F. Kristian Storm

Diagnosis and management of retroperitoneal soft-tissue sarcoma.

Retroperitoneal soft-tissue sarcomas are locally invasive tumors that remain occult for long periods and grow quite large due to the abdominal cavitys remarkable ability to accommodate these slowly expanding masses with a paucity of attendant symptoms. An open biopsy is required to establish diagnosis definitively. Despite improved imaging techniques and preoperative and intraoperative patient management, resectability has not changed significantly in the past 20 years. Even with an aggressive operative approach, only one half the tumors can be resected completely, and of those, more than 90% recur locally and result in the death of the patient. The addition of adjuvant radiotherapy or chemotherapy has not altered this pattern of local failure, in contrast to promising results with extremity soft-tissue sarcoma. Because of the rarity of these tumors, there is an urgent need to establish a national retroperitoneal sarcoma registry and to form cooperative intergroup studies to evaluate, treat, and apply innovative multimodality combination therapies to these otherwise lethal tumors.

Hsp-27 has no diagnostic or prognostic significance in prostate or bladder cancers.

Heat shock protein 27 (hsp-27) is a cytosol protein of unknown function that is concentrated in many estrogen-sensitive normal target organs and is expressed to a varying degree in many tumors, including ductal carcinoma of the breast, malignant fibrous histiocytoma (MFH) of the soft tissues, adenocarcinoma of the prostate, and transitional cell carcinoma (TCC) of the urinary bladder. Overexpression of hsp-27 has independent prognostic significance in patients with breast cancer and MFH, but its potential predictive value with prostate and bladder cancers has not been evaluated. Differential expression of hsp-27 may occur between invasive cancer and host tissue that could aid in diagnosis, and varying expression among invasive cancers may have potential prognostic significance that could influence the use of adjuvant therapy. To test these hypotheses, hsp-27 expression was evaluated by immunohistochemistry in archival formalin-fixed paraffin-embedded sections of primary prostate and bladder carcinomas where the outcome of the patient was known. In 36 prostate cancer specimens from patients who had undergone radical prostatectomy (Stages T1, T2; N0; M0), no normal glandular elements or invasive cancers expressed this protein. In 24 bladder cancer specimens from patients who had undergone radical cystectomy (Stages T2, T3A, T3B, T4A; N0, N1; M0), 12 (50%) cancers overexpressed this protein. Hsp-27 did not correlate with degree of histologic differentiation, T-stage, nodal status, local recurrence, metastases, or survival. From these observations, we conclude that hsp-27 expression has neither diagnostic nor prognostic significance and will not serve as a predictive biologic marker with these important genitourinary cancers.

Heat shock protein 27 overexpression in breast cancer lymph node metastasis

AbstractBackground: Heat shock protein 27 (hsp-27) is overexpressed in ∼67% pure ductal carcinoma in situ (DCIS), in ∼50% DCIS associated with invasive ductal carcinoma (IDC), and in ∼25% IDC alone. If this decrease in hsp-27 expression has a role in the progression of malignancy in IDC, we postulate a further reduction in expression in nodal metastasis. Methods: To test this hypothesis, we evaluated the distribution of hsp-27 in primary IDC and in synchronous regional lymph node metastasis within the same patient by immunohistochemistry. Results: Nine of 30 primary IDCs (30%) and 22 of 30 lymph node metastases (73%) overexpressed hsp-27. Contrary to our hypothesis, of 21 IDCs with no or low hsp-27 expression, 13 (62%) had overexpression of this protein within nodal metastasis. Conclusions: hsp-27 appears to confer cytoprotection for metastatic cells, which may help explain why hsp-27 overexpression is associated with reduced disease-free survival in breast carcinomas.

Heat shock protein 27 stimulates recovery of RNA and protein synthesis following a heat shock

Constitutive expression of human hsp27 resulted in a 100‐fold increase in survival to a single lethal heat shock in CHO cells without effecting the development of thermotolerance. A possible mechanism for the thermoprotective function of hsp27 may be increased recovery of protein synthesis and RNA synthesis following a heat shock. A lethal heat shock (44°C, 30 min) results in a 90% reduction in the rate of protein synthesis in non‐tolerant cells. Control transfected cells recovered protein synthesis to a pre‐heat shock rate 10 h after the heat shock; while cell lines that constitutively express human hsp27 recovered 6 h after the heat shock. Thermotolerant cells had a 50% reduction in protein synthesis, which recovered within 7 h following the heat shock. The same lethal heat shock (44°C, 30 min) reduced RNA synthesis by 60% in the transfected cell lines, with the controls recovering in 7 h; while the hsp27 expressing cell lines recovered within 5 h. Thermotolerant cells had a 40% reduction in RNA synthesis and were able to recover within 4 h. The enhanced ability of hsp27 to facilitate recovery of protein synthesis and RNA synthesis following a heat shock may provide the cell with a survival advantage. J. Cell. Biochem. 66:153–164, 1997.

Distribution of hsp-27 and HER-2/neu in in situ and invasive ductal breast carcinomas

AbstractBackground: The overexpression of heat shock protein 27 (hsp-27) in early-stage breast cancer is associated with histopathologic features of poor prognosis and clinically with an increased probability of disease recurrence. Hsp-27 is overexpressed in 25% of invasive ductal carcinomas (IDC); however, its distribution in ductal carcinoma in situ (DCIS) and DCIS associated with IDC has not been investigated. We postulated that hsp-27 might be detected and variably expressed in DCIS and, like HER-2/neu oncoprotein expression, might be a tumor-specific marker worthy of future clinical investigation. Methods: To test these hypotheses, the distribution of hsp-27 in noncomedo and comedo DCIS, and DCIS associated with IDC, was evaluated by immunohistochemistry and compared with HER-2/neu expression within the same cancers. Results: Hsp-27 was overexpressed in 28 of 47 (∼60%) cases of DCIS; expression in pure DCIS was 16 of 24 (67%), and 12 of 23 (∼50%) in DCIS associated with IDC. Hsp-27 expression by in situ and invasive components of the same neoplasm were concordant in 22 of 23 (∼95%) cases tested. Comedo variants appeared to have somewhat higher hsp-27 expression than noncomedo DCIS, whether or not there was an associated IDC. These results are reminiscent of HER-2/neu oncoprotein expression in DCIS and DCIS associated with IDC observed by others. However, although 4 of 22 (18%) cancers containing DCIS + IDC expressed HER-2/neu, no relationship with hsp-27 expression in the same cancers was observed. Conclusions: We found a high incidence of hsp-27 overexpression in DCIS and in DCIS associated with IDC. This rate is twice that previously observed in IDC alone. Hsp-27 expression is independent of HER-2/neu expression.

Overexpression of 27-kDa heat-shock protein in MCF-7 breast cancer cells: effects on lymphocyte-mediated killing by natural killer and γδ T cells

Overexpression of the heat-shock protein hsp27 protein in primary breast cancers has been associated with early relapse in women with breast cancer. This study was designed to determine the role of the hsp27 protein in lymphocyte recognition of estrogen-receptor(ER)-positive breast cancer cells and to assess the effect of hsp27 expression on lymphocyte-mediated lysis. The hsp27 cDNA was inserted into the pHbAPr-1-neo plasmid expression vector and driven by the constitutive actin promoter. The ER-positive MCF-7 human breast cancer cell line was then transfected with this vector and the resulting clonal cell lines were confirmed to overexpress hsp27. hsp27-transfected clonal cell lines stimulated the proliferation of fresh peripheral blood lymphocytes (PBL) significantly better than control cells transfected with the expression vector alone. When clonal γδ T cell lines were utilized as effectors, hsp27-transfected cell lines were significantly better targets for lysis than a control-transfected MCF-7 cell line. In contrast, hsp27-transfected cell lines had no increase in susceptibility to lymphokine-activated-killer- or natural-killer-mediated lysis. These results suggest that overexpression of the hsp27 protein in ER-positive MCF-7 cells stimulated the proliferation of fresh PBL and the lysis of MCF-7 cells by γδ T cell clones.

Lack of association between tumor necrosis and hsp-27 expression in primary breast cancer

Overexpression of heat shock protein 27 (hsp‐27) is associated with reduced disease‐free survival in early stage breast cancer. Histopathologic evidence of confluent necrosis within primary infiltrating ductal carcinoma (IDC) is similarly an indication of poor prognosis. We postulated that IDC evidencing confluent tumor necrosis (TN) might overexpress this protein, which would help explain why hsp‐27 is associated with higher‐risk cancers. To test this hypothesis, presence of TN (as opposed to individual cell apoptosis) and of hsp‐27 expression by immunohistochemistry were evaluated independently in 48 specimens of IDC. Nineteen (40%) overexpressed hsp‐27 and 10 (21%) displayed necrosis. IDCs with areas of TN are less likely to overexpress hsp‐27, suggesting a lack of association between these histoprognostic variables. This negative correlation, however, supports hsp‐27 as an independent predictor of high‐risk disease.

Toremifene, a novel antiestrogen, can overcome hsp27-induced drug resistance in human breast cancer cells

Human breast cancer cell lines derived from MDA-MB-231 were constructed to express hsp27 constitutively. The elevated presence of this protein resulted in an enhanced ability to survive a heat shock and exposure to doxorubicin, a chemotherapeutic agent. Hsp27 expression was unable to protect cells from doxorubicin if they were cultured in the presence of toremifene. Flow cytometry analysis indicated that wells exposed to both toremifene and doxorubicin accumulate at G2 + M. Protective effects of hsp27 were overcome by addition of an estrogen antagonist at clinically nontoxic levels. Addition of toremifene to chemotherapeutic regimes may enhance the sensitivity of breast cancer cells to doxorubicin.

An unusual presentation of metastatic squamous cell carcinoma of the vulva

Recurrent squamous cell cancer of the vulva metastasized via regional lymphatics. Hematogenous spread is late and unusual. A patient with metastatic disease presented with soft tissue mass in her thigh musculature. We believe this to be the first reported case of noncontiguous skeletal metastasis for this tumor.