Surgical Pathology Unknown Conference SPUC : 01/03/14

1. Surgical Pathology Unknown Conference SPUC: 01/03/14

2. CASE 1 13-year-old boy from Saudi Arabia who noted blood in his urine approximately six weeks ago. Had a cystoscopy showing a multifocal tumor on the lateral and posterior aspects of the bladder. A cystoprostatectomy is performed.

8. Digital Slide 1

21. CASE 1 – DIAGNOSIS Urothelial carcinoma, high grade (WHO 3/ 3), papillary type, multifocal, <60% poorly differentiated, with ~20% sarcomatoid features and ~10% signet ring cells, invading full thickness of the muscularis propria, through perivesical adipose tissue and focally present on posterior serosal surface. - Widespread involvement of adjacent mucosa with urothelial carcinoma in situ (see comment) - Lymphovascular invasion, multifocal - Surgical margins with no evidence of malignancy

22. UROTHELIAL CARCINOMA: Lower urinary tract tumors are uncommon in pediatrics. Transitional cell carcinoma of the bladder (TCCB) is rarely found in the first two decades of life and is exceptional under 10 years of age. Since 1950, there are less than 100 cases of urothelial carcinoma reported in patients less than 30 years, and even less in children and adolescents. Most of the small series describe these tumors as being characteristically superficial and low grade (I-ll). 12 Cases: Benson RC Jr, Tomera KM, Kelalis PP. Transitional cell carcinoma of the bladder in children and adolescents. J Urol. 1983 Jul;130(1):54-5. A review of our records between 1950 and 1980 identified 12 patients with transitional cell carcinoma of the bladder who were less than 21 years old. The tumors were low grade and low stage, and were associated with an excellent prognosis. Only 1 patient had a solitary recurrence. This study supports the contention that transitional cell carcinoma of the bladder is a less aggressive disease in patients who are in the first 2 decades of life than in older patients. 6 Cases: LerenaJ, Krauel L, García-Aparicio L, Vallasciani S, Suñol M, Rodó J. Transitional cell carcinoma of the bladder in children and adolescents: Six-case series and review of the literature. Journal of Pediatric Urology 6:5, 481-485, Oct. 2010

23. CASE 2 72 year-old male diagnosed by primary care physician with "abnormal right testis." This was followed by orchiectomy.

24. Testicular Tumor (40x)

25. Spermatic cord (4x)

26. inhibin-alpha (40x)

27. CASE 2 … continuation Three years later a CT scan shows inguinal and retroperitoneal lymph node enlargement, which increased further in size in new CT scan obtained 3 months later.

29. CASE 2 – DIAGNOSIS MALIGNANT LEYDIG CELL TUMOR

30. MALIGNANT LEIDY'S CELL TUMOR: The majority of Leydig cell tumors are found in men, usually at 5–10 years of age or in middle adulthood (30–60 years). Children typically present with precocious puberty. Due to excess testosterone secreted by the tumour, one-third of female patients present with a recent history of progressive masculinization. Masculinization is preceded by anovulation, oligomenorrhea, amenorrhea and defeminization. Additional signs include acne and hirsutism, voice deepening, clitoromegaly, temporal hair recession, and an increase in musculature. Serum testosterone level is high. Immunohistochemical markers of Leydig cell tumors include inhibin-alpha, calretinin, and melan-A For malignant tumors, the surgery may be radical and usually is followed by adjuvant chemotherapy, sometimes by radiation therapy. In all cases, initial treatment is followed by surveillance. Because in many cases Leydig cell tumour does not produce elevated tumour markers,[3] the focus of surveillance is on repeated physical examination and imaging. The prognosis is generally good as the tumour tends to grow slowly and usually is benign. For malignant tumors (10%) with undifferentiated histology, prognosis is poor.

31. CASE 3 21 year-old male with diagnosis of AIDS, on antiretroviral therapy, end-stage renal disease secondary to FSGS, CMV viremia, now presents with sepsis. A debridement of scrotal and perineal lesion is performed for possible necrotizing fasciitis.

32. Digital Slide 3

33. CASE 3 – DIAGNOSIS Skin and subcutaneous tissue, right scrotal area, tumor excision and debridement: - Kaposi sarcoma with moderate necrosis and extensive hemorrhage, present at all surgical margins

34. Kaposi sarcoma: Kaposi sarcoma (KS) is a tumor caused by human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV). Classic KS, affecting middle aged men of Mediterranean descent African endemic KS KS in iatrogenically immunosuppressed patients AIDS-related KS African endemic KS and AIDS-related KS tend to be more aggressive. The AIDS-related KS lesions often rapidly progress to plaques and nodules affecting the upper trunk, face, and oral mucosa. Despite its name, in general it is not considered a true sarcoma, which is a tumor arising from mesenchymal tissue. KS, in fact, arises as a cancer of lymphatic endothelium and forms vascular channels that fill with blood cells, giving the tumor its characteristic bruise-like appearance. KSHV proteins are uniformly detected in KS cancer cells. KS lesions contain tumor cells with a characteristic abnormal elongated shape, called spindle cells. The tumor is highly vascular, containing abnormally dense and irregular blood vessels, which leak red blood cells into the surrounding tissue and give the tumor its dark color. Inflammation around the tumor may produce swelling and pain. Arch Pathol Lab Med—Vol 137, February 2013

35. CASE 4 30-year-old female status post renal and pancreas transplants, admitted with rapidly increased serum creatinine of 3.6 mg/dL (baseline 0.8 mg/dL). Also, abdominal pain and free fluid in abdomen. A renal allograft biopsy is performed.

36. Digital Slide 4A-First Biopsy

37. CASE 4 … continuation Donor-specific antibody (DSA) is negative; she receives total plasma exchange x6, IVIG, Solu-Medrol; also found to have CMV viremia. The pancreas graft has good function. One month later the renal function deteriorates and a new renal graft biopsy is performed.

38. Digital Slide 4B-Second Biopsy

41. CASE 4 – DIAGNOSIS FIRST DIAGNOSIS: Kidney, allograft, needle core biopsy: - Interstitial capillary thrombosis - Mild transplant glomerulitis - Negative for acute rejection SECOND DIAGNOSIS: Kidney, allograft, needle core biopsy: - Thrombotic microangiopathy, severe, with extensive renal necrosis. - No evidence of T-cell mediated or antibody mediated allograft rejection (C4d negative)

42. Thrombotic microangiopathy after kidney transplantation: Thrombotic microangiopathy (TMA) is a severe complication of kidney transplantation that often causes graft failure. TMA may occur de novo, often triggered by immunosuppressive drugs and acute antibody-mediated rejection, or recur in patients with previous history of hemolytic uremic syndrome (HUS). TMA defines a histopathological lesion of vessel wall thickening (mainly arterioles or capillaries), intraluminal platelet thrombosis and obstruction of the vessel lumina. Consumption of platelets and erythrocytes occurs in the microvasculature of kidney, brain and other organs, which causes laboratory features of thrombocytopenia and microangiopathic hemolytic anemia. Depending on whether brain or renal lesions prevail, two clinical entities have been described: the thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome (HUS).

43. Thrombotic microangiopathy after kidney transplantation: Pathology: Typical histologic changes include glomerular and arteriolar thrombosis, intracapillary accumulation of erythrocytes and red cell fragments, endothelial cell swelling and detachment from the basement membrane, glomerular ischemia and, in the healing phase, onion-skin hypertrophy of the arteriolar walls. Inciting events are difficult to distinguish on the basis of biopsy findings. Signs of cyclosporine nephrotoxicity—such as proximal tubular vacuolization and obliterative arteriopathy—can accompany the typical TMA changes. TMA lesion may also be associated with acute antibody-mediated rejection, in this case intraluminal thrombi, C4d staining of peritubular capillaries and circulating donor-specific antibodies are typical. Differential diagnosis between these two entities is difficult because both share the features of impaired renal function, and do not respond to antirejection therapy and affect kidney vessels. However, predominant endarteritis and general involvement of the entire vascular tree of the graft are peculiar findings of acute antibody-mediated rejection. American Journal of Transplantation 10:7, 1517–1523, July 2010

44. The alternative pathway of complement. The alternative pathway is continuously activated in plasma by low-grade hydrolysis of C3. The latter binds factor B. Factor D cleaves factor B to form the alternative pathway initiation C3 convertase that cleaves C3 to C3b. The activation is then amplified by the covalent binding of C3b to hydroxyl groups on cell-surface carbohydrates and proteins of target cells, such as bacterial cells. This C3b binds factor B, to form the amplification loop C3 convertase C3bBb that cleaves many molecules of C3 to form the anaphylatoxin C3a and C3b resulting in a positive feedback amplification loop. C3b also forms the C5 convertase enzyme C3b2Bb that cleaves C5 to C5a and C5b. The latter then initiates the formation of the membrane-attack complex. A number of membrane-anchored and fluid-phase regulators inactivate complement products formed at various levels in the cascade and protect host tissues. CFB, complement factor B; CFI, complement factor I (degrades C3b and C4b); CFH, complement factor H (acts as a cofactor for factor I for C3b cleavage and favors the decay of the C3 convertase); MCP, membrane cofactor protein (binds C3b and has ccofactor activity); CD59, protectin (prevents the terminal polymerization of the membrane attack complex).

45. CASE 5 55-year-old white male with history of diabetes (Hb-A1c = 6.1%) and aortic aneurism with mural thrombus, who presents with proteinuria, hematuria (30-50 RBC/HPF), anemia, weight loss and uremic symptoms, serum creatinine 7.1 mg/dL, BUN 42 mg/dL, hypoalbuminemia of 2.6 gm/dL, elevated serum levels of kappa light chains (17.67 mg/dL) and lambda light chains (14.26 mg/dL); Negative ANCA-P, ABM and ANA. A renal biopsy is performed.

46. Digital Slide 5A-Trichrome Digital Slide 5B-PAS

47. CASE 5 – DIAGNOSIS Kidney, needle core biopsies: Necrotizing and crescentic glomerulonephritis, active and organizing, with moderate interstitial nephritis component.

48. Necrotizing and crescentic glomerulonephritis Crescentic GN is not a specific disease but rather a structural manifestation of severe glomerular inflammation that can be caused by different entities and pathogenic mechanisms. A crescent is defined as two or more layers of cells that are partially or completely filling Bowman's space. The term necrotizing crescentic glomerulonephritis refers to glomerulonephritis associated with crescent formation and the presence of glomerular necrosis. Crescentic glomerulonephritis often correlates with rapidly progressive glomerulonephritis, which is a clinical term designating glomerulonephritis accompanied by a rapid loss of renal function that can lead to end-stage renal failure within days to weeks. Crescentic glomerulonephritis can be seen in three broad categories: anti-glomerular basement membrane (anti-GBM) antibody associated glomerulonephritis, immune complex mediated glomerulonephritis, and pauci-immune crescentic GN. Anders HJ. Diagnosis and Management of Crescentic Glomerulonephritis: State of the Art. Saudi J Kidney Dis Transpl 2000;11:353-61. Available from: http://www.sjkdt.org/text.asp?2000/11/3/353/36657

49. Pauci-immune glomerulonephritis Pauci-immune glomerulonephritis is another common cause of crescentic glomerulonephritis. It stands for the paucity of glomerular immunoglobulin deposits in renal biopsies of patients with RPGN. Apart from rare cases of idiopathic pauci-immune crescentic glomerulonephritis most patients develop pauci-immune RPGN as a manifes­tation of either c- or p-ANCA-associated vasculitis. The pathogenic role of c- and p­ANCA in systemic vasculitis is still unknown, but ANCA are of substantial diagnostic value. Patients with RPGN and ANCA have a 98% specificity for pauci­immune glomerulonephritis and almost all patients with active systemic Wegener`s granulomatosis have a positive ANCA directed against cytoplasmatic proteinase-3. [11] ANCA-associated systemic vasculitis typically affects the small arteries, arterioles, and venules. Clinical signs of c­ANCA-associated systemic small-vessel vasculitis include skin ulcers, neuropathy, and granulomatous lesions of eyes, sinuses, nose, throat, and lungs, known as Wegener`s granulomatosis. [12] P-ANCA, usually directed against cytoplas-matic myeloperoxidase of neutrophils, is associated with a variety of diseases such as microscopic polyangiitis, Churg-Strauss­syndrome, and non-vasculitic rheumatic or gastrointestinal disorders. [13] When ANCA auto-antibody testing is positive, careful investigation for other manifestations of small vessel vasculitis including ENT examination, neural conduction studies, opthalmoscopy, and computed tomography of the lungs is required. In c- or p-ANCA positive patients with RPGN, a renal biopsy is still required to exclude other forms of crescentic GN with concomitant ANCA auto-antibodies. This is particularly important for patients with underlying immune-complex disease, who require a different therapeutic approach.

50. CASE 6 63-year-old male status post cadaveric renal transplant 10 months ago. Baseline serum creatinine 1.3 mg/dL; now up to 2.0 mg/dL. A renal graft biopsy is performed.