Pathways Case Studies: January 2021

January 2021 — Genitourinary

A 67-year-old female developed gross hematuria. Cystoscopy examination showed an abnormal appearing, irritated bladder mucosa. Her past medical history was significant for endometrial carcinoma and she was status-post hysterectomy and radiation therapy. She also had a history of radiation proctitis. Representative microscopic images from a urinary bladder transurethral resection specimen have been depicted.

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What is your diagnosis?

  • Metastatic endometrial carcinoma
  • Squamous cell carcinoma
  • Urothelial carcinoma with squamous differentiation
  • Pseudocarcinomatous urothelial hyperplasia

The correct answer is...

The correct answer is pseudocarcinomatous urothelial hyperplasia.

Histologic sections show superficial fragments with areas of normal appearing mucosa interspersed with areas that exhibit nests of squamoid appearing cells. These epithelioid nests have prominent cytoplasmic eosinophilia imparting "squamoid" appearance with irregular borders. Also noted are hyalinized vessels, fibrin thrombi, and nests of squamoid cells wrapping around these vessels. The background stroma exhibits edema, areas of hemorrhage, and atypical stromal fibroblasts. Although focally these cells exhibit mild-to-moderate atypia, overall, the histologic findings are most consistent with pseudocarcinomatous urothelial hyperplasia secondary to radiation therapy. This is a benign reactive condition that is often seen in the fifth to sixth decade (range: ages 33-85). Patients present with hematuria, and cystoscopy shows polypoid or erythematous lesions. Frequently, this entity is seen in the setting of radiation therapy/chemotherapy. The average time from radiation to the development of radiation cystitis is approximately 55 months; however, a wide time interval has been reported. In cases with no prior therapy, the pathogenesis often is related to chronic ischemia or chronic irritation of the urinary bladder.

The histologic changes may be misinterpreted as squamous cell carcinoma or urothelial carcinoma with squamous differentiation. However, these epithelial changes are usually limited to the submucosa with no deeply infiltrative cells extending to the muscularis propria. Absence of background radiation changes, stromal reaction, and no increase in mitosis also are helpful features to rule out carcinoma. Knowing the characteristic histologic features and clinical history often aids in the diagnosis of this entity.

References
1. Kryvenko ON, Epstein JI. Pseudocarcinomatous urothelial hyperplasia of the bladder: clinical findings and followup of 70 patients. J Urol. 2013;189(6):2083-2086.
2. Lane Z, Epstein JI. Pseudocarcinomatous epithelial hyperplasia in the bladder unassociated with prior irradiation or chemotherapy. Am J Surg Pathol. 2008;32(1):92-97.

Photo of Prasuna Muppa, M.B.B.S. Prasuna Muppa, M.B.B.S.
Fellow, Surgical Pathology
Mayo Clinic
@PM_path
Photo of Sounak Gupta, M.B.B.S., Ph.D Sounak Gupta, M.B.B.S., Ph.D.
Consultant, Anatomic Pathology
Mayo Clinic
Assistant Professor of Pathology
Mayo Clinic College of Medicine and Science
@Shounak_Gupta

January 2021 — Renal

Sixty-year-old white woman with a history of hypertension, who presented with acute kidney injury, hematuria, and proteinuria (1.9 g/day). Serum creatinine is 2 mg/dL. Serum albumin is 3.9 g/dL. No monoclonal protein was detected on serum or urine protein electrophoresis with immunofixation. A kidney biopsy is performed.

Figure 1: Light Microscopy (LM)
Figure 2: Protocol Immunofluorescence (IF)
Figure 3: IgG subclasses Immunofluorescence (IF)
Figure 4: Electron Microscopy (EM)

What is your diagnosis?

  • Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID)
  • Monoclonal immunoglobulin deposition disease (MIDD)
  • Monoclonal immunotactoid glomerulopathy
  • Membranoproliferative glomerulonephritis (MPGN) with masked monoclonal deposits

The correct answer is...

The correct answer is proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID).

This is a classic case of PGNMID, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. Commonly, it presents in older women as new onset nephrotic syndrome. Approximately 30% of these patients have a detectable monoclonal protein, but multiple myeloma is very rare. The remainder, however, have negative urine and serum protein electrophoresis and bone marrow biopsy. Histologically, PGNMID often presents with an MPGN pattern (like in our case). On LM, you can appreciate mesangial proliferation and matrix expansion (occasionally nodular) along with segmental duplication of the glomerular basement membranes (arrow). Endocapillary hypercellularity (circle) can be present. IF shows granular mesangial and glomerular capillary wall staining for IgG (2+), C1q (1+), C3 (3+), and kappa light chain (1+); lambda is negative. IgG subtypes staining is very important to confirm the diagnosis. About two-thirds of cases of PGNMID show IgG3 subclass restriction (Fig 3), as in this case, and one-fourth show IgG1 restriction. EM shows subepithelial (red arrows), mesangial (green arrow), and subendothelial (yellow arrow) electron dense amorphous deposits (i.e., without substructure). Note that the electron density is not homogenous: indeed, these deposits are characteristically described as variegated (possibly due to partial reabsorption).

Treatment of PGNMID is unclear and depends on multiple factors, including the presence or absence of an underlining clonal disorder as well as the severity of the kidney disease. It may include RAS blockade, immunosuppressive agents (i.e. steroids, mycophenolate mofetil etc.), chemotherapeutic drugs targeting B-cells, such as rituximab, or even antimyeloma agents such as bortezomib or thalidomide. Prognosis is also variable, with nearly one-fourth of patients progressing to end-stage renal disease within 2 ½ years, despite treatment.

Immunotactoid glomerulopathy may show monotypic IgG kappa or lambda IF staining; however, EM would show microtubules.

MPGN with masked monoclonal deposits is incorrect, since the deposits stained positive on standard immunofluorescence on frozen tissue.

MIDD is due to deposition of monoclonal immunoglobulins (light or heavy chains, or bothor) within the glomerular basement membrane, mesangium, and tubular basement membrane. In contrast to MIDD, PGNMID is not characterized by extraglomerular deposits.

References
1. Nasr SH et al. Proliferative glomerulonephritis with monoclonal IgG deposits. Jasn 2009.
2. Bridoux F et al. Proliferative glomerulonephritis with monoclonal immunoglobulin deposits: a nephrologist perspective. Nephrol Dial Transplant 2019. ​

Photo of Alessia Buglioni, M.D Alessia Buglioni, M.D.
Resident, Renal Pathology
Mayo Clinic
Assistant Professor of Medicine
Mayo Clinic College of Medicine and Science
Photo of Samih H. Nasr, M.D. Samih Nasr, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science

January 2021 — Bone and Soft Tissue

The patient is a 22-year-old male presented with a 5.5 cm right thigh soft tissue mass. The tumor cells are strongly and diffusely positive for S100, SOX10 and HMB45. AE1/AE3, TLE1, CD31, desmin, SMA, myogenin, and MYOD1 stains are all negative. EWS/ATF1 gene rearrangement was identified in 91% of tumor cells.

What is the most likely diagnosis?

  • Leiomyosarcoma
  • Clear cell sarcoma
  • Malignant peripheral nerve sheath tumor
  • Malignant melanoma

The correct answer is...

The correct answer is clear cell sarcoma.

Clear cell sarcoma shares significant morphologic and immunophenotypic overlap with malignant melanoma (hence the name melanoma of soft parts). However, unlike melanoma, clear cell sarcoma harbors EWS/ATF1 gene rearrangement (in approximately 90% of cases).

References
1. Mavrogenis A, Bianchi G, Stavropoulos N, Papagelopoulos P, Ruggieri P. Clinicopathological features, diagnosis and treatment of clear cell sarcoma/melanoma of soft parts. Hippokratia. 2013 Oct;17(4):298-302. PMID: 25031505. PMID: 25031505.​

Photo of Mohamed Mustafa, M.B.B.S. Mohamed Mustafa, M.B.B.S.
Fellow, Surgical Pathology
Mayo Clinic
Photo of Andrew Folpe, M.D. Andrew Folpe, M.D.
Consultant, Anatomic Pathology
Mayo Clinic
Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science


January 2021 — Gastroenterology

A 75-year-old woman presented with severe abdominal pain, nausea, and gastrointestinal bleeding. Endoscopic ultrasound revealed a 13 cm circumferential, infiltrative mass within the distal body and antrum involving the serosa. A subtotal gastrectomy and omentectomy was performed for palliative purposes.

Figure 1. Histologic sections demonstrate an undifferentiated malignant neoplasm replacing the gastric wall and involving the serosa, with ulceration and extensive necrosis.
Figure 2. The tumor cells show rhabdoid features with abundant eosinophilic cytoplasm and eccentric, vesicular nuclei with prominent nucleoli (A). Increased mitotic activity (A, arrows) and lymphovascular invasion (B) are also present.
Figure 3. Immunohistochemical stains demonstrate BRG1 loss of expression within tumor cells (A). INI1 expression is retained (B).

What is the diagnosis?

  • Large cell neuroendocrine carcinoma
  • Metastatic alveolar rhabdomyosarcoma
  • Poorly differentiated adenocarcinoma, diffuse type
  • Undifferentiated/rhabdoid carcinoma

The correct answer is...

The correct answer is undifferentiated/rhabdoid carcinoma.

Undifferentiated rhabdoid carcinoma of the stomach is a rare entity. The undifferentiated phenotype is thought to be driven by abnormalities in various components of the switch/sucrose-nonfermenting (SWI/SNF) chromatin remodeling complex, that binds to DNA and histones to mobilize nucleosomes to enhance DNA accessibility for transcription, replication, and repair. As a regulator of chromatin structure and DNA transcription, SWI/SNF complex is involved in cell cycle progression and tissue-specific differentiation. At least eight genes encoding core subunits of the SWI/SNF complex have been identified to date, including SMARCB1 (INI1), SMARCA2 (BRM), and SMARCA4 (BRG1). SMARCB1 (INI1) is the most extensively studied. A variety of neoplasms are known to carry inactivating mutations in this gene, including atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system and its peripheral counterparts of the kidney and soft tissue. Moreover, mutations in other subunits of SWI/SNF complex, including BRG1 and BRM, have been identified in many other tumors that now constitute an expanding family known as SMARC-deficient neoplasms. Immunohistochemistry is widely used as a surrogate to recognize the genetic alterations and help diagnose this heterogenous group of tumors.

These tumors show significant variation in age of onset, clinical presentation, and radiographic or gross features. They arise from many organs including brain, lung, kidney, gastrointestinal (GI) tract, pancreas, liver, endometrium, and ovary. A common clinical feature of these tumors appears to be their highly aggressive biological behavior with poor prognosis and short-term survival. Histologically, they tend to be poorly differentiated or undifferentiated and frequently show rhabdoid features, hence the name of undifferentiated/rhabdoid carcinomas..

Undifferentiated/rhabdoid carcinomas with BRG1 loss in the GI tract more frequently affect the colon, followed by the small bowel, stomach, and esophagus. Histologically, they often form solid and diffuse sheets, show anaplastic cytomorphology with occasional pleomorphic tumor giant cells, and frequently display rhabdoid features characterized by abundant eosinophilic cytoplasm and eccentric, vesicular nuclei with prominent nucleoli. High mitotic activity, extensive necrosis, and lymphovascular invasion are common. The tumor cells are generally immunoreactive for pancytokeratin and vimentin, and show variable CK7, CK20, and CDX2 staining. They characteristically show loss of BRG1 and/or BRM by immunohistochemistry. Some tumors may show variable glandular component or areas of transition to adenocarcinoma, suggesting an origin via a dedifferentiation process.

There are ongoing studies for therapeutic interventions of SMARC-deficient tumors, such as PARP inhibitors or PI3K and AKT inhibitors. It is also worth noting that a subset of GI undifferentiated/rhabdoid carcinomas with BRG1 loss show overexpression of PD-L1, high tumor mutation burden and/or loss of mismatch-repair (MMR) proteins. Although further studies are needed, these findings indicate a potential role of immune checkpoint inhibitor therapy in treating the aggressive tumors.

References
1. Kohashi K, Oda Y. Oncogenic roles of SMARCB1/INI1 and its deficient tumors. Cancer Sci. 2017 Apr;108(4):547-552.
2. Matsubara D, Kishaba Y, Ishikawa S, Sakatani T, Oguni S et al. Lung cancer with loss of BRG1/BRM, shows epithelial mesenchymal transition phenotype and distinct histologic and genetic features. Cancer Sci. 2013 Feb;104(2):266-73.
3. Kolin DL, Quick CM, Dong F, Fletcher CDM, Stewart CJR et al. SMARCA4-deficient Uterine Sarcoma and Undifferentiated Endometrial Carcinoma Are Distinct Clinicopathologic Entities. Am J Surg Pathol. 2020 Feb;44(2):263-270.
4. Herpel E, Rieker RJ, Dienemann H, Muley T, Meister M et al. SMARCA4 and SMARCA2 deficiency in non-small cell lung cancer: immunohistochemical survey of 316 consecutive specimens. Ann Diagn Pathol. 2017 Feb;26:47-51.
5. Ramalingam P, Croce S, McCluggage WG. Loss of expression of SMARCA4 (BRG1), SMARCA2 (BRM) and SMARCB1 (INI1) in undifferentiated carcinoma of the endometrium is not uncommon and is not always associated with rhabdoid morphology. Histopathology. 2017 Feb;70(3):359-366.
6. Agaimy A, Daum O, Märkl B, Lichtmannegger I, Michal M, Hartmann A. SWI/SNF Complex-deficient Undifferentiated/Rhabdoid Carcinomas of the Gastrointestinal Tract: A Series of 13 Cases Highlighting Mutually Exclusive Loss of SMARCA4 and SMARCA2 and Frequent Co-inactivation of SMARCB1 and SMARCA2. Am J Surg Pathol. 2016 Apr;40(4):544-53.
7. Horton RK, Ahadi M, Gill AJ, Said S, Chen ZE et al. SMARCA4/SMARCA2-deficient Carcinoma of the Esophagus and Gastroesophageal Junction. Am J Surg Pathol. 2020 Oct 6. doi: 10.1097/PAS.0000000000001599. Epub ahead of print. PMID: 33027072. ​

Photo of Maria (Adelita) Vizcaino Villalobos, M.D. Maria (Adelita) Vizcaino Villalobos, M.D.
Resident, Anatomic Pathology/Neuropathology
Mayo Clinic
@astroade
Photo of Zong-Ming (Eric) Chen, M.D., Ph.D. Zong-Ming (Eric) Chen, M.D., Ph.D.
Senior Associate Consultant, Anatomic Pathology
Mayo Clinic
Associate Professor of Laboratory Medicine and Pathology
Mayo Clinic College of Medicine and Science
MCL Education (@mmledu)

MCL Education

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