Single organ microenvironment and the common features of tumors of leukemia, lymphoma, and myeloma cells growing there: A literature review.

OBJECTIVE: To explore whether the growth and treatment resistance of lymphoma and myeloma tumors is similar to that previously observed in leukemic and solid tumors growing in the same organ microenvironment. METHODS: All published cases of 3 primary hematologic malignancies in breast, without systemic involvement, were identified, with follow-ups solicited from authors. Treatment approaches were analyzed to highlight the most effective. RESULTS: Similar histologic features and biology among primary tumors of leukemia, lymphoma, plasmacytoma, and solid breast cancer was revealed. Review of treatments: tumor-directed, chemotherapy, or combination showed the benefit of tumor removal, and use of systemic agents in adjunct, not primary, treatment. Optimal assessment is limited by few cases of PET/CT verifying limited tumor extent. The common biology observed and cases of long survival after tumor/stroma eradication point to the complicity of organ microenvironment in the chemoresistance and treatment failure commonly observed in patients. CONCLUSIONS: The interaction of an organ microenvironment, particularly its adipocytes, with malignant cells, results in similar histologic changes, metastatic potential, and chemoresistance in 3 hematologic malignancies and solid cancers. Improved survival in hematologic malignancies could result from adopting PET/CT to find tumor and its extent, eradicating tumor, and elucidating common therapeutic targets.

Extramedullary leukemia behaving as solid cancer: clinical, histologic, and genetic clues to chemoresistance in organ sites.

Recent studies of leukemic tumors in individual extramedullary sites showed they adopt the clinical and metastatic behavior of solid cancers originating in those sites. To elucidate features of leukemic tumors that render them resistant to agents effective against marrow leukemia, we analyzed a series of AML breast tumors by histology, immunohistochemistry, and RNA sequencing. Striking histologic similarities to solid cancers were found: a single-filing architectural pattern virtually identical to that of invasive lobular breast carcinoma and dense desmoplastic keloid-like fibrosis similar to colon, gallbladder, and pancreas carcinomas. Sequencing found 2157 genes significantly downregulated in AML breast tumors compared to normal breast. Comparison to triple-negative breast cancer found 859 genes similarly downregulated. At least 30 of these genes have been associated with poor prognosis in breast cancers. Five were reported in AML marrow studies to correlate with poor prognosis. The findings of this pilot study suggest the seed-and-soil interaction recognized in solid cancer growth may help explain how leukemic cells, in some patients, adopt solid tumor behavior in non-marrow sites. Transformed cells that metastasize from tumor to marrow can impart chemoresistance and be an unrecognized cause of treatment failure and death. Further studies comparing leukemic tumor to simultaneous marrow could potentially identify biomarkers that predict extramedullary resistance and lead to new therapeutic targets. Recognizing the potential for leukemia to adopt solid tumor phenotype, and implementation of body scanning and ablative tumor treatment, could decrease the persistently high rates of marrow resistance and treatment failure.

Leukemia in gastrointestinal organs as cause of treatment failure: 378 cases analyzed.

Leukemia growing as tumors in gastrointestinal organs is an under-investigated cause of treatment failure and death. These present with symptoms often mistaken for common toxicities but may grow large before symptoms. To synthesize experience available only in case reports, 378 were analyzed. Invasive and metastatic behavior typical of solid GI tumors was revealed even when marrow was uninvolved. Within 3 months of diagnosis, 33% had died, 47% within 1 year. Survivals of 4 to 18 years after involvement suggest cure is possible. Evidence is presented that combined local and systemic therapy has successfully treated GI leukemic tumors when identified early.

18 FDG-PET/CT: 21st century approach to leukemic tumors in 124 cases.

Extramedullary tumors remain an obstacle to curing more acute leukemia patients. Their incidence is unknown because the presence of occult tumors that contribute to relapse is not routinely sought as in other cancers. No standard approach exists for treating tumors at most sites, apparent clinical response is typically followed by further tumors, and achievement of lengthy remission is uncommon. Body scanning with (18) FDG PET/CT now provides a means to identify the extent of occult tumors that enables directed tumor eradication and a way to evaluate tumor response. To evaluate its potential benefits, analysis was undertaken of 124 published cases scanned after apparent tumors were diagnosed. Clinical and radiologic exams underestimated extent of disease in over half of 100 cases. Among 70 cases that reported scans after various treatments, 70% achieved negative scans. Half relapsed subsequently but disease-free survivals up to 6 years were documented. These reported cases add to our knowledge of extramedullary leukemia in showing that further tumors are more likely than marrow relapse, clinical and radiologic evaluation of response is inadequate, intensive chemotherapy alone generally does not prevent progression and is associated with significant mortality, and tumor-directed plus systemic therapies appears the most effective approach, particularly to AML tumors. This analysis suggests this technology could increase our ability to eradicate all foci of leukemia, and identify tumors responsible for refractory, residual, and relapsed disease.

A basis for updating our approach to resistant acute leukemia.

No studies exist documenting that chemotherapy alone eradicates tumors composed of leukemic cells in a large group of patients with tumors at any one site. Yet, its use has continued over 40 years in the absence of data. Consensus protocols exist only for testis and meningeal tumors, relying on local therapy. To constitute a body of knowledge about tumors at one site, the breast was chosen and all published cases were analyzed, with follow-up obtained, to document the behavior of acute leukemia tumors and survival after presentation. Among 235 cases (52% published since 2000), overall survival was poor, particularly for the 43% with concurrent morphologic marrow relapse, with 66-73% one-year mortality. Only 4 of 106 patients treated with chemotherapy alone survived 4 years. The majority of AML and ALL tumors were only transiently responsive to anti-leukemia treatments, including transplant, and next relapses were as, or more, common in further tumors than in marrow. A pattern of tumors similar to the metastases of invasive lobular breast cancer was revealed. When relapse occurred in marrow, durable remission was only rarely obtained. These data suggest a potential benefit of incorporating extent of disease workup at diagnosis and relapse into prospective trials. This could yield an accurate incidence of extramedullary tumors and a means to identify occult residual disease which could lead to marrow relapse. This approach could potentially result in greater success in curing acute leukemias.

Post-transplant leukemia relapse in organs: biology. and behavior in 585 reports.

Resistance of extramedullary leukemia growth post-transplant prevents cure. Review of its behavior detailed in 585 published cases should lead to better treatment. Leukemic tumors were found up to 13 years after transplant, most in sites inaccessible to physical exam. In 83%, marrow was not in morphologic relapse; next relapse was most often extramedullary. Induction protocols alone produced few durable responses in acute leukemias and fatal marrow aplasia in 17 %. Overall, 120 patients survived over 2 years, 43 relapse-free up to 18 years, the majority after combined tumor-directed and systemic therapy. Overall median survival was 9 months. This review highlights how results can improve: by defining extent of leukemia involvement with scans before transplant, and emergently when leukemic tumor is found after, ablating tumor directly to abort metastasis, and determining dosing of systemic chemotherapy that protects, without ablating, donor marrow. Monitoring total body remission with body scans should increase transplant cures.

Extramedullary sites of leukemia relapse after transplant.

Recurrent or residual leukemia found in extramedullary sites after intensive treatments adversely affects prognosis. To summarize the sites and outcomes when extramedullary relapses have been reported after stem cell transplants, and to elucidate when long survival has been achieved, 207 cases were analysed. Authors were contacted for follow-up information. The most commonly reported sites are soft tissue in acute leukemias and bone in CML. Extramedullary relapse occurred typically within 2 years in ALL, but later in one-third of myeloid leukemias. Most testicular relapses reported in AML followed non-TBI conditioning. Marrow relapse was not inevitable if aggressive treatment was begun early. Local therapy alone was generally inadequate. Intensive therapy has produced lengthy remissions in cases of acute leukemias involving various sites, whereas CML cases, particularly involving bone, were most resistant to treatment. Heightened awareness and aggressive treatment should improve the prospect for cure after extramedullary relapse.

A clinical review of breast involvement in acute leukemia.

The breast continues to be reported as a site of resistant leukemia despite current curative protocols. To characterize disease behavior and potential for lengthy survival after breast relapse, a study was undertaken of 153 cases reported between 1969 and 2005. Authors were contacted for follow-up. There were 105 AML and 48 ALL cases identified. Ninety percent of female patients were younger than 50 and leukemia was temporally related to pregnancy in 13. Eight cases were males. Remissions were typically of short duration, principally due to further extramedullary relapses, in 3 main sites in both AML and ALL: contralateral breast, gynecologic organs, and CNS. However, there are cases of disease-free survival up to 26+ years after intensive treatment. Leukemia growing in the breast may follow a distinctive pattern, and prompt initiation of intensive multi-cycle treatment, assuming occult site involvement, with consideration of CSF prophylaxis, should increase the potential for disease eradication.

The clinical behavior of 124 leukemic ovarian tumors: clues for improving the poor prognosis.

The clinical behavior of acute leukemic tumors at each organ site must be recognized if relapse is to be prevented. The courses of 124 cases of leukemic ovarian tumors were analyzed with survival durations obtained from authors. Local expansive growth and invasion of contiguous organs similar to epithelial ovarian cancer was seen in both acute myeloid (AML) and lymphoid (ALL) leukemias. Overall, 56% survived 1 year. Tumors at other sites were clinically apparent on presentation in over half the cases without simultaneous marrow relapse, and next relapse was as common in extramedullary sites as in marrow. Leukemic ovarian tumors were generally resistant to chemotherapy, and lengthy survivals were seen most often after complete excision together with systemic therapy. This study documents similar behavior in AML and ALL tumors and that they are rarely isolated to a single ovary. It suggests that scanning could improve our ability to find and eradicate occult tumors which, because of chemoresistance, prevent the cure of leukemia for most patients who develop them.