—  SPECIALTY CONFERENCE  —

Hematopathology

Case 1 - Anaplastic Large Cell Lymphoma, ALK-1 Positive, Presenting with Retroperitoneal Fibrosis

Megan Lim
University of Michigan
Ann Arbor, MI





Virtual Slides as well as Still Images are displayed below.
For the fastest viewing of virtual slides, click:



under each thumbnail image below. You must have Aperio ImageScope installed on your PC.
If you do not already have Aperio ImageScope, Windows users with administrator privileges may download and install a free version in order to view USCAP Virtual Slides. Click the icon on the right to get your free copy:  
Or, click on slide thumbnail images to view each slide
in a Web-based slide viewer, which is somewhat slower.

If you have any difficulties viewing these slides, email or call George Clay at +1.724.449.1137.



Clinical History
A 29-year-old woman presented with a two month history of early satiety, abdominal discomfort, constipation, and progressive fatigue. She underwent gastrointestinal endoscopy and was found to have grade I varices on upper endoscopy with an unremarkable colonoscopy. Computed tomography (CT) and magnetic resonance imaging (MRI) of the abdomen demonstrated peri-pancreatic edema with a possible pancreatic head mass, and portal vein thrombus. An exploratory laparotomy revealed no definitive mass and the biopsy demonstrated fibroadipose tissue with inflammation and fat necrosis. She was discharged from the hospital after experiencing minimal improvement. Over the ensuing six month period she continued to experience unexplained abdominal pain and progressive jaundice. During her final presentation, she suffered from failure to thrive, worsening abdominal pain, and lower extremity claudication. She failed to respond to steroid therapy. She acutely decompensated, developing bacteremia and multi-system organ failure. The patient expired and an autopsy was performed.


Case 1 - Slide 1
Click to view with ImageScope
Click to view with a Web-Based Viewer



Case 1 - Figure 1
Clusters of neoplastic cells are embedded in areas of dense fibrosis.
Case 1 - Figure 2
The neoplastic cells exhibit perivascular growth pattern within the liver. The cells are pleomorphic with wreath-like nuclei and prominent nucleoli.
Case 1 - Figure 3
Neoplastic cells are CD20 negative.

Case 1 - Figure 4
Neoplastic cells are CD3 negative.
Case 1 - Figure 5
The tumors cells express CD30.
Case 1 - Figure 6
The tumor cells express ALK-1 within the nucleus and cytoplasm.

Introduction:
Retroperitoneal fibrosis (RF) is a fibro-inflammatory condition involving the abdominal aorta, iliac vessels, and ureters. This rare phenomenon, with an incidence of 0.1 cases per 100,000, carries a strong correlation with other autoimmune conditions such as IgG4-related sclerosing disease, sclerosing mesenteritis, sclerosing mediastinitis, primary sclerosing cholangitis, Reidel's thyroiditis, autoimmune pancreatitis, and orbital pseudotumor. Most cases are idiopathic, although as many as one third of cases can be attributed to secondary causes including a variety of malignancies. The case is that of a patient who was diagnosed with idiopathic RF until the time of autopsy when disseminated anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive type, was discovered.

Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
Histologic examination showed marked periaortic fibrosis and yellow plaque-like deposits which were infiltrated by aggregates of large discohesive tumor cells. Many of the cells demonstrated wreath-shaped nuclei with prominent nucleoli. Tumor cells were found in the pericardial and pleural serosal surfaces and also formed a thrombus that occluded the portal vein. There were no spindle shaped cells or a dense plasma cell infiltrate. Tumor cells infiltrated the lung parenchyma as well as the muscularis mucosa of the small and large intestine. Immunohistochemical staining revealed the cells to be negative for S-100, pan-cytokeratin, and hematopoietic markers including those of B-cell lineage (CD20) and T-cell lineage (CD2, 3, 4, 7, 8, 43). The neoplastic cells expressed strong CD30 and ALK-1 but did not express CD25 and were Epstein-Barr virus negative by EBER-1 in situ hybridization. A T-cell receptor gene rearrangement study was performed by polymerase chain reaction using DNA extracted from the lymph node which revealed a clonal T-cell population.

Differential Diagnoses:
A broad category of entities that should be considered based on clinical presentation include; reactive inflammatory lesions such as retroperitoneal fibrosis, sclerosing inflammatory diseases including IgG4-related sclerosing diseases. The morphologic features of the tumor raise differential diagnostic considerations including both hematopoietic and non-hematopoietic neoplasms. These include melanoma, carcinoma (anaplastic variants), extramedullary myeloid tumors, histiocytic neoplasms, Hodgkin lymphoma and non-Hodgkin lymphoma. Among the non- Hodgkin lymphomas, diffuse large B-cell lymphomas with anaplastic features and anaplastic large cell lymphoma (ALK- positive and ALK-negative) should be considered.

Final Diagnosis:
Anaplastic large cell lymphoma, ALK-1 positive, presenting with retroperitoneal fibrosis

Case Discussion:
Retroperitoneal fibrosis (RF) is a fibro-inflammatory condition involving the abdominal aorta, iliac vessels, and ureters. This rare phenomenon, with an incidence of 0.1 cases per 100,000 [1], carries a strong correlation with other autoimmune conditions such as IgG4-related sclerosing disease, sclerosing mesenteritis, sclerosing mediastinitis, primary sclerosing cholangitis, Reidel's thyroiditis, autoimmune pancreatitis, and orbital pseudotumor [2]. Most cases are idiopathic, although as many as one third of cases can be attributed to secondary causes including a variety of malignancies [3]. This patient was diagnosed with idiopathic RF until the time of autopsy when disseminated anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive type, was discovered. To our knowledge, this is the first reported case of ALK-positive ALCL presenting with retroperitoneal fibrosis in the English literature. This case highlights the need for careful and thorough assessment for a malignancy in patients who present with unexplained retroperitoneal fibrosis.

Review of the Literature/Treatment Options (if applicable):
ALK-positive ALCL is characterized by the overexpression of CD30 and harbors a chromosomal translocation resulting in the aberrant expression of a fusion oncoprotein, of which nucleophosmin (NPM)/ALK is the most common. ALK-positive ALCL is the most common subtype of peripheral T-cell lymphoma in children and young adolescents. ALCLs downregulate T cell associated antigens and thus their lineage may need to be assessed by molecular studies as in this case. The morphologic spectrum of ALCL can be broad from small cell, lymphohistiocytic, and giant cell variants. Furthermore, a subset of ALCL expresses abundant extracellular matrix proteins resulting in sclerosis and fibrosis that is induced by Th2 associated cytokines. A number of other tumors express the ALK protein due to a variety of genetic mechanisms. ALK expression is detected in 36-62% of inflammatory myofibroblastic tumors and is due to rearrangement involving TPM3, TPM4 and rarely RANBP2. ALK positive IMTs are more common in younger patients similar to ALCLs. The full length ALK receptor protein normally limited to cells of neuronal origin is expressed in a variety of non-hematopoietic tumors including rhabdomyosarcoma, neuroblastoma, glioblastoma, breast carcinoma and melanomas. In addition, amplification of the ALK gene is also observed in cell lines derived from neuroblastomas. Approximately 5% of non-small cell lung cancers express the EML4-ALK fusion protein although the level of the ALK protein is lower than that observed in ALCLs.

Conclusion(s):
Anaplastic large cell lymphomas exhibit a wide morphologic spectrum. The diagnosis of ALK-positive ALCLs should be considered in any peripheral T-cell lymphoma. The presence of deregulated ALK expression is associated with improved clinical outcome. Clinical trials evaluating the efficacy of small molecule inhibitors to ALK for ALCL patients are currently underway.

References:
  1. Cessna MH, Zhou H, Sanger WG, et al. Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases. Mod Pathol 2002;15:931-8.

  2. Chiarle R, Voena C, Ambrogio C, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 2008;8:11-23.

  3. Hammer STG, Jentzen JM and Lim MS. ALK-positive anaplastic large cell lymphoma presenting as retroperitoneal fibrosis. Human Pathol. Manuscript in press.

  4. Kinney MC, Kadin ME. The pathologic and clinical spectrum of anaplastic large cell lymphoma and correlation with ALK gene dysregulation. Am J Clin Pathol. 1999 Jan;111(1 Suppl 1):S56-67

  5. Lim MS, Carlson ML, Crockett DK, et al. The proteomic signature of NPM/ALK reveals deregulation of multiple cellular pathways. Blood 2009;114:1585-95.

  6. Mino-Kenudson M, Chirieac LR, Law K, Hornick JL, Lindeman N, Mark EJ, Cohen DW, Johnson BE, Jänne PA, Iafrate AJ, Rodig SJ. A novel highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry. Clin Cancer Res. 2010 Mar 1;16(5):1561-71.

  7. Rassidakis GZ, Goy A, Medeiros LJ, et al. Prognostic significance of MUC-1 expression in systemic anaplastic large cell lymphoma. Clin Cancer Res 2003;9:2213-20.

  8. Swerdlow SH, Campo E, Harris NL, et al. Pathology and genetics of tumours of hematopoietic and lymphoid tissues. In: World Health Organization classification of tumours. Lyon, France: International Agency for Research on Cancer Press; 2008.

  9. Takahashi H, Yamamoto M, Suzuki C, et al. The birthday of a new syndrome: IgG4-related diseases constitute a clinical entity. Autoimmun Rev 2010;9:591-4.

  10. Tsuchiya T, Ohshima K, Karube K, et al. Th1, Th2, and activated T-cell marker and clinical prognosis in peripheral T-cell lymphoma, unspecified: comparison with AILD, ALCL, lymphoblastic lymphoma, and ATLL. Blood 2004;103:236-41.

  11. Yamamoto H, Yamaguchi H, Aishima S, et al. Inflammatory myofibroblastic tumor versus IgG4-related sclerosing disease and inflammatory pseudotumor: a comparative clinicopathologic study. Am J Surg Pathol 2009;33:1330-40.

  12. Yousef GM, Gabril MY, Al-Haddad S, et al. Invasive lobular carcinoma of the breast presenting as retroperitoneal fibrosis: a case report. J Med Case Reports 2010;4:175.