Abstract
A novel pathogenesis of pulmonary lymphangioleiomyomatosis (PLAM) is presented incorporating a review of clinical and pathology research on the disease together with a review of research in the field of senescence. In this model of pathogenesis it is proposed that: 1) the primary site of origin for this disease is the Mullerian smooth muscle found in the female reproductive tract and this accounts for the striking female predominance of the disease; 2) the tumor spreads to the lungs via a mechanism similar to lymphangitic carcinomatosis and this accounts for its universal symmetric and bilateral distribution; 3) there is a mutational basis for a senescence-associated growth arrest which helps explain the absence of enlarging tumor masses in the lung despite years of disease duration; and 4) PLAM cells have a senescence-associated secretory phenotype with implications for the pathogenesis of the cystic transformation of the lungs. The secretory phenotype of PLAM cells is reviewed and the overlap with the senescence associated secretory phenotype products of known senescent cells is documented. The role of the switch to glycolytic metabolism (Warburg state) by PLAM cells is described. Finally, the “contradictory signals” hypothesis for the induction of the senescent state is explored and its role in PLAM described.
Highlights
Pulmonary lymphangioleiomyomatosis (PLAM) is an enigmatic disease
[1] The cystic transformation seen in the lungs resembles cystic change seen in a variety of chronic interstitial lung diseases, including Langerhans' cell granulomatosis and lymphoid interstitial pneumonia
The primary site for this neoplasm is Mullerian smooth muscle tumors with myomelanocytic differentiation located in the female genital tract, predominantly the uterus
Summary
Pulmonary lymphangioleiomyomatosis (PLAM) is an enigmatic disease. The disease occurs sporadically and in patients with the tuberous sclerosis complex (TSC). In many ways the disease presents clinically and radiographically like chronic interstitial lung disease. [2] PLAM as a neoplastic process has unusual characteristics. For many years, a primary site for these metastases has remained obscure and, as noted above, the clinical and radiographic progression of PLAM more closely resembles a progressive chronic interstitial pneumonia rather than a metastatic neoplasm. [3] over the prolonged clinical course of this disease, enlarging tumor masses do not appear in the lungs, as one might expect with metastases. The primary site of tumor with subsequent spread to the lungs will be proposed to be the Mullerian smooth muscle neoplasms of the female genital tract with myomelanocytic differentiation. International Journal of Clinical and Experimental Medical Sciences 2020; 6(6): 136-148 explored, including the proposal that LAM represents an unusual state that can be characterized as a state of “neoplastic senescence”. [4]
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