Assessing the significance of a Long-Developed Habit: The role of LDH in dermatology
By Warren R. Heymann, MD, FAAD
July 14, 2021
Vol. 3, No. 28
Upon ordering laboratory tests recently for a patient with cutaneous T cell lymphoma, I included a lactate dehydrogenase (LDH) level, as I have done for decades, without giving it much thought. When I came across an article entitled “Lactate dehydrogenase in dermatology practice” by Livesey et al, I asked myself, why have I been ordering an LDH? Is it just a habit? What am I looking for? What is its utility? Is it worth obtaining?
According to Livesey et al, LDH is a tetrameric oxidoreductase enzyme produced by all tissues, present in cytoplasm, where it converts pyruvate to lactate and vice versa. It is a nonspecific marker of tissue turnover. LDH activity per gram in tissue is highest in adipose tissue followed by, in descending order, brain, myocardium, red blood cells, kidney, lymph nodes, lung, skeletal muscle/liver, pancreas/stomach, and uterus. The highest LDH levels are observed in megaloblastic anemia, severe trauma, acute leukemia, and malignancies with diffuse metastases. In dermatology, LDH is characteristically part of the initial staging work-up of cutaneous lymphoma (including lymphomatoid papulosis) and melanoma. (1)
Lebowitz et al evaluated 174 elderly patients with mycosis fungoides (MF) and Sézary syndrome (SS); 76.4% were diagnosed with early-stage (clinical stages IA-IIA) and 23.6% with late-stage MF/SS (IIB-IV). Advanced age was associated with poor overall survival, but not with disease-specific survival (DSS) or progression free survival (PFS). Gender, increasing clinical stage, T and B classifications, elevated LDH levels, and development of large cell transformation were significant predictors of poor survival or disease progression. (2) Agar et al, in a study of 1,502 patients with MF/SS (mean age 54 years, 71% with early-stage disease), using univariate and multivariate models, found disease progression in 34%, with 26% of patients dying due to MF/SS. A significant difference in survival and progression was noted for patients with early-stage disease having patches alone (T1a/T2a) compared with those having patches and plaques (T1b/T2b). Univariate analysis established that advanced skin and overall clinical stage, increased age, male sex, increased LDH, and large-cell transformation were associated with reduced survival and increased risk of disease progression. (3)
Currently, poor prognosis groups for melanoma include those with high tumor burdens, brain metastases, refractoriness to anti-PD1 therapy, and elevated LDH. (4) Wagner et al state: “Serum lactate dehydrogenase (LDH) is a well-known biomarker for metastatic melanoma patients and since 2009 a part of the revised melanoma staging guidelines from the American joint committee on cancer (AJCC). In recent trials with immune checkpoint inhibitors elevated baseline LDH had consistently been shown to correlate with poor survival and poor response rates. Moreover, a retrospective study on 66 patients receiving the PD-1 antibodies nivolumab or pembrolizumab reported that increases in LDH levels between start of treatment and the first staging were associated with poor response and diminished overall survival (OS).” In their retrospective study of 152 patients treated with anti-PD-1, and in 86 patients treated with anti-PD-1 plus anti-CTLA-4 antibodies, they found that in the pembrolizumab group, patients with elevated baseline S100B or LDH exhibited significantly impaired OS compared with patients with normal S100B (P < .0001) and normal LDH (P = .00022), respectively. LDH increases of >25% and S100B increases of >145% compared to baseline were significantly associated with impaired OS (both P < .0001). In patients treated with ipilimumab and nivolumab, baseline S100B and increasing S100B levels of >145% as well as baseline LDH were significantly associated with impaired OS whereas increasing LDH of >25% was not (P = .64). (5)
What about using LDH as a biomarker for other dermatologic disorders? Vekaria et al demonstrated that while LDH levels may be elevated in atopic dermatitis, there was no significant correlation with disease severity (although there was for C-reactive protein). (6) The fact that LDH may be elevated in tissues such as muscle and adiopose tissue suggests that LDH may have potential for monitoring activity in disorders such as dermatomyositis or the panniculitides, respectively, awaits further scrutiny.
Mark Twain observed that “Nothing so needs reforming as other people’s habits.” Unquestionably, I picked up the LDH habit from my teachers long ago. It is a habit worth continuing, but only in the right context — notably for lymphoma and advanced melanoma. Livesey et al are correct in concluding that “there is no evidence yet to recommend LDH as a diagnostic test in dermatology.” LDH is recommended as part of the initial staging investigation for cutaneous lymphoma and metastatic melanoma, and may have use in monitoring these disorders, and potentially other entities with tissue breakdown. (1)
Point to Remember: LDH is part of the staging evaluation for cutaneous lymphomas and advanced melanoma, in addition to monitoring disease progression for these disorders. Its role in other cutaneous disorders remains to be determined.
Our expert’s viewpoint
Ellen J. Kim, MD
As a cutaneous lymphoma dermatologist in practice for nearly 20 years, I have probably ordered LDH 10,000 times, and at the start of my career I too often questioned its true utility in patient management. It is a standard part of the staging work up for newly diagnosed patients of all subtypes of CTCL, and used during follow up for CTCL patients with advanced stage mycosis fungoides/Sezary Syndrome (MF/SS) or other aggressive CTCL subtypes (cutaneous gamma delta TCL). It’s an inexpensive test, but as mentioned, it is highly nonspecific, and can be mild-moderately elevated in many benign inflammatory conditions as well (prompting one of my astute colleagues to remark “LDH really stands for Little D--- Help). LDH is a standard prognostic marker in systemic lymphomas and utilized in well-known prognostic indices utilized by oncologists for risk stratification of patients in both clinical practice and clinical trials (International Prognostic Index/IPI for intermediate/high grade lymphomas; the Follicular Lymphoma International Prognostic Index/FLIPI or FLIPI-2 for indolent follicular lymphoma; the Mantle Cell Lymphoma International Prognostic Index/MIPI). (7) LDH is often normal or only mildly elevated in low grade, indolent systemic lymphomas, but can be markedly elevated in aggressive lymphomas.
Several single-center retrospective studies have demonstrated that while LDH is historically an important prognostic factor in MF/CTCL in univariate analysis, in multivariate analysis, it may not be as important as other factors (age, gender, type of skin lesions, extracutaneous involvement) (3), and in the “Cutaneous Lymphoma Prognostic Index (CLIPI)” proposed in 2013, LDH is not included (8). Currently, there is a large collaborative effort led by Drs. Youn Kim and Julia Scarisbrick (Cutaneous Lymphoma International Consortium) to enroll early and late stage MF/SS patients at diagnosis to examine LDH and other clinical and pathologic prognostic variables and overall survival (PROCLIPI study). (9) By doing this in a prospective, multicenter manner with central pathology review and rigorous data collection, we will hopefully confirm the true value of LDH in MF/SS prognosis.
Frustratingly, there are no studies that define what “clinically significant elevation” of LDH is in MF/SS (unlike melanoma). In my own practice, if it is mildly elevated < 1.5 ULN (a cut-off that has been used in mantle cell lymphoma), and if patients have no palpable lymphadenopathy, B symptoms, or other comorbidities that could contribute to elevated LDH, I will reassure the patient and monitor the LDH over time. Rather than worrying about minor fluctuations in LDH, I find LDH most useful as a marker in CTCL patients whose skin disease is getting worse, have palpable nodes or if they report B symptoms and LDH increases abruptly (>1.5 ULN). Abrupt change raises a concern for a more aggressive tempo of disease (i.e., large cell transformation; the highest LDH I’ve seen in my career was 7x ULN in a Sezary patient with nodal LCT). Moderate-severe elevated LDH may prompt rescanning patients to look for extracutaneous involvement, or even a secondary malignancy (MF/SS patients are at higher risk for secondary malignancies, such as Hodgkin’s lymphoma compared to general population). (10) But like many other lab tests, LDH should always be interpreted in the larger clinical context to guide clinical decisions.
Livesey A, Garty F, Shipman AR, Shipman KE. Lactate dehydrogenase in dermatology practice. Clin Exp Dermatol 2020; 539-543.
Lebowitz E, Geller S, Flores E, Pulitzer M, et al. Survival, disease progression and prognostic factors in elderly patients with mycosis fungoides and Sézary syndrome: A retrospective analysis of 174 patients.
Agar NS, Wedgeworth E, Crichton S, Mitchell TJ. Factors in mycosis fungoides/Sézary syndrome: Validation of the revised International Society for Cutaneous Lymphomas/European Organisation for research and treatment of cancer staging proposal. J Clin Oncol 2010; 28: 4730-4739.
Gellrich FF, Schmitz M, Beissert S, Meier F. Anti-PD-1 and novel combinations in the treatment of melanoma – an update. J Clin Med 2020; 9: 223.
Wagner NB, Forschner A, Leiter U, Garbe C, et al. S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD1 or combined anti-PD-1 plus anti-CTLA-4 antibodies. Br J Cancer 2018; 119: 339-346.
Vekaria AS, Brunner PM, Aleisa AI, Bonomo L, et al. Moderate-to-severe atopic dermatitis patients show increases in serum C-reactive protein levels, correlating with skin disease activity. F1000Res 2017;6:1712.
Hoster E. The FLIPI nowadays: validation and modification. Blood. 2018 Jul 5;132(1):3-4.
Benton EC, Chrichton S, Talpur R, et al. A cutaneous lymphoma international prognostic index (CLIPi) for mycosis fungoides and Sezary syndrome. Eur J Cancer. 2013 Sep;49(13):2859-68.
Scarisbrick JJ, Prince HM, Vermeer MH, et al. Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and Sézary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model. J Clin Oncol. 2015 Nov 10;33(32):3766-73.
Goyal A, O’Leary D, Goyal K, et al. Increased risk of second primary hematologic and solid malignancies in patients with mycosis fungoides: A Surveillance, Epidemiology, and End Results analysis. J Am Acad Dermatol. 2019 Jul 30:S0190-9622(19)32466-1.
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