis, bowel ischemia, intestinal obstruction, renal insufficiency, salivary gland pathology, and macroamylasemia. Amylase may also be raised somewhat by the administration of opioid analgesics, due presumably to contracture of the sphincter of Oddi.
CK-BB (CK1) is found primarily in the brain, with lesser amounts found in what other locations?
Stomach, bladder, and prostate.
In what locations are the natriuretic peptides ANP, BNP, and CNP produced?
ANP is synthesized mainly by atrial myocytes (but synthesis of ANP also takes place in the ventricles, brain, kidney, and adrenals). ANP is stored in granules and stimulation results in a rapid response. BNP is synthesized by ventricular myocytes (predominantly) and brain, as well as atrial myocytes under some conditions. BNP is secreted by a constitutive mechanism; only small amounts are stored and cells are dependent upon activation of the BNP gene when secretion is needed. CNP is synthesized by brain and endothelium.
RCCs in vHL tend to present in young patients (mean 37 to 44 yo) and tend to be multifocal and bilateral. Are they more or less aggressive than the sporadic tumors?
They are somewhat more indolent than sporadic tumors (metastasize only when quite large).
What tumors are seen in patients with vHL disease?
Hemangioblastomas (CNS and retinal), pheochromocytoma, clear cell RCC, pancreatic cysts, islet cell tumors, epididymal and ovarian cystadenomas, endolymphatic sac tumors.
vHL disease can be subtyped according to the clinical manifestations (although these groups often correlate with certain types of mutations present in the VHL gene). What are the subtypes?
Type 1 often has deletion or nonsense mutations. This group manifests mostly as hemangioblastomas whereas clear cell RCC and pheos are rare. Type 2 is subdivided into types 2A, 2B, and 2C, and are characterized mostly by missense mutations. Type 2A is at risk of hemangioblastomas and pheos, but not clear cell RCC. Type 2B is at risk of all 3 tumors, with a higher risk of clear cell RCC. Type 2C is at risk for only pheos. Type 3 has a risk of Chuvash polycythemia.
What tumors are seen commonly in tuberous sclerosis (the “major features” as set forth in a consensus statement from the Diagnostic Criteria Committee of the National Tuberous Sclerosis Association)?
Facial angiofibromas (adenoma sebaceum) or forehead plaque. Nontraumatic ungual or periungual fibroma. >3 hypomelanotic macules. Shagreen patch (connective tissue nevus). Multiple retinal nodular hamartomas. Cortical tuber. Subependymal nodule. SEGA. Cardiac rhabdomyoma, single or multiple. LAM. Renal AML. Definite TSC is either 2 major features or one major plus 2 minor features.
What tumors occur in Carney complex?
Cutaneous lentigenes (simple lentigos). Blue nevi, particularly the cellular blue nevus. Cardiac myxomas (as well as myxomas of breast, female genital tract, and skin (especially on eyelid and external ear)). Endocrine tumors including thyroid follicular adenomas, pituitary adenomas (GH-secreting), and the so-called primary pigmented nodular adrenocortical disease (a form of multinodular hyperplasia of the adrenal cortex that causes Cushing syndrome). Large-cell calcifying Sertoli cell tumor. Psammomatous melanotic schwannoma.
What is eosinophiluria suggestive of?
Acute interstitial nephritis, not UTI.
Bacteria can cause inflammatory (colitic) or noninflammatory infectious diarrhea. List some causes of each.
Noninflammatory bacterial diarrhea: Vibrio spp, E. coli (especially ETEC and EPEC), C. perfringens, S. aureus, and B. cereus. Inflammatory bacterial diarrhea: C. difficile, Salmonella, Shigella, Campylobacter.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): chancroid.
Haemophilus ducreyi.
For the following clinical syndrome(s), give the causative agent(s) (list most common first): lymphogranuloma venereum.
C. trachomatis.
What conditions result in the greatest decrements of serum albumin?
Hepatic synthetic function is poorly reflected in the albumin, since only in end-stage liver disease is serum albumin noticeably decreased. The greatest decrements in serum albumin are seen in protein-losing conditions such as protein-losing enteropathy and nephrotic syndrome.
A prominent “prealbumin” band that is often seen in heparinized patients results from an alteration in beta-lipoprotein such that it migrates in the prealbumin range. In what conditions/situations are true elevations in prealbumin seen?
Alcohol use, renal dysfunction and drugs (corticosteroids and other hormones, high-dose NSAIDs). .
What is the pattern for nephrotic syndrome seen on SPEP?
In nephrotic syndrome due to minimal change disease, there is an especially selective loss of albumin (selective proteinuria). In other forms of nephrotic syndrome, nearly all proteins are lost, including gamma globulins. However, in all types of nephrotic syndrome, larger protein molecules are retained. The result is dimming of all the electrophoretic bands, most prominently the albumin band, with the conspicuous exception of the alpha-2 band which contains the large protein alpha-2 macroglobulin.
What is schistosomiasis (AKA bilharzia)?
Schistosomiasis is caused by digenetic blood trematodes. The three main species infecting humans are Schistosoma haematobium, S. japonicum, and S. mansoni. Two other species, more localized geographically, are S. mekongi and S. intercalatum. In addition, other species of schistosomes, which parasitize birds and mammals, can cause cercarial dermatitis in humans.
What are geographic locations of the main Schistosoma species?
S. mansoni is found in parts of South America and the Caribbean, Africa, and the Middle East; S. haematobium in Africa and the Middle East; and S. japonicum in the Far East. S. mekongi and S. intercalatum are found focally in Southeast Asia and central West Africa, respectively.
What is the vector for Schistosoma spp?
There is no vector; there is direct penetration of skin by free-swimming cercaria. Infection occurs when skin comes in contact with contaminated freshwater in which certain types of snails that carry the parasite are living. The parasite leaves the snail and enters the water where it can survive for about 48 hours.
In UPEP, what is seen in a glomerular proteinuria pattern?
Glomerular proteinuria is due to increased filtration of macromolecules (such as albumin) across the glomerular capillary wall. On UPEP there are strong albumin, alpha-1 and beta bands. Very large proteins, due to the persistence of some filtering function, and very small proteins due to tubular absorption, do not make their way into urine. This leaves the protein in between these, most notably albumin, AAT, and transferrin.
In UPEP, what is seen in a tubular proteinuria paattern?
Weak albumin band and strong alpha-1 and beta bands. This pattern results from the impaired tubular reabsorption of low molecular weight proteins normally filtered freely by the glomerulus and almost completely reabsorbed in the proximal tubules, such as alpha-2-macroglobulin, beta-2-microglobulin, and Ig light chains.
In UPEP, what is seen in an overflow proteinuria pattern?
Increased excretion of LMW proteins can occur with marked overproduction of a particular protein, leading to increased glomerular filtration and excretion. This is almost always due to immunoglobulin light chains in multiple myeloma but may also be due to lysozyme (in acute myelomonocytic leukemia), myoglobin (in rhabdomyolysis), or free hemoglobin (in intravascular hemolysis) that is not bound to haptoglobin. In these settings, the filtered load is increased to a level that exceeds the normal proximal reabsorptive capacity.
DDx of hyponatremia.
Pseudohyponatremia (from hyperglycemia, hyperlipidemia, hyperproteinemia). True hyponatremia with hypovolemia: renal losses (diuretics, medullary renal disease, Addison’s disease, RTA type I) or extrarenal losses (GI losses, third spacing). True hyponatremia with euvolemia: SIADH, psychogenic polydipsia, drugs with ADH-like effect. True hyponatremia with hypervolemia: CHF, cirrhosis, nephrotic syndrome.
What are causes of hypokalemia?
Inadequate potassium intake. Increased potassium excretion (mineralocorticoid excess (endogenous or exogenous), hyperreninism (renal artery stenosis), osmotic diuresis (mannitol, hyperglycemia), increased gastrointestinal losses, drugs, genetic disorders). Transcellular shifts (alkalosis, correction of DKA, refeeding, hypothermia).
Nearly all cases of acidosis are associated with hyperkalemia. What are some exceptions?
The most common cause for metabolic acidosis with hypokalemia is GI loss (eg, diarrhea, laxative use). Other less common etiologies include renal loss of potassium secondary to renal tubular acidosis (types I and II?) or salt-wasting nephropathy.
~__% of the population has HSV-2 seropositivity, but only ~__% of the population has genital herpes.
~20% of the population has HSV-2 seropositivity, but only ~2% of the population has genital herpes.
What are renal metanephric stromal tumors?
MSTs are a group of benign tumors of the kidney, distinct from congenital mesoblastic nephroma with which they were previously grouped. They are now thought to be related more closely to Wilms tumor rather than mesenchymal tumors of the kidney. They were first recognized and referred to as nephrogenic adenofibroma, but were subsequently renamed as MST. They are considered to be part of the spectrum of metanephric tumors ranging from metanephric adenoma to metanephric adenofibroma to MST, all considered to represent the benign end of Wilms tumor.
Histologic appearance of metanephric stromal tumor?
Loose spindle cell proliferation with uniform hyperchromatic nuclei and thin indistinct cytoplasm. No capsule. Subtle infiltration into adjacent renal parenchyma. The spindle cells surround entrapped renal tubules and show condensation around them with a myxoid background giving it a characteristic “onion skin” pattern. There may be areas of prominent cellularity or epithelioid morphology. Prominent vascularity with changes of angiodysplasia. Another feature is the presence of heterologous elements, usually glial or cartilaginous.
What 2 entities are in the main DDx for metanephric stromal tumor, and how can they be differentiated?
Congenital mesoblastic nephroma and clear cell sarcoma of kidney. CMN: Unencapsulated like MST but more infiltrative. Entraps tubules only at the periphery and usually does not have mesenchymal collars like MST. Cellular CMN have the classic cytogenetic abnormality t(12;15). CMN lacks the heterologous elements and angiodysplasia as seen in MST. Are frequently desmin and/or actin positive, reflecting their myofibroblastic nature. CCSK: Is extremely cellular, although some may be composed of large areas of bland spindle cells mimicking MST. Lacks onion-skinning around tubules or heterologous elements. Has a characteristic branching vascular pattern not seen in MST.
Clear cell sarcoma of the kidney metastasizes frequently to ___.
Clear cell sarcoma of the kidney metastasizes frequently to bone (which is unlike Wilms tumor). Bony mets often precede mets to organs, and affected children may be hypercalcemic at presentation. In fact, CCSK was initially referred to as “bone matastasizing renal tumor of childhood”.
What is the classic histologic appearance of clear cell sarcoma of the kidney?
Nests or cords of cells separated by regularly spaced, arborizing fibrovascular septa. Regularly spaced small blood vessels give a “chicken wire” pattern. Slightly variable ovoid nuclei with finely granular chromatin. Frequent empty nuclei. Mitoses are uncommon.
What is the most common cause of glomerulonephritis worldwide?
IgA nephropathy. Accounts for 1-3% of patients with ESRD in USA and Europe.
IgA nephropathy. Age, gender, and race predilections?
Wide age spectrum (1 to >65), peak 20-30 yo. M:F = 2:1. Ethnicity: Asians > Whites > Blacks.
Does IgA nephropathy recur in transplants?
Recurs in transplants in 30%. Graft loss due to recurrence in 5%.
IgA nephropathy AKA Berger disease. Definition?
Glomerulonephritis with predominantly IgA deposits in mesangium in absence of systemic disease.
What is seen on immunofluorescence in IgA nephropathy?
IgA mesangial deposits (100%). Mesangial C3 (90%). Fibrinogen/fibrin usually present in mesangium. Lambda often more prominent than kappa (64%). Mesangial IgG, IgM (50%). Mesangial C1q (10%).
Is Bowman capsule continuous with the glomerular basement membrane?
Yes. Bowman capsule is the layer of basement membrane surrounding Bowman space on which parietal epithelial cells rest; continuous with GBM at base of glomerulus.
Definition of glomerular crescent.
Extracapillary proliferation of >2 cell layers occupying 25% or more of glomerular capsular circumference or >10%. The 3 types of crescents are cellular, fibrocellular, and fibrous.
Define focal, diffuse, segmental, and global for glomerular processes.
Focal: minority of glomeruli (50% in lupus).
What properties do mesangial cells have? What is the definition of mesangial hypercellularity?
Mesangial cells are normal residents of mesangium that have contractile and phagocytic properties. Mesangial hypercellularity: 3 or 4 mesangial nuclei or more in 1 mesangial area in a 3 micron section; lupus classification uses 3; IgA classification uses 4. Mesangial hypercellularity is subdivided into mild (4-5), moderate (6-7), and severe (8 or more).
What is mesangial matrix made of? Define mesangial matrix expansion and mesangiolysis.
Mesangial matrix is the extracellular component of normal mesangium, which includes collagen III, fibronectin, and a variety of glycosaminoglycans. Mesangial matrix expansion is defined as width of mesangial interspace exceeding 2 mesangial cell nuclei in at least 2 glomerular lobules (IgA). Mesangiolysis is defined as loss of integrity of the mesangium so that glomerular capillary forms aneurysmal dilation.
For bone tumors, metastases are far more common than primary bone tumors in a ratio of __:1. The 5 most common primary sites are ___.
For bone tumors, metastases are far more common than primary bone tumors in a ratio of 25:1. The 5 most common primary sites are lung, breast, prostate, kidney, and thyroid. After lungs and liver, skeleton is 3rd most frequent site of metastatic disease.
The effect of PTH on renal tubules causes (increased/decreased) calciium reabsorption and (increased/decreased) phosphate excretion.
The effect of PTH on renal tubules causes increased calciium reabsorption and increased phosphate excretion.
Primary hyperparathyroidism is characterized by increased calcium, decreased phosphate, increased chloride, and increased nephrogenous cAMP. The decreased phosphate is in contrast to many other forms of hypercalcemia, which often have increased phosphate. Why does this occur?
This is because PTH has a dual effect on renal tubules, where there is increased calciium reabsorption and increased phosphate excretion.
A (decreased/increased) nephrogenous cAMP in the presence of (decreased/normal/increased) PTH is highly suggestive of humoral hypercalcemia of malignancy.
An increased nephrogenous cAMP in the presence of normal PTH is highly suggestive of humoral hypercalcemia of malignancy.
PTH and vitamin D. How do they differ in increasing/decreasing calcium and phosphate excretion/absorption by the kidneys?
PTH causes increased calcium reabsorption and increased phosphate excretion. Vitamin D causes increased calcium reabsorption and increased phosphate reabsorption.
There are three major mechanisms by which hypercalcemia of malignancy can occur: osteolytic metastases with local release of cytokines (including osteoclast activating factors); tumor secretion of parathyroid hormone-related protein (PTHrP) (humoral hypercalcemia); and tumor production of 1,25-dihydroxyvitamin D (calcitriol). Additionally, some tumors cause ectopic secretion of PTH. List some malignancies that cause each of the three main types.
Osteolytic metastases: breast cancer, multiple myeloma, lymphoma, leukemia. Humoral hypercalcemia (PTHrP): squamous cell carcinoma, RCC, breast cancer, bladder carcinoma, ovarian carcinoma, non-Hodgkin lymphoma, CML, leukemia, lymphoma. Tumor production of calcitriol: lymphoma (Hodgkin, non-Hodgkin, lymphomatosis/granulomatosis), ovarian dysgerminoma.
What is the correction for ionized calcium level in the setting of hypo/hyperalbuminemia?
The equation used to measure corrected calcium in cases of hypo/hyperalbuminemia is: Corrected (Ca) = Measured total (Ca) + (0.8 x [4.5 - (alb)]). Or, 0.8 mg/dL Ca per 1g/dL protein. While this formula often provides a good estimate of the ionized calcium, its use should be avoided in patients with acid-base disturbances, renal insufficiency, liver disease, and neonates.
What are causes of hypercalcemia?
PTH-mediated: primary hyperparathyroidism, familial (MEN-I and -IIa, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcemia), tertiary hyperparathyroidism. PTH-independent: hypercalcemia of malignancy, vitamin D intoxication, chronic granulomatous disorders, medications (thiazide diuretics, lithium, teriparatide, theophylline toxicity, excessive vitamin A), miscellaneous (hyperthyroidism, acromegaly, pheochromocytoma, adrenal insufficiency, immobilization, parenteral nutrition, milk-alkali syndrome).
What are causes of secondary hyperparathyroidism?
Renal failure (impaired calcitriol production, hyperphosphatemia). Decreased calcium intake. Calcium malabsorption (vitamin D deficiency, bariatric surgery, celiac disease, pancreatic disease (fat malabsorption)). Renal calcium loss (idiopathic hypercalciuria, loop diuretics). Inhibiton of bone resorption (bisphosphonates, hungry bone syndrome).
What are causes of hypocalcemia?
Low PTH (hypoparathyroidism): genetic disorders, post-surgical (thyroidectomy, parathyroidectomy, radical neck dissection), autoimmune, infiltration of the parathyroid gland (granulomatous, iron overload, metastases), radiation-induced destruction of parathyroid glands, hungry bone syndrome, HIV infection. High PTH (secondary hyperparathyroidism in response to hypocalcemia): vitamin D deficiency or resistance, parathyroid hormone resistance, renal disease, loss of calcium from the circulation (hyperphosphatemia, tumor lysis, acute pancreatitis, osteoblastic metastases, acute respiratory alkalosis, sepsis or acute severe illness. Drugs. Disorders of magnesium metabolism.
Renal medullary carcinoma. Rarity? Ages? More common in which kidney? Races? Associated with what conditions? Postulated pathogenesis?
Renal medullary carcinoma is very rare, with less than 100 reported cases. Age range 5 – 39 yo, average age 21 – 24 yo. Much more common in the right kidney than the left. Occurs predominantly in males (>75% of cases) and almost exclusively in African-Americans due to its relationship with sickle cell trait. Almost all reported cases have occurred in the setting of sickle cell trait or sickle cell disease. Most patients have sickle cell trait with Hemoglobin-AS (Hb-AS), however cases have been reported in patients with hemoglobin SC disease (Hb-SC) and sickle cell disease (Hb-SS). In fact, chronic medullary hypoxia due to hemoglobinopathy with subsequent chronic regenerative proliferation of the damaged epithelium has been implicated in the pathogenesis of renal medullary carcinoma.
Renal medullary carcinoma, collecting duct carcinoma, and urothelial carcinoma. INI1 expression?
Renal medullary carcinoma shows loss of INI1, while the other two retain INI1 expression.
Metabolic acidosis can be categorized by presence or absence of anion gap. List causes from each category.
With increased AG (>12): ketoacidosis (diabetic, starvation, EtOH-associated), lactic acidosis, D-lactic acidosis, ingestions (methanol, ethylene glycol, diethylene glycol, propylene glycol, salicylate, toluene (if early or if kidney function is impaired)), pyroglutamic acid (5-oxoproline), CKD/uremia. With normal AG (<12): diarrhea or other intestinal losses, ureteral diversion, ketoacidosis posttreatment, carbonic anhydrase inhibitors, type 1 (distal) RTA, type 2 (proximal) RTA, type 4 RTA (hypoaldosteronism), toluene ingestion (if late and if renal function is preserved - dut to excretion of sodium and potassium hippurate in the urine), CKD and tubular dysfunction (but relatively preserved GFR).
How can toluene ingestion cause metabolic acidosis with increased anion gap in some cases and metabolic acidosis with normal anion gap in other cases?
Toluene ingestion causes increased AG if early after ingestion or if kidney function is impaired. It causes normal AG if late after ingestion and if renal function is preserved - due to excretion of sodium and potassium hippurate in the urine.
Elevated plasma osmolal gap can be seen with or without metabolic acidosis. List causes of each category.
With anion gap metabolic acidosis: ingestion (ethylene glycol, methanol, formaldehyde, paraldehyde); lactic acidosis; diabetic ketoacidosis; alcoholic ketoacidosis; end-stage CKD (GFR <10 mL/min) without regular dialysis. Without metabolic acidosis: ingestion (ethanol, isopropyl alcohol, diethyl ether); infusion of nonconductive glycine, sorbitol, or mannitol solutions; severe hyperproteinemia; severe hyperlipidemia.
Metabolic alkalosis can be categorized by chloride responsive (U Cl 10). List causes of each.
Chloride responsive: diuretic therapy, vomiting, NGT suction, villous adenoma, carbenicillin, contraction alkalosis. Chloride resistant: hyperaldosteronism, Cushing syndrome, exogenous steroids, licorice (glyccrhizic acid), Bartter syndrome, milk-alkali syndrome.
What hormones does the kidney produce?
It secretes hormones that participate in the regulation of systemic and renal hemodynamics (renin, prostaglandins, and bradykinin), red blood cell production (erythropoietin), and calcium, phosphorus, and bone metabolism (1,25-dihydroxyvitamin D3 or calcitriol).
Does BUN underestimate or overestimate GFR?
Urea is freely filtered and partially reabsorbed by the nephron; this reabsorption has the consequence that BUN always slightly underestimates GFR.
Urea is freely filtered and partially reabsorbed by the nephron; this reabsorption has the consequence that BUN always slightly underestimates GFR. What happens in hypovolemia?
Reabsorption increases with hypovolemia; thus BUN underestimates GFR even more in hypovolemic states.
How is creatinine measured?
The creatinine concentration was classically determined, and is still often determined, by the Jaffe reaction - alkaline picrate forms a colored complex with creatinine. Alternative enzymatic (using creatinase) and colorimetric assays are available.
What is creatinine? How does the kidney handle it? Does it underestimate or overestimate GFR?
Creatinine is derived from the metabolism of creatine in skeletal muscle and from dietary meat intake. It is released into the circulation at a relatively constant rate. Creatinine is freely filtered across the glomerulus and is neither reabsorbed nor metabolized by the kidney. However, approximately 10 to 40 percent of urinary creatinine is derived from tubular secretion by the organic cation secretory pathways in the proximal tubule, with the quantity secreted increasing with increasing serum creatinine concentration. At all serum concentrations, creatinine slightly overestimates GFR.
BUN and Cr. Do they underestimate or overestimate GFR?
BUN underestimates GFR. Cr overestimates GFR.
What are the 5 histologic variants of FSGS?
Classic/NOS. Collapsing. Cellular. Perihilar. Tip (AKA glomerular tip lesion).
The 5 histologic variants of FSGS are classic/NOS, collapsing, cellular, perihilar, and tip (AKA glomerular tip lesion). Which type has the best prognosis and which the worst?
The strongest prognostic indicator of outcome is the initial response to therapy regardless of the type of histology. However, some do report an association between histologic variant and prognosis: The collapsing variant has the highest rate of progression to ESRD, while the tip variant has the lowest rate of progression to ESRD.
The simplest way to calculate GFR is based on creatinine clearance. What is the equation?
ClCr = UCr x VUr / PCr. Where UCr is urine creatinine in mg/dL, VUr is volume of urine in mL/24 hrs, and PCr is plasma creatinine in mg/dL. But this formula is overly simplistic and the MDRD study equation is the most widely recommended formula now.
The simplest way to calculate GFR is based on creatinine clearance: ClCr = UCr x VUr / PCr. But what 2 factors weaken the suitability of this formula for clinical use?
Nonlinearity and nonglomerular influences upon creatinine. Nonlinearity: The inverse relationship between GFR and Cr is nonlinear. Mild to moderate degrees of GFR impairment do not cause appreciable increases in Cr concentration; only when GFR is about half of normal does creatinine rise precipitously and begin to linearly reflect changes in GFR. Nonglomerular influences upon creatinine: The serum Cr concentration is increased by muscle mass/activity/injury and protein intake; it is decreased by age; it is influences by race, age, sex, and numerous medications.
The Modification of Diet in Renal Disease Study equation is the most widely recommended formula for calculating eGFR. In what populations has it been studied and validated? What patient variables do you need to know?
The MDRD equation has been studied and validated in adult Caucasian and African American populations with impaired kidney function (GFR
The Modification of Diet in Renal Disease Study equation is the most widely recommended formula for calculating eGFR. How many variations of the equation are there?
4, based on if the lab reports serum Cr in mg/dL (conventional units) or umol/L (SI units), and whether the lab uses a Cr assay that has been (traceable) or has not been (original (non-traceable)) calibrated to be traceable to an isotope dilution mass spectometry (IDMS) method.
The result given by the Modification of Diet in Renal Disease Study equation is multiplied by 0.742 if the patient is ___ and by 1.210 is the patient is ___.
The result given by the Modification of Diet in Renal Disease Study equation is multiplied by 0.742 if the patient is female and by 1.210 is the patient is African American.
What units is eGFR given in?
mL/min/1.73m^2.
What is a normal BUN/Cr ratio? What does it suggest when BUN and Cr are elevated but the ratio is maintained? when the ratio is elevated? when the ratio is decreased?
When BUN and Cr are elevated but the ratio is maintained, it is suggestive of intra-renal disease (GN and TIN) - renal azotemia. When the ratio is elevated, is suggests prerenal azotemia (poor renal perfusion) or postrenal azotemia (renal obstruction). A decreased BUN/Cr is rare and may result from dietary protein insufficiency or severe liver disease.
What is cystatin C and how is it handled by the kidney?
Cystatin C is a cysteine protease inhibitor produced by nearly all cells in the body that is freely filtered by the glomerulus, not reabsorbed, and is metabolized by the proximal tubular epithelium.
Normal proteinuria does not exceed ___ mg/day and consists mainly of ___ and ___.
Normal proteinuria does not exceed 150 mg/day and consists mainly of Tamm-Horsfall protein and minute amounts of albumin.
The urine protein assay is sensitive to all kinds of protein (albumin, globulins, Bence-Jones), and its lower limit of detection is about ___ mg/dL.
The urine protein assay is sensitive to all kinds of protein (albumin, globulins, Bence-Jones), and its lower limit of detection is about 3 mg/dL.
The urine dipstick test is most sensitive to albumin (but not enough to detect microalbuminuria); it is not sensitive to globulins or even to very high levels of Bence-Jones protein. The lower limit of detection of the urine dipstick test for albumin is ___ mg/dL.
The urine dipstick test is most sensitive to albumin (but not enough to detect microalbuminuria); it is not sensitive to globulins or even to very high levels of Bence-Jones protein. The lower limit of detection of the urine dipstick test for albumin is 18 mg/dL.
What are the lower limits of detection of: the urine protein assay for protein, the urine dipstick test for albumin, and the microalbumin assay for albumin?
3 mg/dL, 18 mg/dL, and 0.3 mg/dL, respectively.
What units are the albumin:creatinine ratio and the protein:creatinine ratio reported in?
The albumin:creatinine ratio is reported in mg/g, and the protein:creatinine ratio is reported in mg/mg.
What 2 main entities are in the DDx of a high urine protein concentration with a negative microalbumin assay?
Bence-Jones protein and hook effect (a false negative result with certain immunoassays due to very high concentrations of a particular analyte).
The presence of beta-2-microglobulin and lysozyme in urine suggests what type of kidney dysfunction?
Tubular dysfunction, since these proteins are freely filtered by the glomerulus then completely reabsorbed by the normally functioning proximal convoluted tubule.
How is chronic kidney disease defined?
CKD is defined as the presence of kidney damage (usually detected as urinary albumin excretion of ≥30 mg/day, or equivalent) OR decreased kidney function (defined as eGFR <60 mL/min per 1.73 m^2) for three or more months, irrespective of the cause. The persistence of the damage or decreased function for at least three months is necessary to distinguish CKD from acute kidney disease/injury.
How is chronic kidney disease staged?
The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines stage according to: cause of disease, 6 categories of eGFR (G stages), and 3 categories of albuminuria (A stages).
How do prerenal ARF and renal ARF compare with the following parameters: BUN/Cr ratio, urine specific gravity, urine osmolarity, FENa, FE urea?
Prerenal: >20:1, high (>1.020), high (>500 mmol/kg), 2%, >35%.
Acute kidney injury can be classified into what 3 general categories?
Prerenal - As an adaptive response to severe volume depletion and hypotension, with structurally intact nephrons. Renal/Intrinsic - In response to cytotoxic, ischemic, or inflammatory insults to the kidney, with structural and functional damage. Postrenal - From obstruction to the passage of urine. While this classification is useful in establishing a differential diagnosis, many pathophysiologic features are shared among the different categories.
The most common cause of renal/intrinsic acute kidney injury is ___, the most common causes of which are ___ and ___.
The most common cause of renal/intrinsic acute kidney injury is ATN, the most common causes of which are ischemia and nephrotoxins.
The FENa is almost always low (<1%) in prerenal ARF, the exception being when the patient has been given diuretics or has glycosuria. What can be measured in place of FENa in these patients?
In these patients, fractional excretion of urea can be a useful alternative.
In renal failure, what features on urinalysis can suggest prerenal ARF, GN, ATN, and TIN?
Prerenal ARF: A lack of findings or isolated hyaline casts. GN: Dysmorphic RBCs and RBC casts. ATN: Pigmented casts. TIN: Leukocytes (in the absence of infection - sterile pyuria), WBC casts, and/or eosinophils.
What is hepatorenal syndrome?
HRS is one of many potential causes of AKI in patients with acute or chronic liver disease. Affected patients usually have portal hypertension due to cirrhosis, severe alcoholic hepatitis, or (less often) metastatic tumors, but can also have fulminant hepatic failure from any cause. The HRS represents the end-stage of a sequence of reductions in renal perfusion induced by increasingly severe hepatic injury. It is a diagnosis of exclusion and is associated with a poor prognosis.
What is the most common cause of renal failure in the cirrhotic patient?
Spontaneous bacterial peritonitis.
Hepatorenal syndrome is the development of progressive renal impairment in patients with severe end-stage liver disease in the absence of another identifiable cause of renal disease. What is seen on renal biopsy?
The renal biopsy is essentially normal in HRS, but an abnormal bx must be interpreted cautiously - many patients with cirrhosis due to hepatitis viruses have an associated GN, and cirrhosis can by itself lead to an IgA-like nephropathy.
What is the pathogenesis of hepatorenal syndrome?
Arterial vasodilatation in the splanchnic circulation, which is triggered by portal hypertension, appears to play a central role in the hemodynamic changes and the decline in renal function in cirrhosis. The presumed mechanism is increased production or activity of vasodilators, mainly in the splanchnic circulation, with nitric oxide thought to be most important. As the hepatic disease becomes more severe, there is a progressive rise in cardiac output and fall in systemic vascular resistance; the latter change occurs despite local increases in renal and femoral vascular resistance that result in part from hypotension-induced activation of the renin-angiotensin and sympathetic nervous systems. Thus, the reduction in total vascular resistance results from decreased vascular resistance in the splanchnic circulation. The decline in renal perfusion in this setting is associated with reductions in GFR and sodium excretion and a fall in mean arterial pressure, despite the intense renal vasoconstriction.
Lymphomatoid granulomatosis most commonly presents as multiple pulmonary nodules. What are other common sites of involvement?
Brain, kidney, liver, and skin.
Ethylene glycol is metabolized to what 3 metabolites by the action of alcohol dehydrogenase and aldehyde dehydrogenase? What do these metabolites cause?
Ethylene glycol is metabolized to glycolate, glyoxylate, and oxalate. The parent alcohol (ethylene glycol itself) is relatively nontoxic. The glycolate is responsible for the CNS manifestations and for the anion gap acidosis. Oxalate binds calcium to produce calcium oxalate, which is deposited in tissues, with the process often resulting in hypocalcemia. ARF is primarily due to glycolate-induced damage to tubules, although tubule obstruction from precipitated oxalate crystals may contribute.
Lead enters the body through inhalation and ingestion. About __% of ingested lead is distributed in erythrocytes and bone.
Lead enters the body through inhalation and ingestion. About 95% of ingested lead is distributed in erythrocytes and bone. Some also goes to the kidney where it is toxic to renal tubular cells.
What renal manifestations occur following long term lead toxicity?
Mitochondrial toxicity leads to reduced ATP available to drive the numerous ATP-dependent channels involved in renal tubular epithelial function. Then end-result is aminoaciduria, glycosuria, and phosphaturia (similar to Fanconi renal syndrome). Leads inclusions are detectable ultrastructurally as highly electron-dense founded intracellular bodies.
List diseases associated with colonic pseudomembrane formation.
Amoebic colitis. Antibiotic-associated (pseudomembranous) colitis. Chemotherapy-induced colitis. Colitis complicating obstruction. Heavy metal toxicity (gold salt therapy). Hemolytic uremic syndrome. Ischemic colitis. Neutropenic enterocolitis (typhilitis). Shigellosis.
Goodpasture disease refers to the triad of ___, ___, and ___.
Goodpasture disease refers to the triad of pulmonary (alveolar) hemorrhage, glomerulonephritis of any severity, and serum anti-GBM production. The treatment of choice is plasmapheresis.
Goodpasture disease refers to the triad of pulmonary (alveolar) hemorrhage, glomerulonephritis of any severity, and serum anti-GBM production. What are these circulating antibodies directed against?
The NC1 domain of collagen IV in glomerular and alveolar basement membranes.
What 3 major categories of small vessel vasculitis can cause the pulmonary-renal syndrome?
Anti-GBM disease, ANCA disease, and immune complex-mediated diseases (such as SLE).
What is pulmonary-renal syndrome? What are causes of it?
The combination of acute glomerulonephritis and pulmonary hemorrhage. Causes: ANCA-positive vasculitis (granulomatosis with polyangiitis/Wegener’s, microscopic polyangiitis). Anti-GBM disease (Goodpasture’s). Pulmonary hemorrhage is a rare finding in lupus, HSP (IgAV), and infective endocarditis. Acute glomerulonephritis complicated by pulmonary edema due to fluid overload, as can occur in poststreptococcal glomerulonephritis.
What histologic changes are seen in renal arterioles in calcineurin inhibitor-induced toxicity?
Calcineurin inhibitors include cyclosporin A and tacrolimus. The afferent arterioles show nodular, PAS-positive, protein (hyaline) deposits deep in the medial smooth muscle layers replacing individual (necrotic) myocytes. Hyaline nodules are often seen in a necklace-like pattern along the adventitial aspect of afferent arterioles. The most serious toxic side effect is a fully developed thrombotic microangiopathy.
What are the 7 classic sickle cell nephropathies?
Gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, isosthenuria, pyelonephritis, renal medullary carcinoma.
Is renal medullary carcinoma seen in sickle cell disease, sickle cell trait, or both?
Both.
Sickle cell trait (SA) is usually asymptomatic, but what symptoms can they potentially manifest/are they at risk for?
They may manifest mild isosthenuria, are at risk for splenic infarcts at high altitudes, and have a risk for renal medullary carcinoma.
Adenoviruses are grouped into over 40 serotypes. Most of the respiratory infections are caused by serotypes __-__, with types __ and __ associated with epidemic outbreaks of respiratory disease. Types __ and __ are associated with hemorrhagic cystitis. Types __ and __ are associated with childhood gastroenteritis.
Adenoviruses are grouped into over 40 serotypes. Most of the respiratory infections are caused by serotypes 1-14, with types 4 and 7 associated with epidemic outbreaks of respiratory disease. Types 11 and 21 are associated with hemorrhagic cystitis. Types 40 and 41 are associated with childhood gastroenteritis.
What is the most toxic form of arsenic?
The gaseous form -arsine gas- is the most toxic form of arsenic, capable of producing acute renal failure, hemolysis, and death within 24-48 hrs.
Ingested arsenic is excreted in urine, with most of the remainder distributed into ___, ___, and ___.
Ingested arsenic is excreted in urine, with most of the remainder distributed into skin, nails, and hair.
What is the mechanism of arsenic toxicity, and what are clinical manifestations?
Arsenic inhibits the oxidative production of ATP. Thus, initial toxicity is manifested in dividing tissue such as GI mucosa, with nausea, vomiting, bloody diarrhea, and abdominal pain. The marrow is affected, causing cytopenias (with erythrocyte basophilic stippling similar to that seen in lead toxicity). Chronic toxicity results in peripheral neuropathy, nephropathy, skin hyperpigmentation and hyperkeratosis (particularly palms and soles) and transverse Mees lines in the nails.
Why can mercury toxicity sometimes mimic pheochromocytoma?
Since mercury blocks the degradation pathway of catecholamines (it is suggested to inactivate S-adenosyl-methionine, which is necessary for catecholamine catabolism by catechol-o-methyl transferase), epinephrine excess causes profuse sweating, tachycardia, salivation and elevated blood pressure. There are increased amounts of vanillylmandelic and homovanillic acid in urine.
What are the biochemokinetics of mercury toxicity in its metallic/elemental, inorganic, and organic forms?
Pulmonary absorption of mercury vapor (elemental form) is high; however, this form of mercury is only poorly absorbed from the GI tract and across the skin. The kidney is the major site of deposition for mercury derived from inhalation exposure of mercury vapor. A significant fraction of the mercury vapor taken into the lung is eliminated via exhalation; most of the absorbed mercury is eliminated in the feces. GI absorption of inorganic mercury is on the order of 15 percent. The kidney is the major site of deposition for inorganic mercury compounds. Organic mercury compounds such as methylmercury are highly absorbed from the GI tract and later de-alkylated. The kidney, hair, and CNS are major sites of deposition. Organic mercury readily crosses the placenta, causing severe neurologic impairments in the fetus.
Routine measurements of digoxin concentrations in patients who are stable on therapy is not widely recommended. In what cases may monitoring be indicated, though?
When there is a change in dose, a change in the patient’s renal function, or a change in concomitantly administered medications.
How is digoxin excreted? What is the half-life?
Digoxin is primarily excreted by the kidneys and has a long half-life of around 36 hours.
Digoxin-Like Immunoreactive Substances (DLIS) / Endogenous Digoxin-Like Substances (EDLS) are endogenous or exogenous substances that cross-react with antidigoxin antibodies and falsely elevate serum digoxin concentrations, interfering in interpretation of results for therapeutic digoxin monitoring. In what populations/conditions is it seen?
Elevated DLIS concentrations are encountered in patients with volume-expanded conditions such as uremia, essential hypertension, liver disease, and preeclampsia. They are also seen in neonates, pregnant women, and renal failure.
How is procainamide cleared? What is it metabolized to, and how is the metabolite cleared?
Procainamide is cleared predominantly by the liver. Procainamide is metabolized by hepatic acetyltransferase to N-acetylprocainamide (NAPA), which has pharmacologic activity of its own (in making dosing decisions, the sum of procainamide and NAPA is considered). NAPA is cleared predominantly by the kidneys.
What genetic factor determines the rate of procainamide metabolism?
Pocainamide (hepatic clearance) is metabolized to N-acetylprocainamide (NAPA) (renal clearance), which is also biologically active. The rate of conversion to NAPA is determined by the concentration of hepatic acetyltransferase, which is genetically determined. So-called fast acetylators, who have genetically high levels of acetyltransferase, have higher levels of NAPA.
How are aminoglycosides cleared from the body?
Mainly by the kidneys.
Is calcineurin inhibitor-induced toxicity seen in arteries or arterioles?
Arterioles.
What is the histologic appearance of transplant endarteritis? What is the treatment for it?
Transplant endarteritis shows infiltration of lymphocytes through an activated endothelial cell layer into the subendothelial compartment/intima. The media of the vessels is unaltered. Transplant endarteritis is a common type of acute allograft rejection. Patients usually do not benefit from conventional anti-rejection therapy with bolus steroids, but rather require potent treatment with anti-lymphocytic preparations (ATG or OKT3).
What is the definition of sclerosing transplant vasculopathy (“chronic vascular rejection”)?
A rejection-induced arterial intimal thickening due to de novo deposition of collagens I and III without associated intimal elastosis. During intimal remodeling, myofibroblasts may occasionally form a new rudimentary media under the endothelial layer; Such a (so-called) neo-media formation is almost pathognomonic for “chronic vascular rejection.”
Is the most common cause of the pulmonary-renal vasculitic syndrome ANCA disease or anti-GBM disease?
ANCA disease accounts for ~55% of cases, anti-GBM for 7%, and both ANCA and anti-GBM present in 8% of cases.
Into what 5 morphologic forms is fibromuscular dysplasia classified, and what are their frequencies?
Intimal fibroplasia - <1%. There are 3 types of medial dysplasia: Medial fibroplasia - 75-80%. Perimedial fibroplasia - 10-15%. Medial hyperplasia - 1-2%.
The 3 major ANCA-associated, necrotizing small vessel vasculitides not associated with the deposition of immune complex deposits are Wegener’s granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. How are these 3 differentiated?
Clinical features. Patient’s lacking signs of asthma, lung and sinus inflammation, or peripheral blood eosinophilia are best classified as having microscopic polyangiitis. Necrotizing inflammatory lesions involving the lungs, nasal sinuses and kidneys are typically seen in cases of Wegener’s granulomatosis. Peripheral blood eosinophilia and asthma are defining features of Churg-Strauss syndrome.
The morphologic changes of calcineurin inhibitor-induced toxicity are almost exclusively seen in what organ?
The kidney (either native or transplanted).
The polyoma viruses JC virus and BK virus are typically acquired in childhood and enter latency. If immunosuppression occurs, viral reactivation may lead to progressive multifocal leukoencephalopathy due to JC virus or hemorrhagic cystitis due to BK virus. What cells show viral inclusions in each entitiy?
Urothelial cells with BK virus. Oligodendroglial cells with JC virus.
What are some extrahepatic manifestations of HCV infection?
Hematologic diseases such as essential mixed cryoglobulinemia, lymphoma, and aplastic anemia. Renal disease, particularly membranoproliferative glomerulonephritis. Autoimmune disorders such as thyroiditis and the presence of autoantibodies. Dermatologic conditions such as porphyria cutanea tarda and lichen planus. Diabetes mellitus.
What family of viruses in the hemorrhagic fever virus category causes the so-called hemorrhagic fever with renal syndrome (acute tubular necrosis)?
Bunyaviruses, and specifically, the hantaviruses.
What are some secondary causes of a predominant hypercholesterolemia?
Hypothyroidism, DM, nephrotic syndrome, cholestasis, cyclosporine, thiazide diuretics, or loop diuretics.
What are some secondary causes of a predominant hypertriglyceridemia?
Heavy alcohol consumption, obesity, DM, hepatitis, pregnancy, renal failure, beta blockers, isotretinion, corticosteroids, nephrotic syndrome, and gout.
What are some secondary causes of a mixed hypertriglyceridemia and hypercholesterolemia?
Severe examples of DM, hypothyroidism, or nephrotic syndrome. Also, type III hyperlipidemia, thiazides, loop diuretics, and beta blockers.
How is C-peptide cleared?
Kidneys. Therefore, C-peptide is raised in renal impairment.
What specific complement components are low in the following diseases: lupus, membranoproliferative glomerulonephritis, terminal complement deficiency, properdin deficiency, C1-inhibitor deficiency/hereditary angioedema?
SLE causes low C3 and C4. MPGN causes low C3, but normal C4. Terminal complement deficiency is an inherited autosomal co-dominant condition with low C5, C6, C7, C8, C9 levels that causes susceptibility to infections by Neisseria. Properdin deficiency is an X-linked disorder that also causes susceptibility to neisserial infections. C1-inhibitor deficiency/hereditary angioedema will have low C4 with normal C1 and C3 levels.
What are the 2 main types of immunofluorescence tests for autoantibodies, and how are they performed?
Direct immunofluorescence (DIF) involves incubating cryostat sections of patient tissue with fluorescein-labeled AHG. Positive DIF tests confirm the in vivo presence of bound autoantibodies in the patient’s tissues. Examples include skin IF and renal IF. Indirect immunofluorescence (IIF) involves incubating patient serum with cells/tissue known to contain specific antigens, then adding fluorescein-labeled AHG. Positive IIF tests confirm the presence of circulating autoantibodies.
What is the clinical utility of anti-SS-A and anti-SS-B antibodies?
SS-A (Ro) is present in 70% of patients with Sjogren syndrome and 30% of patients with SLE. SS-B (La) is present in 50% of patients with Sjogren syndrome and 15% of patients with SLE. Anti-SS-A/SS-B are found in children with neonatal lupus. Patients who are ANA+, SS-A+ but SS-B neg are very likely to have lupus nephpritis.
What is the clinical utility of anti-GBM antibodies?
Goodpasture syndrome; the epitope is the M2 subunit of type IV collagen.
What are the 4 (plus one) types of hypersensvitiity reactions, their mediators, and associated diseases?
Type I (allergic, immediate-type): IgE; atopy, asthma, anaphylaxis. Type II (antibody-dependent, cytotoxic, antibody-mediated cellular cytotoxicity): IgM or IgG, complement, MAC; Goodpasture syndrome, autoimmune hemolytic anemia, erythroblastosis fetalis, rheumatic heart disease (also Graves disease and myasthenia gravis, but some classify these as type V). Type III (immune complex): IgG, complement, neutrophils; SLE, serum sickness, Arthus reaction, PSGN. Type IV (delayed-type, cell-mediated immune memory response, antibody-independent): T cells; tuberculin skin test, contact dermatitis, MS. Type V (an additional subtype sometimes used as a distinction from type II) (receptor mediated autoimmune disease): IgM or IgG, complement; Graves disease, myasthenia gravis.
Scleroderma (progressive systemic sclerosis) is associated with obliterative vasculopathy, dermal sclerosis, epidermal atrophy, tenosynovitis, esophageal sclerosis, interstitial lung disease, pulmonary hypertension, telangiectasia, calcinosis, and renal hypertension. What auto-antibodies are associated with scleroderma, and how are they detected?
ANA, anti-nucleolar, anti-Scl-70 (anti-topoisomeraseI). IIF on C. luciliae or HEp-2 cells; ELISA.
Wilms’ tumor/nephroblastoma is a triphasic neoplasm with variable amounts of blastema, epithelial, and stromal components. Describe each component.
Blastema is present in almost all Wilms’ tumors and is characterized by small blue cells with fine chromatin, inconspicuous nucleoli and very scanty cytoplasm. Occasionally, the blastema cells may form rosettes, which may suggest an erroneous diagnosis of neuroblastoma. The cells in the epithelial component are larger and have more abundant cytoplasm than blastema cells. They can form nests, glands, tubules, and glomeruloid bodies. Stroma is present in only one-third of cases and appears as metachromatic, myxoid material with spindle cells. Uncommonly, stromal elements such as muscle, fat, bone, or cartilage may be present.
The hybrid oncocytic chromophobe tumor in the kidney is an indolent tumor that occurs in what 3 settings?
Birt-Hogg-Dube syndrome, renal oncocytosis, and as a sporadic neoplasm.
What immunostains are renal oncocytomas positive for?
CD136 in 100%. S100 in 93%. CK8 in 92%. PAX-8 in 91%. CD117 in 90%. Parvalbumin in 79%. CK18 in 77%. EMA/MUC1 in 74%. PAX-2 in 62%. Vimentin in 56%.
What is the CK7 and CK20 staining for urothelial carcinomas?
CK7+ and CK20+/-. 92% are CK7 positive, and 63% are CK20 positive.
Angiomyolipoma is a member of the PEComa family. What IHC staining pattern does it show?
CD31 in 100%, HMB-45 in 95%, SMA in 88%, melan-A in 86%, mart-1 in 75%, vimentin in 69%, MITF in 65%, desmin in 55%, tyrosinase in 31%, S100 in 29%, panCK in 0%.
Patterns include of nephrogenic rests include intralobar (randomly distributed throughout cortex and medulla with irregular margins, more stroma than blastema or tubules) and perilobar (peripheral with sharply demarcated margins, composed of blastema and tubules with scanty or sclerotic stroma, often solitary). What are intralobar rests associated with? What are perilobar rests associated with?
Intralobar rests have an increased rate of progression to Wilm tumor, and are more commonly associated with WT1 mutations, Denys-Drash syndrome and WAGR syndrome. Perilobar rests are seen in sporadic tumors and are associated with idiopathic hemihypertrophy and Beckwith-Wiedemann syndrome.
What is the primary (immotile) cilium?
The primary cilium is an antenna-like, nonmotile structure that extends from the surface of most mammalian cell types and is critical for chemosensing and mechanosensing in a variety of tissues including cartilage, bone, and kidney.
How are motile and immotile (primary) cilia structurally different?
Microtubular axoneme organization in motile cilia follows a 9+2 assembly, where 9 doublets of microtubules surround a central pair; this arrangement allows specific movement patterns that can lead fluids toward a single direction in vivo by the interacting sliding of the different constitutive parts of doublets. Immotile cilia lack the microtubule central pair, thus cannot be motile.
85-90% of autosomal dominant polycystic kidney disease is due to mutations in the ___ gene on 16p13.3, while 10-15% are due to mutations in the ___ gene on 4q22.
85-90% of autosomal dominant polycystic kidney disease is due to mutations in the PKD1 gene on 16p13.3, while 10-15% are due to mutations in the PKD2 gene on 4q22.
Autosomal recessive polycystic kidney disease is due to mutations in the ___ gene.
Autosomal recessive polycystic kidney disease is due to mutations in the PKHD1 gene. The high phenotypic variability of this disease is due to alternative splicing of 86 exons assembling a variable number of transcripts with the longest being fibrocystin/polyductin.
85-90% of autosomal dominant polycystic kidney disease is due to mutations in the PKD1 gene on 16p13.3, while 10-15% are due to mutations in the PKD2 gene on 4q22. What are the protein products of each gene?
PKD1 gene –> polycystin-1 (PC-1) protein. PKD2 gene –> polycystin-2 (PC-2) protein.
What is renal dysplasia and how is it defined?
Renal dysplasia is an aberrant developmental disease usually diagnosed during the perinatal and childhood years. It is defined as abnormal metanephric differentiation diagnosed histopathologically, which can be diffuse, segmental, or focal. Renal dysplasia may be combined with abnormalities in the collecting system, or associated with complex syndromes.
What are the renal dysplasia-associated syndromes?
Meckel syndrome, VATER association, renal-coloboma syndrome, Herlyn-Werner-Wunderlich syndrome, pruce belly syndrome, branchio-oto-renal dysplasia, renal-hepatic-pancreatic dysplasia, and MEN 2A.
Microscopic features of renal dysplasia?
Renal dysplasia is characterized principally by primitive
ducts with a fibromuscular collar and lobar disorganization. Primitive ducts, which may be cystic, are considered as altered collecting ducts lined by undifferentiated or columnar-to-cuboidal epithelium. The fibromuscular collar is comprised of spindle cells arranged circumferentially around the primitive ducts. Incomplete and abnormal corticomedullary relationships and rudimentary medullary development constitute lobar disorganization. The cysts derived from primitive ducts may be large or small and numerous or scarce, and eventually lead to divergent macroscopic features of multicystic, hypoplastic, or aplastic renal dysplasia. The other pathologic findings include metaplastic cartilage, bone, basement membrane thickening of the primitive ducts, nodular renal blastema, and proliferating nerves.
What entities are in the differential diagnosis of renal dysplasia?
Polycystic kidney disease, fetal kidney, renal hypoplasia, and renal atrophy.
The entities in the differential diagnosis of renal dysplasia are polycystic kidney disease, fetal kidney, renal hypoplasia, and renal atrophy. How can these be distinguished?
The dysplastic kidney contains primitive ducts with or without dilated cysts. The kidney with concomitant multiple cysts and dysplasia is diagnosed as multicystic renal dysplasia, although it grossly resembles polycystic kidney disease. Additionally, these cysts in multicystic renal dysplasia are usually smaller than those in PCKD. The fetal kidney contains poorly differentiated tissues that are compatible with gestational development. The hypoplastic kidney has fewer nephrons than the normal kidney, but no dysplastic elements. The atrophic kidney exhibits segmental loss of parenchyma due to renal scarring, and compensatory hypertrophy in the remnant parenchyma.
2014 ISUP consensus conference on Gleason grading of prostatic carcinoma. What were the major conclusions?
(1) Cribriform glands should be assigned a Gleason pattern 4, regardless of morphology; (2) Glomeruloid glands should be assigned a Gleason pattern 4, regardless of morphology; (3) Grading of mucinous carcinoma of the prostate should be based on its underlying growth pattern rather than grading them all as pattern 4; and (4) Intraductal carcinoma of the prostate without invasive carcinoma should not be assigned a Gleason grade and a comment as to its invariable association with aggressive prostate cancer should be made.
2014 ISUP consensus conference on Gleason grading of prostatic carcinoma. What was the consensus regarding morphologies of Gleason patterns?
(1) Gleason pattern 4 includes cribriform, fused, and poorly formed glands; (2) The term hypernephromatoid cancer should not be used; (3) For a diagnosis of Gleason pattern 4, it needs to be seen at 10x lens magnification; (4) Occasional/seemingly poorly formed or fused glands between well-formed glands is insufficient for a diagnosis of pattern 4; (5) In cases with borderline morphology between Gleason pattern 3 and pattern 4 and crush artifacts, the lower grade should be favored; (6) Branched glands are allowed in Gleason pattern 3; (7) Small solid cylinders represent Gleason pattern 5; (8) Solid medium to large nests with rosette-like spaces should be considered to represent Gleason pattern 5; and (9) Presence of unequivocal comedonecrosis, even if focal is indicative of Gleason pattern 5.
2014 ISUP consensus conference on Gleason grading of prostatic carcinoma. What was the proposed new grading system and terminology (accepted by the WHO for the 2016 edition of Pathology and Genetics: Tumours of the Urinary System and Male Genital Organs)?
Grade Group 1 (Gleason score 6 or less) – Only individual discrete well-formed glands. Grade Group 2 (Gleason score 3+4=7) – Predominantly well-formed
glands with lesser component of poorly-formed/fused/cribriform glands. Grade Group 3 (Gleason score 4+3=7) – Predominantly poorly-formed/
fused/cribriform glands with lesser component of well-formed glands. Grade Group 4 (Gleason score 4+4=8; 3+5=8; 5+3=8) - Only poorly-formed/fused/cribriform glands OR Predominantly well-formed glands and lesser component lacking glands** OR Predominantly lacking glands and lesser component of well-formed
glands**. Grade Group 5 (Gleason scores 9-10) – Lacks gland formation (or with necrosis) with or w/o poorly formed/fused/cribriform glands. *For cases with>95% poorly-formed/fused/cribriform glands or lack of glands on a core or at RP, the component of
What is MUTYH-associated polyposis AKA MYH-associated polyposis AKA MAP?
A condition caused by biallelic pathogenic germline variants in MUTYH characterized by a greatly increased lifetime risk of colorectal cancer (43% to almost 100% in the absence of timely surveillance). Although typically associated with ten to a few hundred colonic adenomatous polyps that are evident at a mean age of about 50 years, colonic cancer develops in some individuals in the absence of polyposis. The colonic phenotype is similar to AFAP but the terminology “FAP/AFAP caused by MYH mutations” is not correct. Extracolonic manifestations include duodenal adenomas/carcinomas, ovarian CA, bladder CA, skin CA.
What is Y-chromosome infertility?
The diagnosis is suspected in otherwise healthy males with abnormal sperm counts ranging from azoospermia to mild oligozoospermia and/or abnormal sperm morphology/motility for whom other causes of infertility have been eliminated. Chromosomal microarray or routine cytogenetic testing reveals chromosome abnormalities in 5%-10% of these men. Molecular testing reveals microdeletions of the long arm of the Y chromosome in another 5%-13% of these males. Pregnancies may be achieved by in vitro fertilization using ICSI (intracytoplasmic sperm injection), but retrieval of sperm has been successful mainly for most males with deletions of AZFc, and rarely for males with deletions of AZFb or AZFa.
Horseshoe kidney has increased risk for what types of tumors?
Wilms’ tumor and neuroendocrine tumors/carcinoids. The relative risk of urothelial carcinoma is increased as well, due to chronic obstruction, stones or infection. However, the incidence of renal cell carcinoma is not increased.
