Extramedullary Hematopoiesis in Mismatch Repair Deficient Colon Cancer Patient on Adjuvant Chemotherapy

Abstract

A 59-year-old male presented with a two-month history of abdominal pain and was found to have an obstructing cecal mass. Colonoscopy and biopsy confirmed invasive adenocarcinoma. Immunohistochemical analyses for mismatch repair (MMR) proteins revealed the loss of MLH1 as well as PMS2 in cancerous nuclei, which makes the tumor MMR deficient. Negative germline testing for MMR proteins ruled out the Lynch syndrome. After negative staging computerized tomography scan for distant metastases, he underwent ileocolectomy with ileotransverse colonic anastomosis. Final pathological analysis revealed poorly differentiated adenocarcinoma with signet ring features, negative margins, and 3/22 lymph nodes positive, classified as stage IIIB (T4aN1bM0). Adjuvant chemotherapy with modified FOLFOX (leucovorin calcium/folinic acid, fluorouracil, and oxaliplatin) was started without the use of any growth factor support. After cycle 9 of 12, he developed mild transaminitis, carcinoembryonic antigen elevation, and interval development of two heterogeneously enhancing hepatic lesions. Biopsy of both of these lesions revealed extramedullary hematopoiesis (EMH), with no evidence of metastatic disease. He completed adjuvant chemotherapy without complication, and these liver lesions have decreased in size during the follow-up period of almost two years thus far. EMH is extremely rare in patients with colon cancer. Contributing factors include therapy-specific (growth factor support), bone marrow suppression secondary to chemotherapy and radiation therapy, and tumor-specific factors (cytokine and growth factors released by the tumor). To the best of our knowledge, this is the first case report of EMH in an MMR deficient colon cancer patient on adjuvant FOLFOX. MMR-deficient tumors show signs of a high degree of infiltration with CD8+ cytotoxic T lymphocytes as well as helper T cells, leading to increased production of cytokines, such as interferon-γ. This could be a potential etiology behind EMH in our patient who was MMR deficient. The role of the MMR-deficient state in the development of EMH should be explored further.

Extramedullary Hematopoiesis of the Liver and Spleen

“…The liver, under normal conditions, has a secretory function, but under certain circumstances, it works to compensate for the bone marrow's deficiency and, together with the spleen, attempts to remedy the lack of functional blood cells. In the liver, they appear as heterogenous masses, which may be confused with metastatic lesions, but at biopsy, EHP is present with dilated and congested sinuses and precursor cells [19]. The spleen is an organ with high metabolic activity, positioned in the upper-left abdomen, underneath the diaphragm, close to the Both the spleen and the liver are major constituents of the portal circulation, which comprises important reticuloendothelial structures that take part in substance exchange and cellular migration.…”

“…The spleen is an organ with high metabolic activity, positioned in the upper-left abdomen, underneath the diaphragm, close to the stomach and the pancreas, and is protected by the ribcage. Its role is to recycle blood particles and iron, and to filter atypical blood cells; to phagocyte aged erythrocytes, damaged platelets, and apoptotic cells; to produce and shelter antibodies; to sustain the immune system in fighting infections by differentiation; and to activate T and B cells [19,20].…”

“…Activation of Tlx1 transcription factor determines the mobilization and proliferation of HSCs and HPCs, leading to the development of a niche-induced extramedullary hematopoiesis in the spleen [29]. Splenic myelopoiesis occurs in cancer, as a supplementary production of myeloid cells, which are important regulators of disease progression in the tumor microenvironment [19]. Scientists explain the effects of epigenetic modifiers on normal and malignant hematopoiesis [42][43][44][45].…”

Myelopoiesis during Solid Cancers and Strategies for Immunotherapy

“…A separate case report identified a patient with mismatch repair deficient (MMRd) colon cancer and EMH, with persistent rising levels of carcinoembryonic antigen (CEA) and a liver lesion while undergoing chemotherapy, both of which are usually consistent with tumor progression. Upon biopsy, it was revealed these lesions were sites of EMH and not sites of metastases [ 64 ]. Furthermore, Wu et al determined patients with hepatocellular carcinoma, kidney, or pancreatic cancer had more CD133 + cells, a marker of human HSCs, as well as more CD11b + cells relative to cirrhotic patients [ 59 ].…”

Pembrolizumab-Induced Lichenoid Dermatitis in a Patient With Metastatic Cancer of Unknown Primary

“…Permission was taken from the original publisher; adapted from De Leo et al [2]. His PDL 1 status was 60% on lymph node biopsy, which was a reasonable choice for starting immunotherapy with pembrolizumab.…”